biocompatible plaster

专利摘要:
Abstract "Method of Ligament or Tendon Repair" The present invention relates to a method of repairing a ligament and / or tendon in a patient comprising applying a patch to said ligament or tendon, wherein the plaster is flexible and biocompatible. and comprises a backing layer and a matrix layer.
公开号:BR112014023404B1
申请号:R112014023404-3
申请日:2013-03-22
公开日:2019-11-05
发明作者:Mathies Burkhard
申请人:Trb Chemedica Int S A；
IPC主号:

专利说明:

BACKGROUND [002] Ligaments are specialized connective soft tissues that connect different organs or tissues and connect bone to bone. In the last box, the ligaments provide stability to the joints because they are flexible enough to allow natural movement of the bones, but they are also strong and inextensible to prevent resistance to the forces applied. The tendons connect the muscle to the bone and are able to withstand tension. In addition, tendons passively modulate forces during locomotion, providing additional stability without active work. Its elastic properties allow tendons to store and recover energy with high efficiency. In tendons and ligaments, bundles of collagen fibers are embedded in a connection matrix produced from components of proteoglycans. These bundles of collagen fibers provide the load-carrying elements. In the tendons, the collagen fibers are arranged in an almost parallel formation, thus allowing to support high unidirectional loads. In ligaments, collagen fibers are arranged in a less parallel formation, thus allowing them to withstand predominant tensile strengths in one direction and minor stresses in others.
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2/60 directions.
[003] Every year, hundreds of thousands of people twist, lacerate or rupture ligaments, particularly in the knee, shoulder, and ankle, or suffer injuries to the tendons of the upper and lower extremities, particularly in the shoulder, knee, foot and ankle. A ligament frequently affected by this type of injury is the anterior cruciate ligament (ACL) of the knee. The ACL serves as a primary stabilizer of the anterior tibial translation and as a secondary stabilizer of the valgus-varus knee angle and is often susceptible to rupture or laceration resulting from the flexion-rotation-valgus force associated with sports injuries and traffic accidents. Ruptures or lacerations often cause: severe mobility limitations; pain and discomfort; and an inability to participate in sports and exercise. More than 200,000 people in the US alone lacerate or rupture their ACL each year, leading to costs of approximately $ 3 billion for ACL reconstructive surgery and intense rehabilitation.
[004] It is widely known that the ACL has few healing capabilities. Total surgical replacement and reconstruction are necessary when the ACL undergoes a significant tear or tear resulting in joint instability. The most common practice is to reconstruct a sprained ACL by replacing the sprained ligament with the patient's own tissue, also known as an autograft. Other options for substitute ligaments include donor tissues from another organism, also known as high grafts, as well as synthetic grafts. However, there are several problems associated with these
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3/60 treatments.
[005] Surgeons considered ligament constructions comprising collagen fibers, biodegradable polymers and their composites. Collagen frameworks for ACL reconstruction seeded with ACL fibroblasts and skin are described, for example, in international patent application WO 95/2550. U.S. patent application No. 20020123805 by Murray, et al. describes the use of a three-dimensional framework composition that includes an inductive core made of collagen or other material, to repair a ruptured anterior cruciate ligament (ACL) and a method for fixing the composition to the ruptured anterior cruciate ligament (see also patent application US No. 20040059416). WO 2007/087353 discloses three-dimensional frameworks to repair torn or torn ligaments. The framework can be made of protein, and can be pretreated with a repair material such as a hydrogel or collagen. U.S. patent application No. 20080031923 by Murray, et al. describes the preparation of a collagen gel and a collagen-MATRIGEL ™ gel that is applied to a lacerated ligament for ligament repair. These collagen matrices are predominantly single-component devices.
[006] Several multicomponent ligament prostheses have been described (see, for example, US Patent Nos. 3,797,047; 4,187,558; 4,483,023. 4,610,688 and 4,792,336). US patent No. 4,792,336 discloses a device with an absorbable component comprising a glycolic or lactic acid ester bond and the remainder of the device comprising a non-absorbable component. 0 device
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4/60 includes a plurality of fibers comprising the absorbable component, which can be used as a flat tape to repair a ligament or tendon. The required tensile strength is achieved by increasing the final denier of the tape. US patent No. 5,061,283 discloses a two-component device comprising polyethylene terephthalate and a polyester / polyether block copolymer for use in ligament repair. US patent No. 5,263,984 describes a prosthetic ligament that is a composite of two densities of bioresorbable filaments. However, there is still a need in the art for a method for ligament and tendon repair that increases the internal growth of the cell and the metaplastic transformation of the graft tissue to obtain a strong functional neo-ligament / neo-tendon.
SUMMARY OF THE INVENTION [007] The present invention provides a method for repair, regeneration or reconstruction of a ligament or tendon in ligament / tendon injury, for example, articular ligament injury that comprises implanting in the area of the damaged ligament / tendon site an biocompatible repair plaster, which supports the internal growth of cells and the formation of new tissue.
[008] The present invention relates to a method for repairing a ligament or tendon in a patient comprising the step of applying a patch to said ligament or tendon, the patch being flexible, and biocompatible and comprising a support layer comprising collagen, and a matrix layer comprising collagen and hyaluronic acid.
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5/60 [009] In several embodiments of this method, the backing layer is a layer of collagen leaf.
[010] In certain modalities of this method, the layer of
support comprises porcine, bovine or equine pericardium membrane or porcine divided skin.
[011] In some embodiments of this method, the support layer is a porous cell.
[012] In various modalities of this method, the support layer comprises a layer of dry porcine split skin (Xenoderma).
[013] In some modalities of this method, the layer of matrix is a porous collagenous layer. [014] In certain modalities of this method, the layer of
matrix comprises a collagen fiber matrix.
[015] In certain embodiments of this method, collagen in the matrix layer comprises collagen of porcine, equine, bovine or vegetable origin.
[016] In some modalities of this method, acid hyaluronic of the matrix layer comprises acid
natural, non-human hyaluronic.
[017] In various modalities of the method, acid hyaluronic natural matrix layer comprises acid hyaluronic natural and non-human from a source of
bacterial fermentation.
[018] In certain modalities of the method, the matrix
comprises hyaluronic acid in the form of fibers, powder, gel
or suspension of cream. [019] In additional modalities of the method, the layer of matrix is a intercalated porous collagenous composite block
with collagen fibers and dispersed natural hyaluronic acid
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6/60 in the empty spaces of collagen fibers.
[020] In some embodiments of the method, the matrix layer additionally comprises one or more compounds selected from analgesics, anti-inflammatory agents, antibiotics, and agents that promote ligament or tendon regeneration.
[021] In certain modalities of the method, agents that promote ligament or tendon regeneration are selected from the group consisting of growth factors, diacerein, reign, chitosan and its derivatives, platelet-rich plasma (PRP), and polylactic acid. Growth factors can be selected from the group consisting of, but not limited to, fibroblast growth factor (FGF), transforming growth factor (TGF-B1), basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF), blood, bone morphogenic proteins (BMPs), osteoinductive factor (IFO), fibronectin (FN), endothelial cell growth factor (ECGF), cement fixation extracts (CAE), ketanserin, human growth hormone (HGH), animal growth hormones, epidermal growth factor (EGF), human alpha thrombin, insulin-like growth factor (IGF-I), platelet-derived growth factors (PDGF, PDGF-AB) , periodontal ligament chemotactic factor (PDLGF), and somatotropin.
[022] In another embodiment, the agents include living cells, for example, fibroblasts and / or stem cells. When stem cells are used, in certain embodiments, human embryonic stem cells are excluded.
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7/69 [023] In additional embodiments of the method, the plaster additionally comprises a third layer, which is arranged on the matrix layer so that the matrix layer is disposed between the support layer and the third layer.
[024] In some modalities of method, the third layer is an collagen leaf layer.[025] In certain modalities of method, the third
layer comprises porcine, bovine, or equine pericardium membrane or porcine divided skin.
[026] In additional methods of the method, the third layer is porous to cells.
[027] In certain modalities of the method, the third layer comprises a layer of dry divided swine skin (Xenoderma).
[028] In some methods of the method, the plaster has a thickness of between 0.5 to 2 mm.
[029] In additional modalities of the method, the ligament or tendon is selected from the group of ligaments connected to the head, neck, back, chest, pelvis, in the upper and lower extremities, for example, shoulder, elbow, wrist, hand, hip, knee, foot, and ankle, and the group of
tendons in upper extremities and lower, in particular, shoulder, elbow, hands, hips, knee, feet, and ankle. [030] In certain method modalities, the ligament is selected of group consisting of in ligament
cricothyroid, periodontal ligament, suspensory ligament of the lens, suspensory ligament of the breast, anterior sacroiliac ligament, posterior sacroiliac ligament,
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8/60 sacrotuberous ligament, sacrospinous ligament, inferior pubic ligament, superior pubic ligament, suspensory ligament of the penis, palmar radiocarpal ligament, dorsal radiocarpal ligament, ulnar collateral ligament, radial collateral ligament, acromioclavicular ligament, coraco-clavicular ligament, cruciate ligament , anterior cruciate ligament (ACL), lateral collateral ligament (LCL), posterior cruciate ligament (PCL), medial collateral ligament (LCM), and patellar ligament.
[031] In several modalities of the method, the tendon is selected from the group of tendons that consists of, but is not limited to, tendons connected to the lower and upper extremities, tendons in the thoracic and abdominal area, back, comprising head and neck, tendons in the hip and pelvic area, knee, foot, and ankle, and quadriceps tendon, patellar tendon, anterior and posterior tibial tendons, peroneal tendons, Achilles tendon, extensor tendons, flexors, abductors and adductors of the foot and fingers, tendons on the shoulder , elbow, and hand, rotator cuff tendons, subscapular tendon, deltoid and pectoral tendons, biceps brachial tendon, triceps brachial tendon, extensor, flexor, and abductor and adductor tendons of the hand and fingers. They are also comprised of any additional ligaments and tendons.
[032] In some modalities of the method, the patient suffers from a disorder that affects a ligament or tendon, comprising inflammation, autoimmune disease, infection, stress, stretching, rupture, torsion, avulsion, overextension, or laceration of the ligament or tendon.
BRIEF DESCRIPTION OF THE DRAWINGS [033] Figure 1 shows a cross-sectional view
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9/60 of a flexible and sterilizable laminated ligament or tendon repair patch 10 comprising two layers, a backing layer 22 and a matrix layer 30, forming a laminate 12 for the method of the present invention, detailing the composition of the matrix of the plaster, in which collagen and hyaluronic acid are arranged as fibers and the support layer is porous (Figure 1 A) or non-porous (Figure 1B).
[034] Figure 2 shows a cross-sectional side view of certain modalities of the sterilizable flexible ligament repair plaster or tendon comprising two or three layers for the method of the present invention, in 2A detailing the composition of the plaster matrix, in that collagen and hyaluronic acid are arranged as fibers, in 2B detailing the composition of the internal plaster matrix, where collagen is arranged as fibers and hyaluronic acid is arranged as a creamy suspension or as a viscoelastic solution, in 2C showing a support and a third layer, both having a mechanical stabilizing element in each layer, in 2D showing a modality that has a support layer with a mechanical stabilizing element, and in 2E showing a modality in which the support layer has mechanical stabilizing elements complexes in it.
[035] Figure 3 shows a side cross-sectional view of a flexible and sterilizable laminate tendon or patch repair patch modality comprising a support, a matrix and a third layer for the method of the present invention. Layer 22 is a porous support layer, where layer 16 is optionally occlusive or porous. The array configuration
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10/60 looks like the one shown in figure 2E.
[036] Figure 4 shows a possible procedure for applying the plaster of the present invention (layer A) to a graft, in which the plaster is attached to the graft using an autologous growth factor-enhanced glue injected between the graft and the plaster and circular wires. If the plaster consists of a support layer and a matrix, it can be applied with the matrix or support layer facing the lesion site, where in some modalities, it is preferable if the matrix layer is facing the site of the lesion. lesion. In additional embodiments, if the plaster comprises a support, matrix, and a third layer, the plaster can be applied with the support or third layer facing the lesion site. Exemplary plasters are detailed in Figures IA, IB, 2A-2E and 3.
[037] Figure 5 shows an additional schematic drawing of a ligament or tendon graft without bone fixations. The patch (layer A) of the present invention, for example, a patch as detailed in Figure ΙΑ, 1B, 2A-2E and 3, is cut to a length and width approximately corresponding to the size of the graft. The patch is attached to the graft using an autologous growth factor-enhanced glue injected between the graft and the patch and circular wires.
[038] Figure 6 shows progenitor cells (60) that migrate from the fibrin-blood clot (59) to the damaged tendon / ligament (61) and to the repair patch matrix (12) differentiating into fibroblasts (62) . Figure 6a: Side view of the repair patch
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11/60 tendon / ligament; Figure 6b: cross section of the tendon / ligament repair process.
DETAILED DESCRIPTION [039] One of the problems faced in the field of ligament and tendon repair is how to promote the regeneration of ligament or tendon tissue at the site of the ligament or tendon injury.
[040] The term ligament or tendon injury, As used here, refers to a chronic or acute condition that affects the ligament or tendon. Examples of ligament or tendon injuries are inflammation, autoimmune disease, infection, stress, stretching, rupture, torsion, avulsion, overextension, or laceration of the ligament or tendon.
[041] It is an object of the present invention to provide a method for repairing the ligament or tendon that leads to the restoration of a functional anatomical ligament or tendon tissue.
[042] The term repair of a ligament or tendon for use in the present invention means that injury to the ligament or tendon, the chronic or acute condition affecting the ligament or tendon, is healed or at least relieved so that the function of the ligament or tendon is at least partially restored or completely restored.
[043] A disadvantage of absorbable prostheses known based only on synthetic and non-collagenous polymers is that the prostheses cannot exhibit the beneficial wound-healing properties of biopolymers, such as collagen. It is well known that injury healing cells, such as fibroblasts, have a special affinity for collagen and certain other biopolymers. This property is
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12/60 called collagen chemotactic effect.
[044] The invention is based on the inventor's surprising finding that a flexible and biocompatible patch comprising a support layer comprising collagen and a matrix layer comprising collagen and hyaluronic acid can be advantageously used in the repair of
ligaments and tendons and can - together with blood subchondral and your MSC's or cell culture fibroblasts added and Glue fibrin - to present an biofactory intensifying tightly O process in repair of ligament or the transformation gives structure of graft of
ligament implanted in a neo-ligament. The same applies to the use of the plaster for tendon repair.
[045] Thus, the present invention relates to methods for repairing a ligament or tendon in an individual, such as a human patient, comprising applying such a patch to a ligament or tendon of said individual.
[046] Consequently, in certain embodiments, the present invention relates to a method for repairing a ligament in an individual, comprising applying such a patch to a ligament of said individual.
[047] Furthermore, in various embodiments, the present invention relates to a method for repairing a tendon in an individual, comprising applying this patch to a tendon of said individual.
[048] The individual may be a human patient.
[049] The claimed method is advantageous, as it promotes faster regeneration of injured ligaments and tendons or ligament and tendon grafts, and therefore provides benefits due to recovery
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13/60 faster and more anatomically functional patients.
[050] In addition, the claimed method is advantageous since the ligament or tendon repair method does not require cell culture like the prior art methods. However, in some modalities the method may include the use of a repair patch that comprises cultured cells to further enhance the repair of the ligament or tendon.
[051] In certain modalities, the method described here does not propagate the formation of fibrous tissue at the injury site.
[052] The present invention, therefore, is related to methods for the repair of a ligament or tendon in a patient, comprising the step of applying a patch to said ligament or tendon, in which the patch is flexible, and biocompatible and comprises a support layer comprising collagen, and a matrix layer comprising collagen and hyaluronic acid.
[053] The patch is biologically acceptable, compatible and easy to use. It has a relatively fast curing time and has the necessary adhesive and cohesive properties. It is non-toxic and non-rigid. In addition, it does not interfere with the healing process or the formation of new ligament or tendon tissue, and does not promote the formation of other interference or undesirable tissues.
[054] Although this invention has been described for use in humans, in certain embodiments, the method of the present invention described herein can be applied to animals, including, but not limited to, mammals and birds. In several modalities, the ligament repair method or
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14/60 tendon is applied to mammals, such as dog, cat, horse, cow, sheep, pig, monkey, simian, chimpanzee, human and other mammals in which one may wish to repair an injured ligament or tendon. However, this list is not exhaustive, and you can easily use this repair patch on any animal.
[055] The term treating, treating, repairing, repairing, curing or curing a condition described herein refers to executing a protocol, which may include administering one or more drugs to an individual (human or another) and / or performing surgery ( minimally invasive or otherwise) in a patient, in an effort to alleviate the signs or symptoms of the conditions described herein, for example, the cutting of or other type of injury to a ligament or tendon. The terms also include the prevention of this condition, for example, by preventing recurrence. Recurrence can happen when a severed or injured ligament or tendon does not heal properly and leaves the joint unstable and painful. In addition, prevention may include inhibiting the formation of scar tissue and / or adhesions that sometimes occur to a ligament during the healing of another type of injury. In addition, treating or treating does not require complete relief of signs or symptoms and does not require a cure.
[056] In certain embodiments, the repair plaster is produced from layers comprising natural polymers and / or synthetic polymers. In various embodiments, the collagen in the backing layer and / or matrix layer comprises collagen of animal or vegetable origin.
[057] In certain embodiments, collagen from the
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Support and / or matrix layer can be obtained from animals, preferably mammals, such as dogs, cats, horses, cows, sheep, pigs, monkeys, apes, chimpanzees, or humans. In certain embodiments, an autologous repair patch is employed, in which the collagen is prepared from the individual who is treated with the repair patch to repair the ligament or tendon. Among these modalities, collagen from a human patient can be isolated to prepare the plaster that is subsequently implanted in the patient for repair of the ligament or tendon.
[058] Collagen sources are collagenous tissues, which in mammals, include (animal) skin, tendon, intestine, fascia, pericardium, and dura mater. One possibility of obtaining collagen is the use of the submucosal layer of the small intestine. The collagen layer can be prepared from dentin and cortical bone, for example, from porcine or bovine dentin and cortical bone.
[059] For example, collagen can be type I, II, III, IV, V, IX or X. Preferably, collagen is type I.
[060] Type I collagen is the predominant component of the extracellular matrix for the human anterior cruciate ligament and provides an example of choice for the manufacture of a biomanipulated framework. Collagen occurs predominantly in a fibrous form, allowing the design of materials with very different mechanical properties by changing the volume fraction, fiber orientation, and degree of collagen crosslinking. The biological properties of the cell infiltration rate and the degradation of the framework can also be altered by
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16/60 variation in pore size, degree of crosslinking, and the use of additional compounds, such as glycosaminoglycans, growth factors, and cytokines. In certain embodiments, the collagen-based layers shown here are manufactured from the patient's own skin, thereby minimizing the antigenicity of the implant.
[061] Cytokines are small cell signaling protein molecules that are secreted by several cells. Cytokines can be proteins, peptides, or glycoproteins. Based on their presumed function, secretion cell, or target for action, cytokines have been classified as lymphokines, interleukins, and chemokines. The group of cytokines includes, but is not limited to IL-2, IL-4, interferon gamma (IFN-γ), TGF-β, 1L-10, IL-13, erythropoietin (EPO), thrombopoietin (TPO), IL -17, and IL-18.
[062] In several embodiments, the backing layer is a layer of collagen leaf.
[063] In certain embodiments, the backing layer is preferably biocompatible, biodegradable, hydrophilic, non-reactive and / or is capable of having or has a defined structure.
[064] In certain embodiments, the support layer of collagen leaf may be porous or non-porous.
[065] Porous in the sense of the present invention means that the layer is permeable to cells and thus comprises holes through which cells can migrate. In certain embodiments, the support layer has pores with a diameter of 1 pm to 2 mm.
[066] On the other hand, non-porous layers do not comprise pores through which cells can migrate. In certain embodiments, the non-porous layers
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17/60 comprise pores through which molecules, but not cells, can migrate. The molecules that can penetrate the layer can be just small molecules, like water or nutrients, like glucose, or, alternatively, they can also be larger molecules, like proteins. In other embodiments, the non-porous layers are completely impermeable. In certain embodiments, the collagen leaf support layer is cell-porous.
[067] In addition, in various embodiments, the backing layer is coated or impregnated with an agent or agents to improve ligament or tendon repair such as hyaluronic acid, angiogenic factors, growth factors, anti-inflammatory compounds, cytokines, and / or collagenase inhibitors. These agents can immediately spread to the body directly to the repair site and / or be released over time or remain resident in the support layer. For the latter effect, agents can be formulated into controlled release formulations, such as prolonged release formulations or delayed release formulations.
[068] In various modalities, the support layer comprises pericardial membrane or divided skin.
[069] The pericardium membrane can be selected from the group that includes, but is not limited to, dog, cat, horse, cow, pig, monkey, simian, chimpanzee, sheep or human pericardium membrane.
[070] Split skin can be selected from the group that includes, but is not limited to, split dog, cat, horse, cow, pig, monkey, ape, chimpanzee, sheep or human skin.
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18/60 [071] In several modalities, the support layer comprises porcine pericardium membrane or divided porcine skin. In some embodiments, the backing layer comprises dry divided porcine skin.
[072] The pores in the collagenous support layer may be of natural origin or may be the result of a process performed after the preparation of the collagen layer. For example, pores can be introduced into the support layer by engraving, punching, mold cutting and / or stamping.
[073] In one embodiment, the support layer comprises a pericardium membrane, which is originally non-porous or essentially without pores, and which is subjected to a process to introduce pores into the membrane. This process leads to the supply of a porous collagenous layer to cells made of pericardium membrane. For example, pores can be introduced into the pericardium membrane by engraving, puncture, die cutting and / or stamping. In certain embodiments, the backing layer comprises porous pericardial cell membrane that is selected from the group that includes, but is not limited to, the porous pericardial membrane of dog, cat, horse, cow, pig, monkey, simian, chimpanzee cells, sheep or human. In a certain embodiment, the support layer comprises porous cell porous pericardium membrane.
[074] In several modalities, the support layer comprises a layer of divided dry skin, in which the divided skin can be selected from the origin of dog, cat, horse, cow, pig, monkey, simian, chimpanzee, sheep or human. In one embodiment, the
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19/60 support comprises a layer of split dry swine skin (Xenoderma).
[075] Thus, as shown in figures IA and 1B, the repair patch used in the present invention can be an implantable ligament or tendon repair patch 10 comprising two layers, which is biocompatible and physiologically absorbable, and which works in situ to promote the regeneration of ligament or tendon tissue in injury to the ligament or tendon. The present ligament or tendon repair patch 10 is a flexible laminate 12 that can be implanted in an injury site and can act to promote tissue regeneration.
ligament or tendon. 0 plaster objective of repair of ligament or tendon 10 is to stimulate repair in fabric in ligament or tendon in situ, for example, after application
arthroscopic or open surgical repair of the ligament or tendon repair patch 10 in patients with ligament and / or tendon injuries. The patch may consist of a support layer (porous in AI, non-porous in 1B) and a matrix layer 30 comprising collagen fibers 36, hyaluronic acid fibers 40, Diacerein 46a, and Reina 46b.
[076] In certain modalities, the ligament or tendon repair patch 10 is biodegradable through the interaction of its constituents with collagenase and other proteases and will be reabsorbed and disappear over time. Under these circumstances, laminate 12 of the ligament or tendon repair patch 10 is constructed entirely of materials that are both biocompatible and physiologically absorbable, so that the ligament or tendon repair patch can be implanted within.
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20/60 of a patient and disappear from the implantation site over time.
[077] In general, a matrix layer can be produced from natural or synthetic material. Synthetic matrices are produced predominantly from polymeric materials. Synthetic matrices offer the advantage of a range of chemical compositions and carefully defined structural arrangements. Some synthetic matrices are not degradable. Although non-degradable matrices can assist in repair, non-degradable matrices are not replaced by remodeling and therefore cannot often be used to completely regenerate ligaments or tendons. It is also undesirable to leave foreign materials permanently in a joint due to the problems associated with the generation of wear particles, so degradable materials are preferred. Degradable synthetic matrices can be manipulated to control the rate of degradation.
[078] In certain embodiments, the matrix layer comprises collagen and hyaluronic acid and is prepared so that it is preferably compressible and / or resilient and has some resistance to degradation, for example, by synovial fluid and catabolic enzymes. inflammatory process. Synovial fluid as part of normal joint activity naturally prevents clot formation.
[079] A matrix layer can be a solid material so that its shape is maintained, or a semi-solid material capable of changing its shape and / or size. An
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21/60 matrix layer can be produced as expandable material that allows it to contract or expand as needed. In certain embodiments, the matrix layer is able to absorb plasma, blood, other body fluids, cells, proteins, polymers, liquid, hydrogel, or other material with which the matrix layer comes into contact or that is added to the matrix.
[080] In additional embodiments, the matrix layer is a porous collagenous layer. In certain embodiments, the pores of the collagenous matrix layer are porous to cells.
[081] In certain embodiments, the collagenous matrix layer is produced from collagen fibers or highly cross-linked collagen.
[082] In certain embodiments, the matrix layer comprises a collagen fiber matrix.
[083] The collagen in the matrix layer can be selected from animal or plant origin.
[084] In certain embodiments, the collagen in the matrix is selected from the group that includes, but is not limited to, collagen of dog, cat, horse, cow, sheep, pig, monkey, simian, chimpanzee, sheep, human or vegetable origin. .
[085] In various modalities, the collagen in the matrix layer comprises collagen of porcine, equine, bovine or vegetable origin.
[086] In certain embodiments, the collagenous matrix layer comprises a biologically acceptable collagenous network of sol-gel, gel, fiber matrix, sponge, foamed collagen, framework, beehive, hydrogel, or polymer.
[087] In several modalities, the matrix is a solution
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22/60 simple sol-gel, a colloidal suspension that, under certain conditions, changes from a liquid material (sol) to a solid (gel). The sol is a suspension of aqueous collagen which is passed, through heat treatment, to a gel.
[088] In several modalities, the matrix layer comprises collagen that can be prepared from type I, II, III, IV, V, VI, VII, VIII, IX, and / or Type X collagen. In certain modalities, the matrix layer is produced from type I collagen, type II collagen, type IV collagen, collagen contracted with cells containing proteoglycans, glycosaminoglycans or glycoproteins, and / or gelatin. In several embodiments, the matrix layer additionally comprises agarose, polymers of aromatic organic acids, fibronectin, laminin, bioactive growth factors, anti-inflammatory compounds, cytokines, elastin, fibrin, natural and / or synthetic polymeric fibers produced from of polyacids such as polylactic, polyglycolic or polyamino acids, polycaprolaciones, polyamino acids, polypeptide gel, copolymers thereof and combinations thereof. In certain embodiments, the matrix comprises a gel solution matrix which can be a thermo-reversible polymeric gelation hydrogel.
[089] In several embodiments, the matrix layer is coated with natural or non-natural polymer (s). The coating comprises a gel, specifically, a hydrogel, selected from the group consisting of sodium alginate, hyaluronic acid, cross-linked hyaluronic acid, cross-linked calcium alginate and a mixture of calcium alginate and cross-linked hyaluronic acid.
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23/60 [090] Hyaluronic acid, also called hyaluronan or hyaluronate, is a glycosaminoglycan. It is a naturally occurring biopolymer that has biological functions from bacteria to higher animals including humans. In animals, it is one of the chief components of the extracellular matrix. It contributes significantly to cell proliferation and migration, and may also be involved in the progression of some malignant tumors. Hyaluronan is found naturally in many tissues of the body such as skin, cartilage and the vitreous humor. It is therefore well suited for biomedical applications that target these tissues. The hyaluronan that can be used in the present invention can be of any molecular weight, for example, from about 100 kDa to several million Da, preferably between 500 kDa and 6000 kDa. In various embodiments, the matrix layer hyaluronic acid comprises natural hyaluronic acid. In certain embodiments, the hyaluronic acid in the matrix is selected from the group that includes, but is not limited to, dog, cat, horse, cow, pig, monkey, ape, chimpanzee, sheep, human, vegetable or microbial origin hyaluronic acid.
[091] In several embodiments, the matrix layer hyaluronic acid comprises natural non-human hyaluronic acid.
[092] In certain embodiments, the natural hyaluronic acid in the matrix layer comprises natural, non-human hyaluronic acid from a source of bacterial fermentation.
[093] The bacterial production of hyaluronic acid (HA) involving a strain of Streptococcus zoocpidemicus was first described in 1989, generating the first
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24/60 marketing of fermented HA.
[094] The ultra-pure sodium hyaluronate sold as HyaCare by Novozymes is produced by fermenting a new, non-pathogenic strain, Bacillus subtilis, from which products are generally considered safe (Generally Regarded As Safe (GRAS) ).
[095] In certain embodiments, hyaluronic acid may be from a source of Streptococcus zooepidemicus or Bacillus subtilis.
[096] In several modalities, the matrix comprises hyaluronic acid in the form of fibers, powder, solution, gel or creamy suspension.
[097] In certain embodiments, the collagen matrix is immersed in a solution or gel of hyaluronic acid. Thus, the matrix is dispersed by hyaluronic acid.
[098] In several modalities, the matrix layer comprises collagen copolymerized with hyaluronic acid.
[099] The repair patch employed in the method of the present invention can comprise a certain range of the weight ratio between collagen and HA, which is advantageous in the repair of the ligament or tendon. In certain embodiments, the weight ratio range between collagen and HA is about 0.1: 99.9 to about 50:50 if HA has a molecular weight between 0.5 and 6 million Daltons.
[0100] In certain embodiments, the matrix layer is a cell-porous collagenous composite block interspersed with collagen fibers and natural hyaluronic acid dispersed in the voids of collagen fibers.
[0101] In some embodiments, the matrix layer comprises collagen, hyaluronic acid and polylactic acid,
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25/60 for example, poly L-lactic acid. For example, the matrix layer may be a cell-porous collagenous composite block interspersed with collagen fibers and natural hyaluronic acid and polylactic acid, for example, poly L-lactic acid, dispersed in the voids of collagen fibers.
[0102] The matrix layer may additionally comprise protein, lyophilized material, or any other suitable material. In this context, a protein can be synthetic, bioabsorbable or a naturally occurring protein. In various embodiments, the matrix layer includes proteins selected from the group of extracellular matrix proteins. The group of extracellular matrix proteins includes, but is not limited to, fibrin, elastin, fibronectin, and laminin.
[0103] Lyophilized material is a material that is capable of swelling when a liquid, gel or other fluid is added or comes into contact with it.
[0104] In several embodiments, the matrix layer additionally comprises glycosaminoglycan (GAG), hyaluronan compositions, and various synthetic compositions.
[0105] Collagen-glycosaminoglycan (CG) copolymers have been used successfully in the regeneration of the dermis and peripheral nerve. Natural porous polymers, manufactured as sponge-like and fibrous frameworks, have been investigated as implants to facilitate the regeneration of selected musculoskeletal tissues including ligaments and tendons. A framework, like a sponge framework, can also be made of tendon
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26/60 (xenograft, allograft, autograft) or ligament or skin or other connective tissue that could be in the original or processed state to facilitate the internal growth of the cell or other biological characteristics.
[0106] In several embodiments, the matrix layer comprises collagen-glycosaminoglycan (CG) copolymers.
[0107] Glycosaminoglycans (GAGs) or mucopolysaccharides are polysaccharides made of residues of glycosidically linked hexoamines and alternated in a more or less regular manner with portions of hexuronic acid or hexose. GAGs are of animal origin and have a tissue-specific distribution (see, for example, Dodgson et al., In Carbohydrate Metabolism and its Disorders, Dickens et al., Eds., Vol. 1, Academic Press (1968)). The reaction with GAGs also provides collagen with another valuable property, that is, inability to trigger an immune reaction (reaction to foreign bodies) from an animal host.
[0108] In certain embodiments, the matrix comprises GAGs that include, but are not limited to those containing sulfate groups, such as hyaluronic acid, heparin, heparin sulfate, chondroitin 6-sulfate, chondroitin 4-sulfate, dermatan sulfate, and keratin sulfate .
[0109] Other GAGs may also be suitable to form the matrix described herein and those skilled in the art will know or be able to verify other suitable GAGs using at most routine experimentation. For a more detailed description of mucopolysaccharides, see Aspinall, Polysaccharides, Pergamon Press, Oxford (1970).
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27/60 [0110] In certain embodiments, the matrix comprises at least one or more collagen-GAG copolymers, which include, but are not limited to hyaluronic acid, heparin, heparin sulfate, chondroitin 6-sulfate, chondroitin 4-sulfate , dermatan sulfate, and keratin sulfate.
[0111] In certain aspects of the invention, the matrix layer comprises a sponge or sponge-like structure.
[0112] The material that establishes the sponge framework can be hydrophilic. A sponge framework is capable of compression and expansion, as desired. For example, a sponge frame can be compacted before or during implantation at a repair site. A compacted sponge frame allows the sponge frame to expand within the repair site. A sponge can be lyophilized and / or compacted when placed at the repair site and expanded once in place. Expansion of a sponge scaffold can occur after contact with blood or other fluid at the repair site or added to the repair site. A sponge frame can be porous. A sponge framework can be saturated or coated with a liquid, gel or hydrogel repair material prior to implantation at a repair site. Coating or saturation of a sponge framework can facilitate implantation in a relatively undefined defect area as well as helping to fill a particularly large defect area. In a preferred embodiment, a sponge frame is treated with a hydrogel. Examples of frameworks and repair materials useful according to the invention are found in US Patent No. 6,964,685 and in
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28/60 US patent applications Nos. 2004/0059416 and 2005/0261736, the complete contents of which are incorporated herein by reference. All matrix coatings revealed in the
gifts documents of the order are here explicitly revealed as suitable coatings for matr. izes in framework in sponge. [0113] In various modalities, collagen establishes one framework in sponge. [0114] In various modalities, the mat] riz
it additionally comprises one or more of the following polymers: natural or synthetic polymers, resorbable or non-resorbable polymers.
[0115] Examples of resorbable polymers include, but are not limited to, poly (alpha hydroxy acids), polylactide-glycolide (PLGA), polylactide (PLA), polyglycolide (PG), polyethylene glycol (PEG) conjugates of poly (alphahydroxy) acids), polyesters, polyaspirins, polyphosphazenes, elastin, silk, cellulose starch, chitosans, gelatin, alginates, cyclodextrin, polydextrose, dextrans, vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, polyethylene glycol copolymer terephthalate and polybutylene terephthalate (PEGT-PBT) (polyactive), methacrylates, poly (N-isopropyl acrylamide), polyethylene oxides (also known as polyoxyethylene or PEO), polypropylene oxide (also known as polyoxypropylene or PPO), poly (aspartic acid) (PAA), PEO-PPO-PEO (Pluronics (R), BASF), ΡΕΟ-ΡΡΟ-ΡΑΆ copolymers, PLGA-PEO-PLGA, polyphosphesters, polyanhydrides, polyester anhydrides, polyamino acids, polyurethane esters , polyphosphazines,
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29/60 polycaprolactones, polytrimethylene carbonates, polydioxanones, polyamide esters, polyketals, polyacetals, glycosaminoglycans, chondroitin sulfate, hyaluronic acid esters, polyethylene-vinyl acetates, silicones, polyurethanes, polypropylene fumarates, aride carbonates, pellets pelidesaminotiresina, pelidesaminotiresina ester carbonates, polyidesaminotyrosine ester arylates, polyortocarbonates, polycarbonates, or copolymers or physical mixtures thereof or combinations thereof.
[0116] The term chitosans and chitosan and their derivatives is related to the group of compounds including, but not limited to, chitosan, chitosan hydrochloride, carboxy methyl chitosan, chitosan lactate, chitosan acetate, chitosan glutamate, chitosan succinate, N- (2-hydroxy) propyl-3-trimethyl ammonium chitosan chloride, N-trimethylene chitosan chloride, and pharmaceutically acceptable salts thereof.
[0117] Non-resorbable polymers may include, but are not limited to, polyethylene, delrina, silicone, polyurethane, silicone and polyurethane copolymers, polyolefins such as polyisobutylene and polyisoprene, acrylamides such as polyacrylic acid and poly (acrylic acrylonitrile acid) ), neoprene, nitrile, acrylates such as polyacrylates, poly (2-hydroxyethyl methacrylate), methyl methacrylate, 2-hydroxyethyl methacrylate, and acrylate copolymers with N-vinyl pyrrolidone, N-vinyl lactams, aerilamide, polyurethanes and polyacrylates and polyacrylates and polyacrylates glycomanane, alkyl celluloses, hydroxyalkylmethyl
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30/60 celluloses, vulcanized rubber and combinations thereof. Examples of polyurethanes include thermoplastic polyurethanes, aliphatic polyurethanes, segmented polyurethanes, hydrophilic polyurethanes, polyether-urethane, polycarbonate-urethane and silicone-urethane polyether. The vulcanized rubber described herein can be produced, for example, by a vulcanization process using a copolymer produced as described, for example, in US Patent No. 5,245,098 to Summers et al. from 1hexene and 5-methyl-1,4-hexadiene.
[0118] Other suitable non-resorbable material includes, but is not limited to, lightly or highly cross-linked homopolymers and copolymers of hydrophilic monomers such as 2-hydroxyalkylacrylates and methacrylates, N-vinyl monomers, and ethylenically unsaturated acids and bases; polycyanoacrylate, block copolymers of poly (ethylene oxide) -polypropylene glycol, polygalacturonic acid, polyvinylpyrrolidone, poly (vinyl acetate), polyalkylene glycols, poly (ethylene oxide), sulfonated polymers, monomers or polymers of vinyl ether, alginates, vinyl ether polyvinyl amines, polyvinyl pyridine, and polyvinyl imidazole.
[0119] In certain embodiments, the above polymers are cross-linked with the collagen and / or hyaluronic acid in the matrix layer.
[0120] Those skilled in the art are well aware that depending on the amount of crosslinking within the bioresorbable polymers, the polymer's degradation time can be reduced, thus allowing control of the matrix degradation rate.
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31/60 [0121] In several embodiments, the matrix layer additionally comprises one or more compounds selected from analgesics, anti-inflammatory agents, antibiotics, and agents that promote ligament or tendon regeneration.
[0122] These compounds are, in the sense of the present invention, selected from the group that comprises, but is not limited to small molecules, proteins, RNA, DNA, PNA.
[0123] In this way, the matrix can incorporate therapeutic proteins including, but not limited to, hormones, cytokines, growth factors, anti-inflammatory compounds, coagulation factors, antiprotease proteins, for example, alpha-1-antitrypsin, angiogenic proteins, for example, vascular endothelial growth factor, fibroblast growth factors, antiangiogenic proteins, for example, endostatin, angiostatin, and other proteins that are present in the blood, bone morphogenic proteins (BMPs), osteoinductive factor (IFO), fibronectin (FN ), endothelial cell growth factor (ECGF), cement fixation extracts (CAE), ketanserin, human growth hormone (HGH), animal growth hormones, epidermal growth factor (EGF), human thrombin alpha, transformation growth (TGF-beta), insulin-like growth factor (IGF-I), platelet-derived growth factors (PDGF), fibroblast growth factors (FGF, bFGF, etc.), and periodontal ligament chemotactic factor (PDLGF), somatotropin, for therapeutic purposes, and
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32/60 extracellular matrix, including, but not limited to, fibrin, elastin, fibronectin, laminin.
[0124] Anti-inflammatory compounds are chemicals that reduce or prevent an inflammatory response at a given location. The group of anti-inflammatory compounds includes, but is not limited to Diacerein and Reina.
[0125] Diacerein 46a and Reina 46b (see figures 1 and 2) inhibit the production and activity of inflammatory cytokines such as interleukin-1 (IL-I), IL-6, nitric oxide (NO), necrosis factor tumor-alpha (TNF-α), ADAMTS (A Disintegrin And Metalloproteinase with Thrombospondin Motifs), free radicals and matrix metalloproteinases, all of which are involved in the inflammation and destruction of the ligament and tendon. Diacerein 46a and Reina 46b also stimulate the production of growth factors such as TGF-β, which in turn stimulates the expression of ligament and tendon components such as hyaluronic acid, proteoglycans, agrecans and collagenase II, all of which are components of ligament and tendon tissue. The growth hormone will also stimulate the growth of ligament and tendon tissue.
[0126] In certain embodiments, the matrix comprises small molecules selected from the group that includes, but is not limited to, aspirin, paracetamol, diclofenac, ibuprofen and water.
[0127] In certain modalities, agents that promote ligament or tendon regeneration are selected from the group consisting of growth factors, diacerein, reina, platelet-rich plasma (PRP), and polylactic acid. Thus, in some modalities, the layer
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33/60 matrix comprises or consists of collagen, hyaluronic acid, and chitosan or chitosans.
[0128] In various modalities, the amounts of Diacerein and / or Reina in the patch are in the range of about 300 ng to 5 mg. In certain embodiments, the amounts of Diacerein and / or Reina in the patch are in the range of about 300 ng to 75 pg. In some embodiments, the amounts of Diacerein and / or Reina in the matrix layer are in the selected range of the group consisting of 300 ng to 5 mg, 300 ng almg, 300nga750pg, 300nga500pg, 300nga250pg, 300 ng to 100 pg, 300 ng a 75 pg, 300 ng to 50 pg, 300 ng to 25 pg, 300 ng to 10 pg, 300 ng to 5 pg, 300 ng to 2.5 pg, and 300 ng to 1 pg.
[0129] Diacerein and / or Reina can be added to the matrix in the form of a powder, as a solution or as an HA gel or cream containing Diacerein and / or Reina.
[0130] Anionic polymers can also be useful to inhibit fibrosis, scarring, or adhesions. In certain embodiments, the matrix additionally comprises anionic polymers. The group of anionic polymers includes, but is not limited to, dextran sulfate, pentosan, chitosans.
[0131] The matrix layer may additionally comprise blood. The term blood includes whole blood, blood plasma, blood serum and isolated blood components, and can be of autologous or heterologous origin. In certain embodiments, the repair patch is first immersed in blood so that the matrix layer comprises blood and is then applied to the injured ligament or tendon. In alternative modalities, the repair patch is first applied to the ligament or tendon
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34/60 injured and then blood is added to the attached patch or received from the injured site so that the matrix layer comprises blood. In particular, the matrix layer of the repair patch may comprise blood serum, which is applied to the patch before or after application of the patch to the injured ligament or tendon.
[0132] Blood plasma in the sense of the present invention includes that part of the blood remaining after separation of cellular components from blood. This fraction corresponds to about 55% of the blood volume. The blood plasma comprises water, proteins, carbohydrates, electrolytes, fats and lipids. The group of blood plasma proteins comprises immunoglobulins, albumin, hormones and clotting factors. The group of coagulation factors comprises fibrinogen (factor I), fibrin (factor la), prothrombin (factor II), thrombin (factor Ha), thromboplastin (also called tissue factor, TF or factor III), proacelerin (factor V), Pro-convertin (factor VII), Anti-hemophilic globulin A (factor VIII), anti-hemophilic globulin B (also called factor IX or Christmas factor), Stuart-Prower factor (factor X), Background Plasma Thromboplasmin (also called PTA, factor XI or Rosenthal factor), Hageman factor (factor XII) and fibrin stabilizing factor (factor XIII). The group of coagulation factors comprises the inactive and activated variants of the coagulation factors. The person skilled in the art marks the clotting factors activated by the addition of an a, for example, Ia, Ila, Illa, Vila, Villa, IXa, Xa, Xla, Xlla, and Xllla.
[0133] The blood serum is the liquid fraction of the blood
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35/60 that remains after blood clotting and separation of cellular components from the blood. Essentially, the blood serum composition corresponds to the blood plasma composition minus the spent clotting factors.
[0134] In various modalities, the plaster comprises,
additionally, a third layer, which is willing
on the matrix layer so that the matrix layer
is arranged between the support layer and the third
layer.
[0135] In certain modalities, the third layer includes,
but is not limited to poly (alpha-hydroxy acids), polylactide-co-glycolide (PLGA), polylactide (PLA), polyglycolide 10 (PG), polyethylene glycol (PEG) poly (alpha-hydroxy acid) conjugates, poly-polyesters, polyaspirins, polyphosphazenes, collagen, elastin, silk, cellulose starch, chitosans, gelatin, alginates, fibronectin, laminin, elastin, fibrin or combinations thereof.
[0136] In various embodiments, the third layer comprises a layer of collagen leaf.
[0137] The collagen origin of the collagen leaf layer can be selected from the group that includes, but not
is limited to dog, cat, horse, cow, pig, monkey,
simian, chimpanzee, sheep or human.
[0138] In several modalities, the third layer
comprises pericardial membrane or skin divided by
example, dry divided swine skin.
[0139] The pericardium membrane can be selected dp
group that includes, but is not limited to, the pericardium membrane of dog, cat, horse, cow, pig, monkey,
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36/60 simian, chimpanzee, sheep or human.
[0140] The split skin can be selected from the group that includes, but is not limited to, the split skin of a dog, cat, horse, cow, pig, monkey, ape, chimpanzee, sheep or human.
[0141] In several modalities, the third layer comprises porcine, bovine, or equine pericardium membrane or divided porcine skin.
[0142] The third collagenous layer can be porous or non-porous to cells.
[0143] In some embodiments, the third collagenous layer is porous to cells.
[0144] If the third collagenous layer comprises pores, the pores in the third collagenous layer may be of natural origin or may be the result of a process carried out after the preparation of the collagen layer.
[0145] In one embodiment, the third layer comprises a pericardium membrane, which is essentially pore-free, and which is subjected to a process to introduce pores into the membrane. This process leads to the supply of a porous collagenous layer to cells made of pericardium membrane. For example, pores can be introduced into the pericardium membrane by engraving, puncture, die cutting and / or stamping. In certain embodiments, the third layer comprises porous pericardial cell membrane that is selected from the group that includes, but is not limited to, the porous pericardial membrane of dog, cat, horse, cow, pig, monkey, simian, chimpanzee, sheep cells or human. In a certain embodiment, the third layer comprises porous cell porous pericardium membrane.
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37/60 [0146] In several modalities, the third layer comprises a layer of divided dry skin, in which the divided skin can be selected from the origin of dog, cat, horse, cow, pig, monkey, simian, chimpanzee, sheep or human. In one embodiment, the third layer comprises a layer of dry porcine split skin (Xenoderma).
[0147] In certain embodiments, the support layer and the third layer are identical in that they are made of the same material. This means that, in various embodiments, the third layer is made of the same materials as those described above for the backing layer.
[0148] In various embodiments, the plaster comprises a support layer and a matrix layer. In several additional embodiments, the plaster comprises a backing layer, a matrix layer and a third layer.
[0149] In alternative modes, the plaster includes the support and matrix layers, where the support layer is made of pericardium membrane, and the membrane is non-porous. In a certain embodiment, the pericardial membrane is porcine pericardial membrane.
[0150] In alternative modalities, the plaster includes the support and matrix layers, in which the support layer is made of pericardium membrane, in which the membrane is porous to cells. In a certain embodiment, the pericardial membrane is porcine pericardial membrane.
[0151] In certain embodiments, the plaster comprises a support layer, a matrix layer, and a third layer, in which the support layer and the third layer are non-porous pericardial membranes. In a certain
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38/60 modality thereof, non-porous pericardial membranes are porous non-porous pericardial membranes.
[0152] In certain embodiments, the plaster comprises a support layer, a matrix layer, and a third layer, in which the support layer and the third layer are pericardial membranes porous to cells. In a certain embodiment, porous pericardial membranes to cells are porous pericardial membrane to cells.
[0153] In alternative modes, the plaster comprises a support layer, a matrix layer, and a third layer, where the support layer and the third layer are pericardial membranes, where the support layer or the third layer it is non-porous and the other layer is cell-porous. In a certain embodiment, pericardial membranes are porcine pericardial membranes. In certain modalities of the same, the plaster is applied in such a way that the non-porous layer faces the site of injury to the ligament or tendon, in which in other modalities, the plaster is applied to the site of injury so that the porous layer to cells face the injured area.
[0154] Under certain circumstances, it may still be advantageous to apply a plaster comprising a non-porous support and / or third layer to the injured ligament or tendon. Thus, growth factors secreted from cells residing below or near the injured site are trapped and concentrated locally leading to increased cell growth at the injured site and faster repair of the ligament or tendon. In addition, compounds and cells adverse to ligament or tendon repair are excluded from the injury site.
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39/60 [0155] Furthermore, plasters comprising a support layer and a matrix layer, in which the support layer is non-porous and the patch is applied to the injured ligament or tendon with the matrix facing the lesion, are advantageous , since growth factors supplied by autologous centrifuged serum fractions, PRP or subchondral blood clot will, together with subchondral, synovial or fat MSCs sown in the collagen support layer or matrix layer, improve the repair process in place ligament and / or tendon injury on the autologous surface, auto- or xenograft. In addition, exogenous compounds, for example, growth factors and anti-inflammatory compounds, which were added to the matrix before applying the plaster to the lesion, are released only towards the injured ligament or tendon. Thus, at the injured site, the concentration of exogenous compounds is increased compared to the conditions under which the compounds are allowed to diffuse in only one direction. This enhances the benefits of exogenous compounds.
[0156] If the plaster comprises a backing layer and a matrix layer, the plaster layers can be laminated together using heat, or chemicals, or other suitable lamination techniques. In certain embodiments, first a layer is formed and then the second on it. For example, first the matrix layer is formed and then the support layer is formed on it.
[0157] Alternatively, first the support layer is formed and then the matrix layer on top of the support layer.
[0158] If the plaster comprises a layer of
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40/60 support, a matrix layer and a third layer, the plaster layers can be laminated together using heat, or chemicals, or other suitable lamination techniques. In certain embodiments, first a layer is formed and then the second on it and the third layer is formed on the composite of the first and second layers. For example, first the matrix layer is formed and then the support layer is formed on top of the matrix layer. In a third step, the third layer is formed on the matrix layer, sandwiching the matrix layer with the support layer. Alternatively, first, the backing layer / third layer is formed, and then the matrix layer over the backing layer / third layer and then the third layer / backing layer over the matrix layer, on the opposite side of the support layer / third layer. In additional embodiments, the three layers are layered on top of each other and the plaster is laminated in a single step.
[0159] The implantable ligament or laminate tendon repair patch is a surgical device that is biocompatible. In certain embodiments, the plaster is physiologically absorbable. In several modalities, the plaster is intended to repair the ligament or tendon in situ.
[0160] In some modalities, the plaster is adapted in that it allows, in certain modalities, the migration of cells from the lesion site passing to the matrix layer. The matrix layer is a collagenous layer and can be a drain for the diffusion of autologous stem cells and other blood components at the injury site. The matrix layer
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41/60 may include chemical components that promote ligament and / or tendon repair in the presence of autologous stem cells of subchondral, synovial, fat, or hematopoietic origin. Thus, in some modalities, the plaster is positioned at the injury site with the matrix layer facing the injured site. Also optionally, the matrix layer can be occluded by the support layer and / or third layer, so that cells cannot pass through the matrix, but allowing other small compounds, such as water, gas and small molecules to pass through. Thus, the present invention provides a method of promoting tissue healing / growth in situ to repair injuries to ligaments or tendons.
[0161] In certain embodiments, the ligament or tendon repair plaster laminate 12 has a third layer, which is an optionally occlusive or porous layer 16, and a porous support layer 22 (see figures 2A to 2C and 3) . In another preferred embodiment, the ligament or tendon repair plaster laminate 12 includes only two layers, a support layer 22 and a matrix layer 30 (see figures 2D and 2E). In several modalities, the support layer aims to face the surface of the ligament or tendon at the injury site. In several modalities, the third layer aims to face a surface of the ligament or tendon at the site of the injury. In other embodiments, the matrix layer of a two-layer plaster faces the site of the ligament or tendon injury (see also figures 4 and 5). The third layer 16 and / or support layer 22 of a three-layer repair patch can
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42/60 be produced from leaf collagen (see Angele et al., US Patent No. 6,737,072, the content of which is incorporated herein by way of reference). An example of a satisfactory source available for collagen leaf commercialization is: XENODERM (tm), mbp GmbH, Germany. In certain embodiments, the matrix layer 30 provides a collagenous substrate in which mesenchymal stem cells or ligament or tendon stem cells are trapped, and a support medium for cell growth on which they will grow and differentiate in the presence of others natural components of the matrix layer 30.
[0162] In several embodiments, the matrix layer 30 is a porous collagenous composite block, interspersed with non-human collagen fibers 36 and fibers of natural hyaluronic acid 40. The natural HA can be supplied in matrix 30 in the form of fibers of natural HA 40 as shown in Figure 2A, or as HA powder 40a in a gel or cream suspension 42 dispersed in the voids of collagen fibers 36 as in Figure 2B.
[0163] In certain embodiments, matrix layer 30 (see figure 2B) also includes one or more tissue growth hormones and / or anti-inflammatory compounds 46. In certain embodiments, the anti-inflammatory compounds are Diacerein 46a and Reigns 46b. In the embodiment illustrated in Figure 2B, suspension 42 also contains Reina 46b and / or Diacerein 46a. In various embodiments, the matrix layer 30 further includes chitosan compositions and / or polylactic acid compositions.
[0164] The repair patch is configured, in various modalities of the method of the present invention, so that
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43/60 autologous mesenchymal stem cells 60 derived from a source external to the repair plaster 10 diffuse to the plaster 10 through the porous support layer 22 and to the matrix layer 30 where they are supported by the fibrous components 5 (fibers of collagen 36 and / or HA fibers 40a) of matrix 30 (for example, figures 2A-2E, 3, 6a and 6b). In various embodiments, the fibers of the matrix 40 & 40a can provide a means of support for stem cells to grow and differentiate into ligament or tendon cells. Exogenous factors 46, such as diacerein, negatively regulate inflammatory parameters (for example, cytokines: IL-1, TNF-alpha, and free radicals) that contribute to inflammation. In certain embodiments, one or more growth hormones are present in the matrix layer. These one or more growth hormones can stimulate the production of ligament and / or tendon tissue.
[0165] In various embodiments, the repair plaster may comprise a backing layer, matrix, and a third layer, wherein the backing layer comprises a perforated divided covering layer, for example, a porcine divided skin layer ( Xenoderma), and the third layer comprises an unperforated divided coating layer, for example, a porcine divided coating layer (Xenoderma). Alternatively, both the backing layer and the third layer comprise a perforated divided coating layer, for example, a porcine divided coating layer (Xenoderm). In certain embodiments, the backing layer and the third layer consist of a divided coating layer. In some embodiments, the matrix layer may comprise
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44/60 collagen, hyaluronic acid and polylactic acid, for example, poly L-lactic acid. For example, the matrix layer may be a cell-porous collagenous composite block interspersed with collagen fibers and natural hyaluronic acid and polylactic acid, for example, poly L-lactic acid, dispersed in the voids of collagen fibers. In some embodiments, the matrix layer may comprise additional compounds, as described here, for example, growth factors, chitosans, Reina, and Diacerein.
[0166] In general, the repair patch of the present invention intensifies tendon and ligament repair, strengthens and favors the integration of autologous ligament and tendon grafts. In certain embodiments, the matrix layer is used as a support structure to exogenously add, adhere, incorporate, include or seed cells, such as fibroblasts, tenocytes, their progenitors, mesenchymal cells, ligament or tendon cells, stem cells from different origins to the treatment site. These cells are added, according to the invention, to increase or provide stimulation to improve the repair process at the injured ligament or tendon site or at the ligament and / or tendon graft site. Suitable cells to be used in this invention are cells that are autologous or heterologous cells, such as allogeneic or xenogenic cells, cell lines and / or prokaryotic cells. Typically, cells added exogenously to the matrix layer or collagenous framework are obtained commercially or isolated from ligaments or tendons cultured in vitro using methods
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45/60 known in the art.
[0167] The method, in one embodiment, comprises the in vitro and ex vivo addition of progenitor cells, mature fibroblasts, ligament or tendon cells or other cells to the device of the invention upon adhesion, incorporation, inclusion or seeding of the cells in the collagenous framework matrix or support / third layer. The cultured cells are added to the matrix layer as they are or are adhered to the support layer and / or the third layer before, during or even after surgery. Exogenously added cells can induce production or produce proteins and matrix components compatible with neo-ligaments or neo-tendons or induce the migration of native cells from the uninjured ligament or tendon to the injury site.
[0168] In several modalities, the plaster has a
thickness of between 0.1 to 10 mm, 0.5 to 2 mm, 0.5 to 1 mm or 0.75 to 1.25 mm. [0169] If the plaster includes layers in Support and rolled matrix, the plaster can be applied to
injured ligament with the matrix layer facing the ligament. In an alternative way, the plaster can be applied to the injured ligament with the support layer facing the ligament. Along with this, the same ways of applying the plaster are presented for application to injured tendons.
[0170] If the plaster includes support layers, matrix and laminated third layer, the plaster can be applied to the injured ligament with the third layer facing the ligament. In an alternative mode, the
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46/60 plaster can be applied to the injured ligament with the support layer facing the ligament. Along with this, the same ways of applying the plaster are presented for application to injured tendons.
[0171] In certain embodiments, the plaster comprises a collagenous support layer porous to cells and a matrix layer and the plaster can be applied to the injured ligament with the support layer facing the ligament. In alternative embodiments, the patch includes a collagenous porous support layer to cells and a matrix layer, and the patch can be applied to the injured ligament with the matrix layer facing the ligament. In additional embodiments, the plaster comprises a third cell-porous collagenous layer, a cell-porous collagenous support layer and a matrix layer and the plaster can be applied to the injured ligament with the third layer or the support layer facing the ligament . In additional embodiments, the plaster comprises a third cell-porous collagenous layer, a non-porous collagenous support layer and a matrix layer and the plaster can be applied to the injured ligament with the third layer or the support layer facing the ligament. In additional embodiments, the plaster comprises a third non-porous collagenous layer, a non-porous collagenous support layer and a matrix layer and the plaster can be applied to the injured ligament with the third layer or the support layer facing the ligament. These ways of applying the patch are similarly suitable for applying to injured tendons.
Petition 870190088042, of 09/06/2019, p. 54/72
47/60 [0172] In certain embodiments, the support layer is coated with the glycosaminoglycans (GAGs) or mucopolysaccharides presented here. In some embodiments, the backing layer is coated with hyaluronic acid, as described here.
[0173] In additional modalities, if the plaster comprises a third layer, the third layer is coated with the glycosaminoglycans (GAGs) or mucopolysaccharides presented here. In several embodiments, the third layer is coated with hyaluronic acid, as described here.
[0174] In certain embodiments, the plaster is designed so that the plaster is completely bioabsorbable. Therefore, when implanted, the plaster degrades automatically over time. The person skilled in the art is well able to design the plaster so that it will degrade during healing of the ligament or tendon or after healing of the ligament or tendon is obtained.
[0175] In several modalities, the plaster is not biodegradable and must be explanted when the ligament or tendon is repaired.
[0176] The methods of the present invention are suitable for repairing ligament and / or tendon.
[0177] In several modalities, the ligament is selected from the group of ligaments, but is not limited to, connected to the lower and upper extremities, head and neck, for example, shoulder, elbow, wrist, hand, hip, knee, ankle and foot and back.
[0178] In certain modalities, the ligament is selected from the group that comprises, but is not limited to, the ligament
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48/60 cricothyroid, periodontal ligament, suspensory lens ligament, suspensory ligament of the breast, anterior sacroiliac ligament, posterior sacroiliac ligament, sacrotuberous ligament, sacro-spinous ligament, inferior pubic ligament, superior pubic ligament, suspensory ligament, palmar radiocarpal ligament , dorsal radiocarpal ligament, ulnar collateral ligament, radial collateral ligament, cruciate ligament, anterior cruciate ligament (ACL), lateral collateral ligament (LCL), posterior cruciate ligament (PCL), medial collateral ligament (LCM), and patellar ligament.
[0179] In several modalities, the tendon is selected from the group of tendons, but is not limited to, tendons connected to the lower and upper extremities, such as tendons in the elbow, hands, knee, foot and ankle, and tendons in the shoulder, hip, and back, thoracic and abdominal tendons.
[0180] In certain modalities, the tendon is selected from the group comprising, but not limited to, the Achilles tendon, brachial tendon of the biceps, brachial tendon of the triceps, long extensor tendon, and peroneal tendon, anterior and posterior tibial tendons, tendon subscapularis, rotator cuff tendons, quadriceps tendon, and patellar tendon. All tendons present in the hand and feet could be included. The method of the present invention can be applied to a patient, in which the patient suffers from a disorder affecting a ligament and / or tendon, comprising, but not limited to, inflammation, autoimmune disease, infection, tension, strain, rupture, torsion , avulsion, over-stretching or laceration of the ligament and / or tendon.
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49/60 [0181] In certain modalities, before the repair patch is applied to the injured ligament and / or tendon, the injury site is prepared to receive the patch.
[0182] In certain modalities, before or after fixation to the injured ligament or tendon, the repair patch is immersed with blood to trap autologous mesenchymal stem cells (MSCs) in the patch and release growth factors at the injured site. These pluripotential MSCs in the presence of the collagen plaster will differentiate into fibroblasts and later mature ligament or tendon cells to repair the ligament or tendon injury site or transform the ligament or tendon graft tissue.
[0183] After the injury site is prepared, additional procedures can be performed.
[0184] In certain modalities, in order to fix the repair patch to the injured ligament or tendon, the patch can be fixed to the ligament or tendon using surgical suture. In certain embodiments, the plaster is attached to the injured ligament or tendon by suturing and / or tying the plaster to the injured ligament / tendon using suture and / or adding glue to the fixation site on the injured ligament or tendon.
[0185] The suture can be produced from material selected from, but is not limited to, todimethylsiloxane, polytetrafluoroethylene (PTFE), in particular, condensed PTFE (cPTFE) or extended PTFE (ePTFE), polyethylene, polylactic acid, polydioxanone , caprolactone, polyglycolic acid, collagen polyester and acrylic-based polymers, for example, acid esters
Petition 870190088042, of 09/06/2019, p. 57/72
50/60 acrylic or methacrylic acid. Specific suitable polymers are, for example, mixed polymers of polypropylene (PP) and polyglecaprone, polymers of poly-pdioxanone, polyester, polyvinylidene fluoride (PVDF), polypropylene (PP), in particular, condensed PP (cPP), polytetrafluoroethylene ( PTFE), polymethylmethacrylate (PMMA), polyethylene terephthalate, polyethercetone (PEK), and polyether ether ketone (PEEK).
[0186] Surgical suture may be biocompatible.
[0187] In several modalities, the repair patch is attached to the injured ligament or tendon by suturing the patch to the ligament or tendon. Typically, biologically absorbable surgical sutures are used to secure the patch. Surgical sutures can be produced from polylactic acid, polydioxanone, and caprolactone, polyglycolic acid and collagen.
[0188] In certain embodiments, the repair patch comprises growth factors, anti-inflammatory compounds and / or antibodies that may be of recombinant origin and / or isolated from blood, for example, autologous blood. Therefore, in some embodiments, the plaster comprises, for example, TGF-βΙ and / or one or more growth factors, as described here.
[0189] In certain modalities, in order to fix the repair patch to the injured ligament or tendon, the patch can be fixed to the ligament or tendon by glue and / or a weld using surgical suture and / or tying with the use of surgical suture .
[0190] Glue and / or surgical suture may be biocompatible.
Petition 870190088042, of 09/06/2019, p. 58/72
51/60 [0191] The glue can be selected from the group that includes, but is not limited to gelatin, alginic acid, agarose, starch, fibrin, collagen, laminin, elastin, fibronectin, proteoglycans and / or glycosaminoglycans, for example, sulphate of heparan, chondroitin sulfate and / or keratan sulfate, casein, dextrans, caramelose, pectin, carrageenan, and xanthan.
[0192] For example, the method of the present system may comprise the preparation and application of fibrin glue / fibrin glue composition to the injured site. The fibrin glue / fibrin glue composition can mix with body fluids to form a fibrin glue composite with body fluid.
[0193] In various embodiments, the method of the present invention may further comprise the step of applying glue, for example, fibrin glue, to the injured ligament or tendon before and / or after applying the repair and / or application patch of glue, for example, fibrin glue to the plaster. In certain embodiments, if the plaster includes a support layer and a matrix layer, glue, for example, fibrin glue, can be applied to the support layer and / or matrix before and / or after applying the plaster to the ligament or injured tendon. In various embodiments, if the plaster includes a support layer, a matrix layer and a third layer, glue, for example, fibrin glue, can be applied to the support layer and / or third layer before and / or after application from the plaster to the injured ligament and / or tendon.
[0194] In certain embodiments, the glue is fibrin or a
Petition 870190088042, of 09/06/2019, p. 59/72
52/60 fibrin composition. The fibrin composition can comprise fibrin and additional components. Additional components may be growth factors, anti-inflammatory compounds and / or antibodies. In certain embodiments, the additional components, for example, growth factors, anti-inflammatory compounds and / or antibodies, are recombinant and / or isolated from the blood. Therefore, in some embodiments, at least one component of the fibrin glue composition is isolated from blood or blood serum, that is, blood serum recovered after centrifugation, including various growth factors, such as TGF-βΙ and / or one or more factors growth, as described here. In various embodiments, the fibrin glue composition comprises at least one autologous growth factor isolated from autologous blood. The fibrin glue composition can then stimulate stem cell differentiation at the interface of the ligament and / or tendon / plaster injury.
[0195] In certain embodiments, glue, for example, fibrin glue, is applied to the injury site, followed by the placement of the flexible laminated repair plaster to the injury site on the injury site. The glue, for example, fibrin glue, can also be applied freely after the repair patch is in place at the injury site to further adhere the repair patch to the injury site. For example, the glue can be injected to reach the covered lesion site. In addition, the plaster can be additionally fixed by surgical suture. When this step is performed, the surgical stages are completed and the repair patch
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53/60 ligament / tendon continues its purpose of healing in situ.
[0196] In certain embodiments, the plaster is applied to the ligament or tendon in situ. Therefore, in certain modalities, the plaster can be applied to the ligament or tendon in an endoscopic procedure, for example, an arthroscopic operation.
[0197] Alternatively, a ligament / tendon graft is collected from the patient and then the plaster is applied as described above and later, the graft is introduced into the prepared surgical site.
[0198] Also presented here is a ligament and / or tendon repair patch as described here.
[0199] Also presented here is a ligament and / or tendon repair patch as described here for use in treating an injured ligament and / or tendon.
[0200] All procedures and devices described here with respect to ligament repair are here also revealed as procedures related to tendon repair and vice versa.
EXAMPLES
Example 1: Preparation of the repair plaster [0201] A sheet of collagen 22 (Xenoderma - collagen type 1 and porcine 3) was used as the backing layer 22. The backing layer had mechanical properties to withstand shear stress and traction and was resorbable in about 6 weeks. Collagen sheet 22 was placed in a form and then loaded with a collagen-HA suspension to which a solution of Diacercein or Diacerein was added to obtain an amount of 0.3 to 75 pg dry weight in the plaster after drying by
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54/60 freezing and sterilization. The result was a two-layer collagen block with the support layer to be arranged at the injured ligament / tendon site. After manufacture and before sterilization, the blocks were placed in a mechanical press to obtain a thickness of 0.5 to 2 mm. The concentration of HA in the freeze-dried final product was in the range of about 0.1% to 2%. HA is natural HA, that is, non-chemically modified HA, originated from fermentation.
Example 2: Production of a pericardial membrane
1. Recovery of raw material of bovine origin [0202] The bovine cardiac bags (pericardium) used as the starting material, after the inspection of conventional meat by an official veterinarian at the slaughterhouse, are first separated from the parts of the fixed organs and the fat and connective tissue are roughly cleaned. Thus, sheet-shaped pieces of approximately 30 cm x 15 cm in size and a weight of about one kilogram per piece are obtained. The bovine pericardiums thus prepared are transported in an ice-cold bag loaded with ice from the slaughterhouse to the production site and, depending on the amount of raw material recovered, stored intermediate there at less than -20 ° C before being further processed.
2. Wet chemical processing [0203] The raw pieces of the pericardium were first rinsed individually with purified water, usually immersed in running water to remove portions of adhered blood and water-soluble protein. After immersion, all macroscopically visible residues of fatty tissue
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55/60 and basement membranes were removed. This was followed by a treatment with 2% aqueous sodium hydroxide solution at room temperature. The pericardium pieces (5,000 grams) remained in the disinfection solution bath (37.5 liters) for a total of 16 hours. Their removal was followed by a rinsing process, taking about 10 minutes in demineralized water, the process of which was repeated until the pH of the rinsing water was reduced to less than 8. This was obtained after about 1 hour. If present, the basement membranes and the rest of the fat were still observable and were then removed at this stage of the process. The very swollen pieces of pericardium were then transferred to 37.5 liters of a 10% aqueous saline solution to adjust the swelling state (partial deflated) as needed for the additional process steps. A treatment with NaCl was carried out at room temperature, which was followed by a rinsing process with demineralized water. In order to remove any interfering heavy metal ions and any possible lime inclusions from the pericardium material, the material was then subjected to a treatment with 37.5 liters of an EDTA solution adjusted to be weakly alkaline and having the concentration of 0.3 g in 100 ml. Then, the material was rinsed with demineralized water, as in the previous process steps to remove excess complexing agent and simultaneously bring the pH value to 8.5. The one-time treatment was then followed with 37.5 liters of acetate buffer (pH 4.8; composition, per 100 ml: 59 parts by volume of a solution of 0.01 moles of sodium acetate plus 3 H ₂ 0 in
Petition 870190088042, of 09/06/2019, p. 63/72
56/60
100 ml and 41 parts by volume of 0.01 moles of acetic acid in 100 ml) served the purpose of buffering all residues, if any, left in the pericardium tissue and preparing a weakly acidic medium for the subsequent bleaching operation. Any excess buffer substances were removed as described above by rinsing with demineralized water.
. Oxidative bleaching [0204] Subsequent to wet chemical processing, the pericardial pieces were subjected to an oxidative bleaching operation taking one hour in
37.5 liters of a 1.5% hydrogen peroxide solution. The bleaching process was carried out, as well as the previous process steps, at room temperature. Thus, on the one hand, the efficiency of the purification operations is guaranteed while, on the other hand, a deterioration of the collagenous tissue is avoided.
4. Washing [0205] In order to remove any excess reagent, the material was subsequently rinsed with demineralized water according to the conventional regime.
5. Degreasing [0206] The rinsed pieces of bovine pericardium were placed in such an amount of acetone that the bovine pericardium tissue was completely covered with acetone. The solvent was changed three times within 8 hours. The pieces of bovine pericardium thus dehydrated were then transferred to a Soxhlet apparatus and extracted with acetone for about 8 hours. After extraction, the pieces of pericardium were left to air dry and,
Petition 870190088042, of 09/06/2019, p. 64/72
57/60 then rehydrated in a transport bottle with demineralized water.
. Freeze drying [0207] The drying was done in an automatically controlled freeze dryer. Freeze drying in detail occurs as follows:
reduce the temperature to + 1 ° C, reduce the temperature to -40 ° C, turn on the vacuum, heat the trays to + 40 ° C and dry with full vacuum.
7. Sterilization [0208] Sterilization was done by sterilization with radiation with 2.5 Mrad (2.5 x 10 ^-4 Gy).
Example 3: Culturing fibroblasts on the flexible and biocompatible repair patch [0209] In order to determine cell viability during the cultivation of fibroblasts on the repair patch of the present invention, the human dermal fibroblast cell line WS 1 was used. This cell line was cultured under standard conditions (37 ° C, 5% CO ₂ ) in Dulbecco's modified Eagle medium (DMEM) and 10% fetal bovine serum (SFB).
[0210] The fibroblasts were transferred to the repair patch of the present invention and a reference material and were grown over a period of time up to 5 weeks under standard conditions (37 ° C, 5% CO2) in DMEM. To determine the rate of cell proliferation WST 1 assays were used. This test is a colorimetric test to measure the activity of cellular enzymes that reduce a tetrazolium dye, WST 1, to its insoluble formazan, giving a purple color. In addition,
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58/60 samples of the medium were analyzed by ELISA to determine their concentrations of pro-collagen type I. Cell viability was analyzed once a week by staining live / dead cells under a fluorescence microscope.
[0211] For the in vitro test of the repair patch of the present invention, fibroblasts were seeded on its surface. The cells were incubated under standard culture conditions for 14 days in a serum-free medium. After 3, 7 and 14 days, cell viability and rate of de novo collagen type 1 synthesis were determined. A second collagen plaster, as well as a single layer culture on cell culture plates, served as a control.
[0212] The results showed that the repair patch of the present invention is qualified for the laying of cells. During the incubation time, fibroblasts survived in patches and synthesized pro-collagen type 1. Staining of live / dead fibroblasts resulted in a higher proportion of live cells in the patches. In addition, an overgrowth of the surface could be determined specifically for the repair patch of the present invention. In comparison to the single-layer reference, fibroblasts growing in the repair patch of the present invention showed an increase in metabolic activity as well as levels of pro-collagen type 1 concentration intensified after 14 days of incubation.
[0213] Although the description above contains many specificities, they should not be considered limitations to the scope of the invention, but rather exemplifications of one or
Petition 870190088042, of 09/06/2019, p. 66/72
59/60 another preferred modality of the same. Many other variations are possible, which would be obvious to one skilled in the art. Consequently, the scope of the invention must be determined by the scope of the appended claims and their equivalents, and not just by the modalities. All documents cited in the present invention are incorporated herein, by reference, in their entirety. The inventions illustratively described here can be properly practiced in the absence of any elements or elements, limitations or limitations that are not specifically presented here. In this way, for example, the terms comprising, including, containing, etc. should be read expansively and without limitation. Additionally, the terms and expressions that have been used here have been used as terms of description and not of limitation, and it is not intended that the use of such terms and expressions would exclude any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claimed invention. Thus, it should be understood that although the present invention has been specifically presented by preferential modalities and optional features, the modification and variation of the inventions presented here can be used by those skilled in the art, and that such modifications and variations are considered within the scope of this invention. The invention has been described here in a broad and generic way. Each of the narrowest species and subgeneric groups that fall within the generic description are also part of the invention. This includes the generic description of the
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60/60 invention with a caveat or negative limitation removing any matter of the kind, regardless of whether the cut material is specifically mentioned here or not. In addition, when features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is thus described in terms of any individual element or subgroup of elements of the Markush group. Additional embodiments of the invention will become apparent from the following claims.

权利要求:
Claims (11)
[1]
1. Biocompatible plaster, characterized by the fact that it comprises:
collagen and hyaluronic acid, a support layer comprising collagen, in which the support layer is porous to cells, and a matrix layer comprising collagen and hyaluronic acid to the ligament or tendon, in which
a) the support layer comprises a layer of dry divided porcine skin; and / or
b) the matrix layer also comprises one or more compounds selected from analgesics, anti-inflammatory agents, antibiotics and agents that promote the regeneration of ligaments and / or tendons, in which the agents that promote the regeneration of ligaments and / or tendons are selected from the group consisting of: growth factors, diacerein, reina, platelet-rich plasma (PRP), polylactic acid and chitosan, chitosan hydrochloride, carboxymethyl chitosan, chitosan lactate, chitosan acetate, chitosan glutamate, succinate chitosan, N- (2-hydroxy) propyl-3-trimethyl ammonium chloride, chitosan N-trimethylene chloride, and pharmaceutically acceptable salts thereof; and / or
c) the composition further comprises a third layer, which is arranged in the matrix layer, so that the matrix layer is arranged between the support layer and the third layer.
[2]
2. Biocompatible plaster according to claim 1, characterized by the fact that the backing layer is a layer of collagen sheet.
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2/3
[3]
3. Biocompatible plaster according to claim 1 or 2, characterized by the fact that the support layer comprises porcine, bovine, equine or divided porcine skin.
[4]
4. Biocompatible plaster according to any one of claims 1 to 3, characterized in that the matrix layer is a porous collagenous layer.
[5]
5. Biocompatible plaster according to claim 4, characterized by the fact that the matrix layer comprises a collagen fiber matrix.
[6]
6. Biocompatible patch according to any one of claims 1 to 5, characterized by the fact that the collagen in the matrix layer comprises collagen of porcine, equine, bovine or vegetable origin.
[7]
7. Biocompatible patch according to any one of claims 1 to 6, characterized in that the hyaluronic acid in the matrix layer comprises natural non-human hyaluronic acid.
[8]
8. Biocompatible plaster according to claim 7, characterized by the fact that the natural hyaluronic acid in the matrix layer comprises natural non-human hyaluronic acid from a bacterial fermentation source.
[9]
9. Biocompatible plaster according to any one of claims 1 to 8, characterized in that the matrix comprises hyaluronic acid in the form of fibers, powder, gel or cream suspension.
[10]
10. Biocompatible plaster according to any one of claims 1 to 9, characterized by the fact that the matrix layer is a collagenous composite block
Petition 870190088042, of 09/06/2019, p. 70/72
3/3 porous intercalated with collagen fibers and natural hyaluronic acid dispersed in the empty spaces of collagen fibers.
[11]
Biocompatible patch according to any one of claims 1 to 10, characterized in that it is for use in a method for repairing a ligament or tendon in an individual, the method comprising applying said composition in the form of a flexible and biocompatible patch. .

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法律状态:
2018-03-27| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2019-06-11| B07A| Technical examination (opinion): publication of technical examination (opinion) [chapter 7.1 patent gazette]|

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2019-10-08| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2019-11-05| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 22/03/2013, OBSERVADAS AS CONDICOES LEGAIS. |

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2021-04-06| B21F| Lapse acc. art. 78, item iv - on non-payment of the annual fees in time|Free format text: REFERENTE A 8A ANUIDADE. |

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2021-08-10| B24J| Lapse because of non-payment of annual fees (definitively: art 78 iv lpi, resolution 113/2013 art. 12)|Free format text: EM VIRTUDE DA EXTINCAO PUBLICADA NA RPI 2622 DE 06-04-2021 E CONSIDERANDO AUSENCIA DE MANIFESTACAO DENTRO DOS PRAZOS LEGAIS, INFORMO QUE CABE SER MANTIDA A EXTINCAO DA PATENTE E SEUS CERTIFICADOS, CONFORME O DISPOSTO NO ARTIGO 12, DA RESOLUCAO 113/2013. |

优先权:

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申请号 | 申请日 | 专利标题

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US201261613998P| true| 2012-03-22|2012-03-22|

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PCT/EP2013/056045|WO2013139955A1|2012-03-22|2013-03-22|Method for repair of ligament or tendon|

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