PHARMACO ELUTION SELF-RETENTION SUTURES

专利摘要:
DRUG ELUTION SELF-RETENTION SUTURES. The present invention relates to a pharmacological retention suture comprising a filament, a plurality of retainers, and a drug impregnated in or coated in the filament. The shape and distribution of the retainers modify the in vivo release kinetics of the drug. The kinetics of drug release can be modified uniformly or region by region. The self-retaining suture can, for example, be used to refix separate nerves and release Neural Growth Factor or other regeneration accelerating agents in the region of the nerve injury.
公开号:BR112013011090B1
申请号:R112013011090-2
申请日:2011-11-03
公开日:2020-11-24
发明作者:Jeffrey M Gross；Lev Drubetsky；Alexander Naimagon；Rui Avelar；William L. D'agostino；Kevin Don Nelson；Brent B. Crow；Nickolas B. Griffin
申请人:Ethicon Llc；Tissuegen, Inc.；
IPC主号:

专利说明:

CROSSED REFERENCE TO RELATED ORDER
[001] This application claims benefit under 35 U.S.C. § 119 (e) of US provisional patent application No. 61 / 409,731 filed on November 3, 2010, the provisional application of which is hereby incorporated by way of reference in its entirety. FIELD OF THE INVENTION
[002] The present invention relates, in general, to self-retaining systems for surgical procedures, methods of manufacturing self-retaining systems for surgical procedures, and uses thereof. BACKGROUND OF THE INVENTION
[003] Wound closure devices such as sutures, staples and pins have been widely used in superficial and deep surgical procedures in humans and animals for wound closure, repair of traumatic injuries or defects, joining tissues together (approximating separate tissues, closing an anatomical space, fixing layers of single or multiple tissues, creating an anastomosis between two hollow / luminous structures, adjacent tissues, fixing or refixing tissues in their correct anatomical location), fixation of foreign elements to the tissues (attachment) medical implants, devices, prostheses and other functional or supportive devices), and for repositioning tissues in new anatomical locations (repairs, tissue elevations, tissue grafting and related procedures), to name just a few examples.
[004] Sutures are often used as devices for closing wounds. Sutures typically consist of a filamentous suture thread attached to a needle with a sharp tip. Suture threads can be produced from a variety of materials including bioabsorbable materials (i.e., that decompose completely in the body over time), or non-absorbable materials (permanent; not degradable). It has been observed that absorbable sutures are particularly useful in situations where removing the suture could impair repair or when the natural healing process makes the support provided by the suture material unnecessary after healing of the wound has been completed; as, for example, when finishing a skin closure without complications. Non-degradable (non-absorbable) sutures are used in wounds where healing can be expected to take a long time or in which suture material is necessary to provide physical support to the wound over long periods of time; such as, for example, in deep tissue repairs, high tension wounds, many orthopedic repairs and some types of surgical anastomoses. In addition, a wide variety of surgical needles are available, and the shape and size of the needle body and the configuration of the needle tip are typically selected based on the needs of the specific application.
[005] To use a common suture, the suture needle is moved through the desired tissue on one side of the wound and then through the adjacent side of the wound. The suture is then formed into an "Iago", which is completed by knotting the suture to secure the closed wound. Tying the knot does take some time and causes a range of complications, including, but not limited to, (i) expulsion (a condition in which the suture, usually a knot, pushes through the skin after a subcutaneous closure), (ii ) infection (bacteria are often able to settle and grow in the spaces created by the knot), (iii) volume / mass (a significant amount of suture material left in a wound and the portion comprising the knot), (iv) slip (they can slip or come loose), and (v) irritation (they serve us as a bulky "foreign body" in an injury). The suture lakes associated with na ligation can lead to ischemia (knots can create tension points that can strangle tissue and limit blood flow to the region) and increase the risk of dehiscence or rupture in the surgical wound. Knotting is also labor intensive and can comprise a significant percentage of the time spent to close a surgical wound. The additional operating procedure time is not only bad for the patient (complication rates increase with time spent on anesthesia), but also contributes to the total cost of the operation (many surgical procedures are estimated between $ 15 and $ 30 per minute of operating time).
[006] Self-retaining sutures (including barbed sutures) differ from conventional sutures in that self-retaining sutures have numerous retaining tissues (such as splinters) that anchor the self-retaining suture in a tissue after positioning and resist the movement of the suture in the opposite direction the ones that the retainers are facing, thus eliminating the need to tie the knots to fix the adjacent fabrics together (a "knotless" closure). Barbed tissue approximation devices have been previously described in, for example, US Patent No. 5,374,268, featuring armed anchors that have barb-like projections, while sets of sutures that have barbed laterals have been described. in US Patent Nos. 5,584,859 and 6,264,675. Sutures that have a plurality of barbs positioned over a larger portion of the suture are described in US patent No. 5,931,855, which features a unidirectional barbed suture, and US patent No. 6,241,747, which features a bidirectional barbed suture. . Methods and apparatus for forming barbs in sutures have been described, for example, in US Patent Nos. 6,848,152. Self-retaining systems for wound closure also result in better approximation of the wound edges, evenly distribute the tension along the length of the wound (reducing areas of tension that can break or lead to ischemia), reduce the volume of the suture material remaining in the wound (by eliminating the knots) and reduce expulsion (the extrusion of suture material - typically knots) through the skin surface. All of these features are designed to reduce the formation of scars, improve cosmesis, and increase wound resistance in relation to wound closure with simple sutures or staples. In this way, the self-retention sutures, due to the fact that these sutures prevent the knotting, allow patients to experience an improved clinical result, and also save time and costs associated with prolonged surgeries and accompanying treatments. It is noted that all patents, patent applications and patent publications identified throughout this DESCRIPTION are hereby incorporated by reference in their entirety.
[007] The ability of self-retaining sutures to anchor and fix tissues in place, even in the absence of tension applied to the suture by a knot, is a feature that also provides superiority over simple sutures. When closing a wound that is under tension, this advantage manifests itself in several ways: (i) the self-retaining sutures have a multiplicity of retainers that can dissipate the tension along the entire length of the suture (by providing hundreds of stitches " anchor ", this produces a superior cosmetic result and reduces the chance that the suture" slips "or passes through) as opposed to interrupted sutures with knots that concentrate the tension at different points; (ii) complicated wound geometries can be closed (circles, arcs, irregular edges) uniformly with more precision and accuracy than those obtained with interrupted sutures; (iii) self-retaining sutures eliminate the need for a "third hand", which is often necessary to maintain tension throughout the wound during traditional suturing and knotting (to avoid "sliding" when tension is momentarily released) during mooring); (iv) self-retaining sutures are superior in procedures where knotting is technically difficult, such as for deep wounds or laparoscopic / endoscopic procedures; and (v) self-retaining sutures can be used to approximate and fix the wound before definitive closure. As a result, self-retaining sutures provide easier handling in anatomically tight or deep locations (such as the pelvis, abdomen and chest) and facilitate tissue approximation in laparoscopic / endoscopic and minimally invasive procedures; all without having to hold the lock for a no. Greater precision allows self-retaining sutures to be used in more complex closure systems (such as those with unpaired diameters, larger defects or pouch thread sutures) that can be performed with simple sutures.
The self-retaining suture may be unidirectional, having one or more retainers oriented in one direction along the length of the suture; or bidirectional, typically having one or more retainers oriented in one direction along a portion of the rose, followed by one or more retainers oriented in another (often opposite) direction over a different portion of the rose (as described in relation to the retainers barbed wire in US Patent Nos. 5,931,855 and 6,241,747). Although any number of sequential or intermittent retainer configurations is possible, a common form of bidirectional self-holding suture involves a needle at one end of a suture thread that has barbed ends that project "away" from the needle to the point of transition (often the midpoint) of the suture will be reached; at the transition point of the splinter configuration it is inverted at about 180 ° (so that the splinters are now turned in the opposite direction) along the remaining length of the suture before attaching to a second needle at the opposite end ( with the result that the splinters on this part of the suture also have points projecting "out" from the next needle). Jutting out of the needle means that the tip of the barb is further away than the needle and the portion of the suture that includes the barb can be pulled more easily through the tissue in the direction of the needle than in the opposite direction . In other words, the splinters in both "halves" of a typical two-way self-retaining suture have points that point towards the middle, with a transition segment (devoid of splinters) interposed between them, and with a needle attached to either end.
[009] With regard to surgical procedures, it may be beneficial to provide a drug to the surgery site during the surgical procedure. It is desirable that the drug is provided in the proper concentration and at the appropriate times so that it is effective for the healing process. Consequently, it would be advantageous to be able to supply such drugs with the application of a suture during the surgical procedure. SUMMARY OF THE INVENTION
[0010] Despite the series of advantages of unidirectional and bidirectional self-retaining sutures, the aspiration to improve the suture design remains to provide additional therapeutic benefits.
[0011] Thus, it would be desirable to provide improved self-entertainment sutures having the ability to anchor in the surrounding tissue, good ability to fix to the tissue and greater therapeutic benefits.
[0012] In accordance with the foregoing background and limitations of the prior art, the present invention provides enhanced self-suturing sutures that have the ability to anchor to the surrounding tissue, the ability to fix the tissue and better clinical performance and therapeutic benefits, as well as methods of manufacturing and using such self-entertainment sutures.
[0013] According to one aspect of the invention, the self-suturing sutures are configured to effectively distribute or resist tension on them when applied to the tissue and also to supply drugs to a tissue to which the self-suture suture is applied.
[0014] In another aspect of the invention, a drug is impregnated in the body with a self-retention suture before the formation of the retainers.
[0015] In another aspect of the invention, a drug is isotropically or anisotropically distributed over the length of a self-healing suture.
[0016] In another aspect of the invention, a drug is isotropically or anisotropically distributed over the radius of a self-retention suture.
[0017] In another aspect of the invention, a suture is provided with one or more tissue retainers that affect the kinetics of the release of a drug associated with the suture.
[0018] In another aspect of the invention, a suture may include one or more tissue retainers having an irregular or rough surface, which affects the release kinetics of a drug associated with the suture.
[0019] In another aspect of the invention, a suture is provided with one or more tissue retainers that affect the release site of a drug associated with the suture.
[0020] In another aspect of the invention, a suture is provided with one or more tissue retainers that anisotropically make the local release of a drug associated with the suture.
[0021] In another aspect of the invention, a self-retaining suture includes a section without tissue retainers disposed away from one end or another of the suture that releases a drug associated with the suture.
[0022] In another aspect of the invention, a self-retaining suture includes an expanded section disposed away from one end or the other of the suture, which affects the release of a drug associated with the suture.
[0023] In another aspect of the invention, a suture with retainers includes a Neural Growth Factor (NGF - Nerve Growth Factor) as a drug useful in nerve repair.
[0024] In another aspect of the invention, a method of use includes a suture that includes an NGF as a drug to repair a nerve.
[0025] Details of one or more modalities are presented in the DESCRIPTION below. Other characteristics, objectives and advantages will be apparent from the DESCRIPTION, drawings, and claims. In addition, the descriptions of all patents and patent applications mentioned herein are hereby incorporated by reference in their entirety. BRIEF DESCRIPTION OF THE DRAWINGS
[0026] The characteristics of the invention, its nature and various advantages will be apparent from the attached drawings and the detailed description below of various modalities.
[0027] Figures 1A and 1B are seen in perspective of a self-retention suture comprising a drug according to an embodiment of the present invention.
[0028] Figures 1C and 1D are alternative sectional views of the suture filament of Figures 1A and 1B, illustrating parameters of the drug delivery.
[0029] Figures 1E and 1F are enlarged sectional views of the suture thread of the self-retaining suture of Figures 1A and 1B illustrating parameters of the retainers and the distribution of retainers.
[0030] Figures 2A, 2B and 2C are sectional views illustrating steps in creating a retainer for a self-restraint suture that comprises a drug according to an embodiment of the present invention.
[0031] Figure 2D is a cross-sectional view of an alternative step in creating a retainer for a self-retention suture comprising a drug according to an embodiment of the present invention.
[0032] Figure 3A illustrates a method and apparatus for the coextrusion of multiple materials to form a composite filament suitable for creating a self-suture suture comprising a drug according to an embodiment of the present invention.
[0033] Figure 3B illustrates a method and apparatus for the coextrusion of a material into a preformed filament to form a composite filament suitable for creating a self-restraint suture comprising a drug according to an embodiment of the present invention.
[0034] Figure 3C illustrates an alternative method and apparatus for depositing a material in a preformed filament to form a composite filament suitable for creating a self-suture suture comprising a drug according to one embodiment of the present invention.
[0035] Figures 3D-3F illustrate alternative configurations of self-filament filaments and structures suitable for the creation of a self-retention suture comprising a drug according to the modalities of the present invention.
[0036] Figures 4A-4E illustrate alternative co-extruded suture stock configurations suitable for creating a self-suture suture comprising a drug according to the modalities of the present invention.
[0037] Figures 4F-4I illustrate alternative geometries of co-extruded suture stock suitable for creating a self-retention suture comprising a drug according to the modalities of the present invention.
[0038] Figures 5A-5C illustrate specific modalities of retainers for the creation of a self-retention suture comprising a drug according to the modalities of the present invention.
[0039] Figure 5D illustrates a sapphire blade configuration for cutting the retainers of figures 5A-5C according to an embodiment of the present invention.
[0040] Figure 5E illustrates an alternative sapphire blade configuration for cutting the retainers of a self-healing suture according to the modalities of the present invention.
[0041] Figure 5F illustrates the configuration of a curved sapphire blade for cutting the retainers of a self-retention suture according to the modalities of the present invention.
[0042] Figure 5G illustrates a circular blade configuration for cutting the retainers of a self-healing suture according to the commodities of the present invention.
[0043] Figure 6A illustrates a simple helix distribution of retainers in a drug eluting self-retention suture according to an embodiment of the invention;
[0044] Figure 6B illustrates a double helix distribution of retainers in a drug eluting self-retention suture according to an embodiment of the invention;
[0045] Figure 6C illustrates a high density quadruple distribution of retainers in a self-retaining drug eluting suture according to an embodiment of the invention;
[0046] Figures 6D-6F illustrate alternative retainer formats for retainers in a self-holding drug eluting suture according to the modalities of the invention.
[0047] Figure 6G illustrates dimensions of sutures that can benefit from the modalities of the invention.
[0048] Figure 7A illustrates a sectional view of a nerve for reference.
[0049] Figure 7B illustrates the kinetics of NGF release from a drug eluting self-retention suture according to an embodiment of the present invention.
[0050] Figures 7C-7I illustrate a nerve repair procedure using a drug eluting self-retention suture according to an embodiment of the present invention.
[0051] Figures 8A and 8B illustrate techniques that use drug eluting self-retaining sutures to reconstruct a defective nerve.
[0052] Figures 9A, 9B and 9C illustrate an alternative technique for reconnecting a sectioned nerve using one or more drug eluting self-retention sutures.
[0053] Figures 10A and 10B show culture responses from PC12 cells to exposure to NGF-loaded suture and NGF-loaded suture, respectively.
[0054] Figures 11A-D show PC12 cell culture responses to NGF-free suture and NGF-loaded suture in varying amounts, respectively, in a green phalloidin dye.
[0055] Figures 12A-C show PC12 cell culture responses, in phase contrast, the suture without NGF load and NGF sutures with 5 cm and 10 cm, respectively.
[0056] Figure 13 is a graph illustrating the dosing response of PC12 cell cultures to varying amounts of NGF-loaded suture. DETAILED DESCRIPTION Definitions
[0057] Definitions of certain terms that can be used later in this document include the following.
[0058] The term "armed suture" refers to a suture that has a suture needle in at least one suture positioning end.
[0059] The term "bidirectional suture" refers to a self-retaining suture that has retainers oriented in one direction at one end and retainers oriented in the other direction at the other end. A bidirectional suture is typically armed with a needle at each end of the suture. Many bidirectional sutures have a transiption segment located between the two orientations of the barb.
[0060] The term "stranded suture" refers to a suture comprising a multifilament suture. The filaments in these sutures are typically stranded, twisted, or woven together.
[0061] The term "degradable suture" (also called "biodegradable suture" or "absorbable suture") refers to a suture which, after being introduced into the tissue, is decomposed and absorbed by the body. Typically, the degradation process is at least partially mediated by, or performed in, a biological system. The term "degradation" refers to a chain cleavage process by which a polymer chain is cleaved into oligomers and monomers. Chain splitting can occur through a variety of mechanisms, including, for example, by chemical reaction (for example, hydrolysis, oxidation / reduction, enzymatic mechanisms or a combination thereof) or by a thermal or photolytic process. The degradation of the polymer can be characterized, for example, using gel permeation chromatography (GPC), which monitors the changes in molecular weight of the polymer during erosion and degradation. The degradable suture material can include polymers such as polydioxanone ("PDO"), polyglycolic acid, copolymers of glycolide and lactide, copolymers of trimethylene carbonate and glycolide with diethylene glycol (e.g. MAXON ™, Tyco Healthcare Group), glycolide compound terpolymer , trimethylene carbonate and dioxanone (e.g. BIOSYNTM [glycolide (60%), trimethylene carbonate (26%) and dioxanone (14%)], Tyco Healthcare Group), glycolide copolymers, caprolactone, trimethylene carbonate and lactide ( for example, CAPROSYNTM, Tyco Healthcare Group). A dissolvable suture may also include a partially deacetylated polyvinyl alcohol. Polymers suitable for use in degradable sutures can be linear polymers, branched polymers or multiaxial polymers. Examples of multiaxial polymers used in sutures are described in US Patent Application Publications No. 20020161168, 20040024169 and 20040116620. Sutures made from degradable suture material lose resistance to trapping depending on the degraded material. Degradable sutures can be in the barbed multifilament or monifilament.
[0062] The term "drug" refers to a chemical capable of administering to an organism, modifying or altering the physiology of the organism. Preferably the "drug" is a substance intended for use in the treatment or prevention of diseases. The term "drug" includes proactive, activated, metabolized and non-metabolized drugs. Pharmaceuticals include, for example, naturally occurring and synthetic toxins and bioactive substances, as well as recognized pharmaceuticals, such as those mentioned in "2010 Physicians' Desk Reference®" (PDR®, 2009) which is incorporated herein by reference. The term "drug" is also intended to encompass pharmaceutical products that have the properties indicated, but that have been discovered or made available after the filing date of this application.
[0063] The term "drug eluting suture" refers to a suture that has a drug associated with it at the time of implantation in a patient's tissue, in which the suture releases the drug into the patient's tissue subsequent to implantation. The association of a drug with a suture can be performed in a variety of ways. The drug is impregnated in the suture before, after or during the creation of the filament. Alternatively, the drug can be coated on the filament, either before or after the formation of the retainer in a self-retaining suture. The drug is incorporated into, for example, (a) fixing the suture directly to a formulation (for example, by spraying the suture with a polymer / drug film or by immersing the suture in a polymer solution / (b) to coat or impregnate the suture with a substance such as a hydrogel, which will absorb the drug, or including the drug at the time of coating, impregnation or creation of the suture (c) interlaced if the thread coated by the drug (or the polymer itself formed in a rose) in the suture structure in the case of sutures with multiple filaments, (d) form the suture itself with the drug in the manufacturing material or with it being the material of manufacturing.
[0064] The term "medical device" or "implant" refers to any object placed on the body for the purpose of restoring physiological function, reducing / relieving symptoms associated with the disease, and / or repairing and / or replacing organs and damaged or diseased tissues. Although they are normally composed of biologically compatible synthetic materials (for example, medical grade stainless steel, titanium and other metals or polymers such as polyurethane, silicon, PLA, PLGA and other materials) that are exogenous, some medical devices and implants include materials derived from animals (for example, "xenografts" as whole bodies of animals; tissues of animals, as heart valves; naturally occurring or chemically modified molecules such as collagen, hyaluronic acid, proteins, carbohydrates and others), human donors (for example, " allografts "as whole organs; tissues such as bone grafts, skin grafts and the like), or from the patients themselves (e.g." autografts "such as saphenous vein grafts, skin grafts, tendon / ligament / muscle transplants). Medical devices that can be used in procedures in connection with the present invention include, but are not limited to, orthopedic implants (artificial joints, ligaments and tendons; screws, plates and other implantable hardware), dental implants, intravascular implants (arterial and vascular grafts hemodialysis access grafts); both autologous and synthetic), skin grafts (autologous, synthetic), tubes, drains, volume forming agents for implantable tissue, pumps, derivations, sealants, surgical networks (for example, hernia repair networks, tissue supports) , fistula treatments, spinal implants (e.g., artificial intervertebral discs, spinal fusion devices, etc.) and the like.
[0065] The term "monofilament suture" refers to a suture comprising a monofilament suture.
[0066] The term "needle fixation" refers to the attachment of a needle to a suture that requires the same positioning in the fabric, and may include methods such as crimping, stranding, use of adhesives, and so on. The suture thread is fixed to the suture needle using methods such as crimping, bonding and adhesives. The fixation of sutures and surgical needles is described in US Patent Nos. 3,981,307, 5,084,063, 5,102,418, 5,123,911, 5,500,991, 5,722,991, 6,012,216 and 6,163,948, and in the publication US patent application No. 20040088003). The point of attachment of the suture with the needle is known as embedding.
[0067] The term "needle diameter" refers to the diameter of a needle positioning the suture at a point wider than the needle. Although the term "diameter" is often associated with a circular periphery, it should be understood in the present invention as indicating a dimension in cross section associated with a periphery of any shape.
[0068] The term "non-degradable suture" (also called "non-absorbable suture") refers to a suture that comprises material that is not degraded by chain cleavage, such as chemical reaction processes (for example, hydrolysis, oxidation / reduction, enzymatic mechanisms or a combination thereof) or by a thermal or photolytic process. The non-degradable suture material includes polyamide (also known as nailon, such as nailon 6 and nailon 6,6), polyester (e.g. polyethylene terephthalate), ethylene polytetrafluoro (e.g., expanded polytetrafluoroethylene), polyester-ester as polybutterester ( block copolymer of butylene terephthalate and polyethylene methyl ether glycol), polyurethane, metal alloys, metal (e.g., stainless steel wire), polypropylene, polyethylene, silk, and cotton. Sutures made of non-degradable suture material are suitable for applications in which the suture must remain permanently or must be physically removed from the structure.
[0069] The term "retainer configurations" refers to retainer fabric configurations and may include features such as size, shape, flexibility, surface features, and so on. They are sometimes called "barbed shapes".
[0070] The term "self-retaining suture" refers to a suture comprising elements on the suture filament to engage the tissue without the need for a suture knot or anchor.
[0071] The term "self-retention system" refers to a self-retention suture together with devices for positioning the suture in the tissue. Such positioning devices include, without limitation, suture needles and other positioning devices, as well as ends sufficiently rigid and sharp in the suture itself to penetrate tissue.
[0072] The term "suture positioning end" refers to an end of the suture to be positioned in the tissue; One or both ends of the suture may be ends of positioning the suture. The positioning end of the suture may be attached to a positioning device, such as a suture needle, or it may be sufficiently sharp and rigid to penetrate the tissue itself.
[0073] The term "suture diameter" refers to the diameter of the suture body. It should be understood that a variety of suture lengths can be used with the sutures described herein and that although the term "diameter" is often associated with a circular periphery, it should be understood in the present invention to indicate a cross-sectional dimension associated with a periphery of any shape. The size of the suture is based on the diameter. The American Pharmacopoeia ("USP") designation of the suture size ranges from 0 to 7 in the largest range and from 1-0 to 11-0 in the smallest range; in the smallest interval, the higher the value that precedes the hyphenated zero, the smaller and the diameter of the suture. The actual diameter of the suture will depend on the material of the suture, so that, for example, a suture of size 5-0 and made of collagen will have a diameter of 0.15 mm, while sutures that have the same size designation USP but made of absorbable synthetic material or a non-absorbable material will each have a diameter of 0.1 mm. The selection of the suture size for a specific purpose depends on factors such as the nature of the tissue to be sutured and the importance of cosmetic care; while smaller sutures can be more easily manipulated through restricted surgical sites and are associated with less scarring, the resistance to swallowing the suture made from a given material tends to decrease with decreasing size. It should be understood that the sutures and methods for making the sutures presented herein are suitable for a variety of diameters, including, but not limited to, 7, 6, 5, 4, 3, 2, 1, 0, 1- 0, 2-0, 3-0, 4- 0, 5-0, 6-0, 7-0, 8-0, 9-0, 10-0 and 11-0.
[0074] The term "suture needle" refers to needles used to position the sutures in the fabric, which are available in many formats, shapes and compositions. There are two main types of needles, traumatic needles and atraumatic needles. The traumatic needles have perforated grooves or ends (that is, holes or eyelets) that are supplied separately from the suture and are threaded in place. The atraumatic needles are without eyelets and are fixed to the suture at the factory by pinching or other methods, so that the suture material is inserted into a channel at the blind end of the needle which is then deformed to a final shape to fix the suture and the needle together. In this way, atraumatic needles do not require extra time at the threading site and the end of the suture at the needle attachment site is generally smaller than the needle body. In the traumatic needle, the thread exits the needle orifice on both sides and the suture often tears the tissues to some extent as it passes through it. More modern sutures are embedded with atraumatic needles. Atraumatic needles can be permanently embedded in the suture or can be designed to come out of the suture in a straight, sharp motion. These "pop-offs" are commonly used for interrupted sutures, where each suture is only passed once and then tied. For barbed sutures, which are uninterrupted, atraumatic needles are preferred. Suture needles can also be classified according to the geometry of the tip or point of the needle. For example, needles can be (i) "tapered" so that the needle body is round and tapers slightly to a point; (ii) "sharp" when the needle body is triangular and has a sharp cutting edge on the inside; (iii) "cut in reverse" so that a cutting edge is on the outside; (iv) "trocar point" or "narrow cut" so that the needle body is round and tapered, but ends at a small triangular cut point; (v) "blind" stitches for sewing cold fabrics; (vi) "lateral cut" or "spatula points" so that the needle is horizontal at the top and bottom with the cut end along the front to one side (These are typically used in eye surgery). Suture needles can also be of various shapes including, (i) straight, (ii) half curved or ski, (iii) 1/4 circle, (iv) 3/8 circle, (v) 1/2 circle , (vi) 5/8 circle, (v) and compound curve. Suture needles are described, for example, in US patents 6,322,581 and 6,214,030 (Mani, Inc., Japan); and 5,464,422 (W.L. Gore, Newark, DE, USA); and 5,941,899; 5,425,746; 5,306,288 and 5,156,615 (US Surgical Corp., Norwalk, CT, USA); and 5,312,422 (Linvatec Corp., Largo, FL, USA); and 7,063,716 (Tyco Healthcare, North Haven, CT, USA). Other suture needles are described, for example, in US Patent Nos. 6,129,741; 5,897,572; 5,676,675; and 5,693,072. The sutures described here can be installed with a variety of needle types (including without limitation curved, straight, long, short, micro, and so on), the needle cutting surfaces (including without limitation, cut, tapered, and and so on), and needle fixation techniques (including without limitation, pierced, crimped ends, and so on). In addition, the sutures described herein may include ends sufficiently rigid and sharp to dispense the need for positioning the needles together.
[0075] The term "suture thread" refers to the filamentary structural component of the suture. The suture thread may be a monofilament, or it may comprise multiple filaments as in a braided suture. The suture thread can be manufactured from any suitable biocompatible material, and can be additionally treated with any suitable biocompatible material, either to enhance strength, resilience, longevity, or other qualities of the suture, or to equip the sutures to fill fungi additional to joining fabrics, repositioning fabrics, or attaching different elements to fabrics.
[0076] The term "tissue elevation procedure" refers to a surgical procedure to reposition the tissue from a lower height to a higher height (i.e., moving the tissue in a direction opposite to the direction of gravity). The retention ligaments of the face support the soft tissue of the face in a normal anatomical position. However, with age, the gravitational effects and the loss of tissue volume cause the tissue to migrate downward and the fat descends to the piano between the superficial and deep facial fascia, thus causing the facial tissue to sag. Face-lift procedures are designed to lift flaccid tissues, and are yet another example of a class of medical procedures commonly known as tissue elevation processes. More generally, a tissue elevation procedure reverses the appearance, which results in changing the effects of aging and gravity over time, and other temporal effects that cause the tissue to fall, such as genetic effects. It should be noted that the tissue can also be repositioned without elevation; in some procedures, the tissues are repositioned laterally (away from the midline), medially (towards the midline) or lower (lowered) in order to restore symmetry (i.e., repositioned so that the sides left and right of the body "coincide").
[0077] The term "tissue retainer" (or simply "retainer") refers to a feature of a suture filament that is adapted to mechanically engage the tissue and resist movement of the suture in at least one axial direction. By way of example only, the fabric retainer or retainers may include hooks, projections, splinters, darts, extenders, protrusions, anchors, protrusions, spurs, bumps, stitches, teeth, fabrics, swallowing devices, surface roughness, irregularities of the surface, surface defects, edges, facets and the like. In certain configurations, the retaining tissues are adapted to engage the tissue to resist the movement of the suture in a direction other than the direction in which the suture is positioned on the tissue by a surgeon, being oriented to substantially face the positioning direction. In some embodiments, the retainers remain pianos when pushed in a positioning direction and open or "spread" when pushed in a direction contrary to the positioning direction. As the penetrating end of the fabric of each retainer turns away from a positioning direction when moving through the fabric during placement, the fabric retainers must not catch or grip the fabric during this phase. Once the self-retention suture has been positioned, a force exerted in another direction (often substantially opposite the positioning direction) causes the retainers to be displaced from the positioning position (i.e., resting substantially along the body of the suture) , forces the ends of the retainer to open (or "spread") from the suture body in a way that grips and penetrates the surrounding tissue, and results in a tissue being trapped between the retainer and the suture body; "anchoring" or fixing the self-suture suture in place. In certain other embodiments, tissue retainers are configured to allow movement of a suture in one direction and to resist movement of the suture in another direction without spreading or implanting. In certain other configurations, the tissue retainers are configured or combined with other tissue retainers to resist movement of the suture filament in both directions. Typically, a suture that has such retainers is positioned through a device, as well as a cannula that prevents contact between the retainers and the tissue until the suture is in the desired location.
[0078] The term "transition segment" refers to a portion without a retainer of a bidirectional suture located between a first set of retainers oriented in one direction and a second set of retainers oriented in another direction. The transiption segment may be around the midpoint of the self-retention suture, or closer to an end of the self-retention suture to form an asymmetric self-retention suture system.
[0079] The term "wound closure" refers to a surgical procedure to close a wound. An injury, specifically one in which the skin or other internal or external surface is cut, torn, punctured, or otherwise broken, is known as an injury. An injury usually occurs when the integrity of all tissue is compromised (for example, skin cut or burns, muscle lacerations, or bone fractures. An injury can be caused by an act, such as a piercing, falling, or surgical procedure; for an infectious disease, or an underlying medical condition. Surgical closure of the wound facilitates the biological healing event by uniting, or approaching the edges of, those wounds where the tissue has been torn, cut, or otherwise separated. directly opposes or approaches the tissue layers, which serves to minimize the amount of new tissue formation needed to fill the gap between the two edges of the wound. Closure can serve both aesthetic and functional purposes. killed by the approximation of subcutaneous tissues, minimization of scar formation by careful epidermal alignment data, and avoid deep scarring by precise eversion of the edges of the skin. Pharmaco Elution Self-Entertainment Sutures
[0080] As discussed above, modalities of the present invention provide compositions, configurations, fabrication methods and methods of using self-restraint systems in surgical procedures in which the ability to anchor to adjacent tissue provides superior fixation resistance and improves clinical performance, while providing a drug to this tissue that surrounds the suture. Self-Healing Suture System
[0081] Figure 1A illustrates a bidirectional self-suture suture system 100. The self-suture system 100 comprises needles 110, 112 attached to the self-suture thread 102. The self-suture thread 102 includes a plurality of retainers 130 distributed over the surface of a filament 120. In the region of the entry area 140 of filament 120, there are no retainers 130. In region 142 of filament 120 there are a plurality of retainers 130 arranged so that the suture can be applied in region 110 , however, resisting movement towards needle 112. In the transiption region 144, there are no retainers 130. In region 146, there are a plurality of retainers 130 arranged so that the suture can be applied in region 112, while resisting , to the movement in the direction of the needle 110. In the region of the entry area 148 of the filament 120, there are no retainers 130. The rupture is shown in each of the regions 140, 142, 144, 146 and 148 to indicate Note that the length of each region can be varied and selected depending on the intended application of the suture. While a bidirectional self-retention suture system 100 is illustrated, the present invention includes self-retention suture systems from a wide variety of retainer and needle configurations described above. Similarly, the configuration of each of the needles 110 and 112 can be on any variety of different surgical needles developed for use in different applications. Needles 110 and 112 can have the same or different configurations.
[0082] Filament 120 comprises a drug 152 (figures 1C, 1D). Drug 152 is in a coating layer on filament 120 or is impregnated on material 150 of filament 120. Various methods can be used to make sutures that carry drugs. For example, these methods include direct extrusion as described in US patent 6,596,296 (TissueGen, Inc., Dallas, TX, USA) to create filaments in which the drug is uniformly distributed, as in figure 1C. Alternatively, "core / envelope" and other multi-component configurations, as shown in Figure 1D, can also be extruded as described in US patent 7,033,603 (TissueGen, Inc., Dallas, TX, USA). Patents 6,596,296 and 7,033,603 are hereby incorporated by reference. Alternative methods can also be used, as a coating (e.g., sprinkling or dipping) all or part of the sutures or an "around the wire" extrusion, as described in US patent 6,858,222 (TissueGen, Inc., Dallas, TX , USA). Additionally, gradients of the drug over the suture are sometimes preferred. These linear anisotropies are described in US patents 6,596,296, 6,858,222 and 7,514,095 (TissueGen, Inc., Dallas, TX, USA), the latter of which is also incorporated herein by reference. In addition, the sutures themselves can be produced, at least in part, from materials that have pharmaceutical activity in or around the place where the sutures are implanted or inserted. In certain embodiments, only selected portions (such as middle sections or sections of self-restraint) of a self-restraint suture are coated or otherwise comprise the drug or drugs. Additionally in certain embodiments, portions of the sutures are selectively left unassociated with a drug or drugs or are associated with a different drug from another drug associated with a different portion of the self-suture suture. For example, in some embodiments, the surfaces of the suture between the retainer and the main body of the suture, in which the tissue is attached, are selectively associated with one or more drugs that enhance healing and prevent the formation of scars. In other embodiments, the temporarily phased release of one or more drugs can be calculated to coincide with known wound healing phases as a means of reducing the formation of scars and enhancing the body's natural wound healing processes. This can be achieved, for example, by multilayer filaments, as described in US patent 7,033,603 or by using multiple means of incorporating the drug into the filament base material, such as the simultaneous use of nanoparticles and microspheres in the same filament as described in US patent 6,858,222. In certain other embodiments, the surface of the suture may comprise one or more cavities, including one or more drugs. In other embodiments, all sections of sutures are coated with the drug (s). The methods of the present invention for applying drugs to sutures include, for example: (a) extruding, (b) attaching the suture directly to a formulation (for example, either by spraying the suture with a polymer / drug film or by immersion of the suture in a polymer / drug solution), (c) coat the suture with a substance such as a hydrogel that, in turn, will absorb the composition, (d) interlace a thread coated by the formulation (or the polymer itself formed in a thread) in the suture structure in the case of sutures with multiple filaments, (e) produce the suture itself with a composition containing the drug.
[0083] Drug-eluting self-retention suture systems 100 (including barbed sutures) differ from conventional sutures in that, in addition to delivering drugs directly to a tissue of interest, the self-suturing sutures have numerous tissue retainers 130 (like splinters) that anchor the self-retention suture system 100 to the tissue after application and resist movement of the suture in a direction opposite to that the retainers are facing, thus eliminating the need to tie us in to fix adjacent tissues one to the other (a "no no" closure). The self-retreating suture systems for drug elution for wound closure also result in a better approximation of the wound edges, evenly distributing the tension along the length of the wound (reducing the areas of tension that can rupture or lead to ischemia), decrease the volume of suture material remaining in the wound (by removing the knots) and reduce the expulsion (the extrusion of suture material - typically in the knots - through the skin's surface. All of these features are designed to reduce the formation of scars, improve cosmesis, and increase the resistance of the wound in relation to the closure of the wound with simple sutures or staples. Thus, the self-retention sutures, due to the fact that these sutures prevent knotting, allow patients to experience an improved clinical result, and also save time and costs associated with prolonged surgeries and follow-up treatments. knotting knots, drug-eluting self-entertaining sutures prevent local drug concentrations close to such knots.
[0084] The ability of the self-healing sutures to elude drugs to anchor to hold tissues in place even in the absence of tension applied to the suture by a knot, and a feature that provides superiority over simple sutures. When closing a wound that is under tension, this advantage manifests itself in several ways: (i) the self-restoring sutures have a multiplicity of retainers that can dissipate the tension along the entire length of the suture (by providing hundreds of stitches " anchor ", this produces a superior cosmetic result and reduces the chance that the suture" slips "or passes through) as opposed to interrupted sutures with knots that concentrate the tension at different points; (ii) complicated wound geometries can be closed (circles, arcs, irregular edges) uniformly with more precision and accuracy than those obtained with interrupted sutures; (iii) the self-retaining sutures eliminate the need for a "third hand", which is often necessary to maintain tension throughout the wound during traditional suturing and knotting (to prevent "slipping" when tension is released) momentarily during mooring); (iv) self-entertainment sutures are superior in procedures where knotting is technically difficult, such as in deep wounds or laparoscopic / endoscopic procedures; (v) self-retention sutures can be used to approximate and fix the wound before definitive closure, (vi) self-eluting self-retention sutures can deliver drugs more uniformly to a tissue through wider and more uniform distribution in the fabric; and (vii) the retainers of a drug eluting self-retention suture provide an additional interface for the distribution of drugs in the tissue. Pharmaceuticals for Incorporation into the Self-Entertainment Suture
[0085] The purpose of the drug eluting self-retention suture determines the type of drug that is applied to or incorporated into the suture. For example, self-suturing sutures that have antiproliferative drugs can be used to close tumor excision sites, self-suturing sutures containing or being coated with neural growth factor (NGF) can be used to repair damaged nerves, while sutures of self-retention with fibrous forming drugs can be used in tissue repositioning procedures and those with scar anti-forming drugs can be used to heal skin wounds. Bone growth factors, such as Bone Morphogenic Proteins (BMP) can also be incorporated into the sutures. Pharmaceuticals can also include a plurality of compositions or joints or in different portions of the suture, where multiple compositions can be selected for different purposes (such as combinations of growth factors, analgesics, anti-infective agents and anti-scarring) or for the synergistic effects of the combination.
[0086] The drug or drugs incorporated or applied as a coating over a self-retaining suture in the embodiments of the present invention include, for example, compositions to promote healing and prevent undesirable effects, such as scar formation, infection, pain and so on. Pharmaceuticals include, but are not limited to, growth factors such as neural growth factor (NGF), bone growth factor (BGF- Bone Growth Factor), tissue repair factors, trophic factors to guide tissue repair, agonists inhibiting agents to suppress factors that inhibit tissue repair, mitogenic agents to promote cell division for tissue repair, antiproliferative agents, anti-angiogenic agents, anti-infective agents, fibrosis-inducing agents, scar anti-forming agents, lubricating agents, agents echogenic, anti-inflammatory agents, cell cycle inhibitors, analgesics and antimicrotubule agents. In one embodiment, a drug can be used in conjunction with the suture (introduced separately or attached to the suture or incorporated into a suture material) to promote fibrosis. Fibrosis-inducing drugs that can be used in conjunction with a drug-eluting self-healing suture in accordance with the present invention are described in US patent 7,166,570, the title of which is "Medical Implants And Fibrosis-Inducing Agents" Hunter et al., which is incorporated by reference. Other drugs that can be used in the drug eluting self-entertainment suture of the present invention include all the drugs and agents disclosed in patent application US 12 / 162,572 whose title is "Sutures And Anti-Scarring Agents" granted to Avelar et al, which and incorporated herein by reference.
[0087] In some embodiments (figure 1C), drug 152 is uniformly distributed in material 150 of filament 120. In other embodiments (figure 1D), drug 152 is distributed in an anisotropic manner. For example, filament 120 may have higher concentrations of a drug in an outer layer of material compared to the inner core of the material or vice versa. In addition, for example, filament 120 may have a higher concentration of a drug at one end compared to the other. In addition, for example, filament 120 may have a higher concentration of a drug in the middle than towards the ends. When a drug is distributed anisotropically in a filament 120, the concentration of drug 152 may gradually change from region to region or there may be changes in concentration from one region to another region. Different regions of filament 120 that have different concentrations of drug, may correspond to regions of filament 120 that have retainers, that have no retainers or retainers in one orientation compared to another orientation. When a drug 152 is distributed anisotropically in a filament 120, filament 120 may be provided with visible or otherwise detectable markers, where these markers indicate regions that have higher or lower concentrations of drug 152, so that said regions are identified during manufacture and / or use of the self-suturing system 100.
[0088] In other modalities, a very thin coating, which includes one among more drug (s) can be applied to the suture using any of the aforementioned techniques before the retainers are formed, so that when the retainers engage, the surface of coupling is substantially free of the coating. In this way, the fabric being sutured comes into contact with a coated surface of the suture as the suture is introduced, but when the retainer engages an uncoated surface, the retainer comes into contact with the tissue. Other modalities that can provide suture surfaces with exposure to the drug include extruded sutures having the drug (s) uniformly dispersed (as) as in Figure 1C, extruded sutures as a multi-layered "core / wrap" arrangement, as shown in figure 1D, and coated sutures after or during the formation of retainers in the suture body if, for example, a selectively coated suture is desired, instead of a fully coated suture. In yet another alternative, a suture is selectively coated, during or after forming retainers by exposing only selected portions of the suture to the coating.
[0089] The specific purpose to which the suture or composition must serve, can determine whether a fully or selectively coated suture is suitable, for example, coatings such as those comprising fibering agents can be applied, suitably, to the entire suture or to part of the suture (such as tissue engagement surfaces). Coatings such as those comprising compounds such as growth factors can be applied appropriately to the entire suture and / or be incorporated into the material from which the filament is made prior to forming the retainers. Methods for preparing drug-loaded filaments are described in: US patent 7,514,095, whose title is "Fabrication Of Drug Loaded Biodegradable Polymer Fibers" and US patent 7,033,603, whose title is "Drug Releasing Biodegradable Fiber For Delivery Of Therapeutics ", both of which are incorporated herein by reference. Additional methods of loading a drug into a preformed filament can also be used, including, but not limited to, dip coating, spray coating, curtain coating and / or chemical deposition (such as chemical vapor deposition) DVQ). Furthermore, if material 152d of filament 120d (figure 1D) is a porous material, drug 152d can be impregnated in filament 120d by immersing filament 120d in a solution of drug 152d. Drug 152d diffuses from the outside of filament 120d towards the center by controlling the time allowed for this diffusion, the concentration of drug 152d in filament 120d in center 162 can be taken less than the concentration in the region of envelope 160.
[0090] The structure of the suture can influence the choice and length of order and / or incorporation of a drug or drugs; for example, sutures that have an expanded segment may include a fibrosis-inducing composition on or over the expanded segment to further secure the segment in position in the tissue. The sutures used in tissue repair may include, for example, a concentration gradient of the trophic factors, so that the surface provides a gradient of trophic factors to the tissue to guide the repair. The structure of the suture and retainers can influence / control the release kinetics of the drug or drugs. The site of incorporation of the drug coating will also influence / control the kinetics of drug release.
[0091] The sutures are formed in a variety of configurations and sizes, the exact dose of drug administered will vary according to the size of the suture, its length, its diameter, its surface area, design and portions of the coated suture. However, certain principles can be applied when ordering this technique. For example, in the context of coated sutures, the dose of drug can be calculated as a function of dose per unit area (of the portion of the suture being coated), or total dose of the drug. The total dose administered can be measured and suitable concentrations of the active drug on the surface can be determined. The total amount of drug administered will typically be substantially less than the equivalent systemic dose, because, when associated with self-retention suture, the drug will be distributed directly close to the target tissue, rather than being uniformly distributed throughout the body. Regardless of the method of ordering the drug to suture, the preferred agents, used alone or in combination, should be administered under the following dosing guidelines:
[0092] In the embodiments of the present invention, drugs are used in concentrations ranging from several times more than, up to 50%, 20%, 10%, 5%, or even less than 1% of the concentration typically used for a systemic dose application. In certain embodiments, the drug is released from the composition in effective concentrations over a period of time that is measured from the time of infiltration into the tissue adjacent to the suture, which ranges from about less than 1 day to about 180 days. In general, the release time can also be from about less than 1 day to about 180 days; from about 7 days to about 14 days; from about 14 days to about 28 days; from about 28 days to about 56 days; from about 56 days to about 90 days; from about 90 days to about 180 days. The release kinetics is affected by the surface area of the retainers in a particular region and, therefore, must be validated for specific configurations of retainers in order to achieve the desired final kinetics.
[0093] For example, when anti-infective agents are associated with a self-retention suture, alone or in combination, they can be administered under the following dosing guidelines. The total amount (dose) of anti-infective agent in the composition can be in the range of about 0.01-1 pg, or about 1-10 pg, or about 10-100 pg or about 100 pg-1 mg or about 1-10 mg, or about 10-100 mg, or about 100 to 250 mg to coat a suture or portion thereof or to infiltrate tissue where a suture has been, is being, or will be implanted, or about 250-1000 mg to infiltrate tissue where a suture has been, is being, or will be implanted. In certain embodiments of the present invention, the dose (amount) of anti-infective agent per unit suture area or tissue surface to which the agent is applied, can be in the range of about 0.01 pg / mm2 to 1 pg / mm2, or about 1 pg / mm2 to 10 pg / mm2, or about 10 pg / mm2 to 100 pg / mm2, or about 100 pg / mm2 to 250 pg / mm2. As different filament materials and retainer configurations will release the anti-infective agent at different rates, the above dosage parameters should be used in combination with the rate of drug release from the filament and the retainers, so that a minimum concentration about 10 "8 Ma 10" 7 M, or about 10 "7 M to 10-6 M or about 10" 6 M to 10 "5 M or about 10" 5 M to 10 "4 M of the agent be kept close to or on the surface of the tissue to maintain the desired therapeutic effect for the period of time required. The minimum concentration required depends on the potency of the agent under consideration and can be determined using standard tests such as the minimum inhibitory concentration test.
[0094] Figure 1B illustrates an enlarged view of the self-suture suture 102 in region 142. As shown in figure 1B, a plurality of retainers 130 are distributed on the surface of filament 120. Fixing the self-suture sutures after positioning in the tissue it involves penetrating the ends of the retainer into the surrounding tissue resulting in the tissue being trapped between the retainer and the suture body. The inner surface of the retainer that is in contact with the fabric that is trapped between the retainer 130 and the filament 120, mentioned in the present invention, as the "engaging surface of the fabric" or "inner surface of the retainer", can be adapted to better engage the tissue and also to better distribute the drugs in a tissue. As shown in Figure 1B, each retainer 130 has a tip 132 and a tissue retaining surface 134. When the self-suture suture 102 is moved in the direction of arrow 138a, retainer 130 is piano next to the body of filament 120. However, when the thread of the self-suturing suture 102 is moved in the direction of the arrow 138b, the tip 132 or the retainer 130 engages the fabric surrounding the filament 120 and causes the retainer 130 to leave the filament 120 and engage the fabric with the face 134, thus preventing movement of the suture in that direction and providing an additional surface from which drugs are delivered to the tissue. It should be noted that the surface area of filament 120 is also increased by the presence of retainers 130 when compared to portions of filament without retainers.
[0095] Figure 1C shows a cross-sectional view of filament 120. As can be seen in figure 1C, filament 120 includes a material 150 and a drug 152. In the embodiment of figure 1C, the distribution of drug 152 is isotropic or homogeneous across the radius of filament 120. Figure 1D shows a cross-sectional view of an alternative filament 120d. As can be seen in figure 1D, filament 120d includes material 150d and drug 152d. In the embodiment of figure 1D, the distribution of drug 152d is anisotropic across the radius of filament 120. Specifically, the concentration of drug 152d is greater in a region of envelope 160 of filament 120d than in the region of nucleus 162.
[0096] In alternative embodiments, a retainer 130 may comprise the material of the region of envelope 160 and also some portion of the region of core 162 or other material than that of the envelope. In such modalities the materials are selected so that the properties of the materials in the retainer allow or enhance the function of the retainer, as facilitating the lifting of the retainer 130. As most of the drug 152d is closer to the surface of the filament 120d when making In comparison with the modality of figure 1C, drug 152d can be expected to be applied to the tissue more quickly than in the modality of figure 1C. On the other hand, when higher concentrations of the drug are found in the region of nucleus 162, drug 152d can be expected to be applied to the tissue less quickly. Thus, the distribution of the drug concentration can be used to control the release kinetics of the drug or drug (s) and / or to sequence the release of drugs from a self-entertainment suture. In alternative modalities, different drugs are provided in the region of the nucleus 162 and in the region of envelope 160. In such a case, the drug in the region of envelope 160 will be supplied before and or faster than the drug in the region of nucleus 162 - allowing the temporal sequencing of drug distribution to tissue.
[0097] Filament 120d is formed by any method known in the art to produce a filament having a drug associated with one or more components thereof (for example a nucleus and / or a wrapper) (drug eluting suture). A suitable method is to coextrude materials that have the required concentration of drug, as disclosed in U.S. Patent 7,033,603 and further described with reference to Figure 3A. Another suitable method is the extrusion of a material over a preformed filament, as disclosed in US patent 6,596,296 (TissueGen, Inc., Dallas, TX, USA), incorporated into the present invention by reference, and which will be further described with with reference to figure 3B. When drugs are incorporated into material 150d before or during the manufacture of filament 120d, care must be taken to ensure that the manufacturing process does not cause denaturation of drug 152d. Furthermore, it is necessary to establish controls so that the manufacturing processes of the filament and the retainer do not cause cross-contamination of the drugs from one suture batch to another suture batch.
[0098] Figure 1E shows a sectional diagram through a retainer 130. It is observed that when a retainer 130 is cut into filament 120, it leaves a cut-out depression 136. The cut-out depression 136 has a cut-off point 135 that corresponds to tip 132 of the retainer 130. The geometry of the retainer 130 (angle of cut of the retainer, depth of cut of the retainer, length of cut of the retainer, distance of cut of the retainer, etc.) and / or the spatial arrangement of the retainers 130, are varied from to improve the engagement of the fabric by the retainers. The retainer 130 is shown elevated above the filament 120 in order to show the parameters related to the retainer and the elevation of the retainer.
[0099] The parameters shown in figure 1E include the longitudinal axis of the AA suture, the diameter of the SD suture, the length of the retainer L, the cutting depth of the retainer D, The cutting angle of the retainer 0 (theta), the angle Lifting height of retainer E (epsilon), the cutting distance of retainer P. The cutting distance Pea is the distance between retainers in adjacent positions measured along the longitudinal axis. It can be measured as the distance from a cutting tip 135 to the cutting tip 139 in an adjacent position. The cutting angle of the retainer 0 and the angle between the cutting depression 136 and the surface of the longitudinal axis AA of the filament 120. The cutting angle 0 can be measured between the cutting depression 136 and the surface of the filament 120, which is parallel to the longitudinal axis AA. The elevation angle of the retainer E is the angle between the inner surface of the retainer 134 and the depression surface of the cut 136. The spiral angle is the angle of rotation about the longitudinal axis between adjacent cutting points 135, 139. When the retainers adjacent are on opposite sides of filament 120, as shown in figure 1E, the spiral angle is 180 degrees. Figure 1F shows a section of an alternative filament configuration when looking along the major axis. As shown in figure 1F, the spiral angle is 120 degrees. Figure 1F also shows a straight line illustrating the position of the base 137 of the cut depression 136. For a straight cut, as shown in figure 1F, the depth of cut D is the maximum distance between the base 137 and the surface of the filament 120 . Retainer Formation and Elevation
[00100] The self-retaining suture threads described herein are produced by any suitable method, including, but not limited to, injection molding, stamping, cutting, laser, extrusion and so on. With regard to cutting, the polymeric thread or filaments are manufactured or purchased for the suture body and the retainers can be cut subsequently in the suture body; the retainers are cut manually, laser cut, or mechanically machined using blades, cutting discs, grinding discs and so on. A drug is coated on the filament or impregnated in the filament material before, during or after the filament is created. During cutting, the cutting device or suture is moved relative to the other, or both are moved, to control the size, shape and depth of the cut and the resulting retainer. The particular methods for cutting barbs into a filament are described in US Patent Application Serial No. 09 / 943,733 entitled "Method of Forming Barbs on a Suture and Apparatus for Performing Same" by Genova et al., And patent application no. US Serial No. 10 / 065,280 entitled "Barbed Sutures" by Leung et al. in which both are incorporated by reference.
[00101] Now with reference to figures 2A, 2B and 2C, where an exemplary process for producing a retainer 130 in filament 120d is provided. Figure 2A shows a longitudinal cross section of filament 120d. As shown in Figure 2A, filament 120d comprises the region of nucleus 162 having a lower concentration of drug 152d in material 150d and a region of envelope 160 which has a higher concentration of drug 152d. In alternative modalities, a different drug or drug (s) are provided in the region of nucleus 162 compared to the region of envelope 160. In alternative modalities, equal concentrations of a drug or drug (s) are provided over the entire radius of the 120d filament.
[00102] As shown in figure 2B, a retainer 130 is formed in filament 120d by making a cut 210 in the envelope region 160 of filament 120d. The 210 cut can be made using any of a wide range of technologies. Such technologies include manual cutting, laser cutting or cutting by mechanical machining using blades, cutting discs, grinding discs and so on. It is observed that in this modality, the depth of cut was selected so that the cut 210 is completely within the region of envelope 160 and does not penetrate the region of the core 162. As shown in figure 2B, the retainer 130 can still be against the piano the surface of filament 120d after cutting 210 has been made in the material of the envelope region 160.
[00103] In order for the retainer 130 to more effectively engage the fabric after positioning, the tip 132 is preferably raised above the surface of the filament 120d. As shown in figure 2C, after the cutting step of the retainer in figure 2B, retainer 130 is mechanically folded away from the body of filament 120d in the direction shown by arrow 220. Tip 132 is moved above the surface of filament 120d and a fabric coupling superffeie 134 and exposed. The cut of the filament super 234 is also exposed. The lifting of the retainer 130 can be achieved by means of several mechanisms. In a simple example, a cutting blade is used to form the cut 210 and then the cutting blade is removed from the cut 210 in a way that folds the retainer 130 away from the body of the filament 120d. In an alternative example, the retainer is mechanically lifted by a device other than the blade. When drug 152d is incorporated into filament 120d before forming retainers 130, care must be taken to ensure that the retainer formation process does not cause denaturation of drug 152d.
[00104] If the material 150d is very elastic, the retainer 130 will return to the previous position of the retainer, flush with the surface of filament 120d (as shown by the dotted line) after lifting the retainer. This is also the case if the material does not have the capacity to undergo permanent deformation. Thus, according to one embodiment of the present invention, material 150d is selected so that it is sufficiently deformable from a plastic point of view, so that after retainer 130 has moved away from filament 120d, retainer 130d remains in its new deformed shape with the tip 132 of the retainer 130 substantially elevated above the surface of the filament 120d and the fabric engaging surface 134 is exposed. The material of the envelope 150d is selected so that the mechanical movement away from the tip 132 of the retainer with respect to the filament 120d is sufficient to plastically deform region 230 of the envelope region 160 at the base of the retainer 130, causing it to assume a new permanent format. In some embodiments, the core region 162 is produced from a different material than the envelope region, thus allowing the selection of a material 162 to be made so as to have significantly lower plasticity and elasticity and / or tensile strength significantly higher than the envelope region. In other embodiments, the filament is produced from a single polymer. In other embodiments, the filament is produced from a single polymer, but the polymer comprises different concentrations of drug in different regions of the filament.
[00105] When a retainer 130 is formed on filament 120d, the surface area of filament 120d and retainer 130 is increased with respect to the filament alone. Essentially, a surface is enlarged by the surface area of the fabric engaging surface 134 and the cut filament surface 234. When a drug 152d is impregnated in material 150d of filament 120d, the release kinetics of the drug is affected by the surface area. Due to the fact that retainers 130d are formed on the surface of filament 120d, retainers 130d are produced, in this embodiment, entirely from envelope region 160 containing a higher concentration of drug 152d. Furthermore, in specific embodiments of the present invention, retainers 130d include little or no core region 162. Thus, the size, number and density of retainers 130, among other factors, can affect the kinetics of drug release in the regions of the retainers 130 that have the filaments. The release kinetics is affected by the surface area of the retainers in a particular region and, therefore, must be validated for specific configurations of retainers to achieve the desired final kinetics.
[00106] In some embodiments, a drug can be distributed homogeneously along the length of filament 120d, and yet, the release kinetics will be made anisotropic by the distribution, shape or size of the retainers 130. For example, in regions of the filament 120 which have a greater density of retainers 130, the drug is released to a tissue faster than in regions that have less retainers or that do not have retainers. In addition, for example, a section of filament 102d that has no retainers, can release the drug more slowly and for a longer period of time. Alternatively, the drug is distributed heterogeneously in regions other than a 102d filament so that the release kinetics is homogeneous in regions that have more retainers, less retainers or that do not have retainers. Furthermore, in some embodiments, filament 120d is provided with a coating (not shown) that slows or prevents the migration of drug 152d out of filament 120d. In such a case, drug 152d will migrate out of filament 120d preferably or faster where the retainers 130 break the coating and expose the interior of filament 120d on the fabric engaging surface 134 and the cut surface of filament 234.
[00107] In other embodiments, the retainer 130 is formed by a process other than cutting it in the filament envelope. For example, as shown in figure 2D, the retainers can be formed by melting the material 150d in region 240 and then, by stretching the filament-like material 120d with the device 244 to form the retainer 130 and, finally, cooling the material 150d. In this embodiment, the material 150d is selected so that it can be melted and manipulated without affecting the drag resistance of the region of the core 162. In alternative embodiments, a retainer is preformed and fixed mechanically, adhesive or by melting to the wrap. The material of the wrapper, in this embodiment, is selected to improve the fastening of the retainer to the filament and the retention of the retainer by the filament. In another embodiment, the molten material is formed into the wrapper in the shape of a retainer and the molten material merges with the material of the wrapper. In this case, the material is selected so that it increases the adhesion or fusion with the externally applied molten material. In some cases, the molten material is the same material as filament 120d and may include drug 152d. When drug 152d is incorporated into the filament or material of the retainer 120d prior to forming the retainers 130, care needs to be taken to ensure that the process of forming the retainer does not cause denaturation of the drug 152d.
[00108] In certain other modalities, the suture is a relatively short suture with sharp pointed ends. This suture can work similarly to a staple when used in connecting tissues and thus allows a surgeon to quickly and securely attach the edges of a wound to a body tissue or reconfigure the tissue without the need to thread and tie numerous individual points or to use complicated tools and / or techniques to insert the suture. This type of suture can therefore be referred to as a "connecting suture". In certain embodiments, the connector suture is a bidirectional self-suture suture. In certain other embodiments, the connecting suture can be made by attaching two relatively short unidirectional self-suturing sutures to form a bidirectional self-suturing suture (see, US patent No. 6,241,747). In other embodiments, the drug-eluting self-entertaining suture is used to anchor a two-dimensional or three-dimensional frame comprising a woven, non-woven or mesh network, wherein said fibers comprise any of the compositions described herein. The network may include additional filaments that may or may not be drug-eluting filaments. Filament Materials
[00109] The filament material is selected so as to have useful properties for the formation, elevation and positioning of the retainer, as well as resistance and flexibility of the self-retention suture. In some embodiments, a different material is used in the core of the suture as opposed to the wrap. In such cases, the core is chosen based on its strength and flexibility properties and the material of the envelope is selected so as to have useful properties for the formation, elevation and positioning of the retainer. The suture materials are non-degradable or biodegradable, as long as the material is suitable for coating or incorporating a drug and releasing said drug in vivo with proper release kinetics. Suitable materials include many materials that are currently used to make sutures. The release kinetics is affected by the surface area of the retainers in a particular region and, therefore, must be validated for particular retainer configurations to achieve the desired final kinetics.
[00110] Suitable non-degradable suture materials include polyamide (also known as nylon, such as nylon 6 and nylon 6), polyester (eg polyethylene terephthalate), polytetrafluoro ethylene (eg polytetrafluoro ethylene expanded), polyether ester as polybutester (butylene terephthalate block copolymer and polyethylene methyl ether glycol), 4-hydroxybutyrate, polyhydroxylalkanoate, polyurethane, metals and metal alloys (for example, stainless steel wire), polypropylene, polyethylene, silk, cotton and / or combinations thereof.
[00111] Biodegradable materials suitable for the filament include single polymer, copolymer or a blend of polymers of poly (L-lactic) acid, poly (p-dioxanone), poly (DL-lactic) acid, polycaprolactone, poly (glycolic acid) , polyanhydride, polyglycolic acid homopolymer, copolymers of glycolide and e-caprolactone, copolymers of glycolide and lactide, copolymers of trimethylene carbonate and glycolide with diethylene glycol (eg MAXON ™, Tyco Healthcare Group), polyhydroxylalkanes (such as poly (4 - hydroxybutyrate) or poly (4-hydroxybutyrate-co-3-hydroxybutyrate)), terpolymer composed of glycolide, trimethylene carbonate and dioxanone (eg BIOSYN ™ [glycolide (60%), trimethylene carbonate (26%), and dioxanone (14%)], Tyco Healthcare Group), glycolide copolymers, caprolactone, trimethylene carbonate, and lactide (for example, CAPROSYN ™, Tyco Healthcare Group). Naturally occurring polymers can also be used, such as reconstituted collagen, fibrin or natural silks, cellulose, starch, chitin, polypeptides, modified polysaccans, modified proteins and / or combinations of the aforementioned with the mentioned synthetic suture materials. Other polymers that can be used in the drug eluting self-healing sutures of the present invention include all of the polymers presented in U.S. patent application 12 / 162,572 whose title is "Sutures And AntiScarring Agents", granted to Avelar et al. which is incorporated by reference. Filament Stock Fabrication
[00112] As described above, a drug eluting suture filament can be produced in many different ways. According to an embodiment of the invention including thermally stable drug (s), a monofilament 320 is formed by coextruding two materials. As shown in figure 3A, satellite extruder 310 heats, melts and extrudes a first material 311 along conduit 312 to main extruder 330. The metering pump 313 in conduit 312 controls the flow of first material 311 to extruder main 330. A second satellite extruder 315 heats, melts and extrudes a second material 316 along the conduit 317 to the main extruder 330. The metering pump 318 in the conduit 317 controls the flow of the second material 316 to the main extruder 330 .
[00113] In the main extruder 330, the two molten materials 311, 316 flow through two flow paths 336, 338 through an extrusion die 332 which controls the arrangement of the two materials 311, 316 when the materials combine in the flow channel flow 339. The two materials can confer different concentrations of a drug. The two materials are combined in the flow channel 339 as shown and are then extruded from the matrix 332 through the outlet of the matrix 334. The matrix 332 and the flow channels 336, 338, 339 are designed and operated so that the two materials 311 and 316 do not mix in flow channel 339. Fiber 340, which is still molten material, is then solidified by liquid or air cooling in the blast cooling stage 350. The blast cooling stage 350 optionally includes a sudden cooling bath (tempera) 352 for liquid cooling. The solidified filament 342 is then drawn on the 360 drawing machine. Typically, the solidified filament is drawn at temperatures between 30-80% of the melting point (Celsius). The suture is usually extruded and then drawn into several cylinders with decreasing temperature. The filament drawing reduces the diameter of the filament while orienting the molecules of the filament polymers and improves the tensile strength of the filament. Typically the drawing is carried out in a continuous process by winding the filament around a series of cylinders, where each cylinder in this series has a slightly higher surface velocity of the cylinder. The speed differential of the cylinders results in the stretching of the filament as the filament passes from one cylinder to another cylinder. The filament can also be tempered by means of one or more heating and cooling steps before, during or after the drawing process. As shown in figure 3A, the drawn filament 344 and quenched in the tempering machine (sudden cooling) 370 as the filament is passed through the heating unit 372. After the filament has been drawn and quenched, the finished monofilament 346 is passed to the winder 364 where the monofilament is wound on the drum 366 until it is requested for the preparation of self-suturing sutures. When a drug is incorporated into material 311 and / or 316 before or during the manufacture of filament 342, care is needed to ensure that the filament manufacturing process does not cause denaturation of the drug. Alternatively, a drug is deposited or impregnated in the filament during or after extrusion of the filament.
[00114] Figure 3B illustrates an alternative method of making a filament suitable for use in embodiments of the present invention that include thermally stable drug (s). As shown in figure 3B, a core filament 380 is drawn through an extrusion die 382. The satellite extruder 385 heats, melts and extrudes an envelope material 386 via conduit 387 to the matrix 382. The metering pump 388 controls the flow of envelope material 386 to the flow path 389 of matrix 382. The material supply rate of envelope 386 and the movement rate of core filament 380 are controlled so that a material of envelope 386 is uniformly coated in the core filament 380 in the desired cross section (as determined by the cross section of the extrusion nozzle 390). A suitable method for manufacturing a filament comprising a core coated with extruded material is described in U.S. Patent 6,183,499, the title of which is "Surgical Filament Construction", granted to Fisher et al. which is incorporated by reference. The finished filament 392 comprising the core filament 380 and the casing material 386 can be abruptly cooled, quenched and stretched and then rolled into a drum as shown in figure 3A. However, in certain embodiments, the core filament 380 may have already been drawn and no further drawing of the finished filament 392 may be necessary or desirable. In some embodiments, for example, a core filament of a core material can be extruded and then drawn. Then, the same material can be extruded onto the core filament (as shown in figure 3B) without subsequent drawing of the filament. The resulting filament has a core and wrap of the same material, however, the wrap material has different physical properties than the core material because the wrap material does not have to go through the drawing process. When a drug is incorporated into material 380 and / or 386 before or during the manufacture of filament 392, care must be taken to ensure that the filament manufacturing process does not cause denaturation of the entire drug.
[00115] In another embodiment, the materials can be spun in the form of fibers to be used as monofilament or multiple filament sutures. In order to produce fibers having the core / wrap structure of Figure 1, the materials constituting the core and wrap are separately fused. The constituent materials are fed separately as polymer melts on a spinner and are combined on the spinner just before the spinner's orifice of spinner. The spinning device can have a spinner or a plurality of spinners. The filament produced by a spinner undergoes subsequent processing such as sudden cooling, drawing and tempering in order to produce a filament suitable for use in the embodiments of the present invention. Specific apparatus and methods for forming suitable monofilaments for use in the present invention can be found in US patent 7,070,610 whose title is "Monofilament Suture And Manufacturing Method Thereof, granted to Im et al. And in US patent 6,315,788 whose title is "Materials And Surgical Articles Made Therefrom" granted to Roby, both of which are hereby incorporated by reference. Although the extrusion in Figures 3A and 3B has been illustrated, any suitable manufacturing process can be used to form the filaments used as a filament starting material for self-retaining suture modalities of the present invention.
[00116] In modalities in which the drug is not thermally stable, other methods of manufacturing the filament can be used to achieve the same "core / envelope" or "around the filament" provisions. Such methods include those described in U.S. Patent 6,596,296 (TissueGen, Inc., Dallas, TX, USA), which is incorporated by reference. According to such an embodiment of the invention, a wrap is applied to a woven core or a woven core. Figure 3C illustrates a method by which the coating can be carried out. As shown in figure 3C, a precursor polymer supply device provides a precursor polymer 316a along the conduit 317a to the coating chamber 301. The metering pump 318a in the conduit 317a controls the flow of precursor polymer 316a to the coating chamber 301. A preformed locked core 381 is drawn through the coating chamber 301 where it is coated by the precursor polymer 316a. The rate of supply of precursor polymer wrapper 316a and the rate of movement of the locked core 381 are controlled in such a way that the precursor polymer 316a is uniformly coated over the core 381. The locked core 381 coated by the precursor polymer 316a passes the chamber coating 301 for the polymerization chamber 302.
[00117] As shown in figure 3C, a polymerization agent delivery device supplies a polymerization agent 316b along the conduit 317b to the polymerization chamber 302. The metering pump 318b in the conduit 317b controls the flow of polymerization agent 316b for the polymerization chamber 302. The preformed locked core 381 is stretched through the polymerization chamber 301, the precursor polymer coating 316a comes into contact with the polymerization agent 316b and causes the polymerization to begin - starting with the surface. The rate of supply of polymerization agent 316b and the rate of movement of the locked core 381 are controlled in such a way that the precursor polymer 316a is uniformly polymerized in the core 381. Locked core 381 is coated with a polymer wrap 355 through the polymerization 302 to the polymerization chamber 302 through the nozzle 391, which guides the configuration of the polymer shell. The finished suture 356 with the locked core 381 and the polymer wrapper 355 can be subjected to suitable post-processing and then rolled into a drum until ready for forming the tissue retainers.
[00118] In certain embodiments, it may not be necessary or desirable to draw the finished suture 356 after forming the 355 polymer wrap. In some embodiments, for example, fibers for the production of a stranded 381 core are extruded and drawn and, subsequently, the fibers are braided to form the stranded core 381. The stranded core 381 can no longer undergo drawing. The polymer wrapper 355 is then deposited on the stranded core 381 (as shown in figure 3C). However, the finished suture 356 is not drawn after the deposition of the polymer wrapper 355. In some embodiments, the polymer wrapper 355 may be of the same polymer as the stranded core 381, however having different physical properties because of the different treatment (that is, the stranded core has different physical properties than the polymer wrap because the fibers of the core were drawn before being stranded and the material of the wrap was not drawn after polymerization)
[00119] In some embodiments, a drug is associated with the 355 polymer wrap during the coating and polymerization stage. In other embodiments, a drug is associated with the stranded core 381 before or after the manufacture of the stranded core 381 and before deposition of the 355 polymer envelope. For example, a drug can be associated with the stranded core 381 by immersing the stranded core in it is a solution that includes the drug and allowing the solution to diffuse to the transcribed nucleus. Subsequently, a 355 polymer wrapper is deposited and seizes the drug inside the trapped nucleus 381 until implantation and release of the drug through the polymer wrapper. In other embodiments, a drug is associated with each 381 locked core and 355 polymer wrapper. .
[00120] Many different sutures and / or braided threads can be used as the braided core 381 of a self-retained braided suture, in accordance with the modalities of the present invention. For example, core 381 may be a conventional braided suture material. For example, closed sutures such as VICRYL ™, SURGICRYL ™, BIOVEK ™, VISORB ™, POLYSORB ™, SURGISORB ™, and DEXON ™ can be provided with a biodegradable wrap suitable for the formation of retainers and the resulting closed self-healing suture will be useful. in applications where it is desired to have an absorbable self-suture suture, which maintains its resistance to swallowing for a period of three to four weeks and which is completely absorbed by hydrolysis over a period of ten weeks. These sutures are manufactured using polyglycolic acid (APG) material braided and can be covered by a polymer wrapper in which the retainers can be cut. The retainers can be formed in the envelope layer creating self-entertaining sutures locked in accordance with the modalities of the present invention.
[00121] In another example, closed sutures such as ARTHREX ™ FIBERWIRE ™ can be provided with a non-biodegradable wrap suitable for the formation of retainers and the resulting closed self-retention suture will be useful in applications where a strong, non-absorbable suture is desired. FIBERWIRE ™ includes a blend of a multi-stranded polyethylene core with ultra high molecular weight with a woven polyester wrap and can have an extruded polyester coating, in which the seals can be cut. The retainers can be formed in the wrapping layer, creating self-entertaining sutures woven in accordance with the modalities of the present invention. Substantial retainers can be suitably provided to engage the soft tissue to approximate, for example, the tissue to the bone. The retainers are designed to be effective in engaging target tissues, for example, hard tissues, fascia, capsule-like structures, meniscus type, glenoid lip in the shoulder, tendon flexors or tendons, rotator cuff. Typically, the suture will attach such tissues to the bone or periosteum. Thus, the strained suture may include a suture Iago of the anchoring device at one end to engage a bone tunnel, bone, periosteum, or other stable anatomical structure I. These strained sutures can be used in arthroscopic applications where desired a strong non-absorbable self-retaining suture. Filament Confiouracbes
[00122] Depending on the configuration of the extruders, the die, the spinning block, the spinner or other manufacturing equipment, a suitable filament can be created to create a self-holding suture for eluting drug, according to the modalities of the present invention , with a wide variety of different devices of different materials. In addition, the filaments can be made using two, three, four or even more different component materials and / or two, three, four or even more different drugs or drug concentrations, if necessary or desired for the particular application . Different filament configurations are useful in specific embodiments of the present invention and will be described below with respect to figures 3D-3F and 4A-4I. The arrangement of materials and drugs or drug concentrations in the filament can be used to control the release kinetics of the drug or drugs contained in the filament. The release kinetics is affected by the surface area of the retainers in a particular region and, therefore, must be validated for particular configurations of retainers to achieve the desired final kinetics.
[00123] Figure 3D shows a perspective and cross-sectional view of a 356d drug-eluting self-suture suture that has a 381 d woven core and a 355d polymer wrap. The stranded suture 356d can be formed by any method known in the art for the production of a stranded suture having a wrap around a stranded core, each having the properties and drug content necessary for the material to function in the fiber or suture thread. A suitable method is the extrusion or deposition of material around a preformed stranded core as previously described. Other methods of forming a wrap in a preformed stripe can also be used including, but not limited to, dip coating, spray coating, curtain coating and / or chemical deposition (for example, vapor deposition DVQ chemicals).
[00124] As shown in figure 3D, a retainer 357d is formed in the self-retreating suture of drug eluipation 356d by making, for example, a cut in the 355d envelope. The 357d retainer can be produced using a wide range of technologies, as discussed above. The depth of cut can be selected so that the cut is completely inside the material of the 355d wrapper, as shown in the 3D figure, and does not penetrate the locked core 381 d. The selected depth of cut is a compromise between the resistance of the retainer and the resistance to trapping of the suture. A very deep cut can cause the suture to have reduced resistance and a very shallow cut can make the retainer not strong enough to effectively engage the tissue. In general, the depth of cut will be selected to be between 10% and 50% of the diameter of the locked suture. The depth of cut can be between 20% and 30% of the diameter of the locked suture.
[00125] In a closed 356d suture, as shown in figure 3D, a primary contribution to the suture tensile strength and the 381 d core tensile strength. In this way, the depth of cut is preferably selected so as not to cut the core 381 d. The thickness of the wrap can be increased or reduced in order to allow the cuts to have a greater or lesser depth. Selecting the depth of the wrap should be done to allow the resulting retainers to be strong enough to engage the fabric effectively. In addition, a strong core 381 d may allow the 355d envelope to fall on the self-retention suture 356d less, thus allowing the use of drug eluting materials for the 355d envelope that might otherwise not be strong enough to the production of a suture. In some cases, the depth of cut used to form a retainer can be selected so that a depth of cut is approximately equal to the depth of the envelope layer. In these cases, the resulting locked self-entertainment suture will depend entirely on the tensile strength of the nucleus.
[00126] As shown in figures 3E and 3F, the filaments can be formed in formats other than round surgical sutures. For example, in the embodiment of figure 3E, the fibers are woven in a two-dimensional structure like a ribbon or flat laminate. Figure 3E shows a flat ribbon 381 and comprising a plurality of stranded fibers. The flat ribbon 381 and has a wrapper 355e deposited thereon, on which a plurality of retainers 357e has been formed. The drug eluting self-holding tape 356e can be particularly useful for supporting fabrics and / or closing openings in the fabric. One or more drugs can be incorporated into the flat ribbon 381 and and / or the wrapper 355e and or coated over the drug elution self-holding ribbon 356e. The drug elution self-retention tape 356e can then deliver those drugs to tissues in which the drug elution self-retention tape 356e is implanted.
[00127] As shown in figure 3F, the fibers can also be woven into a three-dimensional structure like rings or tubes. Figure 3F shows a braided circular tube 381 f comprising a plurality of fibers braided together. The stranded tube 381 f has a casing 355f deposited on it in which a plurality of retainers 357f have been formed. The drug eluting self-holding tube 357f can be particularly useful for supporting tissues and / or surrounding openings in the tissue, in particular applications. Specific three-dimensional structures can be woven or woven to suit a particular application. One or more drugs can be incorporated into the 381 f and / or 355f braided tube or coated over the 357f drug elution self-holding tube. In addition, one or more drugs can be used to fill the lumen 359f of the 357f drug elution self-holding tube in a liquid, gel, or solid vehicle. The drug eluting self-holding tube 357f can then deliver drugs from the 355f wrapper, the 381 f or lumen 359f braided tube to tissues in which the drug eluting self-holding tube 357f is implanted.
[00128] As shown in figures 4A and 4B, single filaments 410, 420 comprise an arrangement of two materials: one material in the nucleus and a second material as a wrap around the nucleus. This arrangement of materials in a filament can be done by coextrusion of the two materials. The materials can be the same polymer, but have different concentrations of a drug or drugs. In a simple variation, the two materials can be used in different quantities, depending on the use for which the filament is intended. For example, in Figure 4A, the material of the core 412 takes up to about 25% of the cross-sectional area of filament 410, with the material of the envelope 414 taking up to 75% of the cross-sectional area. By comparison, in Figure 4B, the core material 422 and the shell material 424 each take up about 50% of the cross-sectional area. In general, the core material can comprise from 10% to 90% of the total cross-sectional area of the filament. Preferably, the core material will comprise 25% to 90% of the total cross-sectional area of the filament. More preferably, the core material will comprise more than 50% of the total cross-sectional area of the filament. The configuration of the materials in the filament will depend on the characteristics of the materials and the amount of material needed for the filament to fulfill its role and achieve the desired release kinetics for any drug or drugs incorporated in the filament. The release kinetics is affected by the surface area of the retainers in a particular region and, therefore, must be validated for specific configurations of retainers to achieve the desired final kinetics.
[00129] Figure 4C illustrates an alternative filament 430 in which a plurality of "islands" 432 is present in an "ocean" 434 of the second material, which surrounds them. a plurality of islands 432 together comprise a segmented core 433 of filament 430. The "ocean" 434 of the second material comprises the envelope and also fills the interstices between segments 432 of the segmented core 433. The materials may be the same polymer, having, however, different concentrations of a drug or drugs. This arrangement of materials in a filament 430 can be made by coextrusion of the two materials. The resulting fiber may show a useful combination of material characteristics. Specific monofilament configurations can be found in U.S. patent 7,070,610, the title of which is "Monofilament Suture And Manufacturing Method Thereof, granted to Im et al., Which is incorporated herein by reference, as well as in the aforementioned U.S. patent 7,033,603.
[00130] Figure 4D illustrates another alternative filament 440 for use in the present invention. The filament of figure 4D is produced from three different materials. A first material forms a core 442 of filament 440. A second material 444 forms a wrap over the outer surface of filament 442. The third material is disposed between core 440 and wrap 444 in intermediate layer 446. The materials can be the same polymer, but have different concentrations of a drug or drugs. This arrangement of materials in a filament can be done by coextrusion of the three materials. The material of the intermediate layer 446 can be selected, for example, for its mechanical properties as interfacing with the core 442 and the envelope 444. Alternatively, the material of the intermediate layer 446 can be selected by the favorable interaction with fabrics in the retainers since the intermediate layer material 446 will only be exposed to the fabric where the retainers are cut in filament 440. For example, the material of intermediate layer 446 may comprise an adhesive component, a therapeutic component or a material that promotes the adherence of the fabric to the retainer or promotes healing the wound as described below.
[00131] Figure 4E illustrates another alternative embodiment in which the core 462 of filament 460 comprises a plurality of fibers 461 braided together. Nucleus 460 is surrounded by a 464 envelope. The materials may be the same polymer, but have different concentrations of a drug or drugs. This filament can be prepared using a stranded thread (like a stranded suture) and extruding the wrap over the stranded thread, as if it had been passed through an extrusion die. In this embodiment, the stranded yarn can be immersed in a solution of the drug before extrusion of the 464 wrapper. During immersion, the drug will migrate to the stranded yarn. It is observed that, as before, the wrapper 464 is thick enough that the creation of seals on the surface of filament 460 does not cut the core 462 or the fibers 461 of the core 462. For example, the maximum depth of a straight cut for a retainer and illustrated by the dashed line EE. In this way, the core 462 and the material of its fibers 461 can be designed to have high resistance to trapping and flexibility, while the envelope 464 is selected based on its ability to form, raise and position the retainers. A suitable method for the production of a filament comprising a stranded core is described in U.S. Patent 6,183,499, the title of which is "Surgical Filament Construction" granted to Fisher et al., Which is incorporated herein by reference.
[00132] Figure 4F illustrates an alternative embodiment in which the core and wrappings of filament 450 have different shapes. In the embodiment of figure 4F, the core 452 has a circular cross-section while the envelope 454 has a triangular cross-section. This arrangement provides a larger volume of the second material at the vertices of the triangle while allowing the core material to provide a high percentage of the total cross section of the filament. The materials can be the same polymer, but have different concentrations of a drug or drugs. In this modality, the retainers are cut at the vertices of the triangular cross section, thus optimizing the use of the material in the 454 envelope. In addition, the configuration of the retainer can be selected so that the retainers with arched bases are cut at the vertices of the triangle. The dashed line F-F illustrates the cut for an arched base of a retainer and illustrates that the cut extends through a greater proportion of the envelope 454 than a straight cut. Methods of manufacturing self-suturing sutures from filaments with triangular cross section or other polyhedron cross section, are presented in US patent 5,342,376 whose title is "Inserting Device For A Barbed Tissue Connector", granted to Ruff which is incorporated herein, by referendum. The placement of materials in a filament shown in figure 4F can be done by coextrusion of the two materials. The extruder nozzle is selected so that it has the desired shape. The shape of the filament cross section corresponds to the shape of the extruder nozzle. Alternatively, the filament can be formed as in figure 4A and then the wrapping material 454 can be formed in a triangular shape by means of post-extrusion manipulations, as with the use of cylinders to form the material under pressure and then heating to perform the annealing of the polymer in the chosen format before creating the retainers.
[00133] Of course, other geometric arrangements of the materials are possible, for example, the envelope can be formed with a square, pentagonal, hexagonal or other polygonal cross section. Figure 4G illustrates a filament 470 that has a wrapper comprising three segments 474, 475, 476 on a circular core 472. In this embodiment, the wrapper is not continuous, but rather, comprises three elements arranged around core 472. In this embodiment In this modality, the retainers are cut at the vertices of segments d 474, 475, 476, thereby optimizing the use of the envelope material for the production of retainers and providing a large cross section of core 472. Figure 4H illustrates a filament 480 that have a square envelope comprising four segments 484, 485, 486, 487 around a square core 482. In this embodiment, the retainers are cut at the vertices of the envelope segments 484, 485, 486, 487, thereby optimizing the use of the material in the envelope and providing a large cross-section of the core 482. Figure 4I illustrates a filament 490 having a circular transverse section, where the core 492 has a triangular cross-section. In this embodiment, the retainers are preferably cut into the thicker portions of the wrapper 494, 495, 496. The materials can be the same polymer, but have different concentrations of a drug or drugs. Retainer Cutting Blades, Retainers and Retainer Distribution
[00134] With reference to figures 5A and 5B, an embodiment of a self-holding suture 500, according to the present invention, can include a retainer 502 with an upper surface 512 extending from a periphery 510 of the filament 518 and a lower surface 514 having at least two facets 516. As seen in the previous view of figure 5B, the retainer can roughly have a pizza slice shape (i.e., wedge). The increased moment of inertia of the cross section of the retainer (also known as the second moment of inertia) increases the strength, from a mechanical point of view, and can improve the resistance to the tendency of a retainer to bend back and lead to a movement of the suture through the tissue, as described above. This retainer additionally reduces stress concentrations along the lower surface of the retainer and the suture when compared to the retainers in figure 2A-2C, made with a straight cut. The retainer does not have to be shaped like a perfect wedge, instead, preferably, it has at least two facets to optimize the resistance to flexing backwards. Thus, for example, the retainer can have a trapezoidal shape, roughly speaking, with three facets. Figure 5C shows a self-suture suture 500c that has an alternative retainer 502c that has two facets 516c and between them, an uncut cord 517c that connects retainer 502c to filament 518c. The cord 517c serves to stabilize the lift of the retainer 502c, thereby improving the engagement of the fabric by the retainer 502c in certain applications.
[00135] Referring to figure 5D, an embodiment of a retaining mechanism 502 in a filament 518 as shown in the figures. 5A and 5B, and illustrated. A V-shaped cutting edge includes two blades 522, 524 arranged close together to form a desired cutting angle and resembling a V. In a preferred embodiment, blades 522, 524 are placed close together to one another. cutting angle at 90 °. In alternative embodiments, blades 522, 524 can be arranged so as to form an obtuse or acute angle, where desired. In other modalities, the V-shaped blade can have any of its surfaces being convex or concave, to allow the selection of a suitable final retainer design, maximizing the moment of inertia of the retainer 502 or the area of the remaining cross-section of the filament 518. The cutting edge 520 can be temperature controlled to ensure an adequate blade temperature to form the retainer 502 without causing the denaturation of any coated or impregnated drug in filament 518.
[00136] In a preferred embodiment, blades 522, 524 of cutting edge 520 are sapphire blades. Sapphire blades are ceramic blades that typically have an edge radius one or two times less than the edge radius of an apo blade, thus allowing precise cutting of retainers in USP 6-0, 8 filaments -0 and under. In addition, sapphire blades generally maintain their mechanical characteristics over desirable temperature variations for cutting polymer and copolymer materials. Maintenance of mechanical characteristics (i.e., the cut geometry produced) can be desired when the retainers are extremely small and therefore sensitive to small changes. Additionally, sapphire blades are more resistant to abrasion than, for example, typical steel blades, providing more repeatable results compared to long-term use. In addition, sapphire blades can be sharpened more effectively than aQO blades. In alternative embodiments, blades 522, 524 can be metal, mineral or ceramic blades, which have a hard coating, mineral coating, ceramic coating and / or carbon coating. For example, the blades can have: coal coating, diamond, diamond-like coating, nano-ceramic coating, ceramic coating, sapphire coating and / or itirated zirconia coating or a ceramic material that has the desired sharpness and durability or other rigid blades or coated coated blades.
[00137] Filament 518 may be wound or otherwise fed or pulled in a z direction after extrusion at a constant speed, generally in a twisted or non-twisted path. In alternative embodiments the speed can be controlled in order to control the distribution - lower speed resulting in a higher density in the retainer and higher speeds resulting in a lower density in the retainer. To manufacture a unidirectional retaining suture, a cutting edge 520 can be arranged in each of the four quadrants of a circle. The sapphire blades oscillate in a Z direction so that the cutting edge 520 alternately penetrates the suture 520 and leaves a cut. The cutting edge can be oscillated by a cam device, for example. In this way, the oscillation creates an array of seals along filament 518 as filament 518 is fed in the z direction. To manufacture a bidirectional retaining suture, a cutting edge can be arranged in each of the four quadrants of a circle in each of two protuberance / penetration directions, resulting in eight cutting edges. The cutting edge may comprise the oscillating sapphire blades, so that the cutting edge alternately penetrates the suture and leaves the cut.
[00138] Alternative modalities of mechanisms for forming retainers in filaments can be used for the generation of retainer arrangements. For example, a cutting edge can be arranged in each of the three zones to form retainers that extend from three circumferential locations along the suture. Additionally, one or more of the cutting edge and the filament can / can be rotated (s) around the long geometric axis of filament 120 as the filament is pulled in the z direction, so that the retainers are helically arranged along the suture. In addition, the cutting edge oscillation may have an increased or reduced frequency or be totally stopped in order to increase or reduce the density of retainers or to stop the formation of retainers in a self-restoring suture or particular region of a self-restoring suture. Retainer patterns suitable for a surgical or cosmetic procedure or application can be formed, and the properties of the material at the site of the procedure or application. As previously stated, patterns of retainers tailored to the surface area of the available filament for eluting a drug can also be selected so that the desired release kinetics for the drug is achieved in the suture or self-retention region resulting from a self-retaining suture. .
[00139] In particular modalities, cutting edge 520 is temperature controlled to optimize the formation and elevation of retainer 502 while preserving the activity of any drug coated or impregnated in filament 518. For the control of the edge temperature cutting blade 520, the sapphire blades are assembled or otherwise placed in conductive communication with a copper temperature control plate 530. The copper plate 530 can effectively heat or cool cutting edge 520 to the desired temperature through driving. The copper plate 530 is temperature controlled using a solid or liquid heat transport system and a closed circuit temperature controller. A cutting edge temperature 520, in this way, can be tightly controlled to a desired temperature range to provide satisfactory retainer formation while preventing the denaturation of a coated or impregnated drug in filament 518. In addition, the filament 518 can also be temperature controlled before, during and after the formation of the retainer to prevent or reduce any detrimental effect of the formation of the retainer on the activity of a drug coated or incorporated in filament 518. In addition, the contact time between the cutting edge 520 and filament 518 can be modulated to reduce the extent to which the temperature of the cutting blade changes the temperature of filament 518 during cutting. For example, in a preferred embodiment, the cutting edge 520 is close, in terms of conductivity, of filament 518 of four to five milliseconds during the formation of a retainer 502. In this way, the effect of the cutting blade temperature is limited to a small region of filament 518 immediately adjacent to cutting edge 520.
[00140] Figure 5E shows an alternative cutting mechanism in which the cutting edge 520e includes two sapphire blades 522e, 524e having a finite distance between the cutting surfaces, resulting in a retainer 502 that resembles the retainer 502c of figure 5C . Additionally, a cutting board with alternative temperature control 530e is shown being in contact with the surface of the blades 522e, 524e, instead of being in contact with the upper edge of the blades 522e, 524e.
[00141] Figure 5F shows an alternative cutting mechanism 550 which has a curved sapphire blade 552. The curved sapphire blade 552 when cutting filament 518, moves transversely (as shown by arrow 559) to the geometric axis z of the filament 518 for cutting a retainer (not shown) in filament 518. Filament 518 is moved in the direction of the geometric axis z to cut retainers in different positions along the filament. Filament 518 can also be rotated about the geometric axis z, as shown by arrow 558 to cut retainers in multiple angular positions around the geometric axis z. The angle of the curved sapphire blade 552 and the height of the blade 552 relative to filament 518 is controlled to adjust the shape and size of a retainer formed by the mechanism and to ensure that the proper cross section of filament 518 remains after formation. retainer. In the cutting mechanism 550, the curved sapphire blade 552 is mounted on a tube 556. Tube 556 is mounted on the cutting equipment in a manner that allows removal, replacement and angular adjustments of blade 552. In the embodiment shown, the sapphire curved blade 552 has a tip with hemispherical edge 554. In alternative modalities, the blades, made of any material, saoretas or curves and can have the hemispherical curve, parabolic or any other curve suitable for cutting the retainer. In embodiments of the present invention, the sapphire blade 552 is used for cutting retainers in the filaments to produce the self-healing sutures with USP 6-0, 8-0 and smaller.
[00142] Figure 5G shows an alternative cutting mechanism 560 that has a circular steel blade 562. The curved steel blade 562 when cutting filament 518, moves transversely (as shown by arrow 569) to the geometric axis z or to the longitudinal geometric axis of filament 518 to cut a retainer (not shown) in filament 518. Filament 518 is moved towards the geometrical axis z to cut retainers in different positions along the filament. Filament 518 can also be rotated about the geometry axis z, as shown by arrow 568 to cut retainers at multiple angular positions around the geometry axis z. The angle of the curved steel blade 562 and the height of the blade 562 in relation to the filament 518 are controlled in order to adjust the shape and size of a retainer formed by the mechanism and to ensure that the proper cross-section of the filament 518 remains after formation. retainer. In the cutting mechanism 560, the curved steel blade 562 is mounted on a block 566. The block 566 is mounted on the cutting equipment in a manner that allows removal, replacement and angular adjustments of the blade 562.
[00143] Self-retention suture retainers can also be cut without a blade, for example, in an alternative embodiment of the present invention, and a laser with picosecond technology is used to remove the material to form a retainer. The laser can be optically controlled and does not need to be in physical contact with the filament, thus allowing very precise conformation and positioning of the retainers in the filament. Other possible seal creation techniques include EDM, wet chemical attack, dry chemical attack, coinage, stamping and the like.
[00144] Figures 6A, 6B, and 6C show a variety of dispensers and retainer patterns that can be used in conjunction with the drug eluting self-retaining suture. Figures 6D, 6E and 6F show a variety of retainer shapes that can be used in conjunction with the drug eluting self-retaining suture. Figure 6G shows the range of suture dimensions that can benefit from the modalities of the invention. Figure 6A illustrates a simple helix distribution of retainers in a self-holding drug eluting suture according to an embodiment of the invention; Figure 6B shows a double helix distribution of retainers in a self-holding drug eluting suture according to an embodiment of the invention; Figure 6C shows a high density quadruple distribution of retainers in a drug eluting self-retention suture according to an embodiment of the invention;
[00145] First, reference is made to figure 6A, which shows a unique helix distribution of the 604 laser cut retainers in a drug eluting self-holding suture. As shown in figure 6B, the self-retaining suture 620 has a filament 602 which is USP 6-0, 7-0, 8-0, 9-0, 10-0, 11-0, 12-0 or less. As shown in figure 6A, the filament is 0.25 mm in diameter which is a 4-0 suture. The self-retaining suture 600 includes a plurality of laser cut retainers 604 arranged in a helical pattern around and along the filament 602. As shown in figure 6A, the helix has a pitch of 4.46 mm (or 2.24 turns) per cm. Each retainer is 0.5 mm from the pressure tip to the cutting base - measured axially - see arrow 616. The distance between the base of a retainer and the base of the adjacent retainer on the same helix (pitch) and 0, 6 mm - measured axially - see arrow 618. In one embodiment, the self-suture suture has a barbed section 612 of at least 60 mm in length and a 100 mm non-barbed wire 610, 614 on each side of the barbed section 612. The barbed section 612 may have retainers 604 in one orientation or in different orientations.
[00146] With reference to figure 6B, a double helix distribution of retainers 624 is shown in a self-retention suture 620. As shown in figure 6B, the self-retention suture 620 has a 622 filament that has USP 6-0, 7-0 , 8-0, 9-0 10-0 or less. As shown in figure 6B, the filament is 0.25 mm in diameter, which corresponds to a 4-0 suture. The self-suture suture 620 includes a plurality of laser cut retainers 624 arranged in a double helix pattern around and along filament 622. As shown in figure 6B, each helix has a 6 mm (or 1.65 turn) pitch. per cm The helices are axially displaced 0.49 mm from each other Each retainer is 0.31 mm from the pressure tip to the cutting base - measured axially - see arrow 636. The distance between the base of a retainer and the base of the adjacent retainer on the same helix (pitch) and 1 mm - measured axially - see arrow 638. In one embodiment, the self-retention suture has a barbed section 632 of at least 100 mm in length and a non-barbed wire 630, 634 of 100 mm on each side of the barbed section 632. The barbed section 632 may have retainers 624 in one orientation or in different orientations.
[00147] Referring to figure 6C, a high density distribution of retainers 644 is shown in a 640 self-retention suture. As shown in figure 6C, the 640 self-retention suture has a 642 filament which is from USP 6-0, 7 -0, 8-0, 9-0, 10-0, 11-0, 12-0 or less. As shown in figure 6C, the filament is 0.25 mm in diameter, corresponding to a 4-0 suture. The self-retention suture 640 includes a plurality of retainers 644 arranged in groups of four retainers each arranged at a 90-degree spacing. Each adjacent set of four retainers and 45 degrees apart from the adjacent sets. Each retainer is 0.18 mm from the pressure tip to the cutting base - measured axially - see arrow 656. The distance between the base of the retainer in a set and the base of the adjacent retainers (pitch) and 0.28 mm - measured axially - see arrow 658. In one embodiment, the self-suture suture has a barbed section 652 of at least 60 mm in length and a non-barbed wire 650, 654 of 100 mm on either side of the barbed section 652. The barbed section 652 can have retainers 644 in one orientation or in different orientations.
[00148] Figures 6D, 6E and 6F show a variety of retainer shapes that can be used in conjunction with the drug eluting self-retention suture. For each retainer, a USP 4-0 660 suture filament is used. Figure 6D shows a parabolic retainer 664 for use with the single helix (figure 6A) or double helix (figure 6B) distribution pattern. The depth of cut D (measured transversely) and 0.060 mm. The cut length L (measured axially) is 0.250 mm. Figure 6E shows a parabolic shape of retainer 662 for use with the high density distribution patterns (figure 6C). The cutting depth D (measured transversely) is 0.036 mm. The cutting length L (measured axially) is 0.170 mm. Figure 6F shows an alternative retainer 668 that has an entry at 30 degrees and then runs parallel to the geometric axis of the suture. The cutting depth D (measured transversely) is 0.036 mm. The cutting length L (measured axially) is 0.234 mm. The entry angle is 0 and 30 degrees from the suture axis. These and other retainer shapes can be used to accommodate the density and distribution of retainers intended for specific applications and with specific filament diameters. Alternative retainer distribution formats and standards are presented in U.S. patent application 12/101885 whose title is "Self-Retaining Systems for Surgical Procedures" filed on April 11, 2008, which is hereby incorporated by reference. Peripheral Nervous Repair
[00149] As described above, the purpose of the suture determines the type of drug that is applied or incorporated in the suture, as well as the diameter of the filament and the shape, size and distribution of the retainers. In one example, drug-eluting self-entertaining sutures contain or are coated with neural growth factor (NGF) to promote healing of damaged nerves. The spectrum of nerve damage includes simple nerve compression injuries, complete transepa- tion and severe laceration. A fast and adequate intervention is crucial for achieving a good clinical result. Preferably, the intervention improves and / or increases the innate healing process.
[00150] By reference, figure 7A is a sectional view of a nerve 700. Nerve 700 comprises a plurality of nerve fibers 710 surrounded by connective tissue 720. Nerve fibers 710 include axons 712 surrounded by Schwann myelination cells 714 Immediately adjacent to the nerve fibers 710 is the first layer of connective tissue - the endoneurium 722. Groups of nerve fibers and the endoneurium are surrounded by a fascia 724 to form a fascicule 702. The fascicles 702 are themselves surrounded by the connective tissue called perineur 726. The perineur and fascicles are surrounded by the inner epineur 727 and the outer epineur 728. The outer epineur is a continuous fascia that surrounds the bundle of fascicles and connective tissue. The outer epineurium 728 is surrounded by a layer of connective tissue called the mesoneurium 729. In repairing a nerve injury, sutures can be applied to the connective tissue to reconnect the separate end of the nerves. To repair a simple nerve transaction, the first step is to prepare the nerve ends.
[00151] An injury to a peripheral nerve triggers an innate healing process. In the innate healing process, the part of the axon distal to the cut, now cut out of the body of the axon cell, quickly disintegrates. The Schwann cells that surround the distal axon quickly lose their myelin and macrophages invade the nerve to absorb myelin. This is an important step for axon regrowth because myelin is an axon growth inhibitor, the Schwann cells that surround the distal axon are also stimulated to proliferate and migrate, allowing them to extend over a minor nerve defect if it is a fibrin matrix is present. Schwann cells around the proximal axon go through the same process, but only in the region adjacent to the injury. In the proximal axon, the lesion is communicated intra-cells to the nucleus, which initiates the expression of the gene necessary to repair the axon. The growing axon responds to contact and chemical signals from the Schwann cells that surround the distal axon to guide regrowth of the axon to the target sensory muscles or cells.
[00152] In one embodiment of the present invention, a drug eluting self-retaining suture is used to deliver a drug or drugs (e.g., NGF) to an injured nerve during the critical period immediately after injury. The kinetics for releasing NGF from the self-retaining suture to the nerve tissue adjacent to the injury is selected to provide NGF in the useful period of nerve repair. Factors that can be used to control / adjust NGF release kinetics include: the amount of NGF in the filament; the filament diameter; the distribution of the NGF in the filament; the formulation / porosity of the filament material; and the shape and distribution of retainers in the filament. As the release kinetics is affected by the surface area of the retainers in a specific region, preferably the kinetics is validated for specific retainer configurations in order to achieve the desired final kinetics.
[00153] In one embodiment, the first order quick release kinetics is used. The graph of figure 7B illustrates a rapid first-order in-vitro release (IVR) kinetics suitable for releasing NGF, for example, from an 8-0 self-retention suture for nerve repair. More than 80% of the NGF is delivered within the first 5 days after in vivo implantation. The remaining NGF is released in the next 20 to 25 days. Thus, the self-retention suture with NGF is suitable for repairing and supporting a lacerated or ruptured nerve and releasing NGF during the initial nerve healing period, leading to a superior healing response and better clinical results. Although NGF is described, a range of other agents that promote nerve healing, as described here, can be used instead of or in addition to NGF.
[00154] Several drugs, in addition to NGF, are known to stimulate nerve growth / repair. In the embodiments of the present invention, the drugs are coated, impregnated or loaded, in some way, by the self-retention suture in a way that allows the release of the drug with proper kinetics in the region of injury to a nerve. Suitable drugs to stimulate nerve growth / repair include: neurotrophs, for example, neural growth factor (NGF), platelet-derived growth factor (PDGF - platelet-derived growth factor), brain-derived neurotrophic factor (BDNF- brain-derived neurotrophic factor), neurotrophins-3 (NT-3), neurotrophin-4/5 (NT4 / 5), neurokines, for example, ciliary neurotrophic factor (CNTF-cilliary neurotrophic factor), leukemia inhibitory factor (LIF- leukemia inhibitory factor); and transforming growth factors, for example, beta transforming growth factors (TGF), glial cell-derived neurotrophic factor growth factor (GDNF). Other drugs that stimulate nerve growth include fibroblast growth factor (FGF-2), insulin-like growth factors I and II, and other agents that stimulate the growth and repair of peripheral nerves. In addition, drugs targeting myelin-associated regeneration inhibitors can also be used to promote nerve regeneration by counteracting these inhibitors. Agonists of myelin-associated inhibitors include, for example, antibodies such as the anti-NOGO antibody, which promote axonal emergence and functional recovery. In addition, other drugs can be used to block the inhibitory effects on axon growth by interrupting the Rho, Rho kinase signal pathway in the axon that responds to myelin-associated regeneration inhibitors.
[00155] The modalities of the invention can include absorbable 8-0 (or smaller) APG or PDO sutures that can be impregnated during the sut formation process, with one or more drugs as the neural growth factor (NGF). The resulting suture can be barbed and formed into a suture. The kinetics of NGF release can be individualized / adapted to promote healing of lacerated and ruptured nerves. This can lead to first order quick release kinetics. Combining the 8-0 APG suture holding resistance to maintain tissue attachment and NGF can produce a superior healing response to the nerve, resulting in better functionality. Although NGF is specifically indicated, it is understood that a wide range of neurotrophic factors, growth factors and neural cytokines can be used. The concept of the modalities of the invention can be extended to the general notion of a drug eluting suture for active healing of damaged tissue (iatrogenic or non-iatrogenic) with the appropriate drugs / growth factors added to the suture material during the manufacturing process .
[00156] A barbed pattern in double helix (figure 6B) or in quadruple helix (figure 6C) can be used to increase the detection resistance. It should be noted that the increase in the surface area of the drug-impregnated self-retention suture can also increase the release kinetics; this can be achieved in several ways, for example, by increasing the density of the retainers (such as splinters) per unit of surface area of the suture, by increasing the size of the retainers, and by increasing the engagement surface of the retainer fabric. .
[00157] Nerve injuries comprise simple injuries of compression of the nerve to lacerations and complete ruptures of the nerve trunk. To repair a nerve laceration or rupture, there are four steps: (1) preparing the nerve ends, (2) approaching the nerve end, (3) coapping the nerve ends, and (4) maintaining the coaptation of the nerve. nerve ends. Steps 2 to 4 require the ability to reference neural tissue in apposition with a function of time. The published literature suggests that current techniques do not always maintain adequate attachment to affect repair. The sutures have demonstrated the ability to place the tissue in apposition under high tension and keep the tissue in the necessary position. Self-entertaining sutures configured for nervous repair can achieve this same effect, as well as remove suture mass, due to the absence of knots. The absence of knots can reduce inflammation in the surrounding tissue. Adipation of NGF and the use of such suture as a drug delivery vehicle provides a controlled mechanism to promote active healing, thereby accelerating the neural repair process for a more consistent clinical outcome.
[00158] Conventional resorbable and nylon sutures, silicone tubes, glues (fibrin and synthetic), PEG hydrogels, alone or in combination, all have been used to ligate lacerations and nerve tears. All of these materials show an inability to control tension or rely on point fixation, so they are not good for maintaining tissue apposition.
[00159] Figures 7C-7F illustrate certain steps in the repair of a separate peripheral nerve 700 using a drug-eluting self-restoring suture. First, the injury site needs to be exposed so that the injury to the nerve is visualized. To repair nerve 700, it is necessary first, as shown in figure 7C, to prepare the separate ends 740a and 740b of the two portions 700a, 700b of nerve 700. The area of damaged / necrotic tissue needs to be defined. A pair of sharp 750 micro-scissors or a surgical blade (not shown) is used to remove any necrotic tissue so that the separate ends 740a, 740b are viable for attachment. The acute debridement of the damaged nerve ends provides a clean border for the fascicules.
[00160] Figure 7D shows the next peripheral nerve repair step in which the separate ends 740a, 740b of the nerve section 700a, 700b are brought together. This approximation stage usually requires the mobilization of the nerve sections so that any small defect (gap) left by injury or debridement can be ligated. The nerve sections 700a, 700b are mobilized by dissecting the nerve from the underlying tissues in the adjacent region of the separate ends 740a, 740b. The separate ends 740a, 740b are then brought together as shown by arrows 752a, 752b. The separated ends are also rotated as shown by the arrow 753 in order to align the fascicle group 702 and / or the longitudinal epineural vessels (not shown). If the nerve ends have retracted, they can be approached by placing a suture through the epineurium, in the soft tissue adjacent to each separate end 740a, 740b.
[00161] After the approximation and alignment of the separate ends of the nerve 740a, 740b, the ends 740a, 740b are sutured together in several ways. Figures 7E, 7F and 7G illustrate a suture technique that uses four bidirectional drug eluting self-holding sutures 760a, 760b, 760c, 760d. Figure 7E shows the first stage of the suture. As shown in figure 7E, each of the four sutures has a straight needle 762a, 762b, 762c, 762d at an end attached to a portion 764a, 764b, 764c, 764d of the suture with retainers oriented to allow movement towards the needle 762 , but not in the other direction. Each portion 764a, 764b, 764c, 764d is attached to a second portion of the suture 766a, 766b, 766c, 766d with retainers oriented so as to allow movement towards a second straight needle 768a, 768b, 768c, 768d, however not in the other direction. In the first step, as shown in figure 7E, the first needles 762a, 762b are directed longitudinally by the epineurium surrounding the separate end 740a and the first needles 762c, 762d are directed by the epineural tissue surrounding the separate end 740b. The needles are spread out around the separate end point 740a, 740b. The first needles 762a, 762b, 762c, 762d, are then used to pull the first portions 764a, 764b, 764c, 764d from the suture to the epineurium until the second portion 766a, 766b, 766c, 766d of the suture to engage the epineurium and prevent advancement further suture towards the first needles 762a, 762b, 762c, 762d. At this point, the first needles 762a, 762b, 762c, 762d and the first portions 764a, 764b, 764c, 764d extending outside the epineurium 727, 728 are cut and removed from the operating field leaving only a longitudinal segment of the first portions 764a, 764b, 764c, 764d embedded in the epineurium 727, 728.
[00162] Figures 7F and 7G show the second suture stage. In the second step, as shown in figure 7F, the second needles 768a, 768b are directed longitudinally by the epineurium surrounding the separate end 740b and the second needles 768c, 768d are directed by the epineural tissue surrounding the separate end 740a. The needles are blown around the separate end point 740a, 740b and care is taken to align the location of the second needles 768a, 768b, 768c, 768d with the corresponding position of the first needles 762a, 762b, 762c, 762d. The second needles 768a, 768b, 768c, 768d, are then used to pull the second portions 766a, 766b, 766c, 766d from the suture through the epineurium to the second portions of the 766a, 766b, 766c, 766d suture, however, without being loose voltage, as shown in figure 7G. From the position shown in figure 7G. As shown in figure 7G, the second needles 768a, 768b, 768c, 768d exit the epineurium 727, 728 of the nerve 700a, 780b at a distance from the separate ends 740a, 740b.
[00163] Figure 7H shows the final suture stage. As shown in figure 7H, the second needles 768a, 768b, 768c, 768d are pulled simultaneously from the separate ends 740a, 740b as shown by arrows 770. The second needles pull the second portions 766a, 766b, 766c, 766d from the suture through the epineurium 727, 728. Due to the fact that the first portions 764a, 764b, 764c, 764d of the suture are embedded in the epineurium 727, 728 on the opposite side of the separated ends 740a, 740b, the act of pulling through the second portions 766a, 766b, 766c .766d stretches the separate ends 740a, 740b towards each other (as shown by arrows 772) and places them in contact in line with each other. The segment of the second portions 766a, 766b, 766c, 766d external to the nerve and the second needles attached 768a, 768b, 768c, 768d can then be cut off and removed from the operating field. Leaving nerve 700a, 700b again fixed with the separate end 740a aligned and touching each other, as shown in figure 7I. Additional conventional or self-restoring sutures can be used to further strengthen the connection between nerves 700a, 700b. Alternatively or additionally, the connection between nerve 700a, 700b can be increased with a fibrin-based surgical adhesive.
[00164] As shown in figure 7I, a segment 761a, 761b, 761c (not shown), 761 d from each self-suture suture 760a, 760b, 760c (not shown), 760d and embedded in nerves 700a, 700b inside the epineurium external (not shown) and covering the separate ends 740a, 740b. Segments 761a, 761b, 761c (not shown), 761d are also uniformly spaced around the nerve. The segments of the self-retention suture 761a, 761b, 761c (not shown), 761 d distribute any tension in the nerve 700a, 700b throughout the segment 761a, 761b, 761c (not shown), 761 d of the self-retention suture rather than concentrating all tension at the separate ends 740a, 740b. The segments are ideally positioned on the external epineurium in order to deliver a drug to enhance nerve regeneration 700a, 700b. In addition, as the length of segments 761a, 761b, 761c (not shown), 761 d of the self-retaining suture embedded in the epineurium can be readily controlled by the surgeon, the amount of drug that will be released by the suture is also well defined for each segment . In a preferred embodiment, the suture is provided with visible markers, such as a dye, to guide the surgeon as to the correct length of segment to be embedded (and / or the location of the retention of the retainers in one direction to retainers in the other direction). The surgeon can also be guided by the length of the first needles 762a, 762b, 762c, 762d and second needles 768a, 768b, 768c, 768d, which determines the size of the bit that is taken through the epineurium. In alternative modalities, 2, 4, 6, 8 or more self-retaining sutures are used, depending on the nerve to be repaired.
[00165] Figures 8A and 8B show techniques that use self-retaining drug eluting sutures to reconstruct a defective nerve. As shown in figure 8A, it may not be possible to place the separate ends 740a, 740b of nerve 700A, 700B in direct contact. The result is a small gap or defect 800 that remains between the separate ends 740a, 740b, as shown in figure 8A. Defect 800 in the nerve is joined by a fibrin cord naturally formed between the separated ends 740a, 740b. Blood and plasma exudates from separate ends 740a, 740b join defect 800 and, subsequently, Schwann cells migrate over the defect using fibrin as a guide. The self-retention sutures 760a, 760b, 760c, 760d that span defect 800 longitudinally, as shown in figure 8A, can serve as a guide for fibrin coagulation, as well as a guide for subsequent migration of Schwann cells. Additional drug-eluting self-retention sutures could then be positioned by the defect, if desired, to provide further guidance and support for axonal migration.
[00166] As shown in figure 8B, in some applications, it may be necessary or desirable to provide additional protection from the defect during the curing process. Thus, it may be desirable to involve defect 812, supported by self-holding drug eluting sutures, in an 810 tube. Tube 810 protects the defect and also serves to concentrate the drugs that elute from the self-holding sutures 760a, 760b, 760c , 760d in the vicinity of defect 812. To facilitate the use of a tube 810, the second needles 768a, 768b, 768c, 768d and the second ends 766a, 766b, 766c, 766d of the self-holding sutures 760a, 760b, 760c, 760d are inserted through the tube between the steps shown in figures 7E and 7F. If so, when the second ends are pulled in step 7H, the separate ends 740a, 740b will be pulled into tube 810 and towards each other. The resulting configuration is as shown in figure 8B, which shows tube 810 in position around the self-holding sutures 760a, 760b, 760c, 760d and defect 812 in nerve 700a, 700b.
[00167] Figures 9A, 9B and 9C show an alternative technique for reconnecting a sectioned nerve using a technique that uses one or more drug eluting self-retention sutures. In the method illustrated in figures 9A, 9B and 9C, a drug eluting self-retaining suture is used to join the separate ends 940a, 940b of a nerve 900 cut into two portions 900a and 900b. First, the injury site needs to be exposed so that the injury to the nerve is visualized. Then, the separate ends 940a and 940b of the two portions 900a, 900b of nerve 900 need to be debrided from any necrotic tissue so that the separate ends 940a, 940b are viable for fixation. The acute debridement of the damaged nerve ends provides a clean border for the fascicules. The separate ends 940a, 940b of the nerve sections 900a, 900b are brought together. This approximation stage usually requires the mobilization of the nerve sections so that any small defect (gap) left by injury or debridement is broken. The nerve sections 900a, 900b, are mobilized by dissecting the nerve from the underlying tissues in the adjacent region of the separate ends 940a, 940b. The separate ends 940a, 940b are then brought together and rotated, as described above, to align the group fascicules 902 and / or the longitudinal epineural vessels (not shown).
[00168] After the approximation and alignment of the separate ends of the nerve 940a, 940b, the ends are sutured together using an anastomosis technique that employs a self-retaining suture for drug elution 960. Figure 9A shows the first stage of the suture. As shown in figure 9A, the self-retaining suture 960 has a curved needle 962 at one end attached to a first suture portion 964 with retainers oriented so as to allow movement in the direction of needle 962, however, not in the other direction. The first portion 964 is joined to a second portion of the suture 966 with the retainers oriented to allow movement towards a second curved needle 968, however, not in the other direction.
[00169] In the first step, illustrated in figure 9A, the first needle 962 is directed through the epineur 928a of the separate end 940a and the second needle 968 is directed through the epineur 928b of the separate end 940b. It is best to start on the distal side of the nerve 900a, 900b and work towards the proximal side. The first and second portions of the self-suturing suture 964 and 966 are pulled until the transip tip is approximately equidistant from its separate ends 940, 940b. Then, each needle 962, 968 is used to capture bits through the epineurium of the opposite separate end, alternating as to depart from the initial bit. As shown in figure 9A, the first needle 962 and the second needle 968 travel in opposite directions around the separate ex-tremors 940a, 940b. In this first step, no tension is applied to the first and second portion 964, 966 of the self-retention suture.
[00170] As shown in figure 9B, when the first and second portions 964, 966 reach the opposite sides of the separate ends 940a, 940b, the self-suture suture can be pulled firmly, causing the separate ends 940a and 940b to be pulled against each other along one half of the defect. Care should be taken to ensure that the suture tightens evenly across the defect to ensure that there are no stress or pressure concentrations at the separate ends 940a, 940b.
[00171] As shown in figure 9C, the next step is to continue with alternating bits of first and second portions of suture 964, 966 towards each other around the proximal edge of the separate ends 940a, 940b. When the first and second portions 964, 966 reach the midpoint on the proximal side of the split ends 940a, 940b, the self-suture suture can be tightened, causing the split ends 940a and 940b to be pulled against each other along the proximal half of the defect. Care must be taken to ensure that the suture tightens evenly across the defect to ensure that there is no concentration of tension or pressure at the separate ends 940a, 940b. As a self-retaining suture is used, none is necessary to complete the repair, thus reducing the chance of uneven tension. A little extra through the epineurium can be taken if you want to secure the ends of the first and second portions of the self-suture suture before cutting the excess self-suture suture and the needles 962, 968.
[00172] As shown in figure 9C, the self-entertainment suture bits 960 are embedded in nerve 900 through the external epineurium (not shown) and covering the separate ends 940a, 940b. The self-retaining suture pieces are also evenly spread around the separate ends 940a, 940b. The self-retaining suture 960 can distribute any tension in the nerve 900 throughout the defect, rather than concentrating the tension in one or more locations. The self-retention suture is ideally positioned on the external epineurium in order to provide a drug to enhance the regeneration of the 900 nerve. In addition, as the length of the self-retention suture embedded in the epineur varies with the circumference of the nerve, the amount of drug that will be released by the suture equals that of the defect. In a preferred embodiment, the suture is provided with visible markers, such as a dye, to guide the surgeon (and / or indicate the location of the retainers in one direction to the retainers in the other direction). The surgeon can also be guided by the length and shape of the curved needles 962, 968, which determines the size of the bit that is picked up through the epineurium 928a, 928b. In alternative modalities, two, four or more self-retaining sutures can be used, depending on the nerve to be repaired. When two self-suturing sutures are placed, they should start on opposite sides of the separate ends 940a, 940b. Pharmaceutical Bioactivity Eluted from Pharmaceutical Load Sutures
[00173] Bioabsorbable polydioxanone (PDO) with NGF nanoparticles filler was manufactured in the form of sutures having diameters of about 0.045 mm (that is, within the USP range for sutures with 8-0 caliber), according to the methods presented in US patent No. 6,596,296. The sutures had an NGF target drug load of 10ng / cm suture length. (Additional sutures were produced with lower target concentrations of NGF, including 1 ng / cm and 0.1 ng / cm, however these were not used in the tests described below.)
[00174] For drug eluting sutures with sizes in the range of USP 12-0 to USP 7-0 (approximately 0.001 mm to 0.069 mm in diameter), and specifically for protein drug eluting sutures (such as, but not limited to a, NGF and VEGF), the drug concentration range per suture length can be about 100 ngFARMAco / emsuTURA to 0.001 ngFARMAco / emsuTURA. For drug-eluting sutures with sizes in the range of USP 6-0 to USP 5 (approximately 0.070 mm to 0.799 mm in diameter), the concentration range of the drug per suture length can be about 15% weight PHARMAco / weights at 0.001 ngFARMAco / cmsuTURA.
[00175] For drug eluting sutures, different filament materials and different eluting drugs (such as protein drugs NGF and VEGF) will release the drug at different rates and the dosage parameters can be used in combination with the release rate of the drug from the filament so that a minimum concentration of about 10-13 M to 10 “12 M, or about 10“ 12 M to 10 “11 M, or about 10“ 11 M to 10 “10 M , or about 10 "10 M to 10" 9 M, or about 10'9 M to 10-8 M, or about 10-8 M to 10-7 M of the agent, is kept close to or on the surface of the tissue, to maintain the desired therapeutic effect for the necessary period of time. The minimum concentration required depends on the potency of the agent under consideration and the desired therapeutic effect.
[00176] Lots of PDO sutures with NGF loading having a diameter of about 0.045 mm (ie, in the USP range for 8-0 sutures, a caliber suitable for nerve repair) were tested in PC12 cell line to determine biologically active NGF eluates from the PDO suture with NGF loading. The PC12 cell line is derived from a pheochromocytoma of the adrenal medulla of the rat and, in the presence of 0.5 ng / ml to 50 ng / ml NGF with medium supplemented with serum, it is known that the cell line undergoes a change dramatic in the phenotype and, mimics the growth of sympathetic neurons by generating long neurites, making it a very useful test for detecting biologically active NGF. Furthermore, maintenance of PC12 neurites requires the continued presence of NGF; if exposure to NGF is discontinued, then PC12 neurites will retract or degenerate and PC12 cells will resume normal proliferation within approximately one week. Two sets of cell cultures, one in the presence of NGF-loaded sutures and the other in the absence of NGF-loaded sutures, were cultured for two days.
[00177] Figure 10A shows non-differentiated PC12 cells with serum supplemented medium without exposure to NGF-loaded sutures. PC12 cells proliferated without cell differentiation or generation of long neurite structures. In contrast, figure 10B shows PC12 cells differentiated with serum supplemented medium that were exposed to NGF-loaded sutures. PC12 cells stopped proliferating and started to differentiate by generating long neurite structures; these structures are clearly visible in figure 10B. As it is known that this phenotype differentiation occurs only when PC12 cells are exposed to NGF with a drug concentration range of 0.5 ng / ml to 50 ng / ml NGF, the cell phenotypic differentiation in figure 10B indicates so much that ( 1) the biological activity of the NGF eluted from the drug-loaded sutures, while (2) the bioactive NGF was in the range of 0.5 ng / ml to 50 ng / ml.
[00178] The correlation of the NGF dosage response to the surface area of the suture material with NGF loading was also tested in the PC12 cell line, by comparing the biological response of the PC12 cell cultures to shorter lengths (i.e., 5 cm ) of NGF-loaded sutures and at longer lengths (i.e., 10 cm) of NGF-loaded sutures. (Although the theoretical loading concentration of these sutures was 500 ng NGF per milliliter, it should be noted that the actual elution of NGF passed in the range of 0.5 ng / ml to 50 ng / ml, as evidenced by the phenotypic differentiation of PC12 cells If the real eluipation had exceeded the range, such a differentiation would not have been seen). As the sutures had the same diameter, the dosage response correlated with the surface area of the sutures and, consequently, exposure to NGF dosing. Figures 11 and 12 show the PC12 cell differentiation in the presence of the longest (10 cm) and shortest (5 cm) lengths of NGF loaded sutures. Figures 11A to 11D show the cultures of PC12 cells, stained with green phalloidin, which were exposed to NGF-free suture (Figure 11A), which were exposed to 5-cm suture with NGF-load (Figures 11B and 11B) and who were exposed to a 10 cm long suture with NGF load (figure 11D). Similarly, figures 12A to 12C show PC12 cell cultures, in phase contrast, which were exposed to NGF-free suture (figure 12A), which were exposed to 5 cm-long suture with NGF-load (figure 12B ), and that were exposed to a suture 10 cm long with NGF load (figure 12C). As can be seen from the comparative bar graph in figure 13, the neunotic processes that were generated in cell cultures exposed to the larger total surface area of the drug-eluting suture (corresponding to the suture lengths of 10 cm), were substantially greater than those exposed to the lower drug eluting surface area (corresponding to 5 cm suture lengths). Thus, the increase in the surface area of the drug-eluting suture correlated with an increase in the kinetics of drug release, which, in turn, correlated with an increased dose response. Additional Clinical Uses
[00179] In addition to general wound closure and soft tissue repair applications, drug-eluting self-healing sutures can be used for a variety of other indications. The self-retention suture with drug elution can be implanted in many sites in the body, including dermal tissues, heart tissue, soft tissues, nerves, the eye, arteries, veins, ducts, bile duct, ureter, urethra, trachea, esophagus, intestine , colon, and connective tissue such as teres, ligaments, muscles and bone. The drug eluting self-retention sutures have the advantage of providing the body not only with the target drug application, but also with mechanical support and retention of tissues without knots or staples.
[00180] The self-suturing sutures described here can be used in various dental procedures, i.e., in oral and maxillofacial surgical procedures and, therefore, they can be called "dental self-suturing sutures". The procedures mentioned above include, but are not limited to, oral surgery (for example, removal of impacted or broken teeth), surgery to provide bone augmentation, surgery to repair dentofacial deformities, repair after trauma (eg, fractures and injuries) osseas facials), surgical treatment of odontogenic and non-odontogenic tumors, reconstruction surgery, repair of the cracked lip or palate, congenital craniofacial deformities and aesthetic facial surgery. Dental self-restoring sutures can be degradable or non-degradable, and can typically vary in size from USP 2-0 to USP 6-0.
[00181] The self-entertaining sutures described herein can also be used in surgical tissue repositioning procedures and, therefore, they may be called "self-entertaining tissue repositioning sutures". Such surgical procedures include, but are not limited to, facial liftings, cervical liftings, frontoplasty, thigh lift and sinus lift. The self-restoring sutures used in tissue repositioning procedures may vary depending on the tissue being repositioned; for example, sutures with larger and additionally stripped retainers can be suitably used with relatively soft fabrics such as fatty fabrics.
[00182] The self-suturing sutures described herein can also be used in microsurgical procedures that are performed under a surgical microscope (and thus can be called "self-microstructure microstructures"). Such surgical procedures include, but are not limited to, reclosing and repairing the peripheral nerves, spinal microsurgery, hand microsurgery, various plastic microsurgical procedures (for example, facial reconstruction), microsurgery of the male or female reproductive system and various types of microsurgery reconstruction. Microsurgical reconstruction is used for complex reconstructive surgery problems, when other options, such as primary closure, healing by second intention, skin graft, local flap transfer and distant flap transfer are not adequate. Micro-sutures for self-restraint have a very small caliber, often as small as USP 9-0 or USP 10-0, and may have a fixed needle of corresponding size. Microsutures can be degradable or non-degradable.
[00183] The self-entertaining sutures described herein can also be used to enhance healing of bone fracture. The self-retention suture can be wrapped around the bone and / or implanted in the bone of other tissues at the fracture site; releasing drugs to promote fracture repair, for example growth hormones. The self-retention suture can also be used to make a 2D or 3D mesh structure to facilitate the positioning of the self-retention suture and / or the application of drugs from the self-retention suture to the target tissue.
[00184] The self-entertaining sutures described herein can be used at similar small gauge intervals for ophthalmic surgical procedures and thus can be referred to as "ophthalmic self-entertaining sutures". Such procedures include, but are not limited to, keratoplasty, cataract, retinal and vitreous surgical procedures. Ophthalmic self-suturing sutures can be degradable or non-degradable, and have a fixed needle of correspondingly small gauge.
[00185] Self-entertainment sutures can be used in a variety of veterinary applications in a large number of surgical and traumatic purposes in animal health. Sterilization
[00186] Additionally, the drug eluting self-entertainment sutures of the present invention should preferably have a stable shelf life for at least several months and can be produced and maintained under sterile conditions. The compositions or sutures can be sterile, either by preparing them in an aseptic environment and / or they can be thermally sterilized using methods available in the art. Many pharmaceutical / medical devices are manufactured to be sterile under criteria defined by US Pharmacopeia (see www.usp.org, Rockville, MD, USA), or AAMi standards defined by the Association for the Advancement of Medical Instrumentation, or ISO defined standards , for example, by The International Organization for Standardization (ISO) or The European Committee for Standardization (CEN). Sterilization can be done by any number of means, including for example, gas sterilization or ionizing radiation. Acceptable gases used for gaseous sterilization include ethylene oxide. Acceptable types of radiation used for ionizing radiation methods include gamma, for example, from a cobalt 60 source and electron beam. A typical dose of gamma radiation is 2.5 MRad. Sterilization can also occur through the use of sterilization methods by gamma radiation or electron beam. A combination of these methods can also be used to prepare compositions and sutures in sterile form. The method and / or doses of sterilization are selected in such a way that sufficient drug activity remains in the sterile drug eluting self-retention suture to cause the desired therapeutic effect. In this regard, problems to be considered in the selection of sterilization methods and / or dosages include whether the method / dosage can cause denaturation of the drug (s), induce the production of free radicals (which can decrease the stability of ( s) drug (s) in the shelf life of the suture and / or change the quantities (quantities) of the drug (s)), or cause loss of potency of the drug (for example, through passive diffusion in the case of sterilization methods involving aqueous solutions). The cost of the sterilization method / dose can also be a consideration. Optional modalities
[00187] The specific modalities that have been described here include the following:
[00188] A suture comprising: a filament; a drug associated with the filament; a plurality of fabric retainers formed in the filament; wherein the kinetics of the release of the therapeutic agent is determined by the distribution of the therapeutic agent in at least one of the filament or retainers. Optionally, said filament includes a nucleus and a wrapper covering said nucleus and wherein said drug is provided in at least one of said nucleus and said wrapper, where in one embodiment the drug is provided in the nucleus, optionally only in the nucleus, while in another embodiment the drug is supplied in the wrapper, optionally only in the wrapper. The drug can be distributed in said envelope isotropically, or it can be distributed anisotropically. The drug can be distributed in said envelope isotropically, or it can be distributed anisotropically. The retainers can be formed in the wrapper, and in this embodiment the drug can be associated with the retainers, optionally to provide anisotropic release of the drug. The drug can be associated with the filament to provide one of the anisotropic release of the drug and the isotropic release of the therapeutic agent. The drug can be delivered to said nucleus in order to provide at least one of the isotropic and anisotropic release of the therapeutic agent. The drug can be distributed in said envelope so as to provide at least one of the isotropic and anisotropic release of the drug. To prepare the suture, four options are to form the wrapper by extruding a two-component fiber with a core / wrap structure, extruding a wrapping material around a core, spraying wrapping material around a nucleus, or immersing the nucleus in a composition containing the wrapper material, including in each case, precursor materials to the wrapper material. In one embodiment, the filament includes one of the neural growth factor (NGF) or Bone Morphogenetic Protein (BMP). Optionally, the filament includes a plurality of suture strands. Optionally, one between the nucleus and the envelope has a higher concentration of said drug than the other between the nucleus and the envelope. Optionally, said filament includes a first end portion, a second end portion and an average portion, and wherein at least one of said first end portion, said second end portion and said average portion has a concentration higher of said drug than the other of said first end portion, said second end portion and said average portion. In an optional embodiment, the drug location is identified by a detectable marker. The kinetics of drug release in the self-retention suture can, among others, be determined by at least one of the distribution of the retainers, density of the retainers, size of the retainers, surface area of the retainers and shape of the retainers. Each and every one of these diverse modalities can be combined with one or more optional modality, as mentioned in the present invention.
[00189] A suture comprising: a filament; a drug associated with the filament; a plurality of fabric retainers formed in the filament; wherein the kinetics of drug release is determined by the distribution of the drug in the suture; and wherein said filament includes a nucleus and an envelope covering said nucleus and wherein said drug is supplied in at least one of said nucleus and said envelope with a distribution selected from isotropic and anisotropic. Optionally, one of the nucleus and the envelope has a higher concentration of said drug than the other between the nucleus and the envelope.
[00190] A suture comprising: a filament; a drug associated with the filament; a plurality of fabric retainers formed in the filament; wherein the kinetics of drug release is determined by the distribution of the therapeutic agent in the suture; and wherein said filament includes a nucleus that includes a plurality of woven threads and a wrapper covering said nucleus and wherein said drug is provided in at least one of said nucleus and said wrapper in at least one of the isotropic ways and anisotropically. Optionally, one of the nucleus and the envelope has a higher concentration of said drug than the other between the nucleus and the envelope.
[00191] Self-retaining suture comprising: a filament; a drug associated with the filament; a plurality of fabric retainers cut into the filament; wherein, after implantation in a tissue, the filament, and retainers release the drug into the tissue, the kinetics of drug release being modified by the shape and distribution of the retainers as compared to that of the filament only.
[00192] Nerve repair method that includes the steps of: selecting a suture that includes a Neural Growth Factor (NGF) and with a plurality of retainers distributed so that the nerve can be repaired and the tension applied to the nerve during repair the suture is spread over the nerve; and apply the suture to the nerve to repair the nerve. Optionally, this method includes selecting a suture in which more than eighty percent of the NGF is released to the nerve within the first five days after the suture is applied to the nerve to repair the nerve. Also optionally, the application step includes applying at least two sutures to the nerve with bidirectional retainers, in which the sutures approach the nerve along a direction parallel to the nerve. Optionally, the application step includes applying the suture to repair the nerve using an anastomosis technique. The application step can optionally be used at least on one of a lacerated nerve or a ruptured nerve. Optionally, the step of removing necrotic tissue from the separate ends of the nerve prior to the application step. Also optionally, said application step can include using said suture to ligate a nerve defect. In addition, said application step may optionally include repairing the nerve without a concentration of one of the tension or pressure on the nerve.
[00193] Nerve repair method that includes the steps of: selecting a suture that includes a Neural Growth Factor (NGF) and with a plurality of retainers distributed so that the nerve can be repaired; and applying the suture to the nerve to repair the nerve, wherein the selection step includes selecting a suture in which more than eighty percent of the NGF is released to the nerve within the first five days after the suture is applied to the nerve to repair the nerve; and wherein said application step includes repairing the nerve without a concentration of one of the tension or pressure in the portion of the nerve being repaired. Optionally, this method provides that the application step includes applying at least two sutures to the nerve with bidirectional retainers, in which the sutures approach the nerve along a direction parallel to the nerve. Also optionally, the application step may include applying the suture to repair the nerve using an anastomosis technique. In addition, said application step can optionally be used at least in one of a lacerated nerve or a ruptured nerve. The method may include the step of removing necrotic tissue from the separate ends of the nerve prior to the application step. As an option, said application step includes the use of said suture to join a nerve defect.
[00194] Nerve repair method that includes the steps of: selecting a suture that includes a Neural Growth Factor (NGF) and with a plurality of retainers distributed so that the nerve can be repaired; and applying the suture to the nerve in order to repair the nerve, where the selection step includes selecting a suitable suture for rapid release kinetics of the NGF drug; and wherein said application step includes repairing the nerve without a concentration of one of the tension or pressure in the portion of the nerve being repaired. As an option, the application step includes applying at least two sutures to the nerve with bidirectional retainers, where the sutures approach the nerve along a direction parallel to the nerve. Another optional modality is that the application step includes applying the suture to repair the nerve using an anastomosis technique. Said application step can optionally be used at least in one of a lacerated nerve or a ruptured nerve. The method may include the step of removing necrotic tissue from separate nerve ends prior to the application step. The application step may optionally include the use of said suture to join a nerve defect. In one embodiment, the selection step includes selecting a suitable suture for rapid release kinetics of the NGF drug.
[00195] The various optional embodiments shown above can be combined with one or more other optional embodiments as presented herein, to provide a statement of the present invention.
[00196] Although the present invention has been shown and described in detail with respect to only some exemplary embodiments of the invention, it should be understood by those skilled in the art that it is not intended to limit the invention to the specific embodiments presented. Various modifications, omissions, and additions can be made in the modalities presented without substantially departing from the innovative teachings and advantages of the invention, particularly in light of the aforementioned teachings. Consequently, it is intended to cover all of these modifications, omissions, additions, and equivalents that may be included in the spirit and scope of the present invention, as defined by the following claims.

权利要求:
Claims (10)
[0001]
1. Suture, characterized by the fact that it comprises: a filament (470), in which the filament includes a circular core (472) and a wrapper covering the nucleus, in which the wrapper does not continue and comprises three elements of wrapping ( 474, 475, 476) arranged circumferentially around the nucleus (472); a drug associated with the filament (470); a plurality of tissue retainers formed in the filament (470), in which the tissue retainers are cut at the vertices of the wrapping elements (474, 475, 476); wherein the drug is supplied in at least one of said nucleus (472) and the wrapper (474, 475, 476) and where the release kinetics of the drug is determined by the distribution of the drug in at least one of the filament (470) and the retainer.
[0002]
2. Suture according to claim 1, characterized by the fact that said drug is distributed in said nucleus at least one isotropic and anisotropically.
[0003]
3. Suture, according to claim 1, characterized by the fact that said drug is distributed in said envelope one isotropic and anisotropic.
[0004]
4. Suture according to claim 1, characterized by the fact that said drug is associated with the retainers to provide an anisotropic release of the therapeutic agent.
[0005]
5. Suture according to claim 1, characterized by the fact that said drug is associated with the filament to provide one of the anisotropic release of the drug and the isotropic release of the drug.
[0006]
6. Suture, according to claim 1, characterized by the fact that said filament includes a drug selected from Neural Growth Factor (NGF) and Bone Morphogenic Protein (BMP).
[0007]
7. Suture according to claim 1 or 6, characterized in that said filament includes a plurality of stranded sutures.
[0008]
8. Suture according to claim 1 or 6, characterized by the fact that one of the nucleus and of the envelope has a higher concentration of said drug than another of the nucleus and the envelope.
[0009]
Suture according to claim 1, characterized by the fact that said filament includes a first end portion, a second end portion and an average portion, and at least one of said first end portion, of the said second end portion and said middle portion have a greater concentration of said drug than another one of said first end portion, said second end portion, and said middle portion.
[0010]
10. Suture according to claim 1, characterized by the fact that a site of said drug is identified by a detectable marker.

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US8916077B1|2014-12-23|Self-retaining sutures with retainers formed from molten material

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NZ617993B2|2015-07-28|Methods and devices for soft palate tissue elevation procedures

同族专利:

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公开号 | 公开日

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CN103747746B|2017-05-10|

---

MX2013005072A|2013-12-02|

---

BR112013011090A2|2017-10-31|

---

JP6342449B2|2018-06-13|

---

ZA201304011B|2014-11-26|

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WO2012061658A2|2012-05-10|

---

JP2016198527A|2016-12-01|

---

WO2012061658A3|2012-07-19|

---

US11007296B2|2021-05-18|

---

EP2635198A2|2013-09-11|

---

EP2635198A4|2015-03-18|

---

CA2816326C|2020-12-15|

---

RU2013125475A|2014-12-10|

---

KR20130140762A|2013-12-24|

---

AU2011323299A1|2013-05-30|

---

RU2608237C2|2017-01-17|

---

NZ610341A|2015-05-29|

---

BR112013011090A8|2019-12-10|

---

NZ706725A|2016-03-31|

---

KR20180101606A|2018-09-12|

---

US20130317545A1|2013-11-28|

---

AU2011323299B2|2016-06-30|

---

JP2014504894A|2014-02-27|

---

KR102236459B1|2021-04-07|

---

CN103747746A|2014-04-23|

---

CA2816326A1|2012-05-10|

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法律状态:
2018-12-18| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2019-09-17| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2020-07-14| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2020-11-24| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 03/11/2011, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US40973110P| true| 2010-11-03|2010-11-03|

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US61/409,731|2010-11-03|

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PCT/US2011/059238|WO2012061658A2|2010-11-03|2011-11-03|Drug-eluting self-retaining sutures and methods relating thereto|

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