Scaffold for connective tissue repair

专利摘要:

公开号:AU2004202223A1
申请号:U2004202223
申请日:2004-05-24
公开日:2005-01-13
发明作者:Joseph Hammer；Julia Hwang；Prasanna Malaviya；Herb Schwartz
申请人:DePuy Mitek LLC；
IPC主号:A61L27-00

专利说明:
P/00/011 Regulation 3.2
AUSTRALIA
Patents Act 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT
ORIGINAL
TO BE COMPLETED BY APPLICANT Name of Applicant: DEPUY MITEK, INC.
Actual Inventors: Julia Hwang, Joseph Hammer, Herb Schwartz and Prasanna Malaviya Address for Service: CALLINAN LAWRIE, 711 High Street, Kew, Victoria 3101, Australia Invention Title: SCAFFOLD FOR CONNECTIVE TISSUE REPAIR The following statement is a full description of this invention, including the best method of performing it known to us:- 21/05/04,eh14149.cov,1 -2- SCAFFOLD FOR CONNECTIVE TISSUE REPAIR FIELD OF THE INVENTION This invention relates to prosthetic devices for repairing and replacing torn or damaged connective tissue such as ligaments and tendons.
BACKGROUND OF THE INVENTION The complete or partial detachment of ligaments, tendons or other soft tissues from their associated bones within the body is a relatively common injury, particularly among athletes. Such injuries generally result from e cessive stresses being placed on these soft tissues. For example, a tissue-detaching injuryi may occur as the result of an accident such as a fall, overexertion during a work-related activity, during the course of an athletic event, or in any one of many other situations and/or activities.
In the case of a partial detachment, commonly referred to under the general term "sprain," the injury will frequently heal itself, if given sufficient time, and if care is taken not to expose the injury to any undue or extraordinary stress during the healing process. If, however, the ligament or tendon is completely detached from its associated bone or bones, or if it is severed as the result of a traumatic inj ury, partial or permanent disability may result. Fortunately, a number of surgical techniques exist for re-attaching such detached tissues and/or completely replacing severely damaged tissues.
One such technique involves the replacement of the detached tissue using autogeneic tissue grafts harvested from elsewhere in the body. For example, an anterior cruciate ligament in a human knee can be replaced and/or repaired using a patellar tendon autograft or hamstring tendons. The patellar tendon is harvested with a bone block from the tibia, using the center third of the patellar tendon, and bone block from the patella.
This graft has the advantage of having high initial strength and having bone plugs that will facilitate fixation. These grafts are implanted by forming bone tunnels through the tibia and/or femur at the points of normal attachmernt of the anterior cruciate ligament. A patellar tendon graft, with a bone plug on each of its ends, is harvested and sized to fit within the bone tunnels. Suture is then attached to the outer end of each bone plug, and thereafter passed through the femoral and/or tibial bone tunnels. The femoral plug and the tibial plug are then inserted into the appropriate bone tunnel behind the suture.
Subsequently, the suture is drawn tight to position the bone plugs in the desired location, and impart the desired degree of tension to the ligament graft. Finally, while holding the 21/05/04,eh14149.spc,2 bone plugs in position, interference screws, cross-pins or other fixation devices are used to securely lock the bone plug in position. The hamstring tendon grafts are implanted in a similar fashion.
While autogeneic tissue grafts have been successfully used to replace connective tissue, the harvesting procedure, like any medical procedure, has associated risks. Two primary concerns are tissue damage at the harvest site during the removal process and donor site morbidity. Complications in harvest have sometimes resulted in patellar fracture. In other cases, patellofemoral pain is observed due to donor site morbidity. Yet, even when the harvesting procedure is successfully performed, the sample may not provide a sufficient supply of tissue for a graft and/or the tissue may not have the desired quality or consistency. In addition, even with a successful surgery, it is possible for patients to rerupture the graft and require revision surgery. For these reasons, there is a need for an alternative source for tissue grafts, which can provide the properties of an autogenic tissue graft.
One example of an alternative graft is allograft tissue. The advantages of using an allograft include elimination of donor site morbidity and decrease in operating time.
However, the graft has potential ability to transmit disease and elicit an immune response.
There is also a lack of consistency in mechanical properties of the graft and the supply is limited.
For these reasons, there is a need to develop a connective tissue graft that is terminally sterilized and made from synthetic materials or biologically-derived materials.
In the past, the initial results using synthetic prosthetic ligament devices looked promising.
However, the long term results, such as those that extend beyond one year, showed the mechanical failure of the these devices. These prostheses have been found to lack sufficient strength and durability to act as a permanent replacement for the lifetime of the patient. Other prostheses, such as some made from synthetic materials, have good physical properties, but can erode or cause bone erosion.
Despite existing technology and techniques, there remains a need for connective tissue implants that can provide an approximation of the natural tissue to be replaced or augmented.
SUMMARY OF THE INVENTION The present invention generally provides a connective tissue scaffold including opposed first and second anchoring segments formed of a plurality of bioresorbable polymeric fibers oriented in a direction substantially parallel to a longitudinal axis of the 21/05/04,eh14149.spc,3 scaffold, and a plurality of bioresorbable polymeric fibers oriented in a direction substantially transverse to a longitudinal axis of the scaffold. A central segment positioned between the first and second anchoring segments is formed of a plurality of bioresorbable polymeric fibers oriented in a direction substantially parallel to the longitudinal axis of the scaffold. This structure creates sufficient void space in the central segment to facilitate tissue ingrowth.
The longitudinally and transversely oriented fibers of the anchoring segments can include binding regions where the longitudinal and transverse fibers are interconnected, such as, for example by joining the fibers in a weave pattern. The binding regions may be continuous, or they may be non-continuous such that one or more areas of longitudinally oriented fibers are separated by one or more regions having transversely oriented fibers interwoven with the longitudinally oriented fibers.
The anchoring segments of the present invention can further include eyelets adjacent to the binding regions. The eyelets can be formed by the orientation of the binding regions to form a loop-like or open area that facilitates fixation of the scaffold.
The longitudinal fibers of the of the central segment can run parallel to each other without interconnecting. In addition the fibers of the central segment can be loosely bundled in an annular pattern, such that a centrally formed space exists between the annularly oriented fibers. Alternatively, the longitudinal fibers can be formed in a braid pattern.
The fibers of the scaffold of the present invention are constructed of a bioresorbable polymeric material such as polymers or copolymers formed from monomers selected from the group consisting of lactide, glycolide, dioxanone, and caprolactone.
In another embodiment of the present invention, the scaffold can further include a biocompatible, bioresorbable material covering at least a portion of the first and second anchoring segments and the central segment. The bioresorbable material can be a biological material, for example a naturally occurring extracellular matrix (ECM) material.
One such naturally occurring ECM, by way of example, is small intestine submucosa. The bioresorbable material may also be formed over the first and second anchoring segments and the central segment as a wrap, sleeve, or sheath.
In yet another embodiment, the scaffold of the present invention can include at least one minced tissue particle that is associated with at least a portion of the scaffold, such that the minced tissue particles includes an effective amount of viable cells that can migrate out of the minced tissue particle and populate the scaffold. In addition to the at least one 21/05/04eh 14149.spc,4 minced tissue particle, the scaffold may include an adhesion agent and/or at least one additional biological component.
The invention also provides methods of using the scaffold to repair or replace connective tissue, such as ligaments and tendons.
BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a schematic view of one embodiment of the connective tissue scaffold of the present invention; FIG. 2 is a schematic view of another embodiment of the connective tissue scaffold; FIG. 3 is a schematic view of another embodiment of the connective tissue scaffold; FIG. 4 is a perspective view of yet another embodiment of the connective tissue scaffold; FIGS. 5A 5F are cross sectional views of representative central segments of the connective tissue scaffolds of the present invention; FIG. 6 is schematic view of another embodiment of the connective tissue scaffold of FIG. 3; and FIG. 7 is a perspective view of another embodiment of the connective tissue scaffold of FIG. 4; and FIGS. 8 and 9 are photomicrographs illustrating the results described in Example 1.
DETAILED DESCRIPTION OF THE INVENTION The tissue scaffold of the invention is useful as an implant to replace or augment damaged or torn connective tissue. This scaffold provides an approximation of the natural tissue to be replaced or augmented. The scaffold should have initial mechanical properties similar or greater than those of the native tissue and at the same time support tissue 21/05/04,eh14149.spc,5 ingrowth and regeneration. Overtime the implant will degrade and become replaced by healthy and functional tissue.
The present invention generally provides a bioresorbable scaffold 10 for the repair or replacement of connective tissue, such as ligaments or tendons. As shown in FIG. 1, the scaffold 10 includes opposed first and second anchoring segments 12a, 12b which can bind together the fibers of the scaffold and can also receive a tissue fixation device for mating the scaffold 10 within a patient. The scaffold 10 also has a central segment 14, positioned between the anchoring segments 12a, 12b, form ed of a plurality of bioresorbable polymeric fibers oriented in a direction substantially parallel to the longitudinal axis of the scaffold.
The scaffold of the present invention is particularly advantageous in that it is preferably made of a bioresorbable polymeric material having sufficient strength to substitute for a tendon or ligament, such as an ACL, and it further allows and encourages regeneration of the failed connective tissue it replaces. In use, the scaffold provides a resorbable, off-the-self replacement for connective tissue which encourages tissue regeneration and results in a native replacemerit for damaged connective tissue without the drawbacks of autograft implants, allograft implants, and permanent synthetic replacements.
Further, by providing an autograft substitute, the bioresorbable scaffold of the present invention eliminates the risks associated with autograft harvesting procedures.
The anchoring segments 12a, 12b of the scaffold 10 of the present invention preferably includes a plurality of fibers 16 oriented in a direction substantially parallel to a longitudinal axis of the scaffold 10 and a plurality of fibers 18 oriented in a direction substantially transverse to a longitudinal axis of the scaffold 10. In one embodiment, the longitudinally oriented fibers 16 ("longitudinal") and transversely oriented ("transverse") fibers 18 form binding regions 20a, 20b whichlbind together the scaffold 10 at its ends. In one embodiment, the longitudinal and transverse fibers 16, 18 of the binding regions form a weave pattern with the longitudinal and transverse fibers 16, 18.
In the simplest form, the weave may be constructed such that transverse fibers 18 interlace with the longitudinal fibers 16 by alternating between one side of one longitudinal fiber or group of fibers 16, and an opposite side of an adjacent longitudinal fiber or group of fibers 16. The woven binding regions 20a, 20b may be constructed from a variety of weave patterns which interconnect the longitudinal and transverse fibers 16, 18. One skilled in the art will appreciate that the weave' can be constructed based on a number of patterns and can have a variety of characteristics such as weave density, but preferably results in a weave sufficient to bind together the longitudinal and transverse fibers 16, 18.
21/05/04,eh14149.spc,6 The transverse fibers can interlock the longitudinal fibers not only in one direction but in two directions so that a three-dimensional woven structure is created. The implant can consist of 40-99% substantially longitudinal direction filaments (x-axis), 1-50% substantially transverse cross direction (y-axis)i filaments, and 1-50% substantially transverse z-direction filaments. The warp consists of longitudinal and z-direction filaments and the weft consists of y-direction filaments. A woven structure is desirable because of its wear and abrasion resistance properties. This characteristic is important for ligament reconstruction as this graft is inserted through a bone tunnel which has sharp edges that can scratch the graft.
In addition to weaving the longitudinal and transverse fibers 16, 18 together, the binding regions 20a, 20b can be constructed in ia variety of other ways. In one alternative embodiment, at least some of the transverse fibers 18 can be wrapped around the outside of the longitudinal fibers 16 to secure the longitudinal and transverse fibers 16, 18. For example, the transverse fibers 18 may be wrapped around the longitudinal fibers 16 to form a knot or whipping. One skilled in the art will appreciate that there are a variety of ways to form a whipping such as, for example an American Whipping, a Sailmaker's Whipping, a West Country Whipping, etc. While the styles vary, whippings work on the same principle; the transverse fiber (or fibers) 18 is tightly wound around the longitudinal fibers 16, while the ends of the transverse fiber 18 are secured by a knot or by tucking.
Although a whipping is preferably formed by Wrapping a transverse fiber (or fibers) 18 around a bundle containing all the longitudinal fibers 16, the longitudinal fibers 16 may be grouped into smaller bundles and whipped. In one embodiment, the longitudinal fibers 16 may be whipped together in a large bundle and additional whippings may be used adjacent to the large bundle. Further, the adjacent whippings may include smaller bundles of the longitudinal fibers 16.
In yet a further embodiment, the longitudinal and transverse fibers 16, 18 of the binding regions 20a, 20b may be interconnected by stitching. The longitudinal fibers 16 can be grouped into a bundle and the transverse fibers 18 can be repeatedly led through the bundle and pulled tight to secure the binding regions 20a, 20b. Further, a three dimensional weave may be simulated or replicited by sewing together two or more plies of two-dimensional weaves. Braiding and/or knitting may also be used to interconnect filaments. A person skilled in the art will appreciate that the transverse 18 and longitudinal fibers 16 can be interconnected by a variety of other techniques. In still yet another embodiment, the fibers of the binding regions 20a, 20b may be interconnected by 21/05/04,eh14149.spc,7 -8physically bonding the longitudinal fibers 16 with the transverse fibers 18, or physically bonding the fibers with another agent such as, for example, an adhesive or a polymer.
Filaments may also be bonded via thermal methods, including but not limited to ultrasonic bonding, infrared bonding, laser bonding, or application of the filaments to a heated electrical surface. Filaments may also be bonded via chemical means, including but not limited to solvent bonding. Filaments may also be bonded the application of suitable adhesives, including but not limited to those that are bioabsorbable and non-bioabsorbable.
Finally, combinations of the above techniques may be used to interconnect or bond fibers or filaments. In addition, the fibers may be interconnected as discussed above, and then physically bound to increase the mechanical strength of the connection.
Regardless of the method of interconnection, the binding regions 20a, 20b may be broken down into several parts, such that the binding regions are not continuous. As illustrated in FIG. 1, for example, the binding regions 20a, 20b can alternate between areas of interconnected longitudinal and transverse fibers 16, 18 and areas of only longitudinal fibers 16. In another embodiment, illustrated in FIG. 2, each binding region 20a, 20b can be formed of continuous zones of longitudinal and transverse fibers 16, 18.
One property contributed by the interconnection of the longitudinal and transverse fibers 16, 18 is that the binding regions 20a, 20b are preferably interconnected to minimize laxity and achieve stiffness similar to that of native tissue. Elastic modulus is a property that varies based on the identity of materials used to construct the fibers and on the technique used to interconnect the longitudinal and transverse fibers 16, 18. Preferably, for cruciate ligament repair, the stiffness of the binding regions 20a, 20b of the graft is higher than 100 N/mm and preferably higher than 150 N/mm.
One function of the binding regions 20a, 20b is to enable the scaffold 10 to be anchored within a patient, such as by receiving a tissue fixation device. A tissue fixation device can affix or anchor the scaffold 10 by extending through the scaffold 10 and/or creating an interference fit between the scaffold 10 and a tissue region. Exemplary tissue fixation devices which can be used with the scaffold 10 of the present invention include screws, sutures, staples, pins, buttons, and combinations thereof.
The binding regions 20a, 20b may be configured to form a receiving area 21 for receiving a tissue fixation device as shown in FIG. 3. The receiving area 21 may be created by the weaving, whipping, knitting, or stitching of the longitudinal and transverse fibers 16, 18 to create an open area devoid of fibers or an areas of reduced fiber density. In 21/05/04,eh 14149.spc,8 -9use, the tissue fixation device can then be pushed through a binding region or binding regions to fix the scaffold to tissue.
In one embodiment, each anchoring segment 12a, 12b can include an eyelet 22 as illustrated in FIG. 4. A suitable eyelet 22 can be formed by a group of fibers extending from a binding region to create a loop 24 around an open area 26. Preferably, the open area 26 of the eyelet 22 is appropriately sized to receive a tissue fixation device such as a tissue fixation pin. The open area 26 of the eyelet 22 can be used alone or in conjunction with a suture to tension the graft during fixation.
In a preferred embodiment, at least one of the anchoring segments 12a, 12b will be affixed within a bone tunnel, such as a femoral and/or a tibial bone tunnel. Therefore the i anchoring segments 12a, 12b should be suitably sized to fit within such a bone tunnel.
Preferably, the length of the anchoring segments 12a, 12b will be approximately equal to or less than the length of a bone tunnel, for example in the range of about 10 mm to mm, and more preferably in the range of about 120 mm to 60 mm. Similarly, the diameter of the anchoring segments 12a, 12b should also be adapted to fit within a bone tunnel. The diameter of the anchoring segments 12a, 12b can be in the range of about 2 mm to 15 mm.
As noted above, the scaffold 10 of the present invention also has a central segment 14 disposed between the anchoring segments 12a, 12b. The central segment 14 includes longitudinally oriented fibers 28 which may or may not be interconnected. The central segment 14 is intended to provide the functionality of the connective tissue which it replaces. For example, if the scaffold 10 is used as a replacement for an anterior cruciate ligament, the fibers 28 of the central segment 14 provide the properties of the native ligament and have the properties to support tissue ingrowth.
The central segment 14 preferably has sufficient length to replace the connective tissue for which it substitutes. A person skilled in the art will appreciate that the length of the central segment 14 will vary depending on the size of the patient and the intended use of the scaffold 10. For example, one skilled in :the art will realize that the sizes will vary greatly for use of this implant in anterior cruciate ligament repair, posterior cruciate ligament repair or flexor tendon repair.
In one embodiment, the fibers 28 of the' central segment 14 do not interconnect with each other and run between the anchoring segments 12a, 12b in bundle of substantially longitudinally oriented fibers 28. FIGS. 5A 5F illustrate exemplary cross sections of the central segment 14, such as, for example, an oval shape (FIG. 5A), a circular shape (FIG. 5B), a rectangular shape (FIGS. 5C, 5D) and an irregular shape (FIG.
21/05/04,eh14149.spc,9 In addition, the longitudinal fibers 28 of the central segment may be tightly packed FIG. 5D or loosely grouped FIG. 5E Where the longitudinal fibers 28 of the central segment 14 are loosely grouped, they may be oriented in an annular pattern such that collectively the longitudinal fibers define a central space 30 as illustrated in FIG. 5F. The annular pattern may be formed in a variety of ways such as by imparting a slight twist to the longitudinal fibers 28 before binding them in the binding regions 20a, 20b. An exemplary twist of the longitudinal fibers 28 between the anchoring segments 12a,: 12b may be in the range of about 00 and 7200.
The fibers 28 of the central segment 14 may alternatively be interconnected with one another. For example, the longitudinal fibers 28 may be loosely braided or twisted together along the central segment 14. A variety of braid patterns may be used. For example the longitudinal fibers 28 of the central region 14 may be grouped into several bundles and the bundles may be braided. The braid pattern preferably orients the fibers 28 of the central segment 14 in an organized pattein.
The interconnection of the fibers 28 of the central segment 14 are characterized by increased flexibility with respect to the binding regions 20a, 20b. The improved flexibility is due to the lower fiber density of the central s~gment 14 because the fibers are not packed and restrained. The fibers preferably have some degree of motion, especially under cyclic load, to move and allow void space or porosity:to be created within the central segment.
Preferably, the minimum amount of void space will be approximately 14% by volume.
The increased density of the binding regions 20a, 20b is based on including not only longitudinal fibers 16 but also transverse fibersi 18, and the longitudinal and transverse fibers 16, 18 being tightly bound together, such as, for example in a hexagonally close packed structure.
In addition to providing physical properties and functionality that mimics that of a natural ligament or tendon. The central segment 14 provides a region that receives and retains any tissue fragments, cells, or bioactives that may be incorporated into the scaffold to initiate regrowth and replacement of a natural ligament or tendon. The lower fiber density allows tissue fragments or cells to be retained within the scaffold 10, and to populate the scaffold 10. Where the fibers 28 of the central segment 14 are configured in an annular pattern to form a central space 30, tissue fragments, cells or bioactives may be seeded within the central space 30. The segments 12a and 12b can also receive and retain 21/05/04,eh 14149.spc, -11*tissue fragments, cells, or bioactives to enhance bone repair and integration of graft with host tissue.
The terms "longitudinal" and "transverse", as used herein, indicate the overall direction in which the fibers (16, 18, 28) are traveling, and include substantially longitudinal and transverse fibers such as those' shown in FIGS. 3 4. Acceptable variation from the longitudinal and transverse orientation include, by non-limiting
I
example, those variations created by interconnecting the fibers or imparting the fibers with a twist. For example, a longitudinal fiber extending from one end of the scaffold to the other may dip and rise as it encounters other fibers in a braid or weave, but overall the fiber extends in the longitudinal direction and travels on a path substantially parallel to adjacent fibers traveling in the longitudinal direction.
The scaffold is preferably made of a biocompatible, bioresorbable material so that after implantation into a patient to replace or repair connective tissue, the scaffold gradually degrades over time. When first implanted, the scaffold preferably has a tensile strength and elastic modulus similar to that of nriative connective tissue, such as, for example a ligament. The preferred tensile strength of the scaffold for an anterior cruciate ligament or a posterior cruciate ligament in the longitudinal direction is between about 500N and 4000N, and more preferably, betweeh about 1000N and 2500N. The preferred stiffness of the scaffold is between about 50N/i and 300N/m, and more preferably, between about 100N/mn and 200N/m. As the fibers of the scaffold resorb and are replaced by natural tissue, the strength of the fibers may diminish. Therefore, the resorption profile of the scaffold should be sufficiently long to reinforce and provide structure to tissue during the regeneration process. A person skilled in the art can determine a suitable resorption profile, depending on the desired use of the scaffold, and can tailor the resorption profile by varying the materials used to construct the scaffold. Preferably, the scaffold has a slow resorption profile, such that resorption requires at least three months, preferably more than six months, and even more preferably, at least ten months.
In one embodiment of the present invention, the fibers of the scaffold can be formed from a biocompatible polymer. A variety of biocompatible polymers can be used to make the fibers according to the present invention including synthetic polymers, natural polymers or combinations thereof. As used hetein the term "synthetic polymer" refers to polymers that are not found in nature, even if the polymers are made from naturally occurring biomaterials. The term "natural polymer" refers to polymers that are naturally occurring. In embodiments where the fibers of the scaffold include at least one synthetic 21/05/04,eh14149.spc, 1I -12polymer, suitable biocompatible synthetic polymers can include polymers selected from the group consisting of aliphatic polyesters, poly(amino acids), copoly(ether-esters), polyalkylene oxalates, polyamides, tyrosine derived polycarbonates, poly(iminocarbonates), polyorthoesters, polyoxaesters, polyamidoesters, polyoxaesters containing amine groups, poly(anhydrides), polyphosphazenes, polyurethanes, poly(ether urethanes), poly(ester urethanes), poly(propylene fumarate), poly(hydroxyalkanoate) and blends thereof. Suitable synthetic polymers for use in the present invention can also include biosynthetic polymers based on sequences found in collagen, elastin, thrombin, silk, keratin, fibronectin, starches, poly(amino acid), gelatin, alginate, pectin, fibrin, oxidized cellulose, chitin, chitosan, tropoelastin, hyaluronic acid, ribonucleic acids, deoxyribonucleic acids, polypeptides, proteins, polysaccharides, polynucleotides and combinations thereof.
For the purpose of this invention aliphatic polyesters include, but are not limited to, homopolymers and copolymers of lactide (which includes lactic acid, and meso lactide); glycolide (including glycolic acid); e-caprolactone; p-dioxanone (1,4-dioxan-2one); trimethylene carbonate (1,3-dioxan-2-one); alkyl derivatives of trimethylene carbonate; 6-valerolactone; P-butyrolactone; y-butyrolactone; e-decalactone; hydroxybutyrate; hydroxyvalerate; 1,4-dioxepan-2-one (including its dimer 1,5,8,12tetraoxacyclotetradecane-7,14-dione); 1,5-dioxepan-2-one; 6,6-dimethyl-1,4-dioxan-2-one; 2,5-diketomorpholine; pivalolactone; a, a diethylpropiolactone; ethylene carbonate; ethylene oxalate; 3-methyl-l,4-dioxane-2,5-dione; 3,3-diethyl-l,4-dioxan-2,5-dione; 6,6dimethyl-dioxepan-2-one; 6,8-dioxabicycloctane-7-one and polymer blends thereof.
Additional exemplary polymer or polymer blends include, by non-limiting example, a polydioxanone, a polyhydroxybutyrate-co-hydroxyvalerate, polyorthocarbonate, a polyaminocarbonate, and a polytrimethylene carbonate. Aliphatic polyesters used in the present invention can be homopolymers or copolymers (random, block, segmented, tapered blocks, graft, triblock, etc.) having a linear, branched or star structure.
Poly(iminocarbonates), for the purpose of this invention, are understood to include those polymers as described by Kemnitzer and Kohn, in the Handbook of Biodegradable Polymers, edited by Domb, et. al., Hardwood Academic Press, pp. 251-272 (1997).
Copoly(ether-esters), for the purpose of this invention, are understood to include those copolyester-ethers as described in the Journal of Biomaterials Research, Vol. 22, pages 993-1009, 1988 by Cohn and Younes, and in Polymer Preprints (ACS Division of Polymer Chemistry), Vol. 30(1), page 498, 1989 by Cohn PEO/PLA). Polyalkylene oxalates, 21/05/04,eh14149.spc,12 -13for the purpose of this invention, include those described in U.S. Patent Numbers 4,208,511; 4,141,087; 4,130,639; 4,140,678; 4,105,034; and 4,205,399.
Polyphosphazenes, co-, ter- and higher order mixed monomer based polymers made from L-lactide, D,L-lactide, lactic acid, glycolide, glycolic acid, para-dioxanone, trimethylene carbonate and e-caprolactone such as are described by Allcock in The Encyclopedia of Polymer Science, Vol. 13, pages 31-41, Wiley Intersciences, John Wiley Sons, 1988 and by Vandorpe, et al in the Handbook of Biodegradable Polymers, edited by Domb, et al., Hardwood Academic Press, pp. 161-182 (1997). Polyanhydrides include those derived from diacids of the form HOOC-C 6
H
4 -O-(CH2)m-O-C6H4-COOH, where is an integer in the range of from 2 to 8, and copolymers thereof with aliphatic alpha-omega diacids of up to 12 carbons. Polyoxaesters, polyoxaamides and polyoxaesters containing amines and/or amido groups are described in one or more of the following U.S. Patent Nos.
5,464,929; 5,595,751; 5,597,579; 5,607,687; 5,618,552; 5,620,698; 5,645,850; 5,648,088; 5,698,213; 5,700,583; and 5,859,150. Polyorthoesters such as those described by Heller in Handbook of Biodegradable Polymers, edited by Domb, et al., Hardwood Academic Press, pp. 99-118 (1997).
As used herein, the term "glycolide" is understood to include polyglycolic acid.
Further, the term "lactide" is understood to include L-lactide, D-lactide, blends thereof, and lactic acid polymers and copolymers.
Elastomeric copolymers are also particularly useful in the present invention, including, but are not limited to, elastomeric copolymers of e-caprolactone and glycolide (including polyglycolic acid) with a mole ratio of e-caprolactone to glycolide of from about 35:65 to about 65:35, more preferably from 45:55 to 35:65; elastomeric copolymers of e-caprolactone and lactide (including L-lactide, D-lactide, blends thereof, and lactic acid polymers and copolymers) where the mole ratio of e-caprolactone to lactide is from about 35:65 to about 65:35 and more preferably from 45:55 to 30:70 or from about 95:5 to about 85:15; elastomeric copolymers of p-dioxanone (1,4-dioxan-2-one) and lactide (including L-lactide, D-lactide, blends thereof, and lactic acid polymers and copolymers) where the mole ratio ofp-dioxanone to lactide is from about 40:60 to about 60:40; elastomeric copolymers of e-caprolactone and p-dioxanone where the mole ratio of e-caprolactone to p-dioxanone is from about from 30:70 to about 70:30; elastomeric copolymers ofpdioxanone and trimethylene carbonate where the mole ratio of p-dioxanone to trimethylene carbonate is from about 30:70 to about 70:30; elastomeric copolymers of trimethylene 21/05/04,eh14149.spc,13 -14 carbonate and glycolide (including polyglycolic acid) where the mole ratio of trimethylene carbonate to glycolide is from about 30:70 to about 70:30; elastomeric copolymers of trimethylene carbonate and lactide (including L-lactide, D-lactide, blends thereof, and lactic acid polymers and copolymers) where the mole ratio of trimethylene carbonate to lactide is from about 30:70 to about 70:30; and blends thereof. Examples of suitable biocompatible elastomers are described in U.S. Patent No. 4,045,418.
In one embodiment, the elastomer is a copolymer of 35:65 e-caprolactone and glycolide, formed in a dioxane solvent. In another embodiment, the elastomer is a copolymer of 40:60 e-caprolactone and lactide; In yet another embodiment, the elastomer is a 50:50 blend of a 35:65 copolymer of e-capiolactone and glycolide and 40:60 copolymer of e-caprolactone and lactide.
The fibers of the present invention can,! optionally, be formed from a bioresorbable or bioabsorbable material that has the ability to resorb in a timely fashion in the body environment. The differences in the absorption time under in vivo conditions can also be the basis for combining two different copolymers when forming the fibers of the present invention. For example, a copolymer of 35:65:e-caprolactone and glycolide (a relatively fast absorbing polymer) can be blended with 40:60 e-caprolactone and L-lactide copolymer (a relatively slow absorbing polymer) to form a biocompatible fiber. Depending upon the processing technique used, the two constituents can be either randomly inter-connected bicontinuous phases, or the constituents could have a gradient-like architecture with a well integrated interface between the two constituent layers.
In an exemplary embodiment, the fibers of the present invention are made from a 95:5 copolymer of lactide and glycolide such asPANACRYL, available from Ethicon, Inc.
In one embodiment, it is desirable to use polymer blends to form fibers which transition from one composition to another composition in a gradient-like architecture.
Scaffolds having this gradient-like architecture are particularly advantageous in tissue engineering applications to repair or regenerate the structure of naturally occurring tissue such as cartilage (articular, meniscal, septal, tracheal, auricular, costal, etc.), tendon, ligament, nerve, esophagus, skin, bone, and vascular tissue. Clearly, one skilled in the art will appreciate that other polymer blends may be used for similar gradient effects, or to provide different gradients different absorption profiles, stress response profiles, or different degrees of elasticity). For example, such design features can establish a concentration gradient for the suspension of minced tissue associated with the prostheis of 21/05/04,eh14149.spc,14 15 the present invention, such that a higher concentration of the tissue fragments is present in one region of the scaffold an interior portion) than in another region outer portions).
The gradient-like transition between compositions can also be oriented in the radial direction of the fibers. For example, some of the fibers of the scaffold may be co-extruded to produce a fiber with a sheath/core construction. Such fibers are comprised of a sheath of biodegradable polymer that surrounds one or more cores comprised of another biodegradable polymer. Fibers with a fast-absorbing sheath surrounding a slowerabsorbing core may be desirable for extended support.
In another embodiment, the fibers can be made of a bioabsorbable glass. Bioglass, a silicate containing calcium phosphate glass, or calcium phosphate glass with varying amounts of solid particles added to control resorption time are examples of materials that could be spun into glass fibers and used for the reinforcing material. Suitable solid particles that may be added include iron, magnesium, sodium, potassium, and combinations thereof.
In embodiments where the fibers includes at least one natural polymer, suitable examples of natural polymers include, but are not limited to, fibrin-based materials, collagen-based materials, hyaluronic acid-based materials, glycoprotein-based materials, cellulose-based materials, silks and combinations thereof. By way of nonlimiting example, the biocompatible scaffold 10 can be constructed from a collagen-based small intestine submucosa.
In another embodiment of the present invention, a biocompatible ceramic material can be incorporated into the anchoring segments 12a and 12b of the scaffold. Suitable biocompatible ceramic materials include, for example, hydroxyapatite, c-tricalcium phosphate, p-tricalcium phosphate, bioactive glass, calcium phosphate, calcium sulfate, calcium carbonate, xenogeneic and allogeneic bone material and combinations thereof.
Suitable bioactive glass materials for use in the present invention include silicates containing calcium phosphate glass, or calcium phosphate glass with varying amounts of solid particles added to control resorption time. Suitable compounds that may be incorporated into the calcium phosphate bioactive glass include, but are not limited to, magnesium oxide, sodium oxide, potassium oxide, and combinations thereof.
One skilled in the art will appreciate that the selection of a suitable material for forming the biocompatible fibers of the present invention depends on several factors.
These factors include in vivo mechanical performance; cell response to the material in 21/05/04,eh14149.spc,15 -16terms of cell attachment, proliferation, migration and differentiation; biocompatibility; and optionally, bioabsorption (or bio-degradation) kinetics. Other relevant factors include the chemical composition, spatial distribution of the constituents, the molecular weight of the polymer, and the degree of crystallinity.
In a further embodiment of the present invention, the scaffold 10 can include bioresorbable fibers of different compositions. The fibers may be selected to create a complementary mixture of fibers having different properties, or fibers having a different composition may be added to the scaffold 10 to perform a specific job, such as for example, cell adhesion. In one embodiment, the longitudinal fibers can be constructed of a different material from the transverse fibers, and preferably have a longer resorption profile.
In addition to the longitudinal and transverse bioresorbable fibers, the scaffold of the present invention can further include at least one sample of viable tissue that is associated with at least a portion of the scaffold. The term "viable," as used herein, refers to a tissue sample having one or more viable cells. Virtually any type of tissue can be used to construct the tissue repair scaffolds of the present invention. Preferably, the tissue used is selected from cartilage tissue, meniscal tissue, ligament tissue, tendon tissue, skin tissue, bone tissue, muscle tissue, periosteal tissue, pericardial tissue, synovial tissue, nerve tissue, fat tissue, kidney tissue, bone marrow, liver tissue, small intestine tissue, bladder tissue, pancreas tissue, spleen tissue, intervertebral disc tissue, embryonic tissue, periodontal tissue, vascular tissue, blood and combinations thereof. The tissue used to construct the tissue scaffolds can be autogeneic tissue, allogeneic tissue, or xenogeneic tissue.
Where the scaffold 10 is useful for ligament or tendon repair, the tissue incorporated into the central segment is preferably bone-free tissue selected from the group consisting of tendon tissue, ligament tissue of the same type that is to be repaired, ligament tissue of a different type than the tissue that is to be repaired, synovial tissue, periosteal tissue, cartilage tissue, meniscus tissue, fascia, skin, and combinations thereof. In one embodiment, bone tissue fragments may be is applied to the anchoring segments 12a, 12b.
For example, during the formation of the tibial and femoral bone tunnels for cruciate repair, an instrument, i.e. a coring reamer, can be used to harvest the bone from the site.
This cored bone then can be used in its entirety or in fragments and placed alongside the anchoring segments 12a, 12b.
The tissue can be obtained using any of a variety of conventional techniques, such as for example, by biopsy or other surgical removal. Preferably, the tissue sample is 21/05/04,eh14149.spc,16
_I
-17obtained under aseptic conditions. Once a sample of living tissue has been obtained, the sample can then be processed under sterile conditions to create a suspension having at least one minced, or finely divided, tissue particle. The particle size of each tissue fragment can vary, for example, the tissue size can be in the range of about 0.1 and 30 mm 3 but preferably the tissue particle is less than 10 mm 3 The shape of the tissue fragments do not need to be isotropic cubic or spherical), instead the tissue fragments can be in the form of strips or sheets of tissue such that one dimension of the tissue is equal to or less than 1mm in thickness.
Preferably, the minced tissue has at least one viable cell that can migrate from the tissue fragment onto the scaffold. More preferably, the tissue contains an effective amount of cells that can migrate from the tissue fragment and begin populating the scaffold 10. In an optional embodiment, the minced tissue fragments may be contacted with a matrixdigesting enzyme to facilitate cell migration out of the extracellular matrix surrounding the cells. The enzymes are used to increase the rate of cell migration out of the extracellular matrix and into the scaffold. Suitable matrix-digesting enzymes that can be used in the present invention include, but are not limited to, collagenase, chondroitinase, trypsin, elastase, hyaluronidase, petidase, thermolysin and protease.
In one embodiment, the minced tissue particles can be formed as a suspension in which the tissue particles are associated with a physiological buffering solution. Suitable physiological buffering solutions include, but are not limited to, saline, phosphate buffer solution, Hank's balanced salts, Tris buffered saline, Hepes buffered saline and combinations thereof. In addition, the tissue can be minced in any standard cell culture medium known to those having skill in the art, either in the presence or absence of serum.
Prior to depositing the suspension of minced tissue on the scaffold or at the site of implantation, the minced tissue suspension can be filtered and concentrated, such that only a small quantity of physiological buffering solution remains in the suspension to prevent the tissue particles from drying out, and the minced tissue particles can be directly applied to the scaffold or site of implantation. Preferably, the minced tissue particles are loaded at a concentration in the range of approximately 1 to 100 mg/cm 2 and more preferably in the range of about 1 to 20 mg/cm 2 The suspension of minced living tissue can be used to create a connective tissue scaffold according to the present invention by depositing the suspension of living tissue upon the scaffold, such that the tissue and the scaffold become associated. Preferably, the tissue is associated with at least a portion of the scaffold. Additionally, the scaffold can be 21/05/04,eh 14149.spc, 17 18implanted in a subject immediately, or alternatively, the tissue seeded scaffold can be incubated under sterile conditions for a duration and under conditions that are effective to maintain the viability of the tissue sample. In embodiments where the construct is incubated, the incubation conditions can vary, but preferably, the scaffold is incubated for a duration in the range of 1 hour to 6 weeks, and more preferably between about 1 week and 6 weeks, at a temperature in the range of about 20 to 40 oC, and in an atmosphere containing between about 5 and 10 carbon dioxide (CO 2 and high humidity, e.g., approximately 100% humidity.
A kit can be used to assist in the preparation of the tissue scaffold of the present invention. According to the present invention, the kit includes a sterile container that houses one or more biocompatible scaffolds, a harvesting tool for collecting the living tissue sample from a subject, and one or more reagents for sustaining the viability of the tissue sample. Suitable reagents for sustaining the viability of the tissue sample include a physiological solution, such as for example, saline, phosphate buffering solution, Hank's balanced salts, standard cell culture medium, Dulbecco's modified Eagle's medium, ascorbic acid, HEPES, nonessential amino acid, L-proline, fetal bovine serum, autologous serum, and combinations thereof. The kit can also include a processing tool for dividing the tissue into minced tissue particles, or alternatively, the harvesting tool can be adapted to collect the tissue sample and to process the sample into finely divided tissue particles.
The kit can, optionally, also include a delivery device for transferring the scaffold from the sterile container to a subject for implantation.
A biological component may, optionally, be incorporated within the tissue scaffolds of the present invention. Preferably, the biological component is incorporated within, or coated on, the scaffolds disclosed above. In embodiments where the biological component is coated onto the scaffold, the biological component is preferably associated with at least a portion of the scaffold. By way of nonlimiting example, the biocompatible scaffold can include an adhesion agent for anchoring the suspension of minced tissue fragments to the scaffold. Preferably, the adhesion agent is an anchoring agent, a cross-linking agent chemical or physical), and combinations thereof.
Suitable anchoring agents include, but are not limited to, hyaluronic acid, fibrin glue, fibrin clot, collagen gel, alginate gel, gelatin-resorcin-formalin adhesive, musselbased adhesive, dihydroxyphenylalanine (DOPA) based adhesive, chitosan, transglutaminase, poly(amino acid)-based adhesive, cellulose-based adhesive, polysaccharide-based adhesive, synthetic acrylate-based adhesives, platelet rich plasma 21/05/04,eh14149.spc,18 -19- (PRP) gel, platelet poor plasma (PPP) gel, Matrigel, Monostearoyl Glycerol co-Succinate (MGSA), Monostearoyl Glycerol co-Succinate/polyethylene glycol (MGSA/PEG) copolymers, laminin, elastin, proteoglycans, and combinations thereof.
Suitable cross-linking agents include, for example, divinyl sulfone (DVS), polyethylene glycol divinyl sulfone (VS-PEG-VS), hydroxyethyl methacrylate divinyl sulfone (HEMA-DIS-HEMA), formaldehyde, glutaraldehyde, aldehydes, isocyanates, alkyl and aryl halides, imidoesters, N-substituted maleimides, acylating compounds, carbodiimide, hydroxychloride, N-hydroxysuccinimide, light blue light and UV light), pH, temperature, and combinations thereof.
The biological components used in the present invention can also be selected from among a variety of effectors that, when present at the site of injury, promote healing and/or regeneration of the affected tissue. In addition to being compounds or agents that actually promote or expedite healing, the effectors may also include compounds or agents that prevent infection antimicrobial agents and antibiotics), compounds or agents that reduce inflammation anti-inflammatory agents), compounds that prevent or minimize adhesion formation, such as oxidized regenerated cellulose INTERCEED and Surgicel®, available from Ethicon, Inc.), hyaluronic acid, and compounds or agents that suppress the immune system immunosuppressants).
By way of example, other types of effectors present within the scaffold of the present invention can include heterologous or autologous growth factors, proteins (including matrix proteins), peptides, antibodies, enzymes, platelets, glycoproteins, hormones, cytokines, glycosaminoglycans, nucleic acids, analgesics, viruses, virus particles, and cell types. It is understood that one or more effectors of the same or different functionality may be incorporated within the scaffold.
Examples of suitable effectors include the multitude of heterologous or autologous growth factors known to promote healing and/or regeneration of injured or damaged tissue.
These growth factors can be incorporated directly into the scaffold, or alternatively, the scaffold can include a source of growth factors, such as for example, platelets. "Bioactive agents" include one or more of the following: chemotactic agents; therapeutic agents antibiotics, steroidal and non-steroidal analgesics and anti-inflammatories, anti-rejection agents such as immunosuppressants and anti-cancer drugs); various proteins short term peptides, bone morphogenic proteins, glycoprotein and lipoprotein); cell attachment mediators; biologically active ligands; integrin binding sequence; ligands; various growth and/or differentiation agents and fragments thereof epidermal growth factor (EGF), 21/05/04,eh14149.spc,19 hepatocyte growth factor (HGF), IGF-I, IGF-II, TGF-B I-III, growth and differentiation factors, vascular endothelial growth factors (VEGF), fibroblast growth factors (FGF), platelet derived growth factors (PDGF), insulin derived growth factor (IGF) and transforming growth factors, parathyroid hormone, parathyroid hormone related peptide, bFGF; TGFB superfamily factors; BMP-2; BMP-4; BMP-6; BMP-12; sonic hedgehog; GDF6; GDF8; MP52, CDMP1); small molecules that affect the upregulation of specific growth factors; tenascin-C; hyaluronic acid; chondroitin sulfate; fibronectin; decorin; thromboelastin; thrombin-derived peptides; heparin-binding domains; heparin; heparan sulfate; DNA fragments and DNA plasmids. Suitable effectors likewise include the agonists and antagonists of the agents noted above. The growth factor can also include combinations of the growth factors listed above. In addition, the growth factor can be autologous growth factor that is supplied by platelets in the blood. In this case, the growth factor from platelets will be an undefined cocktail of various growth factors. If other such substances have therapeutic value in the orthopaedic field, it is anticipated that at least some of these substances will have use in the present invention, and such substances should be included in the meaning of "bioactive agent" and "bioactive agents" unless expressly limited otherwise.
"Biologically derived agents" include one or more of the following: bone (autograft, allograft, and xenograft) and derivates of bone; cartilage (autograft, allograft and xenograft), including, for example, meniscal tissue, and derivatives; ligament (autograft, allograft and xenograft) and derivatives; derivatives of intestinal tissue (autograft, allograft and xenograft), including for example submucosa; derivatives of stomach tissue (autograft, allograft and xenograft), including for example submucosa; derivatives of bladder tissue (autograft, allograft and xenograft), including for example submucosa; derivatives of alimentary tissue (autograft, allograft and xenograft), including for example submucosa; derivatives of respiratory tissue (autograft, allograft and xenograft), including for example submucosa; derivatives of genital tissue (autograft, allograft and xenograft), including for example submucosa; derivatives of liver tissue (autograft, allograft and xenograft), including for example liver basement membrane; derivatives of skin tissue; platelet rich plasma (PRP), platelet poor plasma, bone marrow aspirate, demineralized bone matrix, insulin derived growth factor, whole blood, fibrin and blood clot. Purified ECM and other collagen sources are also intended to be included within "biologically derived agents." If other such substances have therapeutic value in the orthopaedic field, it is anticipated that at least some of these substances will have use in the 21/05/04,eh14149.spc,20 -21present invention, and such substances should be included in the meaning of "biologicallyderived agent" and "biologically-derived agents" unless expressly limited otherwise.
"Biologically derived agents" also include bioremodelable collageneous tissue matrices. The expressions "bioremodelable collagenous tissue matrix" and "naturally occurring bioremodelable collageneous tissue matrix" include matrices derived from native tissue selected from the group consisting of skin, artery, vein, pericardium, heart valve, dura mater, ligament, bone, cartilage, bladder, liver, stomach, fascia and intestine, whatever the source. Although "naturally occurring bioremodelable collageneous tissue matrix" is intended to refer to matrix material that has been cleaned, processed, sterilized, and optionally crosslinked, it is not within the definition of a naturally occurring bioremodelable collageneous tissue matrix to purify the natural fibers and reform a matrix material from purified natural fibers.
The proteins that may be present within the scaffold can include proteins that are secreted from a cell or other biological source, such as for example, a platelet, which is housed within the scaffold, as well as those that are present within the scaffold in an isolated form. The isolated form of a protein typically is one that is about 55% or greater in purity, isolated from other cellular proteins, molecules, debris, etc. More preferably, the isolated protein is one that is at least 65% pure, and most preferably one that is at least about 75 to 95% pure. Notwithstanding the above, one skilled in the art will appreciate that proteins having a purity below about 55% are still considered to be within the scope of this invention. As used herein, the term "protein" embraces glycoproteins, lipoproteins, proteoglycans, peptides, and fragments thereof. Examples of proteins useful as effectors include, but are not limited to, pleiotrophin, endothelin, tenascin, fibronectin, fibrinogen, vitronectin, V-CAM, I-CAM, N-CAM, selectin, cadherin, integrin, laminin, actin, myosin, collagen, microfilament, intermediate filament, antibody, elastin, fibrillin, and fragments thereof.
Glycosaminoglycans, highly charged polysaccharides which play a role in cellular adhesion, may also serve as effectors according to the present invention. Exemplary glycosaminoglycans useful as effectors include, but are not limited to, heparan sulfate, heparin, chondroitin sulfate, dermatan sulfate, keratan sulfate, hyaluronan (also known as hyaluronic acid), and combinations thereof.
The scaffold of the present invention can also have cells incorporated therein.
Suitable cell types that can serve as effectors according to this invention include, but are not limited to, osteocytes, osteoblasts, osteoclasts, fibroblasts, fibrochondrocytes, stem 21/05/04,ehl4149.spc,21 -22cells, pluripotent cells, chondrocyte progenitors, chondrocytes, endothelial cells, macrophages, leukocytes, adipocytes, monocytes, plasma cells, mast cells, umbilical cord cells, stromal cells, mesenchymal cells, epithelial cells, myoblasts, tenocytes, ligament fibroblasts, neurons, and bone marrow cells, synoviocytes, embryonic stem cells; precursor cells derived from adipose tissue; peripheral blood progenitor cells; stem cells isolated from adult tissue; genetically transformed cells; a combination of chondrocytes and other cells; a combination of osteocytes and other cells; a combination of synoviocytes and other cells; a combination of bone marrow cells and other cells; a combination of mesenchymal cells and other cells; a combination of stromal cells and other cells; a combination of stem cells and other cells; a combination of embryonic stem cells and other cells; a combination of precursor cells isolated from adult tissue and other cells; a combination of peripheral blood progenitor cells and other cells; a combination of stem cells isolated from adult tissue and other cells; and a combination of genetically transformed cells and other cells.
If other cells are found to have therapeutic value in the orthopaedic field, it is anticipated that at least some of these cells will have use in the present invention, and such cells should be included within the meaning of "cell" and "cells" unless expressly limited. Cells typically have at their surface receptor molecules which are responsive to a cognate ligand a stimulator). A stimulator is a ligand which when in contact with its cognate receptor induce the cell possessing the receptor to produce a specific biological action. For example, in response to a stimulator (or ligand) a cell may produce significant levels of secondary messengers, like Ca+2, which then will have subsequent effects upon cellular processes such as the phosphorylation of proteins, such as (keeping with our example) protein kinase C. In some instances, once a cell is stimulated with the proper stimulator, the cell secretes a cellular messenger usually in the form of a protein (including glycoproteins, proteoglycans, and lipoproteins). This cellular messenger can be an antibody secreted from plasma cells), a hormone, a paracrine, autocrine, or exocrine hormone), a cytokine, or natural or synthetic fragments thereof.
The scaffold of the invention can also be used in gene therapy techniques in which nucleic acids, viruses, or virus particles deliver a gene of interest, which encodes at least one gene product of interest, to specific cells or cell types. Accordingly, the biological effector can be a nucleic acid DNA, RNA, or an oligonucleotide), a virus, a virus particle, or a non-viral vector. The viruses and virus particles may be, or may be derived from, DNA or RNA viruses. The gene product of interest is preferably selected from the 21/05/04,eh14149.spc,22 23 group consisting of proteins, polypeptides, interference ribonucleic acids (iRNA) and combinations thereof.
Once the applicable nucleic acids and/or viral agents viruses or viral particles) are incorporated into the scaffold, and can then be implanted into a particular site to elicit a type of biological response. The nucleic acid or viral agent can then be taken up by the cells and any proteins that they encode can be produced locally by the cells. In one embodiment, the nucleic acid or viral agent can be taken up by the cells within the tissue fragment of the minced tissue suspension, or, in an alternative embodiment, the nucleic acid or viral agent can be taken up by the cells in the tissue surrounding the site of the injured tissue. One skilled in the art will recognize that the protein produced can be a protein of the type noted above, or a similar protein that facilitates an enhanced capacity of the tissue to heal an injury or a disease, combat an infection, or reduce an inflammatory response. Nucleic acids can also be used to block the expression of unwanted gene product that may impact negatively on a tissue repair process or other normal biological processes.
DNA, RNA and viral agents are often used to accomplish such an expression blocking function, which is also known as gene expression knock out.
One skilled in the art will appreciate that the identity of the biological component may be determined by a surgeon, based on principles of medical science and the applicable treatment objectives.
The biological component or effector of the scaffold can be incorporated before or after manufacture of the scaffold, or before or after the surgical placement of the scaffold.
Prior to surgical placement, the scaffold can be placed in a suitable container comprising the biological component. After an appropriate time and under suitable conditions, the scaffold will become impregnated with the biological component.
Alternatively, the biological component can be incorporated within the scaffold by, for example, using an appropriately gauged syringe to inject the biological agent(s) into the scaffold. Other methods well known to those skilled in the art can be applied in order to load a scaffold with an appropriate biological component, such as mixing, pressing, spreading, centrifuging and placing the biological component into the scaffold.
Alternatively, the biological component can be mixed with a gel-like carrier prior to injection into the scaffold. The gel-like carrier can be a biological or synthetic hydrogel, including an alginate, a cross-linked alginate, hyaluronic acid, collagen gel, fibrin glue, fibrin clot, gelatin-resorcin-formalin adhesive, mussel-based adhesive, dihydroxyphenylalanine (DOPA) based adhesive, chitosan, transglutaminase, poly(amino 21/05/04,eh 14149.spc,23 -24acid)-based adhesive, cellulose-based adhesive, polysaccharide-based adhesive, synthetic acrylate-based adhesives, platelet rich plasma (PRP) gel, platelet poor plasma (PPP) gel, Matrigel, Monostearoyl Glycerol co-Succinatel (MGSA), Monostearoyl Glycerol co- Succinate/polyethylene glycol (MGSA/PEG) copolymers, laminin, elastin, proteoglycanspoly(N-isopropylacrylamide), pdly(oxyalkylene), a copolymer of poly(ethylene oxide)-poly(propylene oxide), poly(vinyl alcohol) and combinations thereof.
Following surgical placement, a scaffold devoid of any biological component can be infused with biological agent(s), or a scaffold that includes at least one biological component can be augmented with a supplemental quantity of the biological component.
One method of incorporating a biological component within a surgically installed scaffold is by injection using an appropriately gauged syringe.
The amount of the biological component included with a biocompatible scaffold will vary depending on a variety of factors, including the size of the scaffold, the material from which the scaffold is made, the density of the scaffold, the identity of the biologically component, and the intended purpose of the tissue scaffold. One skilled in the art can readily determine the appropriate quantity of biological component to include within the scaffold for a given application in order to facilitate and/or expedite the healing of tissue.
The amount of biological component will, of course, vary depending upon the identity of the biological component and the given application.
In another embodiment, the scaffold can include an additional retaining element that is placed over the tissue-laden scaffold. Preferably, in this embodiment, at least a portion of the tissue suspension is associated with at least a portion of the outer surface of the scaffold, such that the tissue suspension is "sandwiched" between the scaffold and the retaining element. The retaining element can be formed from virtually any biocompatible material, and in one embodiment, the retaining! element can be formed using tissue grafts, including grafts obtained from allogeneic tissue, autogeneic tissue, and xenogeneic tissue, an additional biocompatible material selected from the biocompatible materials disclosed above, and combinations thereof. In another embodiment, the retaining element can be a porous mesh, a porous mesh-like material, such as for example, a knit, a weave, a nonwoven, or a thin, perforated elastomeric sheet having pores or perforations to allow tissue ingrowth. The thin, perforated elastomeric sheets are preferably constructed from collagen or silk or blends or copolymers ofpolylactic acid (PLA), polyglycolic acid (PGA), polycaprolactone (PCL) and polydioxanone (PDO). The type of retaining element used can vary according to the desired tissue repair. By way of non-limiting example, in 21/05/04,eh14149.spc,24 one embodiments for ACL repair, the retaining element can be a mesh structure. In embodiments where the retaining element is an allograft or an autograft, preferably the allograft or autograft is selected from periosteum, perichondrium, iliotibial band or fascia lata, gracilis tendon, semitendinosis tendon, patellar tendon, synovium and combinations thereof. In embodiments where the retaining element is a xenograft, the xenograft is preferably selected from the corresponding anatomical structure for small intestine, periosteum, perichondrium, iliotibial band or fascia lata, gracilis tendon, semitendonous tendon, patellar tendon, synovium, and combinations thereof. These retaining elements can be placed over the scaffold 10, or alternatively, the retaining element can be affixed, such as for example, by suturing or stapling, the scaffold 10 to act as a retaining element.
One skilled in the art will appreciate that additional processing of the retaining element, such as for example, the placement of holes within the retaining element, may be determined by a surgeon, based on principles of medical science and the applicable treatment objectives.
In one embodiment, the retaining element is an electrostatically spun fabric added to the scaffold to act as a barrier to hyperplasia and tissue adhesion, thus reducing the possibility of postsurgical adhesions. The fabric barrier is preferably in the form of dense fibrous fabric that is added to the scaffold. Preferably, the fibrous fabric is comprised of small diameter fibers that are fused to the top and/or bottom surface of the scaffold. This enables certain surface properties of the structure, such as porosity, permeability, degradation rate and mechanical properties, to be controlled.
The composition, thickness, and porosity of the fibrous layer may be controlled to provide the desired mechanical and biological characteristics. For example, the bioabsorption rate of the fibrous layer may be selected to provide a longer or shorter bioabsorption profile as compared to the underlying scaffold. The fibrous layer may be constructed from the biocompatible polymers discussed above. Additionally, the fibrous layer may provide greater structural integrity to the composite so that mechanical force may be applied to the fibrous side of the structure. In one embodiment the fibrous layer could allow the use of sutures, staples or various fixation devices to hold the composite in place. Preferably the thickness of the fibrous layer is in the range of about 1 micron to 1000 microns.
In another preferred embodiment, the retaining element is constructed from a naturally occurring extracellular matrix material such as that found in the stomach, bladder, alimentary, respiratory, urinary, integumentary, genital tracts, or liver 21/05/04,eh14149.spc,25 -26basement membrane of animals. Preferably, the ECM is derived from the alimentary tract of mammals, such a cow, sheep, dogs, and most preferably from the intestinal tract of pigs.
The ECM is preferably, small intestine submucosa which can include the tunica submucosa, along with basilar portions of the tunica mucosa, particularly the lamina muscularis mucosa and the stratum compactum.
For the purposes of this disclosure, it is within the definition of a naturally occurring ECM to clean and/or comminute the ECM, or even to cross-link the collagen fibers within the ECM. However, it is not within the definition of a naturally occurring ECM to extract and purify the natural fibers and reform a matrix material from purified natural fibers. Also, while reference is made to SIS, it is understood that other naturally occurring ECMs are within the scope of this disclosure. Thus, as used herein, the terms "naturally occurring extracellular matrix" or "naturally occurring ECM" are intended to refer to extracellular matrix material that has been cleaned, disinfected, sterilized, and optionally cross-linked.
Where SIS is used, a SIS graft 32 can be harvested in a variety of ways, as will be understood by one skilled in the art. The resulting graft material can have a variety of geometries and consistencies including for example, coiled, helical, spring-like, randomized, branched, sheet-like, tubular, spherical, fragmented, fluidized, comminuted, liquefied, foamed, suspended, gel-like, injectable, powdered, ground, and sheared. In a preferred embodiment, the SIS graft 32 is prepared as a tubular or sheet-like shape which can be used to cover the scaffold of the present invention.
In one embodiment illustrated in FIGS. 6 7, a tubular ECM graft 32 SIS) is used as a sleeve to cover at least part of the scaffold. Alternatively, a layer or layers of a sheet-like ECM graft 32 may be wrapped around the exterior of the scaffold.
A ECM graft 32, such as a SIS graft, is particularly advantageous for use with the present invention to provide a smooth exterior surface for easy insertion of the scaffold into a bone tunnel without damaging the longitudinal and/or transverse fibers and to protect minced tissue positioned on the fibers. The ECM graft 32 can cover at least part of the scaffold and a minced tissue and/or a biological component could be positioned between the ECM graft 32 and the scaffold The minced tissue and/or biological component can be added prior to positioning the ECM graft 32, or the scaffold and ECM graft 32 could be implanted and then the minced tissue and/or biological component could be arthroscopically injected between the ECM graft 32 and the scaffold. In one 21/05/04,eh 14149.spc,26 27 embodiment, minced ACL tissue and PRP are arthroscopically injected between the ECM graft 32 and the scaffold.
In an alternative embodiment, the ECM may be mixed with the minced tissue or biological component of the present invention, particularly where the ECM is injectable or spreadable. In one embodiment, the ECM is used as a foam mixed with a minced tissue and/or a biological component as discussed above.
In one embodiment of the present invention, the scaffold is used in the treatment of a tissue injury, such as injury to a ligament or tendon. Repairing such injuries involves the steps of obtaining a sample of the damaged living tissue by any of the variety of techniques known to those having skill in the art, processing that sample of living tissue under sterile conditions, such as for example by cutting the tissue, to create at least one minced, finely divided tissue particle, depositing the tissue sample upon the scaffold, such that the tissue sample becomes associated with the scaffold, and placing the scaffold in a desired position relative to the tissue injury. Repairing tissue injuries may also involve placing the scaffold at the site of tissue injury and then depositing the fine tissue particles onto the scaffold.
The cells in the tissue particles associated with the scaffold can migrate to the scaffold and begin proliferating and integrating with surrounding tissue at the site of implantation, thereby repairing the tissue injury. This method for repairing tissue injuries can include an additional, optional step. Prior to the step of placing the scaffold in a desired position relative to the tissue injury, the scaffold and associated tissue particles can be incubated for a duration and under conditions effective to allow cells within the tissue particles to migrate from the tissue and begin populating the scaffold The tissue samples used in the present invention are obtained from a donor (autogeneic, allogeneic, or xenogeneic) using appropriate harvesting tools. The tissue samples can be finely minced and divided into small particles either as the tissue is collected, or alternatively, the tissue sample can be minced after it is harvested and collected outside the body. In embodiments, where the tissue sample is minced after it is harvested, the tissue samples can be weighed and then washed three times in phosphate buffered saline. Approximately 300 to 500 mg of tissue can then be minced in the presence of a small quantity, such as, for example, about 1 ml, of a physiological buffering solution, such as, for example, phosphate buffered saline, or a matrix digesting enzyme, such as, for example, 0.2 collagenase in Hams F12. Mincing the tissue divides the tissue into particles or small pieces of approximately lmm 3 Mincing the tissue can be accomplished by a variety of methods. In one embodiment, the mincing is accomplished 21/05/04,eh 14149.spc,27 -28with two sterile scalpels using a longitudinal direction, and in another embodiment, the tissue can be minced by a processing tool that automatically divides the tissue into particles of a desired size. In one embodiment, the minced tissue can be separated from the physiological fluid and concentrated using anyof a variety of methods known to those having skill in the art, such as for example, sieving, sedimenting or centrifuging. In embodiments where the minced tissue is filtered and concentrated, the suspension of minced tissue preferably retains a small quantity of fluid in the suspension to prevent the tissue from drying out. In another embodiment, the suspension of minced tissue is not concentrated, and the minced tissue can be directly delivered to the site of tissue repair via a high concentration tissue suspension or other'carrier such as for example, a hydrogel, fibrin glue, or collagen. In this embodiment, the minced tissue suspension can be covered by any of the biocompatible materials described above to retain the tissue fragments in place.
The minced tissue can then be distributed onto the scaffold using a cell spreader so as to cover the entire scaffold. The minced tissue can also be injected into the scaffold.
Optionally, the tissue particles can be adhered to the scaffolds using any of the adhesive agents described above, such as, for example, fibrin glue or platelet rich plasma. In embodiments using fibrin glue or platelet rich plasma, an activator can be used to form a clot or glue. An activator can be, but is not limited to, thrombin, adenosine di-phosphate (ADP), collagen, epinephrine, arachidonic acid, Ristocetin, calcium chloride and combinations thereof. Once the tissue particles and any additional agents have been deposited on the scaffold the scaffold can then implanted immediately, or alternatively, the scaffold can be cultured in vitro for a duration and under conditions sufficient to allow the cells in the tissue particles to migrate from the tissue particles onto the scaffold. In an embodiment where the tissue repair scaffold is incubated prior to implantation, the scaffold is preferably cultured in vitro for approximately 1- 3 weeks in a fibroblast growth medium, such as for example, DMEM-high glucose, supplemented with 20% fetal calf serum (FCS), 100 mg/ml penicillin, 100 mg/ml of streptomycin and 0.25 mg/ml of amphotericin B. In another embodiment, the scaffold may be implanted and then the tissue particles and any addition agents may be deposited onto the scaffold.
The methods of repairing tissue injuries using the tissue scaffolds according to the present invention can be conducted during a surgical operation to repair the tissue injury.
Alternatively, the steps of processing the tissue sample to create minced, finely divided tissue particles, depositing the tissue particles upon the scaffold, and/or incubating the 21/05/04,h 14149.spc28 -29scaffold prior to implantation can be conducted at another, sterile location prior to surgical placement of the scaffold relative to the site of injury.
As noted above, the biological component may be added to the scaffold during or after manufacture of the scaffold or before or after the scaffold is installed in a patient. An additional quantity of the biological component may be added after the scaffold is installed. Once access is made into the affected anatomical site (whether by minimally invasive, open or mini-open surgical technique), the scaffold can be affixed to a desired position relative to the tissue injury. Once the scaffold is placed in the desired position, it can be affixed by using a suitable technique. In one aspect, the scaffold can be affixed by a chemical and/or mechanical fastening technique. Suitable chemical fasteners include glues and/or adhesive such as fibrin glue, fibrin clot, and other known biologically compatible adhesives. Suitable mechanical fasteners include sutures, staples, tissue tacks, suture anchors, darts, screws, buttons, pins and arrows. It is understood that combinations of one or more chemical and/or mechanical fasteners can be used. Alternatively, one need not use any chemical and/or mechanical fasteners. Instead, placement of the scaffold can be accomplished through an interference fit of the scaffold with an appropriate site in the tissue to be treated.
In embodiments where the scaffold is used to repair ligament tissue, the scaffold can be used for tissue augmentation, or alternatively, as a stand-alone device. In embodiments where the scaffold is used for augmentation, the scaffold can be used in conjunction with any of a variety of standard, established repair techniques known to those having skill in the art. In embodiments where the scaffold is used for augmentation during ACL repair, surgeons currently use an autograf# consisting of ligament tissue, bone-patellar tendons, tendon-bone tendons, hamstring tendons, or iliotibial band to repair tissue, and the scaffold of the present invention can be placed either around the autograft, surrounded by the autograft, or alongside the autograft. In embodiments where the tissue repair element is used as a stand-alone device, the ruptured ligament can be removed and completely replaced by the scaffold, with the ruptured ligament preferably providing source for minced tissue. The scaffold can then be affixed to bone. In the case of ACL repair, one end of the scaffold can be stabilized at the original origin site of the femur, while the other end can be placed at the original insertion site on the tibia.
The following examples are illustrative of the principles and practice of this invention. Numerous additional embodiments within the scope and spirit of the invention will become apparent to those skilled in the art.
21/05/04,eh 14149.sp,29 EXAMPLE 1 Native anterior cruciate ligament (ACL) tissue was excised from a goat knee and the ACL was reconstructed using a ligament graft resembling that of the type shown in FIG. 4. The graft was formed of PANACRL, a 95:5 copolymer of lactide and glycolide, and was prepared for implantation by incorporating into the graft about 2 ml. of platelet rich plasma (PRP). In one evaluation about 600 mg. minced ACL fragments (about 1 mm.
in size) was also incorporated into the graft. The purpose of this study was to evaluate the potential of synthetic scaffolds with autologous growth factors and/or minced tissue to regenerate the ACL. The grafts were 3.5mm in diameter and the PRP and the minced tissue were placed on the graft before insertion into the tibial and femoral bone tunnels. A VICRYL mesh was sutured around the PANACRYL graft and minced tissue to help retain the tissue on the graft. Fixation of the device was achieved on both the femoral and tibial side using a screw/washer system. After 12 weeks, the ligament portion of the ACL was excised, preserved in 10% buffered formalin fixative, and processed for histology.
Histological sections were stained with Hematoxylin and Eosin. FIG. 8 shows the implant that was formed of PANACRYL and PRP only in which newly generated collagen is deposited along the fibers of the scaffold. FIG. 9 shows an image acquired under polarized light of a graft that was formed of PANACRYL, PRP and minced tissue in which new collagen is formed between the fibers and there is order within the new collagen as evidenced by birefringence.
EXAMPLE 2 A synthetic ACL graft of the type shown in FIG. 4 and formed of PANACRYL, a 95:5 copolymer of lactide and glycolide, was tested mechanically in tension with a gauge length of 8 inches and a strain rate of 1 inch/min. The stiffness was measured to be 160 N/mm and the graft was found to have an ultimate tensile strength of 2600N. One skilled in the art will appreciate further features and advantages of the invention based on the above-described embodiments. Accordingly, the invention is not to be limited by what has been particularly shown and described, except as indicated by the appended claims.
All publications and references cited herein are expressly incorporated herein by reference in their entirety.
21/05/04,eh14149.spc,30

权利要求:
Claims (41)
[1] 1. A connective tissue scaffold, comprising: opposed first and second anchoring segments formed of a plurality of bioresorbable polymeric fibers oriented in a dilrection substantially parallel to a longitudinal axis of the scaffold and a plurality ofbioresorbable polymeric fibers oriented in a direction substantially transverse to a longitudinal axis of the scaffold; and a central segment, adjoining the first and second anchoring segments, formed of a plurality of bioresorbable polymeric fibers oriented in a direction substantially parallel to the longitudinal axis of the scaffold.
[2] 2. The scaffold of claim 1, wherein the fibers are formed of a material selected from the group consisting of a synthetic polymer, a natural polymer,, and combinations thereof.
[3] 3. The scaffold of claim 1, wherein the fibers of the scaffold take longer than six months to resorb when implanted in a biological system.
[4] 4. The scaffold of claim 1, wherein the fibers of the first and second anchoring segments are joined in a weave pattern. The scaffold of claim 4, wherein the weave pattern comprises one or more regions having a plurality of longitudinally oriented fibers separated by one or more regions having transversely oriented fibers woven with longitudinally oriented fibers.
[5] 6. The scaffold of claim 1, wherein the fibers of the central segment are joined in a braid pattern.
[6] 7. The scaffold of claim 1, wherein the first and second anchoring segments comprise a mesh.
[7] 8. The scaffold of claim 1, wherein the fiber density of the central segment is less that the fiber density of the first and second anchoring segments. 21/05/04,eh14149.spc,31 -32-
[8] 9. The scaffold of claim 1, wherein the fibers of the central segment are oriented in an annular pattern and a space is centrally formed between the annularly oriented fibers. The scaffold of claim 1, wherein the scaffold further includes a biocompatible, bioresorbable material covering at least a portion of the first and second anchoring segments and the central segment.
[9] 11. The scaffold of claim 10, wherein the bioresorbable material is a biological material.
[10] 12. The scaffold of claim 11, wherein the bioresorbable material is small intestine submucosa.
[11] 13. The scaffold of claim 12, wherein the bioresorbable material is formed over the first and second anchoring segments and the central segment as a wrap, sleeve, or sheath.
[12] 14. The scaffold of claim 1, further comprising at least one minced tissue particle that is associated with at least a portion of the scaffold, wherein the at least one minced tissue particle includes an effective amount of viable cells that can migrate out of the minced tissue particle and populate the scaffold. The scaffold of claim 14, wherein the at least one minced tissue particle comprises a bone-free tissue type selected from the group consisting of tendon, ligament, patellar tendon, anterior cruciate ligament, posterior cruciate ligament, medial collateral ligament, lateral collateral ligament, periosteum, perichondrium, iliotibial band or fascia lata, gracilis tendon, semitendinosis tendon, synovium, skin, and combinations thereof.
[13] 16. The scaffold of claim 14, wherein the at least one minced tissue particle comprises a bone tissue type that is placed in the first and second anchoring segments of the scaffold.
[14] 17. The scaffold of claim 14, wherein the scaffold further comprises an adhesion agent.
[15] 18. The scaffold of claim 17, wherein the adhesion agent comprises an anchoring agent selected from the group consisting of hyaluronic acid, fibrin glue, fibrin clot, collagen gel, gelatin-resorcin-formalin adhesive, mussel-based adhesive, dihydroxyphenylalanine 21/05/04,eh14149.spc,32 -33 (DOPA) based adhesive, chitosan, transglutaminase, poly(amino acid)-based adhesive, cellulose-based adhesive, synthetic acrylate-based adhesives, platelet rich plasma (PRP) gel, platelet poor plasma (PPP) gel, Matrigel, Monostearoyl Glycerol co-Succinate (MGSA), Monostearoyl Glycerol co-Succinate/polyethylene glycol (MGSA/PEG) copolymers, laminin, elastin, proteoglycans, and combinations thereof.
[16] 19. The scaffold of claim 17, wherein the adhesion agent comprises a cross-linking agent selected from the group consisting of divinyl sulfone (DVS), polyethylene glycol, divinyl sulfone (VS-PEG-VS), hydroxyethyl miethacrylate divinyl sulfone (HEMA-DIS- HEMA), formaldehyde, glutaraldehyde, aldehydes, isocyanates, alkyl and aryl halides, imidoesters, N-substituted maleimides, acylatirig compounds, carbodiimide, hydroxychloride, N-hydroxysuccinimide, light, pH, temperature, and combinations thereof. The scaffold of claim 14, wherein the at least one minced tissue particle comprises autogeneic tissue.
[17] 21. The scaffold of claim 1, wherein the bioresorbable polymeric fibers of the scaffold are made from polymers or copolymers formed from monomers selected from the group consisting of lactide, glycolide, dioxanone, and caprolactone.
[18] 22. The scaffold of claim 21, wherein the bioresorbable polymeric fibers of the scaffold are made from a copolymer having a ratio of monomers of about 95:5 lactide and glycolide.
[19] 23. The scaffold of claim 1, wherein the bioresorbable polymeric fibers of the scaffold are made from polymers or polymer blends selected from the group consisting of aliphatic polyesters, a polylactide, a polyglycolide, a polydioxanone, a polycaprolactone, a polyhydroxybutyrate, a polyhydroxybutyrate-co-hydroxyvalerate, a polyorthocarbonate, a polyaminocarbonate, a polytrimethylene carbonate, poly(amino acids), copoly(ether- esters), polyalkylene oxalates, polyamides, tyrosine derived polycarbonates, poly(iminocarbonates), polyorthoesters, polyoxaesters, polyamidoesters, polyoxaesters containing amine groups, poly(anhydrides), polyphosphazenes, polyurethanes, poly(ether urethanes), poly(ester urethanes), poly(propylehe fumarate), poly(hydroxyalkanoate), and copolymers which incorporate monomers which form such polymers. 21/05/04,eh14149.spc,33 -34-
[20] 24. The scaffold of claim 1, wherein the biosynthetic polymers of the scaffold are made from polymers or copolymers based on repeating units found in collagen, elastin, thrombin, silk, keratin, fibronectin, starches, poly(amino acid), gelatin, alginate, pectin, fibrin, oxidized cellulose, chitin, chitosan, tropoelastin, hyaluronic acid, ribonucleic acids, deoxyribonucleic acids, polypeptides, proteins, polysaccharides, polynucleotides, and combinations thereof. The scaffold of claim 1, wherein the scaffold comprises a ligament graft.
[21] 26. The scaffold of claim 1, wherein the scaffold comprises a cruciate ligament graft.
[22] 27. The scaffold of claim 14, wherein the scaffold further comprises at least one additional biological component applied thereto.
[23] 28. The scaffold of claim 27, wherein the at least one additional biological component comprises heterologous or autologous growth factors, proteins, matrix proteins, peptides, antibodies, antibiotics, anti-inflammatories, therapeutic agents, chemotactic agents, cell attachment mediators, biologically active ligands, integrin binding sequence, enzymes, cytokines, glycosaminoglycans, viruses, virus particles, nucleic acids, analgesics, cells, platelets, and combinations thereof.
[24] 29. The scaffold of claim 1, further comprising an eyelet formed on opposed ends of the first and second anchoring segment.
[25] 30. A connective tissue scaffold, comprising: opposed first and second anchoring eyelets formed of a plurality of bioresorbable polymeric fibers and defining an open area; first and second binding regions adjacent the opposed first and second eyelets, the first and second binding regions being formed of a plurality of bioresorbable polymeric fibers oriented in a direction substantially parallel to a longitudinal axis of the scaffold and in a direction that is not substantially parallel to the longitudinal axis; and a central segment, adjoining the first and second binding regions, formed of a plurality of bioresorbable polymeric fibers oriented in a direction substantially parallel to the longitudinal axis of the scaffold. 21/05/04,ehl4149.spc,34
[26] 31. The scaffold of claim 30, wherein the fibers of the first and second binding regions are joined in a weave pattern.
[27] 32. The scaffold of claim 30, wherein the scaffold further includes a biocompatible, bioresorbable material covering at least a portion of the first and second binding regions and the central segment.
[28] 33. The scaffold of claim 32, wherein the bioresorbable material is a biological material.
[29] 34. The scaffold of claim 33, wherein the bioresorbable material is small intestine submucosa.
[30] 35. The scaffold of claim 33, wherein the bioresorbable material is formed over the first and second anchoring eyelets, the first and second binding regions, and the central segment as a wrap, sleeve, or sheath.
[31] 36. The scaffold of claim 30, further comprising at least one minced tissue particle that is associated with at least a portion of the scaffold, wherein the at least one minced tissue particle includes an effective amount of viable cells that can migrate out of the at least one minced tissue particle and populate the scaffold.
[32] 37. The scaffold of claim 36, where in the at least one minced tissue particle comprises a bone-free tissue type selected from the group consisting of tendon, ligament, patellar tendon, anterior cruciate ligament, posterior cruciate ligament, medial collateral ligament, lateral collateral ligament, periosteum, perichondrium, iliotibial band or fascia lata, gracilis tendon, semitendinosis tendon, synovium, skin and combinations thereof.
[33] 38. The scaffold of claim 36, wherein the at least one minced tissue particle comprises a bone tissue type that is placed in the first and second anchoring segments of the scaffold.
[34] 39. The scaffold of claim 36, wherein the scaffold further comprises an adhesion agent. 21/05/04,eh 14149.spc,35 -36- The scaffold of claim 39, wherein the adhesion agent comprises an anchoring agent selected from the group consisting of hyaluronic acid, fibrin glue, fibrin clot, collagen gel, gelatin-resorcin-formalin adhesive, mussel-based adhesive, dihydroxyphenylalanine (DOPA) based adhesive, chitosan, transglutaminase, poly(amino acid)-based adhesive, cellulose-based adhesive, synthetic acrylate-based adhesives, platelet rich plasma (PRP), Matrigel, Monostearoyl Glycerol co-Succinate (MGSA), Monostearoyl Glycerol co- Succinate/polyethylene glycol (MGSA/PEG) copolymers, laminin, elastin, proteoglycans, and combinations thereof.
[35] 41. The scaffold of claim 39, wherein the adhesion agent comprises a cross-linking agent selected from the group consisting of divinyl sulfone (DVS), polyethylene glycol divinyl sulfone (VS-PEG-VS), hydroxyethyl methacrylate divinyl sulfone (HEMA-DIS- HEMA), formaldehyde, glutaraldehyde, aldehydes, isocyanates, alkyl and aryl halides, imidoesters, N-substituted maleimides, acylating compounds, carbodiimide, hydroxychloride, N-hydroxysuccinimide, light,'pH, temperature, and combinations thereof.
[36] 42. The scaffold of claim 30, wherein the bioresorbable polymeric fibers of the scaffold are made from polymers or copolymers formed from monomers selected from the group consisting of lactide, glycolide, dioxanone, and caprolactone.
[37] 43. The scaffold of claim 42, wherein the bioresorbable polymeric fibers of the scaffold are made from a copolymer having a ratio of monomers of about 95:5 lactide and glycolide.
[38] 44. The scaffold of claim 30, wherein the scaffold comprises a ligament graft. The scaffold of claim 44, wherein the scaffold comprises a cruciate ligament graft.
[39] 46. The scaffold of claim 36, wherein the scaffold further comprises at least one additional biological component applied thereto.
[40] 47. The scaffold of claim 46, wherein the at least one additional biological component comprises heterologous or autologous growth factors, proteins, matrix proteins, peptides, antibodies, antibiotics, anti-inflammatories, chemotactic agents, cell attachment mediators, 21/05/04,eh14149.spc,36 -37- biologically active ligands, integrin binding sequence, enzymes, cytokines, glycosaminoglycans, viruses, virus particles, nucleic acids, analgesics, cells, platelets, and combinations thereof.
[41] 48. A connective tissue scaffold, substantially as hereinbefore described with reference to the accompanying drawings. Dated this 2 1 st day of May, 2004 DEPUY MITEK, INC. By Their Patent Attorneys CALLINAN LAWRIE k 21/05/04,eh14149.spc,37

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引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

US259260A||1882-06-06||Adolf baeyer |

---

US206200A||1878-07-23||Improvement in fountain-pen holders |

---

US224226A||1880-02-03||Frank rhind |

---

GB1008193A|1961-03-01|1965-10-27|Ethicon Inc|Improvements in or relating to surgical implants|

---

US3272204A|1965-09-22|1966-09-13|Ethicon Inc|Absorbable collagen prosthetic implant with non-absorbable reinforcing strands|

---

AT261800B|1966-08-22|1968-05-10|Braun Internat Gmbh B|Process for the manufacture of tubular, smooth or threaded tissue-blood vessel prostheses|

---

US3857932A|1970-09-09|1974-12-31|F Gould|Dry hydrophilic acrylate or methacrylate polymer prolonged release drug implants|

---

US3739402A|1970-10-15|1973-06-19|Cutter Lab|Bicuspid fascia lata valve|

---

US3812017A|1972-07-26|1974-05-21|Kennecott Copper Corp|Desulfurized char with phosphoric acid|

---

US4057537A|1975-01-28|1977-11-08|Gulf Oil Corporation|Copolymers of L--lactide and epsilon caprolactone|

---

US4045418A|1975-01-28|1977-08-30|Gulf Oil Corporation|Copolymers of D,L-lactide and epsilon caprolactone|

---

US4130689A|1976-06-11|1978-12-19|International Paper Company|Production of high strength hollow rayon fibers|

---

US4141087A|1977-01-19|1979-02-27|Ethicon, Inc.|Isomorphic copolyoxalates and sutures thereof|

---

US4208511A|1977-01-19|1980-06-17|Ethicon, Inc.|Isomorphic copolyoxalates and sutures thereof|

---

US4105034A|1977-06-10|1978-08-08|Ethicon, Inc.|Poly absorbable coating for sutures|

---

US4140678A|1977-06-13|1979-02-20|Ethicon, Inc.|Synthetic absorbable surgical devices of poly|

---

US4205399A|1977-06-13|1980-06-03|Ethicon, Inc.|Synthetic absorbable surgical devices of poly|

---

US4149277A|1977-06-22|1979-04-17|General Atomic Company|Artificial tendon prostheses|

---

US4130639A|1977-09-28|1978-12-19|Ethicon, Inc.|Absorbable pharmaceutical compositions based on isomorphic copolyoxalates|

---

US4344193A|1980-11-28|1982-08-17|Kenny Charles H|Meniscus prosthesis|

---

US4553272A|1981-02-26|1985-11-19|University Of Pittsburgh|Regeneration of living tissues by growth of isolated cells in porous implant and product thereof|

---

US4585458A|1981-06-10|1986-04-29|Kurland Kenneth Z|Means and method of implanting bioprosthetics|

---

US4520821A|1982-04-30|1985-06-04|The Regents Of The University Of California|Growing of long-term biological tissue correction structures in vivo|

---

US4801299A|1983-06-10|1989-01-31|University Patents, Inc.|Body implants of extracellular matrix and means and methods of making and using such implants|

---

GB2151487A|1983-12-15|1985-07-24|Showell A W|Replacements for ligaments and tendons|

---

US4609551A|1984-03-20|1986-09-02|Arnold Caplan|Process of and material for stimulating growth of cartilage and bony tissue at anatomical sites|

---

US4837285A|1984-03-27|1989-06-06|Medimatrix|Collagen matrix beads for soft tissue repair|

---

NL8402178A|1984-07-10|1986-02-03|Rijksuniversiteit|ENT PIECE, SUITABLE FOR TREATMENT OF RECONSTRUCTIVE SURGERY OF DAMAGED DAMAGES.|

---

US4597766A|1984-10-26|1986-07-01|American Hospital Supply Corporation|Implantable bioprosthetic tendons and ligaments|

---

CH665768A5|1985-05-03|1988-06-15|Sulzer Ag|ARTIFICIAL TAPE MADE OF TEXTILE HOSE.|

---

US5061281A|1985-12-17|1991-10-29|Allied-Signal Inc.|Bioresorbable polymers and implantation devices thereof|

---

US5904717A|1986-01-28|1999-05-18|Thm Biomedical, Inc.|Method and device for reconstruction of articular cartilage|

---

US6005161A|1986-01-28|1999-12-21|Thm Biomedical, Inc.|Method and device for reconstruction of articular cartilage|

---

CH668900A5|1986-03-07|1989-02-15|Sulzer Ag|ARTIFICIAL CROSSBAND FOR A KNEE JOINT.|

---

US5902741A|1986-04-18|1999-05-11|Advanced Tissue Sciences, Inc.|Three-dimensional cartilage cultures|

---

US5863531A|1986-04-18|1999-01-26|Advanced Tissue Sciences, Inc.|In vitro preparation of tubular tissue structures by stromal cell culture on a three-dimensional framework|

---

US5266480A|1986-04-18|1993-11-30|Advanced Tissue Sciences, Inc.|Three-dimensional skin culture system|

---

FR2605513B1|1986-10-28|1989-06-16|Cerol Bandeira Maria|DEVICE FOR ANCHORING ON A BONE OF A LIGAMENT OR TENDANT PROSTHESIS PROVIDED WITH END WRAPS, AND PROSTHESIS ASSEMBLY COMPRISING SUCH A DEVICE|

---

US5041138A|1986-11-20|1991-08-20|Massachusetts Institute Of Technology|Neomorphogenesis of cartilage in vivo from cell culture|

---

US5736372A|1986-11-20|1998-04-07|Massachusetts Institute Of Technology|Biodegradable synthetic polymeric fibrous matrix containing chondrocyte for in vivo production of a cartilaginous structure|

---

DE3644588C1|1986-12-27|1988-03-10|Ethicon Gmbh|Implant and process for its manufacture|

---

NL8700113A|1987-01-19|1988-08-16|Groningen Science Park|INK, SUITABLE FOR TREATMENT BY RECONSTRUCTIVE SURGERY, WITH TISSUE-SPECIFIC POROSITY, AND METHOD FOR MANUFACTURING THE ENTAGMENT.|

---

JPS63203154A|1987-02-20|1988-08-23|Asahi Chemical Ind|Artificial tendon|

---

US5425766A|1987-03-09|1995-06-20|Astra Tech Aktiebolag|Resorbable prosthesis|

---

US5681353A|1987-07-20|1997-10-28|Regen Biologics, Inc.|Meniscal augmentation device|

---

US5306311A|1987-07-20|1994-04-26|Regen Corporation|Prosthetic articular cartilage|

---

US5263984A|1987-07-20|1993-11-23|Regen Biologics, Inc.|Prosthetic ligaments|

---

US5007934A|1987-07-20|1991-04-16|Regen Corporation|Prosthetic meniscus|

---

US5078744A|1987-09-04|1992-01-07|Bio-Products, Inc.|Method of using tendon/ligament substitutes composed of long, parallel, non-antigenic tendon/ligament fibers|

---

SU1535542A1|1987-11-18|1990-01-15|Всесоюзный Научно-Исследовательский Институт Глазных Болезней|Method of treating secondary graucoma|

---

GB8803697D0|1988-02-17|1988-03-16|Deltanine Research Ltd|Clinical developments using amniotic membrane cells|

---

US5053050A|1988-04-29|1991-10-01|Samuel Itay|Compositions for repair of cartilage and bone|

---

CA1318466C|1988-07-01|1993-06-01|Steven J. May|Abrasion resistant prosthetic device|

---

US4902508A|1988-07-11|1990-02-20|Purdue Research Foundation|Tissue graft composition|

---

US4917700A|1988-08-01|1990-04-17|Zimmer, Inc.|Prosthetic ligament|

---

US4938763B1|1988-10-03|1995-07-04|Atrix Lab Inc|Biodegradable in-situ forming implants and method of producing the same|

---

US6171338B1|1988-11-10|2001-01-09|Biocon, Oy|Biodegradable surgical implants and devices|

---

FI85223C|1988-11-10|1992-03-25|Biocon Oy|Biodegrading surgical implants and agents|

---

US5258028A|1988-12-12|1993-11-02|Ersek Robert A|Textured micro implants|

---

JP2805798B2|1989-02-28|1998-09-30|三菱瓦斯化学株式会社|Laminates for electricity with ultraviolet absorption|

---

JPH02256824A|1989-03-28|1990-10-17|Kubota Ltd|Passage opening adjusting device for spiral suction port of direct ignition type diesel engine|

---

US5147400A|1989-05-10|1992-09-15|United States Surgical Corporation|Connective tissue prosthesis|

---

US5487897A|1989-07-24|1996-01-30|Atrix Laboratories, Inc.|Biodegradable implant precursor|

---

US5076807A|1989-07-31|1991-12-31|Ethicon, Inc.|Random copolymers of p-dioxanone, lactide and/or glycolide as coating polymers for surgical filaments|

---

US4946377A|1989-11-06|1990-08-07|W. L. Gore & Associates, Inc.|Tissue repair device|

---

GB8928250D0|1989-12-14|1990-02-21|Erba Carlo Spa|Use of supercritical fluids to obtain porous sponges of biodegradable polymers|

---

US5290494A|1990-03-05|1994-03-01|Board Of Regents, The University Of Texas System|Process of making a resorbable implantation device|

---

EP0447355A1|1990-03-12|1991-09-18|Gebrüder Sulzer Aktiengesellschaft|Implant for the human body|

---

JP2822550B2|1990-03-13|1998-11-11|三菱化学株式会社|Azulene derivative, liquid crystal composition and liquid crystal device using the same|

---

US5108807A|1990-03-14|1992-04-28|First Brands Corporation|Degradable multilayer thermoplastic articles|

---

US5108989A|1990-04-04|1992-04-28|Genentech, Inc.|Method of predisposing mammals to accelerated tissue repair|

---

US5269785A|1990-06-28|1993-12-14|Bonutti Peter M|Apparatus and method for tissue removal|

---

CA2045222A1|1990-07-12|1992-01-13|Norman R. Weldon|Composite biosynthetic graft|

---

JPH0494329A|1990-08-08|1992-03-26|Ibiden Co Ltd|Housing magazine for putting on electronic parts|

---

EP0475889B1|1990-09-07|1995-05-03|SULZER Medizinaltechnik AG|Implant serving as ligament or tendon|

---

US5654135A|1990-10-02|1997-08-05|Imedex, Societe Anonyme|Biomaterial based on collagen and its application|

---

FR2667246B1|1990-10-02|1995-06-02|Imedex||

---

US5100433A|1990-11-08|1992-03-31|Ethicon, Inc.|Suture coated with a copolymer coating composition|

---

US6197325B1|1990-11-27|2001-03-06|The American National Red Cross|Supplemented and unsupplemented tissue sealants, methods of their production and use|

---

US6054122A|1990-11-27|2000-04-25|The American National Red Cross|Supplemented and unsupplemented tissue sealants, methods of their production and use|

---

US5206023A|1991-01-31|1993-04-27|Robert F. Shaw|Method and compositions for the treatment and repair of defects or lesions in cartilage|

---

US5320624A|1991-02-12|1994-06-14|United States Surgical Corporation|Blends of glycolide and/or lactide polymers and caprolactone and/or trimethylene carbonate polymers and absorbable surgical devices made therefrom|

---

FR2679250B1|1991-07-19|1995-07-13|Inoteb|USE OF POROUS CALCIUM CARBONATE AS A SUPPORT MATERIAL FOR THE IN VITRO CULTURE OF EUKARYOTIC CELLS.|

---

FR2679439A1|1991-07-22|1993-01-29|Cendis Medical|Element for consolidation or replacement of a ligament in the shape of a quadrilateral|

---

US6773458B1|1991-07-24|2004-08-10|Baxter International Inc.|Angiogenic tissue implant systems and methods|

---

FR2679778B1|1991-08-02|1995-07-07|Coletica|USE OF CROLAGEN CROSSLINKED BY A CROSSLINKING AGENT FOR THE MANUFACTURE OF A SLOW RESORPTIVE, BIOCOMPATIBLE, SUTURABLE MEMBRANE, AS WELL AS SUCH A MEMBRANE.|

---

US5281422A|1991-09-24|1994-01-25|Purdue Research Foundation|Graft for promoting autogenous tissue growth|

---

US5681572A|1991-10-18|1997-10-28|Seare, Jr.; William J.|Porous material product and process|

---

IT1254170B|1991-12-18|1995-09-11|Mini Ricerca Scient Tecnolog|COMPOSITE MEMBRANES FOR GUIDED REGENERATION OF FABRICS|

---

US6537574B1|1992-02-11|2003-03-25|Bioform, Inc.|Soft tissue augmentation material|

---

US5326357A|1992-03-18|1994-07-05|Mount Sinai Hospital Corporation|Reconstituted cartridge tissue|

---

FR2688690B1|1992-03-19|1998-04-10|Laboureau Jacques|ARTIFICIAL LIGAMENT.|

---

GB9206509D0|1992-03-25|1992-05-06|Jevco Ltd|Heteromorphic sponges containing active agents|

---

US5320646A|1992-05-22|1994-06-14|The Dow Chemical Company|Process for improving the dyeability of fabrics and fibers|

---

US5366756A|1992-06-15|1994-11-22|United States Surgical Corporation|Method for treating bioabsorbable implant material|

---

US5800537A|1992-08-07|1998-09-01|Tissue Engineering, Inc.|Method and construct for producing graft tissue from an extracellular matrix|

---

US5468253A|1993-01-21|1995-11-21|Ethicon, Inc.|Elastomeric medical device|

---

US5514378A|1993-02-01|1996-05-07|Massachusetts Institute Of Technology|Biocompatible polymer membranes and methods of preparation of three dimensional membrane structures|

---

US5656492A|1993-02-12|1997-08-12|Brigham And Women's Hospital, Inc.|Cell induction device|

---

GB9306737D0|1993-03-31|1993-05-26|Surgicarft Ltd|Ligament augmentation device|

---

AT190633T|1993-04-27|2000-04-15|Cytotherapeutics Inc|ACRYLNITRILE POLYMER MEMBRANE|

---

US5709854A|1993-04-30|1998-01-20|Massachusetts Institute Of Technology|Tissue formation by injecting a cell-polymeric solution that gels in vivo|

---

AT183078T|1993-08-10|1999-08-15|Gore & Ass|CELL ENCLOSURE DEVICE|

---

AU7564494A|1993-08-13|1995-03-14|Smith & Nephew Richards Inc.|Microporous polymeric foams and microtextured surfaces|

---

US5455041A|1993-09-13|1995-10-03|Research Foundation Of State University Of New York At Buffalo|Method for inducing periodontal tissue regeneration|

---

GB2281861B|1993-09-21|1997-08-20|Johnson & Johnson Medical|Bioabsorbable wound implant materials containing microspheres|

---

WO1995008354A1|1993-09-24|1995-03-30|Takiron Co., Ltd.|Implantation material|

---

GB2282328B|1993-09-29|1997-10-08|Johnson & Johnson Medical|Absorbable structures for ligament and tendon repair|

---

US5393594A|1993-10-06|1995-02-28|United States Surgical Corporation|Absorbable non-woven fabric|

---

GB9400163D0|1994-01-06|1994-03-02|Geistlich Soehne Ag|Membrane|

---

US5626611A|1994-02-10|1997-05-06|United States Surgical Corporation|Composite bioabsorbable materials and surgical articles made therefrom|

---

US5723331A|1994-05-05|1998-03-03|Genzyme Corporation|Methods and compositions for the repair of articular cartilage defects in mammals|

---

US5855608A|1994-05-13|1999-01-05|Thm Biomedical, Inc.|Device and methods for in vivo culturing of diverse tissue cells|

---

US5571189A|1994-05-20|1996-11-05|Kuslich; Stephen D.|Expandable fabric implant for stabilizing the spinal motion segment|

---

AU2731295A|1994-07-08|1996-02-09|Sulzer Medizinaltechnik Ag|Method of manufacturing implant materials|

---

US5769899A|1994-08-12|1998-06-23|Matrix Biotechnologies, Inc.|Cartilage repair unit|

---

FR2724563B1|1994-09-15|1997-02-14|||

---

TW369414B|1994-09-30|1999-09-11|Yamanouchi Pharma Co Ltd|Bone formation transplant|

---

US5641501A|1994-10-11|1997-06-24|Ethicon, Inc.|Absorbable polymer blends|

---

US6110212A|1994-11-15|2000-08-29|Kenton W. Gregory|Elastin and elastin-based materials|

---

US5891558A|1994-11-22|1999-04-06|Tissue Engineering, Inc.|Biopolymer foams for use in tissue repair and reconstruction|

---

US5632745A|1995-02-07|1997-05-27|R&D Biologicals, Inc.|Surgical implantation of cartilage repair unit|

---

US6485723B1|1995-02-10|2002-11-26|Purdue Research Foundation|Enhanced submucosal tissue graft constructs|

---

US6592588B1|1995-02-16|2003-07-15|Arthrex, Inc.|Apparatus for osteochondral autograft transplantation|

---

US5919196A|1995-02-16|1999-07-06|Arthrex, Inc.|Method and apparatus for osteochondral autograft transplantation|

---

GB9503492D0|1995-02-22|1995-04-12|Ed Geistlich S Hne A G F R Che|Chemical product|

---

US5618552A|1995-03-06|1997-04-08|Ethicon, Inc.|Absorbable polyoxaesters|

---

US5595751A|1995-03-06|1997-01-21|Ethicon, Inc.|Absorbable polyoxaesters containing amines and/or amido groups|

---

US5464929A|1995-03-06|1995-11-07|Ethicon, Inc.|Absorbable polyoxaesters|

---

US5700583A|1995-03-06|1997-12-23|Ethicon, Inc.|Hydrogels of absorbable polyoxaesters containing amines or amido groups|

---

US5698213A|1995-03-06|1997-12-16|Ethicon, Inc.|Hydrogels of absorbable polyoxaesters|

---

US5648088A|1995-03-06|1997-07-15|Ethicon, Inc.|Blends of absorbable polyoxaesters containing amines and/or amide groups|

---

US5607687A|1995-03-06|1997-03-04|Ethicon, Inc.|Polymer blends containing absorbable polyoxaesters|

---

US5597579A|1995-03-06|1997-01-28|Ethicon, Inc.|Blends of absorbable polyoxaamides|

---

US5859150A|1995-03-06|1999-01-12|Ethicon, Inc.|Prepolymers of absorbable polyoxaesters|

---

US5904716A|1995-04-26|1999-05-18|Gendler; El|Method for reconstituting cartilage tissue using demineralized bone and product thereof|

---

US6121042A|1995-04-27|2000-09-19|Advanced Tissue Sciences, Inc.|Apparatus and method for simulating in vivo conditions while seeding and culturing three-dimensional tissue constructs|

---

US6123727A|1995-05-01|2000-09-26|Massachusetts Institute Of Technology|Tissue engineered tendons and ligaments|

---

US6027742A|1995-05-19|2000-02-22|Etex Corporation|Bioresorbable ceramic composites|

---

US6132463A|1995-05-19|2000-10-17|Etex Corporation|Cell seeding of ceramic compositions|

---

GB9510624D0|1995-05-25|1995-07-19|Ellis Dev Ltd|Textile surgical implants|

---

US6096532A|1995-06-07|2000-08-01|Aastrom Biosciences, Inc.|Processor apparatus for use in a system for maintaining and growing biological cells|

---

FR2737663B1|1995-08-07|1997-10-03|Centre Nat Rech Scient|COMPOSITION FOR BIO-MATERIAL, METHOD OF PREPARATION|

---

FI98136C|1995-09-27|1997-04-25|Biocon Oy|A tissue-soluble material and process for its manufacture|

---

US5716413A|1995-10-11|1998-02-10|Osteobiologics, Inc.|Moldable, hand-shapable biodegradable implant material|

---

EP0862616B1|1995-11-06|2008-07-30|Mount Sinai Hospital|Reconstituted mineralized cartilage tissue|

---

US6200606B1|1996-01-16|2001-03-13|Depuy Orthopaedics, Inc.|Isolation of precursor cells from hematopoietic and nonhematopoietic tissues and their use in vivo bone and cartilage regeneration|

---

US5842477A|1996-02-21|1998-12-01|Advanced Tissue Sciences, Inc.|Method for repairing cartilage|

---

US5788625A|1996-04-05|1998-08-04|Depuy Orthopaedics, Inc.|Method of making reconstructive SIS structure for cartilaginous elements in situ|

---

US5755791A|1996-04-05|1998-05-26|Purdue Research Foundation|Perforated submucosal tissue graft constructs|

---

AT439849T|1996-04-19|2009-09-15|Osiris Therapeutics Inc|THE RECONSTRUCTION AND REINFORCEMENT OF BONES BY MEANS OF MESENCHYMAL STEM CELLS|

---

AU2759397A|1996-05-28|1998-01-05|1218122 Ontario Inc.|Resorbable implant biomaterial made of condensed calcium phosphate particles|

---

EP0922093B1|1996-06-04|2003-09-24|Sulzer Orthopedics Ltd.|Method for making cartilage and implants|

---

US6666892B2|1996-08-23|2003-12-23|Cook Biotech Incorporated|Multi-formed collagenous biomaterial medical device|

---

US6120514A|1996-08-30|2000-09-19|Vts Holdings, Llc|Method and kit for autologous transplantation|

---

US5759190A|1996-08-30|1998-06-02|Vts Holdings Limited|Method and kit for autologous transplantation|

---

US6569172B2|1996-08-30|2003-05-27|Verigen Transplantation Service International |Method, instruments, and kit for autologous transplantation|

---

US5989269A|1996-08-30|1999-11-23|Vts Holdings L.L.C.|Method, instruments and kit for autologous transplantation|

---

DE59706445D1|1996-09-10|2002-03-28|Mediphore Biotechnologie Ag Wi|METHOD FOR PRODUCING AN IMPLANT, CONSTRUCTING A RESORBABLE SUPPORT MATERIAL, A MEDICAL ACTIVE SUBSTANCE, LIKE A PHARMACEUTICAL, ANTIBIOTIC, CYTOSTATIC OR HORMONE CONTAINING|

---

US5964805A|1997-02-12|1999-10-12|Stone; Kevin R.|Method and paste for articular cartilage transplantation|

---

JPH10129048A|1996-10-31|1998-05-19|Canon Inc|Image processor, image processing method, and storage medium for storing program readable by computer|

---

EP0873145A2|1996-11-15|1998-10-28|Advanced Bio Surfaces, Inc.|Biomaterial system for in situ tissue repair|

---

US6187053B1|1996-11-16|2001-02-13|Will Minuth|Process for producing a natural implant|

---

FR2755846B1|1996-11-20|1998-12-31|Jacques Philippe Laboureau|PRE-ORIENT PROSTHETIC LIGAMENT AND METHOD OF MAKING|

---

US5782914A|1996-11-29|1998-07-21|Bio-Vascular, Inc.|Method for preparing heterogeneous tissue grafts|

---

US5914121A|1997-02-12|1999-06-22|The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services|Formation of human bone in vivo using ceramic powder and human marrow stromal fibroblasts|

---

US6110209A|1997-08-07|2000-08-29|Stone; Kevin R.|Method and paste for articular cartilage transplantation|

---

CA2280814A1|1997-02-13|1998-08-20|Barry N. Gellman|Stabilization sling for use in minimally invasive pelvic surgery|

---

JPH10234844A|1997-02-25|1998-09-08|Gunze Ltd|Base material for regenerating cartilaginous tissue and regenerating method of cartilaginous tissue using the same|

---

GB9704749D0|1997-03-07|1997-04-23|Univ London|Tissue Implant|

---

US6001352A|1997-03-31|1999-12-14|Osteobiologics, Inc.|Resurfacing cartilage defects with chondrocytes proliferated without differentiation using platelet-derived growth factor|

---

GB9708692D0|1997-04-30|1997-06-18|Jahoda Colin A B|Dermal sheath tissue and/or cells derived therefrom in wound healing|

---

JP3283786B2|1997-05-23|2002-05-20|京セラミタ株式会社|Drum unit and ground plate used for drum unit|

---

JP4132089B2|1997-05-30|2008-08-13|オステオバイオロジックス，インコーポレイテッド|Fiber reinforced porous biodegradable implantation device|

---

US6113640A|1997-06-11|2000-09-05|Bionx Implants Oy|Reconstructive bioabsorbable joint prosthesis|

---

US20030064917A1|1998-07-23|2003-04-03|Crawford Susan E.|Methods and compositions for inhibiting angiogenesis|

---

US6042592A|1997-08-04|2000-03-28|Meadox Medicals, Inc.|Thin soft tissue support mesh|

---

US6241771B1|1997-08-13|2001-06-05|Cambridge Scientific, Inc.|Resorbable interbody spinal fusion devices|

---

US6511958B1|1997-08-14|2003-01-28|Sulzer Biologics, Inc.|Compositions for regeneration and repair of cartilage lesions|

---

CA2304296C|1997-10-01|2005-02-15|Boston Scientific Limited|Pelvic floor reconstruction|

---

US6165217A|1997-10-02|2000-12-26|Gore Enterprise Holdings, Inc.|Self-cohering, continuous filament non-woven webs|

---

US7141072B2|1998-10-05|2006-11-28|Ed. Geistlich Soehne Ag Fuer Chemische Industrie|Method for promoting regeneration of surface cartilage in a damaged joint using multi-layer covering|

---

EP1023004A4|1997-10-10|2003-03-26|John D Corbitt|Breast implant|

---

AT255920T|1999-02-01|2003-12-15|Genetics Inst Llc|METHODS AND COMPOSITIONS FOR HEALING AND REPAIRING ARTICULATED CARTILAGE|

---

US6117166A|1997-10-27|2000-09-12|Winston; Thomas R.|Apparatus and methods for grafting blood vessel tissue|

---

EP1030676B1|1997-10-30|2005-09-14|The General Hospital Corporation|Bonding of cartilaginous matrices using isolated chondrocytes|

---

US7456012B2|1997-11-06|2008-11-25|Cellectricon Ab|Method and apparatus for spatially confined electroporation|

---

SE9704076D0|1997-11-06|1997-11-06|Holdingbolaget Vid Goeteborgs|Method for permeabilization of cell structures and use thereof|

---

WO1999025863A1|1997-11-14|1999-05-27|Cedars-Sinai Medical Center|Transfection and transfer of male germ cells for generation of transgenic species|

---

US6080579A|1997-11-26|2000-06-27|Charlotte-Mecklenburg Hospital Authority|Method for producing human intervertebral disc cells|

---

US6197586B1|1997-12-12|2001-03-06|The Regents Of The University Of California|Chondrocyte-like cells useful for tissue engineering and methods|

---

US6187329B1|1997-12-23|2001-02-13|Board Of Regents Of The University Of Texas System|Variable permeability bone implants, methods for their preparation and use|

---

US6291240B1|1998-01-29|2001-09-18|Advanced Tissue Sciences, Inc.|Cells or tissues with increased protein factors and methods of making and using same|

---

DE19803673A1|1998-01-30|1999-08-05|Norbert M Dr Meenen|Biohybrid joint replacement|

---

WO1999039724A1|1998-02-10|1999-08-12|Oregon Health Sciences University|Treatment of bony defects with osteoblast precursor cells|

---

US6179872B1|1998-03-17|2001-01-30|Tissue Engineering|Biopolymer matt for use in tissue repair and reconstruction|

---

DE19812195C2|1998-03-19|2000-03-30|Uwe Storch|Process for producing a tissue-forming implant and its use|

---

US6471958B2|1998-03-24|2002-10-29|University Of North Texas Health Science Center|Non-contracting tissue equivalent|

---

US6143293A|1998-03-26|2000-11-07|Carnegie Mellon|Assembled scaffolds for three dimensional cell culturing and tissue generation|

---

US6662805B2|1999-03-24|2003-12-16|The Johns Hopkins University|Method for composite cell-based implants|

---

US6378527B1|1998-04-08|2002-04-30|Chondros, Inc.|Cell-culture and polymer constructs|

---

US6886568B2|1998-04-08|2005-05-03|The Johns Hopkins University|Method for fabricating cell-containing implants|

---

PL186960B1|1998-05-04|2004-04-30|Adamed Sp Z Oo|Intravaginal set and therapeutic method employing that set|

---

JPH11319068A|1998-05-12|1999-11-24|Menicon Co Ltd|Base material for artificial skin and production thereof|

---

EP0998311B1|1998-05-19|2003-11-26|American National Red Cross|Hemostatic sandwich bandage comprising a thrombin layer between two fibrinogen layers|

---

JP2003513682A|1998-07-24|2003-04-15|ファーマカル、バイオテクノロジーズ、インコーポレーテッド|Bone tissue restoration system and method|

---

US6605294B2|1998-08-14|2003-08-12|Incept Llc|Methods of using in situ hydration of hydrogel articles for sealing or augmentation of tissue or vessels|

---

US6551355B1|1998-08-14|2003-04-22|Cambridge Scientific, Inc.|Tissue transplant coated with biocompatible biodegradable polymer|

---

US6132468A|1998-09-10|2000-10-17|Mansmann; Kevin A.|Arthroscopic replacement of cartilage using flexible inflatable envelopes|

---

US6530956B1|1998-09-10|2003-03-11|Kevin A. Mansmann|Resorbable scaffolds to promote cartilage regeneration|

---

US6183499B1|1998-09-11|2001-02-06|Ethicon, Inc.|Surgical filament construction|

---

DE19841698A1|1998-09-11|2000-03-16|Curative Technologies Gmbh|Composition for accelerating healing of tissue damage in cartilage or wounds, comprises thrombocyte growth factor, fibrin or fibrinogen and polymer|

---

AU5529499A|1998-09-14|2000-04-03|Nikon Corporation|Exposure apparatus and its manufacturing method, and device producing method|

---

EP1128838B1|1998-10-14|2008-07-02|DePuy Spine, Inc.|Extracellular matrix containing gdf-5 for inducing or enhancing chondrogenesis|

---

US6214055B1|1998-10-30|2001-04-10|Mures Cardiovascular Research, Inc.|Method and kit for rapid preparation of autologous tissue medical devices|

---

US6328765B1|1998-12-03|2001-12-11|Gore Enterprise Holdings, Inc.|Methods and articles for regenerating living tissue|

---

US6147135A|1998-12-31|2000-11-14|Ethicon, Inc.|Fabrication of biocompatible polymeric composites|

---

US6727224B1|1999-02-01|2004-04-27|Genetics Institute, Llc.|Methods and compositions for healing and repair of articular cartilage|

---

US6656489B1|1999-02-10|2003-12-02|Isotis N.V.|Scaffold for tissue engineering cartilage having outer surface layers of copolymer and ceramic material|

---

EP1027897B1|1999-02-10|2005-04-13|IsoTis N.V.|Cartillage tissue engineering|

---

US6197061B1|1999-03-01|2001-03-06|Koichi Masuda|In vitro production of transplantable cartilage tissue cohesive cartilage produced thereby, and method for the surgical repair of cartilage damage|

---

ES2295021T3|1999-03-25|2008-04-16|Metabolix, Inc.|USE AND MEDICAL APPLICATIONS OF POLYMER POLYMERS .|

---

US6287316B1|1999-03-26|2001-09-11|Ethicon, Inc.|Knitted surgical mesh|

---

US6103255A|1999-04-16|2000-08-15|Rutgers, The State University|Porous polymer scaffolds for tissue engineering|

---

US6287340B1|1999-05-14|2001-09-11|Trustees Of Tufts College|Bioengineered anterior cruciate ligament|

---

US6312952B1|1999-05-27|2001-11-06|The Research Foundation Of State University Of New York|In vitro cell culture device including cartilage and methods of using the same|

---

GB9912240D0|1999-05-27|1999-07-28|Smith & Nephew|Implantable medical devices|

---

DE19926083A1|1999-06-08|2000-12-14|Universitaetsklinikum Freiburg|Biological joint construct|

---

US7131943B2|2000-03-09|2006-11-07|Ethicon, Inc.|Surgical instrument and method for treating organ prolapse conditions|

---

US6667049B2|1999-06-14|2003-12-23|Ethicon, Inc.|Relic process for producing bioresorbable ceramic tissue scaffolds|

---

US20040059416A1|1999-06-22|2004-03-25|Murray Martha M.|Biologic replacement for fibrin clot|

---

US6306424B1|1999-06-30|2001-10-23|Ethicon, Inc.|Foam composite for the repair or regeneration of tissue|

---

US6333029B1|1999-06-30|2001-12-25|Ethicon, Inc.|Porous tissue scaffoldings for the repair of regeneration of tissue|

---

US6652872B2|1999-07-06|2003-11-25|Ramat At Tel Aviv University Ltd.|Scaffold formed of tissue treated to eliminate cellular and cytosolic elements|

---

US6179840B1|1999-07-23|2001-01-30|Ethicon, Inc.|Graft fixation device and method|

---

US6499486B1|1999-07-29|2002-12-31|Ethicon, Inc.|Method for reconstructing a ligament|

---

WO2001010355A1|1999-08-06|2001-02-15|Cook Biotech Incorporated|Tubular graft construct|

---

AU776260B2|1999-08-30|2004-09-02|I.D.M. Immuno-Designed Molecules|New humanized biomaterials, a process for their preparation and their applications|

---

JP2001129073A|1999-11-02|2001-05-15|Olympus Optical Co Ltd|Bone prosthesis material and tool for implanting bone prosthesis material|

---

AU1598701A|1999-11-12|2001-06-06|Kwan-Ho Chan|Tissue-engineered ligament|

---

AU4159401A|2000-02-18|2001-08-27|Regeneration Tech Inc|Implantable tissues infused with growth factors and other additives|

---

US20020133229A1|2000-03-24|2002-09-19|Laurencin Cato T.|Ligament and tendon replacement constructs and methods for production and use thereof|

---

US6629997B2|2000-03-27|2003-10-07|Kevin A. Mansmann|Meniscus-type implant with hydrogel surface reinforced by three-dimensional mesh|

---

AU5576701A|2000-04-28|2001-11-12|Curis Inc|Methods and reagents for tissue engineering of cartilage in vitro|

---

GB0011244D0|2000-05-11|2000-06-28|Smith & Nephew Inc|Tissue regrafting|

---

WO2001092001A1|2000-05-26|2001-12-06|University Of Virginia Patent Foundation|Multifunctional periodic cellular solids and the method of making thereof|

---

US6991652B2|2000-06-13|2006-01-31|Burg Karen J L|Tissue engineering composite|

---

US20010053839A1|2000-06-19|2001-12-20|Koken Co. Ltd.|Biomedical material and process for making same|

---

EP1167517A1|2000-06-22|2002-01-02|IsoTis N.V.|Tissue engineering|

---

AU2001268882B2|2000-06-29|2006-07-06|Smith & Nephew Orthopaedics Ag|Composition and method for the repair and regeneration of cartilage and other tissues|

---

KR20030036620A|2000-07-19|2003-05-09|오스테오테크 주식회사|Osteoimplant and method of making same|

---

US8366787B2|2000-08-04|2013-02-05|Depuy Products, Inc.|Hybrid biologic-synthetic bioabsorbable scaffolds|

---

WO2003007847A1|2001-07-16|2003-01-30|Depuy Products, Inc.|Hybrid biologic-synthetic bioabsorable scaffolds|

---

US6638312B2|2000-08-04|2003-10-28|Depuy Orthopaedics, Inc.|Reinforced small intestinal submucosa |

---

CA2777791A1|2000-09-18|2002-03-21|Organogenesis Inc.|Methods for treating a patient using a bioengineered flat sheet graft prostheses|

---

GB0024903D0|2000-10-11|2000-11-22|Ellis Dev Ltd|A textile prothesis|

---

JP2002165345A|2000-11-27|2002-06-07|Meishin Denki Kk|Anchor cover for wire and auxiliary anchor cover for the wire|

---

US6752831B2|2000-12-08|2004-06-22|Osteotech, Inc.|Biocompatible osteogenic band for repair of spinal disorders|

---

US8758438B2|2000-12-08|2014-06-24|Warsaw Orthopedic, Inc.|Implant for orthopedic applications|

---

US20020127265A1|2000-12-21|2002-09-12|Bowman Steven M.|Use of reinforced foam implants with enhanced integrity for soft tissue repair and regeneration|

---

US6599323B2|2000-12-21|2003-07-29|Ethicon, Inc.|Reinforced tissue implants and methods of manufacture and use|

---

US6852330B2|2000-12-21|2005-02-08|Depuy Mitek, Inc.|Reinforced foam implants with enhanced integrity for soft tissue repair and regeneration|

---

CA2365376C|2000-12-21|2006-03-28|Ethicon, Inc.|Use of reinforced foam implants with enhanced integrity for soft tissue repair and regeneration|

---

US6652450B2|2001-01-23|2003-11-25|American Medical Systems, Inc.|Implantable article and method for treating urinary incontinence using means for repositioning the implantable article|

---

KR20040008125A|2001-01-30|2004-01-28|오르쏘젠 인크.|Compositions and methods for the treatment and repair of defects or lesions in articular cartilage using synovial-derived tissue or cells|

---

US20020176893A1|2001-02-02|2002-11-28|Wironen John F.|Compositions, implants, methods, and kits for closure of lumen openings, repair of ruptured tissue, and for bulking of tissue|

---

AUPR289601A0|2001-02-05|2001-03-01|Commonwealth Scientific And Industrial Research Organisation|Method of tissue repair|

---

US20030050709A1|2001-02-23|2003-03-13|Ulrich Noth|Trabecular bone-derived human mesenchymal stem cells|

---

US6652585B2|2001-02-28|2003-11-25|Sdgi Holdings, Inc.|Flexible spine stabilization system|

---

US6827743B2|2001-02-28|2004-12-07|Sdgi Holdings, Inc.|Woven orthopedic implants|

---

US7252982B2|2001-03-15|2007-08-07|Massachusetts Institute Of Technology|Tissue engineering enhanced by the transfer of a growth factor gene|

---

FI20010540A0|2001-03-16|2001-03-16|Yli Urpo Antti|Composite for the correction of defects in soft and hard tissue and the use of said composite|

---

US6378572B1|2001-03-28|2002-04-30|Siemens Corporate Research, Inc.|Image processing system for inspection of tablets in slab filler packaging machines|

---

US6656488B2|2001-04-11|2003-12-02|Ethicon Endo-Surgery, Inc.|Bioabsorbable bag containing bioabsorbable materials of different bioabsorption rates for tissue engineering|

---

US6699252B2|2001-04-17|2004-03-02|Regeneration Technologies, Inc.|Methods and instruments for improved meniscus transplantation|

---

US6444222B1|2001-05-08|2002-09-03|Verigen Transplantation Services International Ag|Reinforced matrices|

---

RU2187261C1|2001-05-21|2002-08-20|Новокузнецкий государственный институт усовершенствования врачей|Method for treating nasal septal deformation in sportsmen|

---

CN100502808C|2001-05-25|2009-06-24|肯弗默斯股份有限公司|Compositions for articular resurfacing|

---

US7618451B2|2001-05-25|2009-11-17|Conformis, Inc.|Patient selectable joint arthroplasty devices and surgical tools facilitating increased accuracy, speed and simplicity in performing total and partial joint arthroplasty|

---

US6626950B2|2001-06-28|2003-09-30|Ethicon, Inc.|Composite scaffold with post anchor for the repair and regeneration of tissue|

---

JP3646162B2|2001-07-04|2005-05-11|独立行政法人産業技術総合研究所|Transplant for cartilage tissue regeneration|

---

EP1406561A4|2001-07-16|2008-03-12|Edwards Lifesciences Corp|Tissue engineered heart valve|

---

AU2002354913B2|2001-07-16|2008-07-17|Depuy Products, Inc.|Unitary surgical device and method|

---

JP4294474B2|2001-07-16|2009-07-15|デピュイ・プロダクツ・インコーポレイテッド|Meniscus reproduction device|

---

WO2003007790A2|2001-07-16|2003-01-30|Depuy Products, Inc.|Hybrid biologic/synthetic porous extracellular matrix scaffolds|

---

US8337537B2|2001-07-16|2012-12-25|Depuy Products, Inc.|Device from naturally occurring biologically derived materials|

---

WO2003007786A2|2001-07-16|2003-01-30|Depuy Products, Inc.|Porous delivery scaffold and method|

---

EP1425024A4|2001-07-16|2007-04-18|Depuy Products Inc|Porous extracellular matrix scaffold and method|

---

AT499908T|2001-07-16|2011-03-15|Depuy Products Inc|DEVICE FOR THE REPAIR OF CARTILING MATERIAL|

---

US8012205B2|2001-07-16|2011-09-06|Depuy Products, Inc.|Cartilage repair and regeneration device|

---

US7153518B2|2001-08-27|2006-12-26|Regeneration Technologies, Inc.|Processed soft tissue for topical or internal application|

---

US6736815B2|2001-09-06|2004-05-18|Core Medical, Inc.|Apparatus and methods for treating spinal discs|

---

US6902932B2|2001-11-16|2005-06-07|Tissue Regeneration, Inc.|Helically organized silk fibroin fiber bundles for matrices in tissue engineering|

---

JP2005509495A|2001-11-16|2005-04-14|チルドレンズメディカルセンターコーポレーション|Enhancement of organ function|

---

US7326426B2|2002-03-29|2008-02-05|Ethicon, Inc.|Compositions and medical devices utilizing bioabsorbable liquid polymers|

---

JP2003320008A|2002-04-30|2003-11-11|Olympus Optical Co Ltd|Living tissue filling body and method of manufacturing the same|

---

JP2004008437A|2002-06-06|2004-01-15|Olympus Corp|Cultural bone|

---

DE10234742A1|2002-07-30|2004-02-19|Bionethos Holding|Method and device for growing cells|

---

US20040062753A1|2002-09-27|2004-04-01|Alireza Rezania|Composite scaffolds seeded with mammalian cells|

---

US20040078090A1|2002-10-18|2004-04-22|Francois Binette|Biocompatible scaffolds with tissue fragments|

---

US7824701B2|2002-10-18|2010-11-02|Ethicon, Inc.|Biocompatible scaffold for ligament or tendon repair|

---

JP2004195103A|2002-12-20|2004-07-15|Japan Tissue Engineering:Kk|Oral cavity graft|

---

US8940292B2|2003-01-28|2015-01-27|Wake Forest University Health Sciences|Enhancement of angiogenesis to grafts using cells engineered to produce growth factors|

---

US8197837B2|2003-03-07|2012-06-12|Depuy Mitek, Inc.|Method of preparation of bioabsorbable porous reinforced tissue implants and implants thereof|

---

US7368124B2|2003-03-07|2008-05-06|Depuy Mitek, Inc.|Method of preparation of bioabsorbable porous reinforced tissue implants and implants thereof|

---

US7067123B2|2003-04-29|2006-06-27|Musculoskeletal Transplant Foundation|Glue for cartilage repair|

---

US7081135B2|2003-06-09|2006-07-25|Lane Fielding Smith|Mastopexy stabilization apparatus and method|

---

ES2554343T3|2003-06-27|2015-12-18|DePuy Synthes Products, Inc.|Postpartum cells derived from umbilical cord tissue and methods of preparing and using them|

---

US8226715B2|2003-06-30|2012-07-24|Depuy Mitek, Inc.|Scaffold for connective tissue repair|

---

US7262020B2|2003-07-03|2007-08-28|The Regents Of The University Of California|Methods for comparing relative flux rates of two or more biological molecules in vivo through a single protocol|

---

US10583220B2|2003-08-11|2020-03-10|DePuy Synthes Products, Inc.|Method and apparatus for resurfacing an articular surface|

---

US7316822B2|2003-11-26|2008-01-08|Ethicon, Inc.|Conformable tissue repair implant capable of injection delivery|

---

EP1537839A1|2003-12-02|2005-06-08|Dr. h. c. Robert Mathys Foundation|Prosthetic device for cartilage repair|

---

US7901461B2|2003-12-05|2011-03-08|Ethicon, Inc.|Viable tissue repair implants and methods of use|

---

US20050177249A1|2004-02-09|2005-08-11|Kladakis Stephanie M.|Scaffolds with viable tissue|

---

JP4292094B2|2004-02-24|2009-07-08|グンゼ株式会社|Nerve regeneration tube|

---

US8657881B2|2004-04-20|2014-02-25|Depuy Mitek, Llc|Meniscal repair scaffold|

---

US8137686B2|2004-04-20|2012-03-20|Depuy Mitek, Inc.|Nonwoven tissue scaffold|

---

US8221780B2|2004-04-20|2012-07-17|Depuy Mitek, Inc.|Nonwoven tissue scaffold|

---

KR101256360B1|2004-10-20|2013-04-30|에디컨인코포레이티드|A reinforced absorbable multilayered fabric for use in medical devices and method of manufacture|

---

EP1831356B1|2004-12-23|2017-01-25|DePuy Synthes Products, Inc.|Postpartum cells derived from umbilical cord tissue, and methods of making and using the same|

---

US20060280768A1|2005-06-13|2006-12-14|Julia Hwang|Meniscal repair device and method|

---

US20060293760A1|2005-06-24|2006-12-28|Dedeyne Patrick G|Soft tissue implants with improved interfaces|

---

WO2009054878A2|2007-09-11|2009-04-30|University Of Florida Research Foundation|Compositions and methods for the treatment of neoplasia|US6893462B2|2000-01-11|2005-05-17|Regeneration Technologies, Inc.|Soft and calcified tissue implants|

---

US20040059416A1|1999-06-22|2004-03-25|Murray Martha M.|Biologic replacement for fibrin clot|

---

US6964685B2|1999-06-22|2005-11-15|The Brigham And Women's Hospital, Inc.|Biologic replacement for fibrin clot|

---

US6179840B1|1999-07-23|2001-01-30|Ethicon, Inc.|Graft fixation device and method|

---

US20020095157A1|1999-07-23|2002-07-18|Bowman Steven M.|Graft fixation device combination|

---

US20060083767A1|2003-02-27|2006-04-20|Kai Deusch|Surgical prosthesis having biodegradable and nonbiodegradable regions|

---

CA2410637C|2000-05-31|2007-04-10|Mnemoscience Gmbh|Shape memory polymers seeded with dissociated cells for tissue engineering|

---

CA2365376C|2000-12-21|2006-03-28|Ethicon, Inc.|Use of reinforced foam implants with enhanced integrity for soft tissue repair and regeneration|

---

US8048444B2|2002-07-31|2011-11-01|Mast Biosurgery Ag|Apparatus and method for preventing adhesions between an implant and surrounding tissues|

---

US20100266663A1|2003-09-10|2010-10-21|Calhoun Christopher J|Tissue-treating implantable compositions|

---

US20120010726A1|2003-09-10|2012-01-12|Lukas Bluecher|Adhesion-Resistant Surgical Access, Reinforcement and Closure Prosthetic|

---

US7704520B1|2002-09-10|2010-04-27|Mast Biosurgery Ag|Methods of promoting enhanced healing of tissues after cardiac surgery|

---

US7824701B2|2002-10-18|2010-11-02|Ethicon, Inc.|Biocompatible scaffold for ligament or tendon repair|

---

US20040078090A1|2002-10-18|2004-04-22|Francois Binette|Biocompatible scaffolds with tissue fragments|

---

US20080119877A1|2005-08-12|2008-05-22|Kai Deusch|Surgical prosthesis having biodegradable and nonbiodegradable regions|

---

US20080091277A1|2004-08-13|2008-04-17|Kai Deusch|Surgical prosthesis having biodegradable and nonbiodegradable regions|

---

US8197837B2|2003-03-07|2012-06-12|Depuy Mitek, Inc.|Method of preparation of bioabsorbable porous reinforced tissue implants and implants thereof|

---

US7794408B2|2003-03-28|2010-09-14|Ethicon, Inc.|Tissue collection device and methods|

---

US9060770B2|2003-05-20|2015-06-23|Ethicon Endo-Surgery, Inc.|Robotically-driven surgical instrument with E-beam driver|

---

US20070084897A1|2003-05-20|2007-04-19|Shelton Frederick E Iv|Articulating surgical stapling instrument incorporating a two-piece e-beam firing mechanism|

---

US8226715B2|2003-06-30|2012-07-24|Depuy Mitek, Inc.|Scaffold for connective tissue repair|

---

US10583220B2|2003-08-11|2020-03-10|DePuy Synthes Products, Inc.|Method and apparatus for resurfacing an articular surface|

---

US7611473B2|2003-09-11|2009-11-03|Ethicon, Inc.|Tissue extraction and maceration device|

---

US8034003B2|2003-09-11|2011-10-11|Depuy Mitek, Inc.|Tissue extraction and collection device|

---

US7326247B2|2003-10-30|2008-02-05|Arthrex, Inc.|Method for creating a double bundle ligament orientation in a single bone tunnel during knee ligament reconstruction|

---

US7316822B2|2003-11-26|2008-01-08|Ethicon, Inc.|Conformable tissue repair implant capable of injection delivery|

---

US7901461B2|2003-12-05|2011-03-08|Ethicon, Inc.|Viable tissue repair implants and methods of use|

---

WO2005069884A2|2004-01-16|2005-08-04|Osteobiologics, Inc.|Bone-tendon-bone implant|

---

US20050177249A1|2004-02-09|2005-08-11|Kladakis Stephanie M.|Scaffolds with viable tissue|

---

US20090216252A1|2004-02-13|2009-08-27|The University Of Cincinnati|A coupling device enabled by mechanical continuity of cellular scaffolding across tissue boundaries|

---

EP1729675A4|2004-03-05|2011-05-18|Univ Columbia|Multi-phased, biodegradable and osteointegrative composite scaffold for biological fixation of musculoskeletal soft tissue to bone|

---

US8137686B2|2004-04-20|2012-03-20|Depuy Mitek, Inc.|Nonwoven tissue scaffold|

---

US8221780B2|2004-04-20|2012-07-17|Depuy Mitek, Inc.|Nonwoven tissue scaffold|

---

US8215531B2|2004-07-28|2012-07-10|Ethicon Endo-Surgery, Inc.|Surgical stapling instrument having a medical substance dispenser|

---

CA2573564C|2004-08-13|2010-04-06|Mast Biosurgery Ag|Surgical prosthesis having biodegradable and nonbiodegradable regions|

---

US8128658B2|2004-11-05|2012-03-06|Biomet Sports Medicine, Llc|Method and apparatus for coupling soft tissue to bone|

---

US9078644B2|2006-09-29|2015-07-14|Biomet Sports Medicine, Llc|Fracture fixation device|

---

US9271713B2|2006-02-03|2016-03-01|Biomet Sports Medicine, Llc|Method and apparatus for tensioning a suture|

---

US8500818B2|2006-09-29|2013-08-06|Biomet Manufacturing, Llc|Knee prosthesis assembly with ligament link|

---

US8137382B2|2004-11-05|2012-03-20|Biomet Sports Medicine, Llc|Method and apparatus for coupling anatomical features|

---

US8088130B2|2006-02-03|2012-01-03|Biomet Sports Medicine, Llc|Method and apparatus for coupling soft tissue to a bone|

---

US9149267B2|2006-02-03|2015-10-06|Biomet Sports Medicine, Llc|Method and apparatus for coupling soft tissue to a bone|

---

US8801783B2|2006-09-29|2014-08-12|Biomet Sports Medicine, Llc|Prosthetic ligament system for knee joint|

---

US9538998B2|2006-02-03|2017-01-10|Biomet Sports Medicine, Llc|Method and apparatus for fracture fixation|

---

US9918826B2|2006-09-29|2018-03-20|Biomet Sports Medicine, Llc|Scaffold for spring ligament repair|

---

US8562645B2|2006-09-29|2013-10-22|Biomet Sports Medicine, Llc|Method and apparatus for forming a self-locking adjustable loop|

---

US10517587B2|2006-02-03|2019-12-31|Biomet Sports Medicine, Llc|Method and apparatus for forming a self-locking adjustable loop|

---

US8298262B2|2006-02-03|2012-10-30|Biomet Sports Medicine, Llc|Method for tissue fixation|

---

US8303604B2|2004-11-05|2012-11-06|Biomet Sports Medicine, Llc|Soft tissue repair device and method|

---

US9468433B2|2006-02-03|2016-10-18|Biomet Sports Medicine, Llc|Method and apparatus for forming a self-locking adjustable loop|

---

US8574235B2|2006-02-03|2013-11-05|Biomet Sports Medicine, Llc|Method for trochanteric reattachment|

---

US11259792B2|2006-02-03|2022-03-01|Biomet Sports Medicine, Llc|Method and apparatus for coupling anatomical features|

---

US8597327B2|2006-02-03|2013-12-03|Biomet Manufacturing, Llc|Method and apparatus for sternal closure|

---

US8118836B2|2004-11-05|2012-02-21|Biomet Sports Medicine, Llc|Method and apparatus for coupling soft tissue to a bone|

---

US8361113B2|2006-02-03|2013-01-29|Biomet Sports Medicine, Llc|Method and apparatus for coupling soft tissue to a bone|

---

US8672969B2|2006-09-29|2014-03-18|Biomet Sports Medicine, Llc|Fracture fixation device|

---

US8968364B2|2006-02-03|2015-03-03|Biomet Sports Medicine, Llc|Method and apparatus for fixation of an ACL graft|

---

US8652171B2|2006-02-03|2014-02-18|Biomet Sports Medicine, Llc|Method and apparatus for soft tissue fixation|

---

US8652172B2|2006-02-03|2014-02-18|Biomet Sports Medicine, Llc|Flexible anchors for tissue fixation|

---

US10092288B2|2006-02-03|2018-10-09|Biomet Sports Medicine, Llc|Method and apparatus for coupling soft tissue to a bone|

---

US8562647B2|2006-09-29|2013-10-22|Biomet Sports Medicine, Llc|Method and apparatus for securing soft tissue to bone|

---

US8998949B2|2004-11-09|2015-04-07|Biomet Sports Medicine, Llc|Soft tissue conduit device|

---

US7909851B2|2006-02-03|2011-03-22|Biomet Sports Medicine, Llc|Soft tissue repair device and associated methods|

---

US7905904B2|2006-02-03|2011-03-15|Biomet Sports Medicine, Llc|Soft tissue repair device and associated methods|

---

EP1816987A4|2004-11-09|2011-03-09|Proxy Biomedical Ltd|Tissue scaffold|

---

US8251998B2|2006-08-16|2012-08-28|Biomet Sports Medicine, Llc|Chondral defect repair|

---

US7651528B2|2004-11-18|2010-01-26|Cayenne Medical, Inc.|Devices, systems and methods for material fixation|

---

WO2006089267A2|2005-02-18|2006-08-24|Synthasome Inc.|Synthetic structure for soft tissue repair|

---

US20070041952A1|2005-04-18|2007-02-22|Duke University|Three-dimensional fiber scaffolds for tissue engineering|

---

US20090148486A1|2005-04-28|2009-06-11|Helen Lu|Compositions and methods for treating pulp inflammations caused by infection or trauma|

---

EP2664340B1|2005-06-24|2020-02-12|Duke University|A direct drug delivery system based on thermally responsive biopolymers|

---

DE102005030614B4|2005-06-30|2014-05-08|Biotissue Ag|Cell-free graft, its use, process for its preparation, matrix thus produced with gel and process for the preparation of this matrix with gel|

---

GB0516846D0|2005-08-17|2005-09-21|Knight David P|Meniscal repair device|

---

US7934630B2|2005-08-31|2011-05-03|Ethicon Endo-Surgery, Inc.|Staple cartridges for forming staples having differing formed staple heights|

---

US7669746B2|2005-08-31|2010-03-02|Ethicon Endo-Surgery, Inc.|Staple cartridges for forming staples having differing formed staple heights|

---

US11246590B2|2005-08-31|2022-02-15|Cilag Gmbh International|Staple cartridge including staple drivers having different unfired heights|

---

US20070194079A1|2005-08-31|2007-08-23|Hueil Joseph C|Surgical stapling device with staple drivers of different height|

---

US9237891B2|2005-08-31|2016-01-19|Ethicon Endo-Surgery, Inc.|Robotically-controlled surgical stapling devices that produce formed staples having different lengths|

---

US10159482B2|2005-08-31|2018-12-25|Ethicon Llc|Fastener cartridge assembly comprising a fixed anvil and different staple heights|

---

CA2925688C|2005-09-09|2019-10-22|Farshid Guilak|Tissue engineering methods and compositions|

---

US8920827B2|2005-10-21|2014-12-30|Wake Forest University Health Sciences|Keratin bioceramic compositions|

---

US7899533B2|2005-10-25|2011-03-01|Medtronic, Inc.|System and method of AV interval selection in an implantable medical device|

---

US20070106317A1|2005-11-09|2007-05-10|Shelton Frederick E Iv|Hydraulically and electrically actuated articulation joints for surgical instruments|

---

US20070128243A1|2005-12-02|2007-06-07|Xylos Corporation|Implantable microbial cellulose materials for various medical applications|

---

US20070150063A1|2005-12-22|2007-06-28|Depuy Spine, Inc.|Devices for intervertebral augmentation and methods of controlling their delivery|

---

US20070150064A1|2005-12-22|2007-06-28|Depuy Spine, Inc.|Methods and devices for intervertebral augmentation|

---

US20070150059A1|2005-12-22|2007-06-28|Depuy Spine, Inc.|Methods and devices for intervertebral augmentation using injectable formulations and enclosures|

---

US8070810B2|2006-01-12|2011-12-06|Histogenics Corporation|Method for repair and reconstruction of ruptured ligaments or tendons and for treatment of ligament and tendon injuries|

---

EP1981435A2|2006-01-25|2008-10-22|Children's Medical Center Corporation|Methods and procedures for ligament repair|

---

US20080220042A1|2006-01-27|2008-09-11|The Regents Of The University Of California|Biomolecule-linked biomimetic scaffolds|

---

WO2007090102A2|2006-01-27|2007-08-09|The Regents Of The University Of California|Biomimetic scaffolds|

---

US8708213B2|2006-01-31|2014-04-29|Ethicon Endo-Surgery, Inc.|Surgical instrument having a feedback system|

---

US7845537B2|2006-01-31|2010-12-07|Ethicon Endo-Surgery, Inc.|Surgical instrument having recording capabilities|

---

US7753904B2|2006-01-31|2010-07-13|Ethicon Endo-Surgery, Inc.|Endoscopic surgical instrument with a handle that can articulate with respect to the shaft|

---

US20110295295A1|2006-01-31|2011-12-01|Ethicon Endo-Surgery, Inc.|Robotically-controlled surgical instrument having recording capabilities|

---

US11207064B2|2011-05-27|2021-12-28|Cilag Gmbh International|Automated end effector component reloading system for use with a robotic system|

---

US8186555B2|2006-01-31|2012-05-29|Ethicon Endo-Surgery, Inc.|Motor-driven surgical cutting and fastening instrument with mechanical closure system|

---

US8820603B2|2006-01-31|2014-09-02|Ethicon Endo-Surgery, Inc.|Accessing data stored in a memory of a surgical instrument|

---

US9861359B2|2006-01-31|2018-01-09|Ethicon Llc|Powered surgical instruments with firing system lockout arrangements|

---

US11224427B2|2006-01-31|2022-01-18|Cilag Gmbh International|Surgical stapling system including a console and retraction assembly|

---

US20120292367A1|2006-01-31|2012-11-22|Ethicon Endo-Surgery, Inc.|Robotically-controlled end effector|

---

US9357991B2|2011-11-03|2016-06-07|Biomet Sports Medicine, Llc|Method and apparatus for stitching tendons|

---

US9381013B2|2011-11-10|2016-07-05|Biomet Sports Medicine, Llc|Method for coupling soft tissue to a bone|

---

US9370350B2|2011-11-10|2016-06-21|Biomet Sports Medicine, Llc|Apparatus for coupling soft tissue to a bone|

---

US9314241B2|2011-11-10|2016-04-19|Biomet Sports Medicine, Llc|Apparatus for coupling soft tissue to a bone|

---

US7749250B2|2006-02-03|2010-07-06|Biomet Sports Medicine, Llc|Soft tissue repair assembly and associated method|

---

WO2007109280A2|2006-03-20|2007-09-27|Cayenne Medical, Inc|Devices, systems, and methods for material fixation|

---

US8992422B2|2006-03-23|2015-03-31|Ethicon Endo-Surgery, Inc.|Robotically-controlled endoscopic accessory channel|

---

US7985408B2|2006-03-23|2011-07-26|The University Of Western Australia|Tenocyte cell culturing method|

---

US8236010B2|2006-03-23|2012-08-07|Ethicon Endo-Surgery, Inc.|Surgical fastener and cutter with mimicking end effector|

---

ES2720582T3|2006-05-09|2019-07-23|Lifecell Corp|Biological reinforced tissue|

---

US8322455B2|2006-06-27|2012-12-04|Ethicon Endo-Surgery, Inc.|Manually driven surgical cutting and fastening instrument|

---

JP2010509943A|2006-09-28|2010-04-02|チルドレンズメディカルセンターコーポレーション|Method of repairing tissue and collagen product therefor|

---

US10130359B2|2006-09-29|2018-11-20|Ethicon Llc|Method for forming a staple|

---

US11259794B2|2006-09-29|2022-03-01|Biomet Sports Medicine, Llc|Method for implanting soft tissue|

---

US10568652B2|2006-09-29|2020-02-25|Ethicon Llc|Surgical staples having attached drivers of different heights and stapling instruments for deploying the same|

---

US8348131B2|2006-09-29|2013-01-08|Ethicon Endo-Surgery, Inc.|Surgical stapling instrument with mechanical indicator to show levels of tissue compression|

---

US7658751B2|2006-09-29|2010-02-09|Biomet Sports Medicine, Llc|Method for implanting soft tissue|

---

EP1908820A1|2006-10-06|2008-04-09|Stichting Voor De Technische Wetenschappen|Stem cell and/or progenitor cell enrichment|

---

DE102006047346A1|2006-10-06|2008-04-10|Transtissue Technologies Gmbh|Matrix gel graft without cells|

---

JP4671307B2|2006-10-24|2011-04-13|カイエンメディカルインコーポレイテッド|Substance fixing method and substance fixing system|

---

US9011439B2|2006-11-20|2015-04-21|Poly-Med, Inc.|Selectively absorbable/biodegradable, fibrous composite constructs and applications thereof|

---

ES2395149T3|2006-12-22|2013-02-08|Laboratoire Medidom S.A.|On-site system for repair of intra-articular chondral and bone tissue|

---

WO2008085490A2|2006-12-27|2008-07-17|Shriners Hospitals For Children|Methods of making high-strength ndga polymerized collagen fibers and related collagen-prep methods, medical devices and constructs|

---

US8652120B2|2007-01-10|2014-02-18|Ethicon Endo-Surgery, Inc.|Surgical instrument with wireless communication between control unit and sensor transponders|

---

US8684253B2|2007-01-10|2014-04-01|Ethicon Endo-Surgery, Inc.|Surgical instrument with wireless communication between a control unit of a robotic system and remote sensor|

---

US11039836B2|2007-01-11|2021-06-22|Cilag Gmbh International|Staple cartridge for use with a surgical stapling instrument|

---

US8827133B2|2007-01-11|2014-09-09|Ethicon Endo-Surgery, Inc.|Surgical stapling device having supports for a flexible drive mechanism|

---

AU2008213973A1|2007-02-02|2008-08-14|Tornier, Inc.|System and method for repairing tendons and ligaments|

---

US8753391B2|2007-02-12|2014-06-17|The Trustees Of Columbia University In The City Of New York|Fully synthetic implantable multi-phased scaffold|

---

CA2678821C|2007-02-20|2015-12-01|Shriners Hospitals For Children|In vivo hydraulic fixation including bio-rivets using biocompatible expandable fibers|

---

US20090005809A1|2007-03-15|2009-01-01|Hess Christopher J|Surgical staple having a slidable crown|

---

JP2010522042A|2007-03-20|2010-07-01|セリカテクノロジーズインコーポレイティッド|Tendon prosthesis and method of manufacturing the same|

---

US8893946B2|2007-03-28|2014-11-25|Ethicon Endo-Surgery, Inc.|Laparoscopic tissue thickness and clamp load measuring devices|

---

US9017381B2|2007-04-10|2015-04-28|Biomet Sports Medicine, Llc|Adjustable knotless loops|

---

FI20075246A0|2007-04-12|2007-04-12|Bioretec Oy|Medical agent|

---

US9549809B2|2007-04-21|2017-01-24|Kyon Ag|ACL prosthesis and anchor therefor|

---

NZ580786A|2007-04-24|2012-05-25|Univ Western Australia|Tenocyte containing bioscaffolds and treatment using the same|

---

US8931682B2|2007-06-04|2015-01-13|Ethicon Endo-Surgery, Inc.|Robotically-controlled shaft based rotary drive systems for surgical instruments|

---

US20100070020A1|2008-06-11|2010-03-18|Nanovasc, Inc.|Implantable Medical Device|

---

EP2160153A1|2007-06-11|2010-03-10|Nanovasc, Inc.|Stents|

---

EP2167144A4|2007-06-13|2012-11-21|Fmc Corp|Biopolymer based implantable degradable devices|

---

US7753245B2|2007-06-22|2010-07-13|Ethicon Endo-Surgery, Inc.|Surgical stapling instruments|

---

US8408439B2|2007-06-22|2013-04-02|Ethicon Endo-Surgery, Inc.|Surgical stapling instrument with an articulatable end effector|

---

GB2450870A|2007-07-07|2009-01-14|Ellis Dev Ltd|Tissue engineering scaffold of interconnected embroidery stitches|

---

EP2162142B1|2007-07-10|2015-12-02|Lifecell Corporation|Acellular tissue matrix compositions for tissue repair|

---

US20100310632A1|2009-06-08|2010-12-09|Von Waldburg-Zeil Erich Graf|Micro-membrane implant with cusped opening|

---

US20100034869A1|2007-08-27|2010-02-11|Joerg Tessmar|Block-polymer membranes for attenuation of scar tissue|

---

EP2195041A2|2007-08-27|2010-06-16|MAST Biosurgery AG|Resorbable barrier micro-membranes for attenuation of scar tissue during healing|

---

WO2009047767A1|2007-10-11|2009-04-16|Tavor [I.T.N] Ltd.|Ligament and tendon prosthesis|

---

US20090163936A1|2007-12-21|2009-06-25|Chunlin Yang|Coated Tissue Engineering Scaffold|

---

US8561870B2|2008-02-13|2013-10-22|Ethicon Endo-Surgery, Inc.|Surgical stapling instrument|

---

US8657174B2|2008-02-14|2014-02-25|Ethicon Endo-Surgery, Inc.|Motorized surgical cutting and fastening instrument having handle based power source|

---

US7866527B2|2008-02-14|2011-01-11|Ethicon Endo-Surgery, Inc.|Surgical stapling apparatus with interlockable firing system|

---

US8758391B2|2008-02-14|2014-06-24|Ethicon Endo-Surgery, Inc.|Interchangeable tools for surgical instruments|

---

US7819298B2|2008-02-14|2010-10-26|Ethicon Endo-Surgery, Inc.|Surgical stapling apparatus with control features operable with one hand|

---

US8636736B2|2008-02-14|2014-01-28|Ethicon Endo-Surgery, Inc.|Motorized surgical cutting and fastening instrument|

---

RU2493788C2|2008-02-14|2013-09-27|Этикон Эндо-Серджери, Инк.|Surgical cutting and fixing instrument, which has radio-frequency electrodes|

---

US8573465B2|2008-02-14|2013-11-05|Ethicon Endo-Surgery, Inc.|Robotically-controlled surgical end effector system with rotary actuated closure systems|

---

US9179912B2|2008-02-14|2015-11-10|Ethicon Endo-Surgery, Inc.|Robotically-controlled motorized surgical cutting and fastening instrument|

---

US9585657B2|2008-02-15|2017-03-07|Ethicon Endo-Surgery, Llc|Actuator for releasing a layer of material from a surgical end effector|

---

EP2244639B8|2008-02-22|2016-10-26|MiMedx Group, Inc.|Biostaples suitable for wrist, hand and other ligament replacements or repairs|

---

AT546170T|2008-03-03|2012-03-15|Arthrex Inc|WUNDNESS WITH BIOLOGICAL MATERIAL|

---

GB2458878A|2008-03-04|2009-10-07|Xiros Plc|An implantable prosthetic cord|

---

US8858565B1|2008-05-08|2014-10-14|Cayenne Medical, Inc.|Inserter for soft tissue or bone-to-bone fixation device and methods|

---

US8123806B1|2008-05-09|2012-02-28|Cayenne Medical, Inc|Method of tensioning a tissue graft having suture bundles using a cleated bar|

---

JP5777510B2|2008-05-09|2015-09-09|エボニック コーポレイションＥｖｏｎｉｋ Ｃｏｒｐｏｒａｔｉｏｎ|Biocompatible and biodegradable elastomeric polymers|

---

EP2291143B1|2008-05-16|2020-07-08|Mimedx, Inc.|Medical constructs of twisted lengths of collagen fibers and methods of making same|

---

US8114156B2|2008-05-30|2012-02-14|Edwin Burton Hatch|Flexibly compliant ceramic prosthetic meniscus for the replacement of damaged cartilage in orthopedic surgical repair or reconstruction of hip, knee, ankle, shoulder, elbow, wrist and other anatomical joints|

---

US20090304779A1|2008-06-08|2009-12-10|Von Waldburg-Zeil Erich Graf|Micro-membrane implant with cusped opening|

---

US9295757B2|2008-06-10|2016-03-29|Cook Biotech Incorporated|Quilted implantable graft|

---

CA2728240C|2008-06-10|2016-11-15|Cook Biotech Incorporated|Quilted implantable graft|

---

TWI397393B|2008-07-06|2013-06-01|Mast Biosurgery Ag|Resorbable membrane for reducing adhesions|

---

US8333802B2|2008-08-19|2012-12-18|Dougherty Christopher P|Single tunnel double bundle anterior cruciate ligament reconstruction|

---

US9387280B2|2008-09-05|2016-07-12|Synovis Orthopedic And Woundcare, Inc.|Device for soft tissue repair or replacement|

---

US7954686B2|2008-09-19|2011-06-07|Ethicon Endo-Surgery, Inc.|Surgical stapler with apparatus for adjusting staple height|

---

US9005230B2|2008-09-23|2015-04-14|Ethicon Endo-Surgery, Inc.|Motorized surgical instrument|

---

US9386983B2|2008-09-23|2016-07-12|Ethicon Endo-Surgery, Llc|Robotically-controlled motorized surgical instrument|

---

US8210411B2|2008-09-23|2012-07-03|Ethicon Endo-Surgery, Inc.|Motor-driven surgical cutting instrument|

---

CA2740009C|2008-10-09|2017-09-26|Mimedx, Inc.|Methods of making collagen fiber medical constructs and related medical constructs, including nerve guides and patches|

---

US8608045B2|2008-10-10|2013-12-17|Ethicon Endo-Sugery, Inc.|Powered surgical cutting and stapling apparatus with manually retractable firing system|

---

GB2464952A|2008-10-30|2010-05-05|Xiros Plc|Surgical cord|

---

CA2744232C|2008-11-21|2017-05-02|Lifecell Corporation|Reinforced biologic material|

---

EP2373231A1|2008-12-09|2011-10-12|Connective Orthopaedics|Activation and delivery devices for therapeutic compositions|

---

US9326840B2|2008-12-15|2016-05-03|Allergan, Inc.|Prosthetic device and method of manufacturing the same|

---

US9204953B2|2008-12-15|2015-12-08|Allergan, Inc.|Biocompatible surgical scaffold with varying stretch|

---

US9308070B2|2008-12-15|2016-04-12|Allergan, Inc.|Pliable silk medical device|

---

US9204954B2|2008-12-15|2015-12-08|Allergan, Inc.|Knitted scaffold with diagonal yarn|

---

EP2992856A1|2008-12-15|2016-03-09|Allergan, Inc.|A prosthetic device and method of manufacturing the same|

---

US8353966B2|2009-01-15|2013-01-15|The Curators Of The University Of Missouri|Scaffold for bone and tissue repair in mammals|

---

US9456890B2|2009-01-15|2016-10-04|The Curators Of The University Of Missouri|Scaffold for bone and tissue repair in mammals|

---

US20100291182A1|2009-01-21|2010-11-18|Arsenal Medical, Inc.|Drug-Loaded Fibers|

---

US20130071463A1|2009-11-17|2013-03-21|Maria Palasis|Implants for postoperative pain|

---

US8517239B2|2009-02-05|2013-08-27|Ethicon Endo-Surgery, Inc.|Surgical stapling instrument comprising a magnetic element driver|

---

US8444036B2|2009-02-06|2013-05-21|Ethicon Endo-Surgery, Inc.|Motor driven surgical fastener device with mechanisms for adjusting a tissue gap within the end effector|

---

US20110024477A1|2009-02-06|2011-02-03|Hall Steven G|Driven Surgical Stapler Improvements|

---

US20110006101A1|2009-02-06|2011-01-13|EthiconEndo-Surgery, Inc.|Motor driven surgical fastener device with cutting member lockout arrangements|

---

GB2468307A|2009-03-04|2010-09-08|Xiros Plc|Suture having a core and a braided mantle including strands running parallel to the axis of the suture|

---

US8206446B1|2009-03-10|2012-06-26|Cayenne Medical, Inc.|Method for surgically repairing a damaged ligament|

---

CN102348464B|2009-03-10|2016-05-25|悉尼大学|Injectable biomaterials|

---

US8308814B2|2009-03-27|2012-11-13|Depuy Mitek, Inc.|Methods and devices for preparing and implanting tissue scaffolds|

---

US20120301507A1|2009-03-27|2012-11-29|Orthocell Pty Ltd|Method of tissue repair|

---

US8241298B2|2009-03-27|2012-08-14|Depuy Mitek, Inc.|Methods and devices for delivering and affixing tissue scaffolds|

---

NL2002742C2|2009-04-09|2010-10-12|Univ Delft Tech|Mechanical device for tissue regeneration.|

---

US10806833B1|2009-05-11|2020-10-20|Integra Lifesciences Corporation|Adherent resorbable matrix|

---

EP2432426B1|2009-05-22|2017-05-31|Biorez, Inc.|Mechanically competent scaffold for ligament and tendon regeneration|

---

US20100305710A1|2009-05-28|2010-12-02|Biomet Manufacturing Corp.|Knee Prosthesis|

---

US9597430B2|2009-07-31|2017-03-21|Synthasome, Inc.|Synthetic structure for soft tissue repair|

---

FR2948556B1|2009-07-31|2012-08-31|Lars|PROSTHETIC LIGAMENT FOR TRANSVERSE FASTENING AND METHOD FOR PREPARING THE SAME|

---

NZ598691A|2009-09-11|2014-05-30|Allergan Inc|Prosthetic device and method of manufacturing the same|

---

US20120251593A1|2009-09-28|2012-10-04|The Baoard Of Regents Of The University Of Texas System|Silk fibroin-decorin scaffolds|

---

US8220688B2|2009-12-24|2012-07-17|Ethicon Endo-Surgery, Inc.|Motor-driven surgical cutting instrument with electric actuator directional control assembly|

---

WO2011087976A1|2010-01-15|2011-07-21|University Of Miami|Fan-folded fascia lata for cruciate ligament substitution and method and apparatus for making the same|

---

US20110190886A1|2010-01-29|2011-08-04|Wisconsin Alumni Research Foundation|Braided tertiary nanofibrous structure for ligament, tendon, and muscle tissue implant|

---

SG183406A1|2010-02-19|2012-09-27|Agency Science Tech & Res|Fiber-assembled tissue constructs|

---

WO2011115420A2|2010-03-16|2011-09-22|Kollodis Biosciences, Inc.|Adhesive extracellular matrix mimetic|

---

CN102892382B|2010-03-23|2015-09-02|波士顿科技西姆德股份有限公司|Annuloplasty devic|

---

US9757132B2|2010-03-24|2017-09-12|Biorez, Inc.|Mechanically competent scaffold for rotator cuff and tendon augmentation|

---

EP2380526B1|2010-04-23|2019-01-02|Biotronik AG|Implant and method for producing the same|

---

US8464925B2|2010-05-11|2013-06-18|Ethicon Endo-Surgery, Inc.|Methods and apparatus for delivering tissue treatment compositions to stapled tissue|

---

US8646674B2|2010-05-11|2014-02-11|Ethicon Endo-Surgery, Inc.|Methods and apparatus for delivering tissue treatment compositions to stapled tissue|

---

US10130736B1|2010-05-14|2018-11-20|Musculoskeletal Transplant Foundation|Tissue-derived tissuegenic implants, and methods of fabricating and using same|

---

US8834928B1|2011-05-16|2014-09-16|Musculoskeletal Transplant Foundation|Tissue-derived tissugenic implants, and methods of fabricating and using same|

---

US9352003B1|2010-05-14|2016-05-31|Musculoskeletal Transplant Foundation|Tissue-derived tissuegenic implants, and methods of fabricating and using same|

---

US8883210B1|2010-05-14|2014-11-11|Musculoskeletal Transplant Foundation|Tissue-derived tissuegenic implants, and methods of fabricating and using same|

---

US8858577B2|2010-05-19|2014-10-14|University Of Utah Research Foundation|Tissue stabilization system|

---

US9320523B2|2012-03-28|2016-04-26|Ethicon Endo-Surgery, Llc|Tissue thickness compensator comprising tissue ingrowth features|

---

US9517063B2|2012-03-28|2016-12-13|Ethicon Endo-Surgery, Llc|Movable member for use with a tissue thickness compensator|

---

US9629814B2|2010-09-30|2017-04-25|Ethicon Endo-Surgery, Llc|Tissue thickness compensator configured to redistribute compressive forces|

---

RU2644272C2|2012-03-28|2018-02-08|Этикон Эндо-Серджери, Инк.|Limitation node with tissue thickness compensator|

---

US20120080498A1|2010-09-30|2012-04-05|Ethicon Endo-Surgery, Inc.|Curved end effector for a stapling instrument|

---

CN104321024B|2012-03-28|2017-05-24|伊西康内外科公司|Tissue thickness compensator comprising a plurality of layers|

---

US9220501B2|2010-09-30|2015-12-29|Ethicon Endo-Surgery, Inc.|Tissue thickness compensators|

---

US9314246B2|2010-09-30|2016-04-19|Ethicon Endo-Surgery, Llc|Tissue stapler having a thickness compensator incorporating an anti-inflammatory agent|

---

US9364233B2|2010-09-30|2016-06-14|Ethicon Endo-Surgery, Llc|Tissue thickness compensators for circular surgical staplers|

---

JP6026509B2|2011-04-29|2016-11-16|エシコン・エンド−サージェリィ・インコーポレイテッドＥｔｈｉｃｏｎ Ｅｎｄｏ−Ｓｕｒｇｅｒｙ，Ｉｎｃ．|Staple cartridge including staples disposed within a compressible portion of the staple cartridge itself|

---

US9204880B2|2012-03-28|2015-12-08|Ethicon Endo-Surgery, Inc.|Tissue thickness compensator comprising capsules defining a low pressure environment|

---

US9386984B2|2013-02-08|2016-07-12|Ethicon Endo-Surgery, Llc|Staple cartridge comprising a releasable cover|

---

US9241714B2|2011-04-29|2016-01-26|Ethicon Endo-Surgery, Inc.|Tissue thickness compensator and method for making the same|

---

US9282962B2|2010-09-30|2016-03-15|Ethicon Endo-Surgery, Llc|Adhesive film laminate|

---

RU2013119928A|2010-09-30|2014-11-10|Этикон Эндо-Серджери, Инк.|A STAPLING SYSTEM CONTAINING A RETAINING MATRIX AND A LEVELING MATRIX|

---

US9414838B2|2012-03-28|2016-08-16|Ethicon Endo-Surgery, Llc|Tissue thickness compensator comprised of a plurality of materials|

---

US10945731B2|2010-09-30|2021-03-16|Ethicon Llc|Tissue thickness compensator comprising controlled release and expansion|

---

US9295464B2|2010-09-30|2016-03-29|Ethicon Endo-Surgery, Inc.|Surgical stapler anvil comprising a plurality of forming pockets|

---

US9332974B2|2010-09-30|2016-05-10|Ethicon Endo-Surgery, Llc|Layered tissue thickness compensator|

---

US9433419B2|2010-09-30|2016-09-06|Ethicon Endo-Surgery, Inc.|Tissue thickness compensator comprising a plurality of layers|

---

US8695866B2|2010-10-01|2014-04-15|Ethicon Endo-Surgery, Inc.|Surgical instrument having a power control circuit|

---

US9561093B2|2010-10-28|2017-02-07|Novus Scientific Ab|Elastically deformable and resorbable medical mesh implant|

---

AU2011329839B2|2010-11-17|2016-12-08|Wake Forest University Health Sciences|Keratin compositions for treatment of bone deficiency or injury|

---

US9168231B2|2010-12-05|2015-10-27|Nanonerve, Inc.|Fibrous polymer scaffolds having diametrically patterned polymer fibers|

---

WO2012098419A1|2011-01-20|2012-07-26|Centre National De La Recherche Scientifique|Device for tissue repair|

---

WO2012103343A1|2011-01-28|2012-08-02|The Board Of Trustees Of The Leland Stanford Junior University|Functional targeted brain endoskeletonization|

---

US8968626B2|2011-01-31|2015-03-03|Arsenal Medical, Inc.|Electrospinning process for manufacture of multi-layered structures|

---

US9194058B2|2011-01-31|2015-11-24|Arsenal Medical, Inc.|Electrospinning process for manufacture of multi-layered structures|

---

US9034240B2|2011-01-31|2015-05-19|Arsenal Medical, Inc.|Electrospinning process for fiber manufacture|

---

US8852214B2|2011-02-04|2014-10-07|University Of Utah Research Foundation|System for tissue fixation to bone|

---

WO2012121986A2|2011-03-08|2012-09-13|Mimedx, Inc..|Collagen fiber ribbons with integrated fixation sutures and methods of making the same|

---

US8574296B2|2011-03-31|2013-11-05|Biomet Manufacturing Corporation|Dual tendon bundle|

---

US10973622B2|2011-04-25|2021-04-13|Arthrex, Inc.|Internal brace for tissue repairs and reinforcements|

---

US9198662B2|2012-03-28|2015-12-01|Ethicon Endo-Surgery, Inc.|Tissue thickness compensator having improved visibility|

---

US8771352B2|2011-05-17|2014-07-08|Biomet Sports Medicine, Llc|Method and apparatus for tibial fixation of an ACL graft|

---

US9072535B2|2011-05-27|2015-07-07|Ethicon Endo-Surgery, Inc.|Surgical stapling instruments with rotatable staple deployment arrangements|

---

US9694106B2|2011-07-11|2017-07-04|Mimedx Group, Inc.|Synthetic collagen threads for cosmetic uses including skin wrinkle treatments and associated methods|

---

US9700631B2|2011-08-17|2017-07-11|KeraNetics, LLC|Low protein percentage gelling compositions|

---

WO2013025928A2|2011-08-17|2013-02-21|Keranetics Llc|Methods for extracting keratin proteins|

---

US9050084B2|2011-09-23|2015-06-09|Ethicon Endo-Surgery, Inc.|Staple cartridge including collapsible deck arrangement|

---

ES2415960B1|2011-10-06|2014-05-27|Jose Manuel Abascal Rubio|TENSION DEVICE OF ONE OR MORE FASCICULAR BRANCHES OF SOFT MATERIAL OVERHEADING BY A BONE TUNNEL.|

---

US8869841B2|2011-10-20|2014-10-28|New Horizon Elastic Fabric Co., Ltd|Fabric straps with tubular structure containing free-floating yarns and varied width|

---

US9260804B2|2011-10-20|2016-02-16|New Horizon Elastic Fabric Co., Ltd.|Fabric straps with tubular structure containing free-floating yarns and varied width|

---

US8506597B2|2011-10-25|2013-08-13|Biomet Sports Medicine, Llc|Method and apparatus for interosseous membrane reconstruction|

---

WO2013067294A1|2011-11-02|2013-05-10|Mimedx Group, Inc.|Implantable collagen devices and related methods and systems of making same|

---

US9101458B2|2011-11-10|2015-08-11|Lifecell Corporation|Device for tendon and ligament treatment|

---

WO2013074691A1|2011-11-14|2013-05-23|Arthrocare Corporation|Tissue repair assembly|

---

US9017404B2|2012-01-23|2015-04-28|Lloyd P. Champagne|Devices and methods for tendon repair|

---

US9204959B2|2012-02-02|2015-12-08|Smith & Nephew, Inc.|Implantable biologic holder|

---

WO2013116624A1|2012-02-03|2013-08-08|The Trustees Of The University Of Pennsylvania|Aligned fibrous materials with spatially varying fiber orientation and related methods|

---

US9044230B2|2012-02-13|2015-06-02|Ethicon Endo-Surgery, Inc.|Surgical cutting and fastening instrument with apparatus for determining cartridge and firing motion status|

---

US20150289967A1|2012-03-22|2015-10-15|The Curators Of The University Of Missouri|Nanocomposites for soft tissue repair and replacement|

---

RU2639857C2|2012-03-28|2017-12-22|Этикон Эндо-Серджери, Инк.|Tissue thickness compensator containing capsule for medium with low pressure|

---

US9307989B2|2012-03-28|2016-04-12|Ethicon Endo-Surgery, Llc|Tissue stapler having a thickness compensator incorportating a hydrophobic agent|

---

GB2502959A|2012-06-11|2013-12-18|Xiros Ltd|Synthetic ligament assembly|

---

US9101358B2|2012-06-15|2015-08-11|Ethicon Endo-Surgery, Inc.|Articulatable surgical instrument comprising a firing drive|

---

US11202631B2|2012-06-28|2021-12-21|Cilag Gmbh International|Stapling assembly comprising a firing lockout|

---

US9028494B2|2012-06-28|2015-05-12|Ethicon Endo-Surgery, Inc.|Interchangeable end effector coupling arrangement|

---

US9101385B2|2012-06-28|2015-08-11|Ethicon Endo-Surgery, Inc.|Electrode connections for rotary driven surgical tools|

---

US9408606B2|2012-06-28|2016-08-09|Ethicon Endo-Surgery, Llc|Robotically powered surgical device with manually-actuatable reversing system|

---

US9561038B2|2012-06-28|2017-02-07|Ethicon Endo-Surgery, Llc|Interchangeable clip applier|

---

US9125662B2|2012-06-28|2015-09-08|Ethicon Endo-Surgery, Inc.|Multi-axis articulating and rotating surgical tools|

---

RU2636861C2|2012-06-28|2017-11-28|Этикон Эндо-Серджери, Инк.|Blocking of empty cassette with clips|

---

US9282974B2|2012-06-28|2016-03-15|Ethicon Endo-Surgery, Llc|Empty clip cartridge lockout|

---

US9072536B2|2012-06-28|2015-07-07|Ethicon Endo-Surgery, Inc.|Differential locking arrangements for rotary powered surgical instruments|

---

US20140001231A1|2012-06-28|2014-01-02|Ethicon Endo-Surgery, Inc.|Firing system lockout arrangements for surgical instruments|

---

US9289256B2|2012-06-28|2016-03-22|Ethicon Endo-Surgery, Llc|Surgical end effectors having angled tissue-contacting surfaces|

---

US20140005718A1|2012-06-28|2014-01-02|Ethicon Endo-Surgery, Inc.|Multi-functional powered surgical device with external dissection features|

---

US9480515B2|2012-07-12|2016-11-01|Exsomed International IP, LLC|Metacarpal bone stabilization device|

---

EP2687188A1|2012-07-20|2014-01-22|Le Centre National De La Recherche Scientifique|Artificial tendon or ligament with varying stiffness along its length|

---

US10835241B2|2012-07-30|2020-11-17|Conextions, Inc.|Devices, systems, and methods for repairing soft tissue and attaching soft tissue to bone|

---

US9427309B2|2012-07-30|2016-08-30|Conextions, Inc.|Soft tissue repair devices, systems, and methods|

---

US10390935B2|2012-07-30|2019-08-27|Conextions, Inc.|Soft tissue to bone repair devices, systems, and methods|

---

US10219804B2|2012-07-30|2019-03-05|Conextions, Inc.|Devices, systems, and methods for repairing soft tissue and attaching soft tissue to bone|

---

US11253252B2|2012-07-30|2022-02-22|Conextions, Inc.|Devices, systems, and methods for repairing soft tissue and attaching soft tissue to bone|

---

CN104350372B|2012-08-09|2018-03-02|斯坦福大学托管董事会|For preparing the method and composition of the biological specimen for microscopic analysis|

---

US9237888B2|2012-09-20|2016-01-19|Medos International Sarl|Methods and devices for threading sutures|

---

EP3269335B1|2012-10-02|2019-03-06|McCullen, Seth|Implantable devices for musculoskeletal repair and regeneration|

---

CN102908212B|2012-10-15|2015-06-17|复旦大学附属华山医院|Sectional-type annular suspended artificial ligament|

---

CN102908209B|2012-10-15|2015-10-14|复旦大学附属华山医院|Double-hole suspension type artificial ligament|

---

US9688741B2|2012-10-23|2017-06-27|Elastagen Pty Ltd|Elastic hydrogel|

---

EP2917337B1|2012-11-08|2020-01-08|InGeneron Inc.|Media for culturing, preserving, and administering regenerative cells|

---

AU2013360011B2|2012-12-10|2017-02-02|Allergan Pharmaceuticals International Limited|Scalable three-dimensional elastic construct manufacturing|

---

ES2751398T3|2013-01-15|2020-03-31|Tepha Inc|Implants for regeneration of soft tissue and hard tissue|

---

WO2014121067A1|2013-02-01|2014-08-07|Children's Medical Center Corporation|Collagen scaffolds|

---

JP6382235B2|2013-03-01|2018-08-29|エシコン・エンド−サージェリィ・インコーポレイテッドＥｔｈｉｃｏｎ Ｅｎｄｏ−Ｓｕｒｇｅｒｙ，Ｉｎｃ．|Articulatable surgical instrument with a conductive path for signal communication|

---

JP6345707B2|2013-03-01|2018-06-20|エシコン・エンド−サージェリィ・インコーポレイテッドＥｔｈｉｃｏｎ Ｅｎｄｏ−Ｓｕｒｇｅｒｙ，Ｉｎｃ．|Surgical instrument with soft stop|

---

US9782169B2|2013-03-01|2017-10-10|Ethicon Llc|Rotary powered articulation joints for surgical instruments|

---

US9757119B2|2013-03-08|2017-09-12|Biomet Sports Medicine, Llc|Visual aid for identifying suture limbs arthroscopically|

---

US9433489B2|2013-03-12|2016-09-06|Soft Tissue Regeneration, Inc.|Absorbable synthetic braided matrix for breast reconstruction and hernia repair|

---

US9345481B2|2013-03-13|2016-05-24|Ethicon Endo-Surgery, Llc|Staple cartridge tissue thickness sensor system|

---

US9918827B2|2013-03-14|2018-03-20|Biomet Sports Medicine, Llc|Scaffold for spring ligament repair|

---

US9687230B2|2013-03-14|2017-06-27|Ethicon Llc|Articulatable surgical instrument comprising a firing drive|

---

US9629629B2|2013-03-14|2017-04-25|Ethicon Endo-Surgey, LLC|Control systems for surgical instruments|

---

US9585695B2|2013-03-15|2017-03-07|Woven Orthopedic Technologies, Llc|Surgical screw hole liner devices and related methods|

---

US10238772B2|2013-03-15|2019-03-26|The Curators Of The University Of Missouri|Biodegradable composite scaffold for repairing defects in load-bearing bones|

---

US9827245B2|2013-03-15|2017-11-28|KeraNetics, LLC|Keratin compositions comprising halofuginone|

---

EA024600B1|2013-03-18|2016-10-31|Сара Ариф кызы Балогланова|Method of surgical access to middle ear cavities|

---

US9332984B2|2013-03-27|2016-05-10|Ethicon Endo-Surgery, Llc|Fastener cartridge assemblies|

---

US9795384B2|2013-03-27|2017-10-24|Ethicon Llc|Fastener cartridge comprising a tissue thickness compensator and a gap setting element|

---

US9572577B2|2013-03-27|2017-02-21|Ethicon Endo-Surgery, Llc|Fastener cartridge comprising a tissue thickness compensator including openings therein|

---

US20160296664A1|2013-04-12|2016-10-13|The Trustees Of Columbia University In The City Of New York|Methods for host cell homing and dental pulp regeneration|

---

US9826976B2|2013-04-16|2017-11-28|Ethicon Llc|Motor driven surgical instruments with lockable dual drive shafts|

---

US9574644B2|2013-05-30|2017-02-21|Ethicon Endo-Surgery, Llc|Power module for use with a surgical instrument|

---

CA2919374C|2013-07-30|2019-12-03|Musculoskeletal Transplant Foundation|Acellular soft tissue-derived matrices and methods for preparing same|

---

KR20210154881A|2013-08-13|2021-12-21|앨러간 파마슈티컬스 인터내셔널 리미티드|Regeneration of damaged tissue|

---

US9283054B2|2013-08-23|2016-03-15|Ethicon Endo-Surgery, Llc|Interactive displays|

---

JP6416260B2|2013-08-23|2018-10-31|エシコン エルエルシー|Firing member retractor for a powered surgical instrument|

---

US11259849B2|2013-10-02|2022-03-01|ExsoMed Corporation|Full wrist fusion device|

---

KR20160098251A|2013-12-20|2016-08-18|아서로케어 코포레이션|Knotless all suture tissue repair|

---

US10136886B2|2013-12-20|2018-11-27|Biomet Sports Medicine, Llc|Knotless soft tissue devices and techniques|

---

US9839428B2|2013-12-23|2017-12-12|Ethicon Llc|Surgical cutting and stapling instruments with independent jaw control features|

---

US9724092B2|2013-12-23|2017-08-08|Ethicon Llc|Modular surgical instruments|

---

US20150173756A1|2013-12-23|2015-06-25|Ethicon Endo-Surgery, Inc.|Surgical cutting and stapling methods|

---

US9585662B2|2013-12-23|2017-03-07|Ethicon Endo-Surgery, Llc|Fastener cartridge comprising an extendable firing member|

---

US9622523B2|2014-01-06|2017-04-18|Exsomed International IP, LLC|Ergonomic work gloves|

---

US9962161B2|2014-02-12|2018-05-08|Ethicon Llc|Deliverable surgical instrument|

---

EP3104809B1|2014-02-13|2017-12-27|Antonio Sambusseti|Non-absorbable tissue reconstruction device, in particular for tissues such as ligaments|

---

US9775608B2|2014-02-24|2017-10-03|Ethicon Llc|Fastening system comprising a firing member lockout|

---

JP6462004B2|2014-02-24|2019-01-30|エシコン エルエルシー|Fastening system with launcher lockout|

---

US20170071605A1|2014-03-11|2017-03-16|Antonio Sambusseti|Absorbable tissue reconstruction device, in particular for tissues such as ligaments|

---

WO2015138760A1|2014-03-12|2015-09-17|Conextions, Inc.|Soft tissue repair devices, systems, and methods|

---

US11259799B2|2014-03-26|2022-03-01|Cilag Gmbh International|Interface systems for use with surgical instruments|

---

US9913642B2|2014-03-26|2018-03-13|Ethicon Llc|Surgical instrument comprising a sensor system|

---

US9750499B2|2014-03-26|2017-09-05|Ethicon Llc|Surgical stapling instrument system|

---

US9804618B2|2014-03-26|2017-10-31|Ethicon Llc|Systems and methods for controlling a segmented circuit|

---

US20150272557A1|2014-03-26|2015-10-01|Ethicon Endo-Surgery, Inc.|Modular surgical instrument system|

---

US10299792B2|2014-04-16|2019-05-28|Ethicon Llc|Fastener cartridge comprising non-uniform fasteners|

---

CA2947898A1|2014-05-30|2015-12-03|The Board Of Trustees Of The Leland Stanford Junior University|Methods and devices for imaging large intact tissue samples|

---

US9615822B2|2014-05-30|2017-04-11|Biomet Sports Medicine, Llc|Insertion tools and method for soft anchor|

---

US9700291B2|2014-06-03|2017-07-11|Biomet Sports Medicine, Llc|Capsule retractor|

---

US10045781B2|2014-06-13|2018-08-14|Ethicon Llc|Closure lockout systems for surgical instruments|

---

US9907593B2|2014-08-05|2018-03-06|Woven Orthopedic Technologies, Llc|Woven retention devices, systems and methods|

---

US8956394B1|2014-08-05|2015-02-17|Woven Orthopedic Technologies, Llc|Woven retention devices, systems and methods|

---

US10039543B2|2014-08-22|2018-08-07|Biomet Sports Medicine, Llc|Non-sliding soft anchor|

---

BR112017004361A2|2014-09-05|2017-12-05|Ethicon Llc|medical overcurrent modular power supply|

---

US9737301B2|2014-09-05|2017-08-22|Ethicon Llc|Monitoring device degradation based on component evaluation|

---

US20160074071A1|2014-09-16|2016-03-17|Woven Orthopedic Technologies, Llc|Methods of using woven retention devices and systems|

---

AU2015320722A1|2014-09-23|2017-04-13|Cytex Therapeutics, Inc.|Articular cartilage repair|

---

MX2017003960A|2014-09-26|2017-12-04|Ethicon Llc|Surgical stapling buttresses and adjunct materials.|

---

US10206677B2|2014-09-26|2019-02-19|Ethicon Llc|Surgical staple and driver arrangements for staple cartridges|

---

WO2016054463A1|2014-10-02|2016-04-07|Mccullen Seth|Anatomically designed meniscus implantable devices|

---

US10076325B2|2014-10-13|2018-09-18|Ethicon Llc|Surgical stapling apparatus comprising a tissue stop|

---

US9924944B2|2014-10-16|2018-03-27|Ethicon Llc|Staple cartridge comprising an adjunct material|

---

USD740427S1|2014-10-17|2015-10-06|Woven Orthopedic Technologies, Llc|Orthopedic woven retention device|

---

US10517594B2|2014-10-29|2019-12-31|Ethicon Llc|Cartridge assemblies for surgical staplers|

---

US11141153B2|2014-10-29|2021-10-12|Cilag Gmbh International|Staple cartridges comprising driver arrangements|

---

US10265438B1|2014-11-03|2019-04-23|BioDlogics, LLC|Methods and compositions for the repair and replacement of connective tissue|

---

US9844376B2|2014-11-06|2017-12-19|Ethicon Llc|Staple cartridge comprising a releasable adjunct material|

---

US9517062B2|2014-12-03|2016-12-13|Smith & Nephew, Inc.|Closed loop suture for anchoring tissue grafts|

---

US10925716B2|2015-02-25|2021-02-23|Smith & Nephew, Inc.|Closed loop suture for anchoring tissue grafts|

---

US10736636B2|2014-12-10|2020-08-11|Ethicon Llc|Articulatable surgical instrument system|

---

US9987000B2|2014-12-18|2018-06-05|Ethicon Llc|Surgical instrument assembly comprising a flexible articulation system|

---

US10085748B2|2014-12-18|2018-10-02|Ethicon Llc|Locking arrangements for detachable shaft assemblies with articulatable surgical end effectors|

---

US10117649B2|2014-12-18|2018-11-06|Ethicon Llc|Surgical instrument assembly comprising a lockable articulation system|

---

US10188385B2|2014-12-18|2019-01-29|Ethicon Llc|Surgical instrument system comprising lockable systems|

---

US9844375B2|2014-12-18|2017-12-19|Ethicon Llc|Drive arrangements for articulatable surgical instruments|

---

US10004501B2|2014-12-18|2018-06-26|Ethicon Llc|Surgical instruments with improved closure arrangements|

---

US9844374B2|2014-12-18|2017-12-19|Ethicon Llc|Surgical instrument systems comprising an articulatable end effector and means for adjusting the firing stroke of a firing member|

---

US9238090B1|2014-12-24|2016-01-19|Fettech, Llc|Tissue-based compositions|

---

CN104606713B|2015-01-04|2017-04-19|浙江大学|Three-dimensional parallel collagenous fiber-silk bracket as well as preparation method and application thereof|

---

EP3250678A4|2015-01-30|2018-08-01|The University of North Carolina at Chapel Hill|Methods to generate gastrointestinal epithelial tissue constructs|

---

US9955980B2|2015-02-24|2018-05-01|Biomet Sports Medicine, Llc|Anatomic soft tissue repair|

---

US11154301B2|2015-02-27|2021-10-26|Cilag Gmbh International|Modular stapling assembly|

---

US10045779B2|2015-02-27|2018-08-14|Ethicon Llc|Surgical instrument system comprising an inspection station|

---

US10180463B2|2015-02-27|2019-01-15|Ethicon Llc|Surgical apparatus configured to assess whether a performance parameter of the surgical apparatus is within an acceptable performance band|

---

US10226250B2|2015-02-27|2019-03-12|Ethicon Llc|Modular stapling assembly|

---

US9993248B2|2015-03-06|2018-06-12|Ethicon Endo-Surgery, Llc|Smart sensors with local signal processing|

---

US10052044B2|2015-03-06|2018-08-21|Ethicon Llc|Time dependent evaluation of sensor data to determine stability, creep, and viscoelastic elements of measures|

---

US10687806B2|2015-03-06|2020-06-23|Ethicon Llc|Adaptive tissue compression techniques to adjust closure rates for multiple tissue types|

---

US10045776B2|2015-03-06|2018-08-14|Ethicon Llc|Control techniques and sub-processor contained within modular shaft with select control processing from handle|

---

US9808246B2|2015-03-06|2017-11-07|Ethicon Endo-Surgery, Llc|Method of operating a powered surgical instrument|

---

US9895148B2|2015-03-06|2018-02-20|Ethicon Endo-Surgery, Llc|Monitoring speed control and precision incrementing of motor for powered surgical instruments|

---

US10245033B2|2015-03-06|2019-04-02|Ethicon Llc|Surgical instrument comprising a lockable battery housing|

---

US9901342B2|2015-03-06|2018-02-27|Ethicon Endo-Surgery, Llc|Signal and power communication system positioned on a rotatable shaft|

---

US10617412B2|2015-03-06|2020-04-14|Ethicon Llc|System for detecting the mis-insertion of a staple cartridge into a surgical stapler|

---

US9924961B2|2015-03-06|2018-03-27|Ethicon Endo-Surgery, Llc|Interactive feedback system for powered surgical instruments|

---

US10213201B2|2015-03-31|2019-02-26|Ethicon Llc|Stapling end effector configured to compensate for an uneven gap between a first jaw and a second jaw|

---

US9974534B2|2015-03-31|2018-05-22|Biomet Sports Medicine, Llc|Suture anchor with soft anchor of electrospun fibers|

---

WO2016164566A1|2015-04-08|2016-10-13|The Trustees Of Columbia University In The City Of New York|Spatiotemporal delivery system embedded in 3d-printing|

---

GB2537367B|2015-04-13|2017-11-15|Cook Medical Technologies Llc|Medical device with connected legs|

---

WO2016186847A1|2015-05-19|2016-11-24|Exsomed International IP, LLC|Distal radius plate|

---

EP3297694A1|2015-05-21|2018-03-28|Musculoskeletal Transplant Foundation|Modified demineralized cortical bone fibers|

---

US10178992B2|2015-06-18|2019-01-15|Ethicon Llc|Push/pull articulation drive systems for articulatable surgical instruments|

---

WO2017004136A1|2015-06-30|2017-01-05|Tela Bio, Inc.|Corner-lock stitch patterns|

---

EP3324882A1|2015-07-21|2018-05-30|Tela Bio, Inc.|Compliance control stitching in substrate materials|

---

US10912864B2|2015-07-24|2021-02-09|Musculoskeletal Transplant Foundation|Acellular soft tissue-derived matrices and methods for preparing same|

---

WO2017024277A1|2015-08-05|2017-02-09|Woven Orthopedic Technologies, Llc|Tapping devices, systems and methods for use in bone tissue|

---

US10835249B2|2015-08-17|2020-11-17|Ethicon Llc|Implantable layers for a surgical instrument|

---

US11052175B2|2015-08-19|2021-07-06|Musculoskeletal Transplant Foundation|Cartilage-derived implants and methods of making and using same|

---

MX2018002388A|2015-08-26|2018-08-01|Ethicon Llc|Surgical staple strips for permitting varying staple properties and enabling easy cartridge loading.|

---

US9931196B2|2015-08-26|2018-04-03|Albert Einstein Healthcare Network|Connector for attaching tissue to bone|

---

US10517599B2|2015-08-26|2019-12-31|Ethicon Llc|Staple cartridge assembly comprising staple cavities for providing better staple guidance|

---

US11213295B2|2015-09-02|2022-01-04|Cilag Gmbh International|Surgical staple configurations with camming surfaces located between portions supporting surgical staples|

---

US10238390B2|2015-09-02|2019-03-26|Ethicon Llc|Surgical staple cartridges with driver arrangements for establishing herringbone staple patterns|

---

US10076326B2|2015-09-23|2018-09-18|Ethicon Llc|Surgical stapler having current mirror-based motor control|

---

US10105139B2|2015-09-23|2018-10-23|Ethicon Llc|Surgical stapler having downstream current-based motor control|

---

US10085751B2|2015-09-23|2018-10-02|Ethicon Llc|Surgical stapler having temperature-based motor control|

---

US10363036B2|2015-09-23|2019-07-30|Ethicon Llc|Surgical stapler having force-based motor control|

---

US10327769B2|2015-09-23|2019-06-25|Ethicon Llc|Surgical stapler having motor control based on a drive system component|

---

US10238386B2|2015-09-23|2019-03-26|Ethicon Llc|Surgical stapler having motor control based on an electrical parameter related to a motor current|

---

US10299878B2|2015-09-25|2019-05-28|Ethicon Llc|Implantable adjunct systems for determining adjunct skew|

---

US10433846B2|2015-09-30|2019-10-08|Ethicon Llc|Compressible adjunct with crossing spacer fibers|

---

US10980539B2|2015-09-30|2021-04-20|Ethicon Llc|Implantable adjunct comprising bonded layers|

---

US10327777B2|2015-09-30|2019-06-25|Ethicon Llc|Implantable layer comprising plastically deformed fibers|

---

AU2016344019B2|2015-10-30|2021-07-15|New York Society For The Relief Of The Ruptured And Crippled, Maintaining The Hospital For Special Surgery|Suture sleeve patch and methods of delivery within an existing arthroscopic workflow|

---

CN105237645B|2015-11-09|2017-11-07|齐鲁工业大学|Macromolecules cross-linking agent, its gelatin film and preparation method based on oxycellulose|

---

DE102015225218A1|2015-12-15|2017-06-22|Kneesearch Gmbh|Band-holding implant|

---

US10368865B2|2015-12-30|2019-08-06|Ethicon Llc|Mechanisms for compensating for drivetrain failure in powered surgical instruments|

---

US10245091B2|2015-12-30|2019-04-02|Exsomed Holding Company, Llc|Dip fusion spike screw|

---

US10292704B2|2015-12-30|2019-05-21|Ethicon Llc|Mechanisms for compensating for battery pack failure in powered surgical instruments|

---

US10265068B2|2015-12-30|2019-04-23|Ethicon Llc|Surgical instruments with separable motors and motor control circuits|

---

US11147604B2|2016-01-12|2021-10-19|ExsoMed Corporation|Bone stabilization device|

---

KR101812871B1|2016-01-29|2018-01-30|한양대학교 산학협력단|Glucose sensing artificial muscle and method for preparing the same|

---

US10702260B2|2016-02-01|2020-07-07|Medos International Sàrl|Soft tissue fixation repair methods using tissue augmentation scaffolds|

---

ITUB20160291A1|2016-02-01|2017-08-01|Oxidea Soc A Responsabilita Limitata Semplificata|PREPARATION FOR RESTRICTIVE USE FOR MEDICAL USE, AND SPECIAL USE OF SUCH PREPARATION|

---

US10588625B2|2016-02-09|2020-03-17|Ethicon Llc|Articulatable surgical instruments with off-axis firing beam arrangements|

---

US11213293B2|2016-02-09|2022-01-04|Cilag Gmbh International|Articulatable surgical instruments with single articulation link arrangements|

---

US11254974B2|2016-02-10|2022-02-22|The Board Of Trustees Of The Leland Stanford Junior University|RNA fixation and detection in clarity-based hydrogel tissue|

---

US11224426B2|2016-02-12|2022-01-18|Cilag Gmbh International|Mechanisms for compensating for drivetrain failure in powered surgical instruments|

---

US10448948B2|2016-02-12|2019-10-22|Ethicon Llc|Mechanisms for compensating for drivetrain failure in powered surgical instruments|

---

US10258331B2|2016-02-12|2019-04-16|Ethicon Llc|Mechanisms for compensating for drivetrain failure in powered surgical instruments|

---

PL232907B1|2016-03-24|2019-08-30|Robert Mrugas|Synthetic ligament, method for producing synthetic ligament and its application|

---

US10617413B2|2016-04-01|2020-04-14|Ethicon Llc|Closure system arrangements for surgical cutting and stapling devices with separate and distinct firing shafts|

---

US10376263B2|2016-04-01|2019-08-13|Ethicon Llc|Anvil modification members for surgical staplers|

---

EP3439673A4|2016-04-07|2020-03-04|Molecular Rebar Design, LLC|Stem cell, bone, tissue and nerve scaffolding from discrete carbon nanotubes|

---

US10357247B2|2016-04-15|2019-07-23|Ethicon Llc|Surgical instrument with multiple program responses during a firing motion|

---

US10492783B2|2016-04-15|2019-12-03|Ethicon, Llc|Surgical instrument with improved stop/start control during a firing motion|

---

US10405859B2|2016-04-15|2019-09-10|Ethicon Llc|Surgical instrument with adjustable stop/start control during a firing motion|

---

US10426467B2|2016-04-15|2019-10-01|Ethicon Llc|Surgical instrument with detection sensors|

---

US10828028B2|2016-04-15|2020-11-10|Ethicon Llc|Surgical instrument with multiple program responses during a firing motion|

---

US10456137B2|2016-04-15|2019-10-29|Ethicon Llc|Staple formation detection mechanisms|

---

US10335145B2|2016-04-15|2019-07-02|Ethicon Llc|Modular surgical instrument with configurable operating mode|

---

US11179150B2|2016-04-15|2021-11-23|Cilag Gmbh International|Systems and methods for controlling a surgical stapling and cutting instrument|

---

US10368867B2|2016-04-18|2019-08-06|Ethicon Llc|Surgical instrument comprising a lockout|

---

EP3448308A4|2016-04-26|2020-01-08|Tela Bio, Inc.|Hernia repair grafts having anti-adhesion barriers|

---

US10194923B2|2016-05-10|2019-02-05|Exsomed International IP, LLC|Tool for percutaneous joint cartilage destruction and preparation for joint fusion|

---

KR101916153B1|2016-05-24|2019-01-30|주식회사 아모라이프사이언스|Yarn for cell culture scaffold, and fabric comprising the same|

---

KR101856575B1|2016-05-25|2018-06-19|주식회사 아모그린텍|Yarn for cell culture scaffold and fabric comprising the same|

---

USD850617S1|2016-06-24|2019-06-04|Ethicon Llc|Surgical fastener cartridge|

---

US10893863B2|2016-06-24|2021-01-19|Ethicon Llc|Staple cartridge comprising offset longitudinal staple rows|

---

USD826405S1|2016-06-24|2018-08-21|Ethicon Llc|Surgical fastener|

---

USD847989S1|2016-06-24|2019-05-07|Ethicon Llc|Surgical fastener cartridge|

---

US10022231B2|2016-07-22|2018-07-17|Cytex Therapeutics, Inc.|Articular cartilage repair|

---

US10973509B2|2017-12-20|2021-04-13|Conextions, Inc.|Devices, systems, and methods for repairing soft tissue and attaching soft tissue to bone|

---

US10687810B2|2016-12-21|2020-06-23|Ethicon Llc|Stepped staple cartridge with tissue retention and gap setting features|

---

US10945727B2|2016-12-21|2021-03-16|Ethicon Llc|Staple cartridge with deformable driver retention features|

---

US10517595B2|2016-12-21|2019-12-31|Ethicon Llc|Jaw actuated lock arrangements for preventing advancement of a firing member in a surgical end effector unless an unfired cartridge is installed in the end effector|

---

US10758229B2|2016-12-21|2020-09-01|Ethicon Llc|Surgical instrument comprising improved jaw control|

---

US10568625B2|2016-12-21|2020-02-25|Ethicon Llc|Staple cartridges and arrangements of staples and staple cavities therein|

---

US10492785B2|2016-12-21|2019-12-03|Ethicon Llc|Shaft assembly comprising a lockout|

---

US20180168608A1|2016-12-21|2018-06-21|Ethicon Endo-Surgery, Llc|Surgical instrument system comprising an end effector lockout and a firing assembly lockout|

---

CN110087565A|2016-12-21|2019-08-02|爱惜康有限责任公司|Surgical stapling system|

---

US20180168647A1|2016-12-21|2018-06-21|Ethicon Endo-Surgery, Llc|Surgical stapling instruments having end effectors with positive opening features|

---

US10779823B2|2016-12-21|2020-09-22|Ethicon Llc|Firing member pin angle|

---

US10426471B2|2016-12-21|2019-10-01|Ethicon Llc|Surgical instrument with multiple failure response modes|

---

US10499914B2|2016-12-21|2019-12-10|Ethicon Llc|Staple forming pocket arrangements|

---

US10675026B2|2016-12-21|2020-06-09|Ethicon Llc|Methods of stapling tissue|

---

US10617414B2|2016-12-21|2020-04-14|Ethicon Llc|Closure member arrangements for surgical instruments|

---

US10993715B2|2016-12-21|2021-05-04|Ethicon Llc|Staple cartridge comprising staples with different clamping breadths|

---

US11134942B2|2016-12-21|2021-10-05|Cilag Gmbh International|Surgical stapling instruments and staple-forming anvils|

---

US20180168625A1|2016-12-21|2018-06-21|Ethicon Endo-Surgery, Llc|Surgical stapling instruments with smart staple cartridges|

---

US10639034B2|2016-12-21|2020-05-05|Ethicon Llc|Surgical instruments with lockout arrangements for preventing firing system actuation unless an unspent staple cartridge is present|

---

US10588632B2|2016-12-21|2020-03-17|Ethicon Llc|Surgical end effectors and firing members thereof|

---

US10772986B2|2017-01-26|2020-09-15|Allosource|Fascia fibrous compositions and methods for their use and manufacture|

---

US10624633B2|2017-06-20|2020-04-21|Ethicon Llc|Systems and methods for controlling motor velocity of a surgical stapling and cutting instrument|

---

USD890784S1|2017-06-20|2020-07-21|Ethicon Llc|Display panel with changeable graphical user interface|

---

US10813639B2|2017-06-20|2020-10-27|Ethicon Llc|Closed loop feedback control of motor velocity of a surgical stapling and cutting instrument based on system conditions|

---

US10327767B2|2017-06-20|2019-06-25|Ethicon Llc|Control of motor velocity of a surgical stapling and cutting instrument based on angle of articulation|

---

US10881399B2|2017-06-20|2021-01-05|Ethicon Llc|Techniques for adaptive control of motor velocity of a surgical stapling and cutting instrument|

---

US10779820B2|2017-06-20|2020-09-22|Ethicon Llc|Systems and methods for controlling motor speed according to user input for a surgical instrument|

---

US10646220B2|2017-06-20|2020-05-12|Ethicon Llc|Systems and methods for controlling displacement member velocity for a surgical instrument|

---

US10307170B2|2017-06-20|2019-06-04|Ethicon Llc|Method for closed loop control of motor velocity of a surgical stapling and cutting instrument|

---

US10888321B2|2017-06-20|2021-01-12|Ethicon Llc|Systems and methods for controlling velocity of a displacement member of a surgical stapling and cutting instrument|

---

US10980537B2|2017-06-20|2021-04-20|Ethicon Llc|Closed loop feedback control of motor velocity of a surgical stapling and cutting instrument based on measured time over a specified number of shaft rotations|

---

US10390841B2|2017-06-20|2019-08-27|Ethicon Llc|Control of motor velocity of a surgical stapling and cutting instrument based on angle of articulation|

---

USD879808S1|2017-06-20|2020-03-31|Ethicon Llc|Display panel with graphical user interface|

---

US11090046B2|2017-06-20|2021-08-17|Cilag Gmbh International|Systems and methods for controlling displacement member motion of a surgical stapling and cutting instrument|

---

US11071554B2|2017-06-20|2021-07-27|Cilag Gmbh International|Closed loop feedback control of motor velocity of a surgical stapling and cutting instrument based on magnitude of velocity error measurements|

---

US10368864B2|2017-06-20|2019-08-06|Ethicon Llc|Systems and methods for controlling displaying motor velocity for a surgical instrument|

---

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---

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---

US10993716B2|2017-06-27|2021-05-04|Ethicon Llc|Surgical anvil arrangements|

---

US10856869B2|2017-06-27|2020-12-08|Ethicon Llc|Surgical anvil arrangements|

---

US10772629B2|2017-06-27|2020-09-15|Ethicon Llc|Surgical anvil arrangements|

---

US11090049B2|2017-06-27|2021-08-17|Cilag Gmbh International|Staple forming pocket arrangements|

---

US10765427B2|2017-06-28|2020-09-08|Ethicon Llc|Method for articulating a surgical instrument|

---

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---

US11246592B2|2017-06-28|2022-02-15|Cilag Gmbh International|Surgical instrument comprising an articulation system lockable to a frame|

---

US10716614B2|2017-06-28|2020-07-21|Ethicon Llc|Surgical shaft assemblies with slip ring assemblies with increased contact pressure|

---

US20190000477A1|2017-06-28|2019-01-03|Ethicon Llc|Surgical instrument comprising a shaft including a housing arrangement|

---

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---

US11259805B2|2017-06-28|2022-03-01|Cilag Gmbh International|Surgical instrument comprising firing member supports|

---

US10211586B2|2017-06-28|2019-02-19|Ethicon Llc|Surgical shaft assemblies with watertight housings|

---

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---

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---

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---

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---

US10932772B2|2017-06-29|2021-03-02|Ethicon Llc|Methods for closed loop velocity control for robotic surgical instrument|

---

US11007022B2|2017-06-29|2021-05-18|Ethicon Llc|Closed loop velocity control techniques based on sensed tissue parameters for robotic surgical instrument|

---

US10898183B2|2017-06-29|2021-01-26|Ethicon Llc|Robotic surgical instrument with closed loop feedback techniques for advancement of closure member during firing|

---

US10258418B2|2017-06-29|2019-04-16|Ethicon Llc|System for controlling articulation forces|

---

US10398434B2|2017-06-29|2019-09-03|Ethicon Llc|Closed loop velocity control of closure member for robotic surgical instrument|

---

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---

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---

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---

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---

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---

US10743872B2|2017-09-29|2020-08-18|Ethicon Llc|System and methods for controlling a display of a surgical instrument|

---

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---

USD907647S1|2017-09-29|2021-01-12|Ethicon Llc|Display screen or portion thereof with animated graphical user interface|

---

USD907648S1|2017-09-29|2021-01-12|Ethicon Llc|Display screen or portion thereof with animated graphical user interface|

---

US10765429B2|2017-09-29|2020-09-08|Ethicon Llc|Systems and methods for providing alerts according to the operational state of a surgical instrument|

---

US10729501B2|2017-09-29|2020-08-04|Ethicon Llc|Systems and methods for language selection of a surgical instrument|

---

US10796471B2|2017-09-29|2020-10-06|Ethicon Llc|Systems and methods of displaying a knife position for a surgical instrument|

---

US11090075B2|2017-10-30|2021-08-17|Cilag Gmbh International|Articulation features for surgical end effector|

---

US11134944B2|2017-10-30|2021-10-05|Cilag Gmbh International|Surgical stapler knife motion controls|

---

US10842490B2|2017-10-31|2020-11-24|Ethicon Llc|Cartridge body design with force reduction based on firing completion|

---

US10779903B2|2017-10-31|2020-09-22|Ethicon Llc|Positive shaft rotation lock activated by jaw closure|

---

US11197670B2|2017-12-15|2021-12-14|Cilag Gmbh International|Surgical end effectors with pivotal jaws configured to touch at their respective distal ends when fully closed|

---

US11033267B2|2017-12-15|2021-06-15|Ethicon Llc|Systems and methods of controlling a clamping member firing rate of a surgical instrument|

---

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---

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---

US10828033B2|2017-12-15|2020-11-10|Ethicon Llc|Handheld electromechanical surgical instruments with improved motor control arrangements for positioning components of an adapter coupled thereto|

---

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---

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---

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---

US11071543B2|2017-12-15|2021-07-27|Cilag Gmbh International|Surgical end effectors with clamping assemblies configured to increase jaw aperture ranges|

---

US11006955B2|2017-12-15|2021-05-18|Ethicon Llc|End effectors with positive jaw opening features for use with adapters for electromechanical surgical instruments|

---

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---

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---

US11020112B2|2017-12-19|2021-06-01|Ethicon Llc|Surgical tools configured for interchangeable use with different controller interfaces|

---

US10716565B2|2017-12-19|2020-07-21|Ethicon Llc|Surgical instruments with dual articulation drivers|

---

US10835330B2|2017-12-19|2020-11-17|Ethicon Llc|Method for determining the position of a rotatable jaw of a surgical instrument attachment assembly|

---

US10729509B2|2017-12-19|2020-08-04|Ethicon Llc|Surgical instrument comprising closure and firing locking mechanism|

---

USD910847S1|2017-12-19|2021-02-16|Ethicon Llc|Surgical instrument assembly|

---

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---

US20190192151A1|2017-12-21|2019-06-27|Ethicon Llc|Surgical instrument having a display comprising image layers|

---

US11129680B2|2017-12-21|2021-09-28|Cilag Gmbh International|Surgical instrument comprising a projector|

---

US11076853B2|2017-12-21|2021-08-03|Cilag Gmbh International|Systems and methods of displaying a knife position during transection for a surgical instrument|

---

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---

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---

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---

US10912559B2|2018-08-20|2021-02-09|Ethicon Llc|Reinforced deformable anvil tip for surgical stapler anvil|

---

US10779821B2|2018-08-20|2020-09-22|Ethicon Llc|Surgical stapler anvils with tissue stop features configured to avoid tissue pinch|

---

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---

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---

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---

US11045192B2|2018-08-20|2021-06-29|Cilag Gmbh International|Fabricating techniques for surgical stapler anvils|

---

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---

US10842492B2|2018-08-20|2020-11-24|Ethicon Llc|Powered articulatable surgical instruments with clutching and locking arrangements for linking an articulation drive system to a firing drive system|

---

USD914878S1|2018-08-20|2021-03-30|Ethicon Llc|Surgical instrument anvil|

---

US11207065B2|2018-08-20|2021-12-28|Cilag Gmbh International|Method for fabricating surgical stapler anvils|

---

US11172929B2|2019-03-25|2021-11-16|Cilag Gmbh International|Articulation drive arrangements for surgical systems|

---

US11147551B2|2019-03-25|2021-10-19|Cilag Gmbh International|Firing drive arrangements for surgical systems|

---

US11147553B2|2019-03-25|2021-10-19|Cilag Gmbh International|Firing drive arrangements for surgical systems|

---

US11253254B2|2019-04-30|2022-02-22|Cilag Gmbh International|Shaft rotation actuator on a surgical instrument|

---

US11224497B2|2019-06-28|2022-01-18|Cilag Gmbh International|Surgical systems with multiple RFID tags|

---

US11051807B2|2019-06-28|2021-07-06|Cilag Gmbh International|Packaging assembly including a particulate trap|

---

US11219455B2|2019-06-28|2022-01-11|Cilag Gmbh International|Surgical instrument including a lockout key|

---

US11246678B2|2019-06-28|2022-02-15|Cilag Gmbh International|Surgical stapling system having a frangible RFID tag|

---

US11259803B2|2019-06-28|2022-03-01|Cilag Gmbh International|Surgical stapling system having an information encryption protocol|

---

US11229437B2|2019-06-28|2022-01-25|Cilag Gmbh International|Method for authenticating the compatibility of a staple cartridge with a surgical instrument|

---

FI20195638A1|2019-07-15|2021-01-16|Ambrocio Oy|Fiber-reinforced composite device for the management and treatment of musculoskeletal and dental disorders with functionalized spatial arrangement of continuous fibers|

---

CN110755175B|2019-10-15|2021-08-27|东华大学|Integrally-formed gradient-degradable woven artificial ligament and preparation method thereof|

---

US11234698B2|2019-12-19|2022-02-01|Cilag Gmbh International|Stapling system comprising a clamp lockout and a firing lockout|

法律状态:
2006-06-01| FGA| Letters patent sealed or granted (standard patent)|

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2020-12-24| MK14| Patent ceased section 143(a) (annual fees not paid) or expired|

优先权:

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申请号 | 申请日 | 专利标题

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US10/610,362|US8226715B2|2003-06-30|2003-06-30|Scaffold for connective tissue repair|

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US10/610,362||2003-06-30||

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