KR101367978B1 - Block-polymer membranes for attenuation of scar tissue - Google Patents

Abstract

A precut, user shapeable, resorbable polymer microfilm is disclosed. Microfilms are made of resorbable polymers engineered to attenuate coalescence and to be absorbed into the body relatively slowly over time. The film can be formed to have a very thin thickness, such as from about 0.010 mm to about 0.300 mm, while maintaining adequate strength. Membranes can be extruded from polylactide polymers having relatively high viscosity properties, stored in sterile packages, and preformed with relatively high reproducibility during the implantation procedure.

Description

BLOCK-POLYMER MEMBRANES FOR ATTENUATION OF SCAR TISSUE

Cross-reference to related application

This application is incorporated by reference in US Provisional Application No. 61 / 059,795, filed on June 8, 2008, entitled "Block-Polymer Membrane for Damping Scar Tissue," the disclosure of which is hereby expressly incorporated by reference in its entirety. US Application No. 12 / 199,760, filed on August 27, 2008, filed with the title “Resorbable barrier microfilm for attenuating scar tissue during healing” on August 27, 2008. MB8039P), US Patent Application Ser. No. 10 / 385,399 filed on March 10, 2003, entitled " Resorbable Barrier Microfilm for Attenuating Scar Tissue During Healing. &Quot; (Currently US Pat. No. 6,673,362).

This application also discloses US application Ser. No. 10 / 631,980, filed Jul. 31, 2003, Representative Application No. MA9604P, US application Ser. No. 11 / 203,660, filed Aug. 12, 2005, Representative Application No. MB9828P, U.S. Application No. 10 / 019,797, filed July 26, 2002 (Agent No. MB9962P), U.S. Provisional Application No. 60 / 966,782, filed Aug. 27, 2007 (Agent No. MB8039PR), and 8, 2007 US Provisional Application No. 60 / 966,861, filed May 29, Representative Application No. MB8039PR2. The above applications are commonly assigned, the entire contents of each of which are expressly incorporated herein by reference in their entirety.

1. Field of the Invention

The present invention generally relates to medical implants and, more particularly, to resorbable membranes and methods of using such membranes and their use as medical implants.

2. Description of Related Technology

A major clinical problem associated with surgical repair or inflammatory disease is adhesions that occur during the early stages of the disease or postoperative healing process. Adhesion is a condition involving the formation of abnormal tissue connections caused by the formation of fibrous scar tissue. Such a connection can, for example, impair body function, cause infertility, block the intestines and other parts of the gastrointestinal tract (intestinal obstruction), and cause general discomfort, such as pelvic pain. The condition can be life threatening in some cases. One of the most common forms of adhesion occurs as a result of surgical intervention, but adhesion is the result of other processes or events such as pelvic inflammatory disease, Khron disease, peritonitis, mechanical damage, radiation therapy, and the presence of foreign substances. May occur.

Various attempts have been made to prevent adhesions, especially postoperative adhesions. For example, in order to minimize the additional growth of the membrane surface, modification of surgical techniques such as laparoscopy, heparinized solution, use of pre-coagulant, microscopic or laparoscopic technique, removal of talc from surgical gloves, more The use of small sutures and the use of physical barriers (membrane, gel or solution) have all been attempted. Unfortunately, these methods have only had limited success. In addition, various forms of barrier materials such as membranes and intraperitoneal viscous solutions designed to limit tissue addition growth have also been limited to success. Such barrier materials may include cellulose barriers, polytetrafluoroethylene materials, and dextran solutions.

US Pat. No. 5,795,584 to Tokahura et al. Discloses films or membranes for preventing adhesion or reducing scar tissue and US Pat. No. 6,136,333 to Cohn et al. Discloses similar structures. In Tokafura et al., The bioabsorbable polymer is copolymerized with a suitable carbonate and then formed into a non-porous single layer adhesion barrier such as a film. In Conn et al., The use of urethane chemistry results in the formation of polymeric hydrogels for anti-adhesion without crosslinking. All of these patents included relatively complex chemical preparations and / or reactions to create specific structures for use as surgical adhesion barriers. There is a continuing need for improved membranes.

The present invention is used in various surgical situations, for example during tissue healing, for example to inhibit, delay or prevent tissue adhesion and to reduce scar formation, and then improved ash that can be absorbed or dissolved after a suitable period of time. It provides an absorbable microfilm. The film can be formed to have a very thin thickness, such as from about 0.010 mm to about 0.300 mm, while maintaining adequate strength.

The present invention provides an improved resorbable microfilm that is easily and surely formed and can be disposed on, around, or adjacent to an anatomical structure comprising hard or soft tissue. The membrane can be used in various surgical situations, such as to delay or prevent tissue adhesion and to reduce scar formation. In addition, the copolymers of the present invention may facilitate the provision of relatively simple chemical reactions and / or preparations, and / or may be strengthened or slightly compared to other poly (esters), for example mother poly (esters). It may facilitate the provision of one or more of more controllable mechanical strength and / or accelerated or more controllable degradation.

According to one exemplary implementation of the present invention, a resorbable microfilm comprising a diblock copolymer of substantially uniform composition can be provided. The diblock copolymer comprises a first block comprising, consisting essentially of, or consisting of one or more polylactides and / or polyglycolides (eg, PLA, PGA, or PLGA), and one A second block may comprise, consist essentially of, or consist of, any of the above polyethylene glycols (eg, PEG). The first block, referred to as the PLA / PGA block, may comprise hydrophobic and biodegradable PLA / PGA blocks, and the second block, called the PEG block, may comprise a hydrophilic PEG block.

According to another feature of the invention, a first block, comprising, consisting essentially of, or consisting of polylactide and / or polyglycolide (eg, PLA, PGA or PLGA), one A second block comprising, consisting essentially of, or consisting of, any of the above polyethylene glycols (eg, PEG), and polylactide and / or polyglycolide (eg, PLA, PGA or PLGA A material comprising, consisting essentially of, or consisting essentially of a triblock copolymer of substantially uniform composition, which may comprise, consist essentially of, or may comprise a third block which may consist of An absorbable microfilm is provided. The first and third blocks, each referred to as PLA / PGA blocks, may preferably comprise one or more hydrophobic and biodegradable PLA / PGA blocks, and the second block, referred to as PEG blocks, preferably comprises one or more hydrophilic PEGs. It may include a block.

If the first and third blocks share the same or more than one common feature, they may all be referred to as "A" blocks and the second block may be referred to as "B" blocks.

The first PLA / PGA block and the second PEG block may together form a PLA / PGA-PEG (ie, AB) copolymer, and the addition of the third PLA / PGA block all together form PLA / PGA-PEG-PLA / PGA (ie ABA) copolymers can be formed. The PLA / PGA-PEG (and / or PLA / PGA-PEG-PLA / PGA) copolymer membrane may be formed, for example, by extrusion, for example in initial relatively high viscosity properties. Initially high viscosity properties can promote reliable formation of the membrane during the extrusion process, for example by attenuating the occurrence of fracture or rupture of the membrane. After processing and sterilization, the viscosity or viscosity characteristics of the membrane comprising the polymer (s) may typically be degraded. According to another aspect of the present invention, different viscosity properties, for example, to increase the strength of PLA / PGA-PEG (and / or PLA / PGA-PEG-PLA / PGA) copolymer materials during fabrication processes such as extrusion processes (Eg, relatively high viscosity properties) can be used. In a modified embodiment, the initial viscosity property may not be relatively high. Extrusion manufacturing processes can provide membranes with biased molecular orientation.

According to another feature, the membrane has a first substantially smooth surface and a second substantially smooth surface and is non-porous and between the first substantially smooth surface and the second substantially smooth surface. The thickness measured at is from about 0.01 mm to about 0.300 mm. The membrane can thus have several cross-sectional thicknesses. For example, the membrane may comprise at least one relatively thick portion that may form at least a segment of the edge of the membrane. In other embodiments, the membrane can have a uniform thickness.

The apparatus and method are or will be described in terms of functional description for grammatical flexibility, but the claims are to be construed as being limited in any way by the construction of "means" or "steps" limitations unless otherwise indicated. It should be clearly understood that it is consistent with the meaning of the claim language and the full scope of the equivalents under the legal principles of equivalents.

Any feature or combination of features described herein is included within the scope of the present invention unless the features included in any such combination are inconsistent with one another as would be apparent from the context, the specification, and the knowledge of those skilled in the art. In addition, any feature or combination of features described herein may be specifically excluded from any embodiment of the present invention. For purposes of summarizing the invention, certain aspects, advantages and novel features of the invention are described. Of course, it is to be understood that not all such aspects, advantages, and features need necessarily be embodied in any particular implementation of the invention. Further advantages and aspects of the invention are apparent from the following detailed description and claims.

1 illustrates the ABA-triblock copolymer showing the basic structure of the PLA-PEG-PLA (ABA) embodiment, and the molecular weight decrease of the polymer over time.
2 illustrates a starblock copolymer showing the basic structure of a star form PEG embodiment with PLA and / or PGA / PEG arms, and a molecular weight decrease of the polymer over time.
3 illustrates the molecular weight reduction of BAB-triblock copolymers, and polymers over time.
4 illustrates the molecular weight reduction of certain ABA-triblock copolymers, and polymers over time.
5 illustrates the molecular weight reduction of certain PLA and PEG mixtures, and polymers over time.
6 illustrates certain PLA and ABA triblock copolymer mixtures, and molecular weight decreases over time.

Reference will now be made in detail to the presently preferred embodiments of the invention, examples of which are illustrated in the accompanying drawings. Wherever possible, the same or similar reference numerals are used in the drawings and the specification to refer to the same or similar parts. It is to be noted that the drawings are simplified and are not to scale. With respect to the disclosure herein, for purposes of convenience and clarity only, indicating a direction such as top, bottom, left, right, top, bottom, on, on, under, under, under, back and front The terminology is used with reference to the accompanying drawings. Terms indicating this direction should not be construed as limiting the scope of the invention in any way.

While the disclosure herein refers to certain illustrated embodiments, it should be understood that these embodiments are presented by way of example and not as limitation. The intention of the present disclosure is to be described in detail in the following detailed description of all the modifications, alternatives and equivalents of such embodiments as may fall within the spirit and scope of the invention as defined by the appended claims. It is intended to be included in the description.

The barrier membranes of the present invention may be composed of various biodegradable materials, such as resorbable polymers. According to one embodiment, non-limiting polymers that can be used to form the barrier membranes of the invention can include diblock copolymers. As embodied herein, the diblock copolymer comprises an agent comprising, consisting essentially of, or consisting of polylactide and / or polyglycolide (eg, PLA, PGA, or PLGA). One block, and a second block comprising, consisting essentially of, or consisting of polyethylene glycol (eg, PEG). The first block, referred to as a PLA / PGA block, may comprise one or more hydrophobic and biodegradable PLA / PGA blocks, and the second block, referred to as a PEG block, may comprise a hydrophilic PEG block. The first PLA / PGA block may be referred to as an "A" block and the second PEG block may be referred to as a "B" block. The first PLA / PGA block and the second PEG block may together form a PLA / PGA-PEG (ie A-B, or AB) diblock copolymer.

Other non-limiting block polymers that can be used to form the barrier membranes of the present invention include three-block copolymers or starblock copolymers. As embodied herein, the triblock copolymer comprises a first block, polyethylene glycol (eg, which may comprise or consist of polylactide and / or polyglycolide (eg, PLA, PGA, or PLGA) For example, a second block, which may comprise or consist of PEG), and a third block, which may comprise, or consist of polylactide and / or polyglycolide (eg, PLA, PGA or PLGA) It may include a block. The first block, referred to as the PLA / PGA block, may comprise hydrophobic and biodegradable PLA / PGA blocks, and the second block, referred to as the PEG block, may comprise a hydrophilic PEG block, referred to as the PLA / PGA block. The third block may comprise hydrophobic and biodegradable PLA / PGA blocks. If the first PLA / PGA block and the third PLA / PGA block share the same or more than one common feature, they may each be referred to as an "A" block and the second PEG block is referred to as a "B" block. Can be. The first PLA / PGA block, the second PEG block, and the third PLA / PGA block may together form a PLA / PGA-PEG-PLA / PGA (ie A-B-A, or ABA) triblock copolymer.

Combination block copolymers can alternatively be characterized as PEG-PLA / PGA-PEG (ie, B-A-B, or BAB) triblock copolymers.

In another implementation, a combinatorial block copolymer is formed of, for example, PEG blocks (ie, B blocks) formed with, coupled to, or disposed between three or more PLA / PGA blocks (ie, A blocks). It may be a four plus (ie four or more blocks) block copolymer comprising a. The 4-plus block copolymers are alternatively formed, for example, PLA / PGA blocks (ie, A blocks) formed with, coupled to, or disposed between three or more PEG blocks (ie, B blocks). It may include.

The 4-plus block copolymer couples (ie, to or to them) three or more PLA / PGA (or PLA and / or PGA / PEG) blocks (ie, A blocks) whose number may comprise, for example, 4 PEG blocks (ie, B blocks) having one or more symmetrical or star forms, with regions (eg, arms, branches, or points) connected with them). See, eg, FIG. 2 for embodiments of the star block copolymers. In a preferred implementation, the number of regions is equal to the number of PLA / PGA blocks. Alternatively, the four plus block copolymer has regions (eg, arms, branches, or points) that couple (ie, link to or with them) coupling three or more PEG blocks (ie, B blocks). , PLA / PGA blocks (ie, A blocks) having one or more symmetrical or star shapes. The number of regions may be equal to the number of PEG blocks, as in the previous example, and may include 4 in specific examples.

Combination block copolymer membranes may be formed by extrusion at an initial relatively high viscosity property. Initially high viscosity properties can promote reliable formation of the membrane during the extrusion process, for example by damping the occurrence of breakage or rupture of the membrane. After processing and sterilization, the viscosity characteristics of the membrane can typically be degraded. According to another aspect of the present invention, other relatively high viscosity properties can be used, for example, to increase the strength of the material. The extrusion procedure can advantageously provide for efficient production of the membrane. In addition, membranes produced by such extrusion techniques can be left in the absence of solvent collections in the membrane, and can also be provided to have molecular deflections, including, for example, predetermined molecular deflections. Monoaxial or biaxial extrusion may be used to prepare the membrane.

The composition of the combination block copolymer can be extruded to form the film of the present invention. In certain embodiments, the following polymers: 1. poly (L-lactide-co-PEG), 2. poly (L-lactide-co-DL-lactide-co-PEG), and 3. poly (L- PLA / PGA-PEG block copolymers taking one or more forms of lactide-co-glycolide-co-PEG); The following polymers: 4. poly (L-lactide-co-PEG-co-L-lactide), 5. poly (L-lactide-co-PEG-co-L-lactide-co-DL-lactide ), 6. poly (L-lactide-co-PEG-co-L-lactide-co-glycolide), 7. poly (L-lactide-co-DL-lactide-co-PEG-co- L-lactide-co-DL-lactide), 8.poly (L-lactide-co-DL-lactide-co-PEG-co-L-lactide-co-glycolide), 9.poly ( L-lactide-co-glycolide-co-PEG-co-L-lactide-co-glycolide), and 10. combinations and / or combinations of the above for star block and / or 4-plus block copolymers PLA / PGA-PEG-PLA / PGA block copolymers can be prepared or obtained in the form of other forms of substitution (in combination with any one or more other items disclosed herein or as referenced herein, as the case may be). have. For example, such items can be made or obtained from, but not limited to, Boehringer Ingelheim KG, Germany, for extrusion into the membranes of the present invention.

Exemplary chemical structures, and synthesis and nomenclature, as used herein, are as follows.

here,

R ₁ = CH ₃ for this block

R ₁ = A for triblock

Scheme B again shows that, by the action of a catalyst, polyethylene glycol (PEG) units are incorporated into the block copolymer with PLGA. PEG also has low systemic toxicity and is currently used in a variety of medical and pharmaceutical agents.

The resulting block copolymer can be represented schematically as follows.

Commercially available PLGA: PEG block copolymers include the RESOMER® PEG product from Schöllinger Ingelheim.

One preferred (but non-exclusive) product is Resomer® PEG sample MD type LRP d 70 5 5 , where LR means Resomer initial LR (A-block) and P is PEG (B-block) 70 means the molar ratio in the A-block, the first 5 means the weight percentage of PEG and the second 5 means the molecular weight of PEG divided by 1000.

Typical non-limiting examples of PLA / PGA-PEG (and / or PLA / PGA-PEG-PLA / PGA) copolymers are as follows: For controlled release functionality (CR), polymers typically range from about 5% to Will contain about 15% PEG. For medical devices (MD), the polymer will typically contain less than about 5% PEG. For controlled release, the A blocks can contain, for example, D, L-lactide-co-glycolide (RG). For medical devices, the A block may contain L lactide (L), L-lactide-co-D, L-lactide (LR), or L lactide-co-glycolide (LG), for example. Can be.

1-6 illustrate certain compositions and features of the designed embodiments according to the present invention. The membrane of the present invention may have at least one substantially smooth surface. Preferably, the membranes of the present invention have two (opposite) substantially smooth surfaces. The thickness of the film of the invention measured between the opposing surfaces may be from about 0.01 mm to about 0.3 mm, more preferably from about 0.01 mm to about 0.1 mm. In a preferred embodiment, the thickness of the membrane of the present invention is about 0.015 mm to about 0.025 mm. In another preferred embodiment, the maximum thickness of the membrane of the present invention is about 0.02 mm. Preferred microfilms of the present invention may include one or more substantially uniform compositions and molecular orientations that are biased within the film, for example as a result of extrusion.

As used herein, the term “non-porous” refers to a material that is generally waterproof and according to preferred embodiments is not fluid permeable. However, in a modified embodiment of the invention, the micropores (fluid-permeable but not cell-like) in the micromembrane of the invention to the extent that they do not, for example, substantially disrupt the smoothness of the resorbable micromembrane surface, resulting in scar formation of tissue. May not be permeable). In embodiments that are substantially modified for a particular application, pores may be prepared and used that are cell permeable but not vascular permeable.

As embodied in the present invention, many thinner film thicknesses may be sufficiently present without heating to the glass transition temperature. As embodied herein, the resorption of the resorbable membrane may be about 2 to 24 months. In one embodiment, the membranes of the present invention may be from about 18 months or less or about 24 months or less, for example from about 10-20 weeks or about 20-30 weeks, or according to another implementation, from an initial transplant of the membrane into the mammalian body. It can be reabsorbed (ie, absorbed by the mammalian body) within the above period. The resorbable membrane may be reabsorbed in the patient's body until the point where there is no longer any significant intensity within a period of about one year. Complete resorption of the resorbable membrane may then occur after a total period of 1.5 to 2 years from the initial transplant. In other embodiments, the resorbable membrane may comprise, in whole or in part, a non-resorbable plastic or metallic material.

The micromembrane has numerous surgical applications, including surgical repair of orbital wall fractures, surgical repair of septal and torn tympanic membranes, protective collection to promote bone formation, surgical repair of anatomical urethral structures, and repair of urethral stenosis, skull Prevention of osteoadhesion in completed orthodontic surgery for fusion and forearm fractures, alleviation of soft tissue fibrosis or bone growth, temporary cover for prenatal rupture restraints during staged repair procedures, induced tissue regeneration between teeth and gingival margins, tympanic repair, hardening Membrane covers and nerve repair, cardiovascular repair, hernia repair, tendon conjugation, temporary joint spacers, wound dressings, scar covers, and covers for parquela. The microfilm of the present invention may be particularly suitable for preventing tissue from joining together abnormally like fibrosis after surgery, which may lead to abnormal scar formation and / or interfere with normal physiological function. In some cases, such scar formation may require and / or interfere with follow-up, correction or other surgery.

The very thin configuration of these membranes is believed to substantially accelerate the rate of absorption of the membrane compared to the rate of absorption of thicker membrane implants of the same material. However, it is contemplated that reabsorption of the membrane into the body too quickly may in some cases undesirably lower local pH levels, for example to introduce / raise local inflammation, discomfort and / or external antibody responses. In addition, uneven (eg, cracked, broken, rough or flaky) surfaces of the resulting microfilm that disintegrate too quickly may undesirably cause tissue disturbances between tissues, for example before proper healing occurs. This can potentially lead to the risk of tissue inflammation and / or scar formation as well as tissue adhesion formation, thus defeating the purpose of the membrane. In other cases, according to one aspect of the present invention, the substance of the membrane, because different (eg, faster) resorption may be desirable in one or more zones of the patient and / or at one or more time points upon one or more surgeries. Or by changing a portion thereof, the rate of absorption may be temporarily and / or spatially altered or contoured.

The microfilm according to one aspect of the invention may be provided, for example, in a rectangular shape, each side of several centimeters, or may be formed by cutting into other specific shapes, shapes and sizes by the manufacturer prior to packaging and sterilization. In modified embodiments, for example, various known formulations and copolymers of polylactide can affect the physical properties of the microfilm. The microfilm of the present invention is flexible enough to fit well on and / or around anatomical structures, but for thicker shapes, some heating in a high temperature bath may be required. In a modified embodiment, for example at a thickness of 0.25 mm or more, it can be somewhat more rigid and brittle and can be softened by forming with other polymers, copolymers and / or other monomers such as epsilon-caprolactone. The formation of microfilms can be carried out with certain polylactide.

In addition, according to another aspect of the present invention, the micromembrane is a chemotactic substance for affecting cell migration, an inhibitory substance for affecting cell migration, a mitotic growth factor for affecting cell proliferation, and a cell It may include substances for cell control, such as one or more of the growth factors to affect differentiation. Such materials may be disposed on and / or impregnated onto the membrane, but may also be coated on one or more surfaces of the membrane. In addition, the substance may be contained in discrete units on or within the membrane that may be effective in promoting selective release of the substance when the membrane is inserted into a patient. Other shapes may be formed to accommodate different anatomical structures. For example, it can be designed to form a conical structure for fitting around a base with a protrusion, for example extending through the center of the membrane. Suture pores may be formed around the distal periphery of the membrane, and cell and vascular permeable pores may also be included.

In general, any feature, feature, or combination thereof (in whole or in part, in the structure or steps) described or cited herein, is disclosed in US Application No. 11 / 203,660 and US Provisional Application No. 60 / 966,861 and / or US The entirety in any combination or permutation described in or cited in any document cited herein, including, without limitation, application 10 / 019,797 (which, in its structure or steps, would be deemed possible or possible by those skilled in the art). May be combined with any feature, feature or combination thereof (whole or partial in structure or step) provided that the feature or feature contained in any such combination is not inconsistent with each other. Each such patent application is expressly incorporated herein by reference.

According to one implementation of the invention, the preformed microfilm may be preformed and sealed in a sterile package for subsequent use by the surgeon. Since one object of the micromembrane of the present invention may be to mitigate sharp edges and surfaces, preformation of the membrane, in some cases to a lesser extent, promotes rounding the edges to reduce friction, tissue disturbance and inflammation. I think it helps. In other words, it is believed that the surface of the microfilm and any sharp edges can potentially decompose very weakly over time, in response to exposure of the film to moisture in the air, thereby forming more rounded edges. This is thought to be an extremely secondary effect. It is also conceivable that any initial heating of the precut membrane to the glass temperature just prior to implantation will further round any sharp edges. In addition, the very fine membranes of the present invention may be particularly sensitive to this phenomenon, at least theoretically, and perhaps more sensitively to rupture or damage due to handling, indicating that the preformation of the micromembrane is potentially advantageous for preserving its integrity. You can do that.

According to one aspect of the invention, a surgical prosthesis (eg, a micromembrane system for resorption of scar tissue reduction) may comprise an adhesion-resistant region (eg, a biodegradable region, a biodegradable cotton, Membranes and / or microfilm), and optionally tissue-growth regions (eg, another membrane, crosslinked membrane, biodegradable region and / or biodegradable cotton or mesh as recited herein). It may further include.

Surgical prostheses (eg, biodegradable surgical prostheses) can be configured for use in repairing soft tissue defects such as soft tissue defects due to incisions and other hernias and soft tissue defects due to tumor eradication surgery. Surgical prostheses may also be used in cancer surgery, such as surgery involving the sarcoma of the limbs whose goal is to preserve the limbs. Other applications of the surgical prosthesis of the present invention include laparoscopic surgery in the inguinal or standard hernia repair, umbilical hernia repair, hernia repair by paracolostomy, femoral hernia repair, lumbar hernia repair, and other abdominal wall. Defects, chest wall defects and diaphragmatic hernia and repair of defects may be included.

According to one aspect of the invention, the tissue-ingrowth region and adhesion-resistant region may differ in both (A) surface appearance and (B) surface function. For example, a tissue-ingrowth region may promote either the strength, longevity or lack of tissue-ingrowth region, and / or substantial fibroblast response in host tissue, for example, relative to the anti-adhesion region. It may be configured to have at least one of the surface shape (appearance) and the surface composition (function) that can be. On the other hand, the adhesion-resistant region may comprise at least one of the surface morphology and surface composition, either of which may promote the anti-adhesion effect between the biodegradable surgical implant and the host tissue as compared to the tissue-ingrowth region. It can be configured to have.

A. Surface Shape (Appearance):

The tissue-growth region may be formed to have an open and / or non-smooth and / or characteristic surface comprising, for example, vesicles and / or pores distributed regularly or irregularly. In a further embodiment, the tissue-ingrowth region is uneven, which can cause tissue disturbances (eg, potential tissue inflammation and / or scar formation) between the host tissue and the tissue-ingrowth region as described above. It can be formed to additionally or alternatively have a surface (eg, cracked, broken, rough or flaky).

With regard to the tissue-ingrowth region, over time, the patient's fibrous and collagen tissues can substantially overgrow in the tissue-ingrowth region, grow over the tissue-ingrowth region, and attach to it. . In one implementation, the tissue-ingrowth region comprises a plurality of vesicles or holes visible to the naked eye, and the host tissue can grow through or grow over it to achieve substantial fixation.

As an example, pores can be formed in the tissue-growth region by punching or other machining, or by using laser energy. The non-smooth surface may be formed, for example, by abrading the tissue-growth region into a relatively rough surface (eg having 40, or preferably more than a sandpaper surface), or, alternatively, smoothing An unsurfaced surface can be created by bringing the tissue-growth region to its softening or melting temperature and marking it with a mold (a sandpaper surface, to use the same example). Marks can be made, for example, during the initial formation process or at a later point in time.

On the other hand, the adhesion-resistant regions may be formed to have a closed and / or continuous and / or smooth and / or non-porous surface. In an exemplary embodiment, at least some of the adhesion-resistant regions do not comprise protrusions, vesicles or vascular permeable pores and are smooth to attenuate the occurrence of adhesions between the tissue-ingrowth regions and host tissue.

In molding embodiments, one side of the press may be formed to create any of the tissue-ingrowth region surfaces discussed above, and the other side of the press is formed to create an adhesion-resistant region surface as discussed above. Can be. Additional features (eg roughening or hole formation) may subsequently be added to further define the surface of the tissue-growth region, for example. In one extrusion embodiment, one side of the output orifice may be formed (eg, rib bond) to create a tissue-growth region where subsequent processing such as adding transverse ribs / features and / or vesicles may be performed. The surface can be further defined), the other side of the orifice can be formed to create an adhesion-resistant biodegradable region surface. In one embodiment, the adhesion-resistant regions are extruded to have a smooth surface, and in another embodiment the adhesion-resistant regions are further processed (eg, smoothed) after extrusion.

B. Surface Composition (Function):

As embodied herein, the tissue-ingrowth region comprises a first material and the adhesion-resistant region comprises a second material different from the first material. In a modified embodiment, the tissue-ingrowth region and adhesion-resistant region may comprise the same or substantially the same material. In other embodiments, the tissue-growth region and adhesion-resistant region may comprise different materials derived from adducts introduced into at least one of, for example, the tissue-ingrowth region and adhesion-resistant region.

In accordance with one implementation of the present invention, the adhesion-resistant region is configured to minimize the occurrence of adhesion of host tissue (eg, body viscera) to the surgical prosthesis. In a modified embodiment, the adhesion-resistant and tissue-growth regions of the surgical prosthesis may be formed functionally speaking of the same material or a material that is relatively not significantly different, wherein the adhesion-resistant region is the point of implantation of the surgical prosthesis. For example, with anti-inflammatory gels applied to the adhesion-resistant regions. According to another broad embodiment, the adhesion-resistant region and the tissue-growth region are any of the materials or combinations of materials discussed herein (including embodiments in which the two regions share a layer of the same material), or It can be formed of their substantial equivalents, and the adhesion-resistant areas can be used with anti-inflammatory gels applied at the time of implantation of the surgical prosthesis, for example to the adhesion-resistant areas.

The tissue-ingrowth region is similar to that described above and / or promotes its strength, lifespan or deficiency, and / or induces postoperative cell colonization, for example, by eliciting a substantial fibroblast response in host tissue. It can be formed of different materials. In an exemplary embodiment, the tissue-ingrowth region is configured for substantial incorporation into host tissue and / or for substantially increasing structural integrity of the surgical prosthesis. After implantation of the surgical prosthesis, body tissue (eg, subcutaneous tissue and / or fascia) begins to incorporate itself into the tissue-ingrowth region. Without wishing to be bound by theory, when the body senses the presence of the tissue-ingrowth region of the present invention, the body grows within, around, and / or through the tissue-ingrowth region and at least partially in-tissue itself. It is believed that there is a tendency to release the fibrous tissue which is intertwined with the growth zone. In this way, surgical prostheses can be securely attached to host body tissue.

With respect to different materials, according to one aspect of the invention, the tissue-ingrowth region exhibits one or more features that differ from the features or characteristics of the biodegradable (eg, resorbable) polymer composition of the adhesion-resistant region. Biodegradable (eg, resorbable) polymer compositions. Different features include (1a) the time or rate of biodegradation affected by the additive, (1b) the time or rate of biodegradation affected by the polymer structure / composition, (2) the polymer composition affecting strength or structural integrity, and ( 3) the ability to promote fibroblast responses.

According to the method of the invention, a surgical prosthesis can be used, for example, to promote repair of a hernia in the abdominal region of the body. Implanted surgical prostheses may be provided having both adhesion-resistant regions disposed on the first side of the surgical prosthesis and tissue-growth growth regions disposed on the second side. The abdominal wall may comprise muscles enclosed by the outer and inner fascia and fixed in place. An inner layer called the peritoneum may cover the inner surface of the inner fascia. The peritoneum is a softer, more flexible layer of tissue that forms a bag-shaped enclosure for the intestines and other intestines. The outer fascia is covered by the skin layer and the subcutaneous fat layer.

Surgical repair of soft tissue defects (eg, hernias) can be performed using, for example, conventional techniques or improved laparoscopic surgery methods to close substantially all soft tissue defects. According to one implementation, an incision can be made through the skin and subcutaneous fat, and then the skin and fat can be peeled off and any protruding viscera (not shown) can be placed internally to the hernia. In certain implementations, an incision may be made in the peritoneum, and then the surgical prosthesis is inserted securely into the hernia opening by inserting the surgical prosthesis into the hernia opening. One or both of the tissue-ingrowth and adhesion-resistant regions can be attached, for example, by sutures to the same layer of the abdominal wall, for example, a relatively strong fascia. Alternatively, the adhesion-resistant region may be attached to another body part, such as the internal fascia and / or peritoneum. Tissue-ingrowth regions may be attached to the fascia by surgery, while adhesion-resistant regions may be tissue-using, for example, using thermal bonds, sutures, and / or other attachment protocols disclosed herein or substantial equivalents thereof. It may be attached to the growth zone and / or optionally to the fascia. Those skilled in the art will appreciate that other methods of cutting / modifying / orienting / attaching the surgical prosthesis of the present invention to a suitable size may be performed depending on the particular surgical situation.

The size of the surgical prosthesis will typically be determined by the size of the defect. Using surgical prostheses in a tension-free closed state can be associated with less pain and less fluid accumulation after surgery. Exemplary sutures may be used to suture the surgical prosthesis to the abdominal wall structure at least partially. Sutures may be used such that no lateral tension is applied to the fascia and / or muscles. Upon collapse, the skin and fats can be returned to their normal position, for example the incised edges of the skin and fat are sutured against each other using suitable means, such as subsurface sutures.

In a modified embodiment of the invention, one or both of the tissue-ingrowth and adhesion-resistant areas of the surgical prosthesis may be thermally bonded (or in other embodiments, may be otherwise attached, such as by sutures). ). Thermal bonding can be achieved, for example, by bipolar electrocauterization, ultrasonic bonding, or similar sealing directly between the tissue-growth region and the adhesion-resistant region and / or to surrounding tissue. Such a device may be used to heat a surgical prosthesis at various locations, such as at the edges and / or intermediate points, at least above the glass transition temperature of the surgical prosthesis, preferably above its softening point temperature. The material is heated so that the two components bind to each other at their interface, for example along adjacent tissues. Thermal bonding may also be used first to fix, for example, the tissue-ingrowth region to the adhesion-resistant region. Because tissue-ingrowth regions provide a load-bearing function, some exemplary embodiments may exclude thermal bonds as the sole means to securely anchor the region to host tissue. In other embodiments, the technique of thermally bonding the surgical prosthesis to itself or to body tissue may be combined with another method of attachment for enhanced anchoring. For example, a surgical prosthesis can be temporarily attached in place using two or more thermal bonding points using an electrical cauterization device, and then (or alternatively alternatively in other embodiments) surgically added with a suture, staple or adhesive. The prosthesis can be reliably fixed in place.

The tissue-growth region and adhesion-resistant region may be arranged to form more than one layer or substantially one layer, or both regions may belong to a single layer formed integrally. For example, the tissue-ingrowth region and the opposing adhesion-resistant region can be arranged in two layers, where one of the regions is disposed above and opposite the other region.

In one embodiment, the tissue-growth region and the adhesion-resistant region can be combined on a single side of a surgical prosthesis, for example, substantially one layer, wherein the regions are adjacent to each other on one side of the surgical prosthesis. Doing. As slightly modified, a surgical prosthesis having a tissue-ingrowth region on at least one (preferably both) face (s) can be prepared using any of the techniques described herein, followed by The zones are smoothed, filled or otherwise processed by suitable materials or techniques as disclosed herein (eg, coating or filling with liquid or flowable polymer compositions, and / or mechanical smoothing) to bond to the tissue-growth regions. By forming an adhesion-resistant region having a resistance characteristic, for example, the adhesion-resistant region can be formed on one side.

Similarly, a patch of adhesion-resistant regions is cut to a suitable size and attached upon direct implantation into at least one of the tissue-ingrowth region and surrounding host tissue (eg, thermal bonding such as by bipolar electrocauterization devices). , Ultrasonic bonding or similar attachment). In modified embodiments, attachment can be accomplished using, for example, press or adhesive bonding, or sutures. In further embodiments, at least some of the attachment may be at the time of preparation of the surgical prosthesis prior to packaging. Alternatively, a patch of adhesion-resistant regions may be applied (eg, at its non-terminal periphery or center) to a region (eg, at the non-terminal periphery or center) of the tissue-ingrowth region (eg, By partially attaching (using the techniques listed in this paragraph), the surgeon at the time of the implantation while the adhesion-resistant biodegradable implant is attached to the tissue-ingrowth region may allow the surgeon to adhere to the adhesion-resistant region (and / or tissue-intracellular). Growth zones). For example, on one side of the surgical prosthesis, the tissue-ingrowth region may substantially surround the adhesion-resistant region, and on the other side of the surgical prosthesis, only the tissue-ingrowth region may be formed. In this practice, the adhesion-resistant region of the surgical prosthesis can be made of a size and shape suitable to substantially cover any openings created by soft tissue defects, wherein the tissue-ingrowth region is at least one side of the surgical prosthesis. Preferably, surgically attached and incorporated into the host tissue on both sides.

In a modified embodiment, the tissue-ingrowth region and / or adhesion-resistant region on a given surface or surfaces of the surgical prosthesis can each be of any size or shape tailored to a particular soft tissue defect. For example, any of the tissue-growth and / or adhesion-resistant regions on a given surface of the surgical prosthesis may have ovals, rectangles, and various complex shapes or other shapes, where for each such performance, The two regions may have essentially the same or different ratios and / or dimensions relative to each other.

In general, various techniques can be used to make surgical prostheses having one or two layers, typically defining a tissue-ingrowth region and an adhesion-resistant region. Useful techniques include solvent evaporation, phase separation, interfacial, extrusion, molding, injection molding, thermocompression, and the like as are known to those skilled in the art. The tissue-growth region and adhesion-resistant region may comprise two separate layers and may be integrally formed together as one layer.

The tissue-ingrowth regions and adhesion-resistant regions may be formed partially or substantially entirely or joined together. Bonding can be accomplished by mechanical methods such as the use of sutures or metal clips, such as hemoclips, or by other methods such as chemical or thermal bonding.

The foregoing embodiments are provided by way of example, and the invention is not limited to these examples. Given the above description, those skilled in the art will appreciate that many variations and modifications to the disclosed embodiments are to the extent that they are not mutually exclusive. In addition, other combinations, omissions, substitutions and variations will be apparent to those skilled in the art in light of the disclosure herein. As repeated above, any feature or combination of features described and recited herein is intended to be used herein unless the features included in any such combination are inconsistent with each other as would be apparent from the context, the specification, and the knowledge of those skilled in the art. It is included in the range of. For example, any implant and implant component, subcomponent, or use thereof, and any feature or feature, or other feature, including method steps and techniques, may be used in any other structure and process described or recited herein. In whole or in part, together with any combination or order. Accordingly, the invention is not to be limited by the disclosed embodiments, but is defined by reference to the appended claims.

Claims (34)

delete delete Has a pre-graft shape defined as the shape of the system just before the system is formed between the post-surgical site being healed and adjacent surrounding tissue,
A resorbable polymer substrate having a first smooth side and a second smooth side and comprising a single layer of resorbable polymer base material between the first smooth side and the second smooth side. A flat layer of material, wherein the single layer of resorbable polymer based material comprises at least one hydrophobic block having one or more of (a) lactide, glycolide, or a mixture of lactide and glycolide, and (b ) Comprises a single hydrophilic block polyethylene glycol having more than two hydroxyl ends, and (c) a polymer form having four or more branches and a composition consisting essentially of one or more of lactide, glycolide, mixture and polyethylene glycol It is to include,
A micro-membrane system for resorptive scar-tissue reduction after in vivo surgery at the post-operative site for attenuating or preventing post-operative scar-tissue formation between the post-operative site being healed and adjacent surrounding tissue. The method of claim 3,
The single layer of resorbable polymer based material has a uniform composition;
The thickness measured between the first smooth side and the second smooth side of the single layer of resorbable polymeric base material is between 10 micrometers and 300 micrometers;
The single layer of resorbable polymer based material is non-porous;
A flat membrane of the resorbable polymer based material is disposed in the package
Micromembrane system for resorption of scar-tissue reduction. 4. The hydrophobic block of claim 3 wherein the single layer of resorbable polymer based material comprises (i) a first hydrophobic block having at least one of lactide, glycolide, or a mixture of lactide and glycolide, and (ii) linear Or a second hydrophilic block with branched polyethylene glycol. 6. The micromembrane system of claim 5, wherein the single layer of resorbable polymer based material comprises a star copolymer. 4. The resorbable scar of claim 3, wherein the single layer of resorbable polymer based material comprises (i) a first hydrophobic PLA / PGA block and (ii) a star block copolymer having three or more branches. Microfilm system for tissue reduction. 4. The method of claim 3, wherein the single layer of resorbable polymer based material is in (i) a first hydrophobic block having at least one polyethylene glycol and (ii) a lactide, glycolide, or a mixture of lactide and glycolide, respectively. A micromembrane system for resorption of scar-tissue reduction, comprising a plurality of branches having one or more branches. The micromembrane system of claim 8, wherein the single layer of resorbable polymer based material comprises a star block copolymer. 4. The method of claim 3, wherein the single layer of resorbable polymer based material comprises a star block copolymer having (i) at least one first hydrophobic PEG block and (ii) at least three second hydrophilic PLA / PGA blocks. And a micromembrane system for resorption of scar-tissue reduction. The method of claim 3, wherein the single layer of resorbable polymer based material comprises at least one first hydrophobic block of lactide, glycolide, or a mixture of lactide and glycolide, a second hydrophilic block of at least one polyethylene glycol, And triblock or 4-plus block copolymers comprising lactide, glycolide, a mixture of lactide and glycolide, and at least one third block of polyethylene glycol. Microfilm system. 4. The micromembrane system of claim 3, wherein the maximum thickness is 100 micrometers. 4. The micromembrane system of claim 3, wherein the maximum thickness is 200 micrometers. 4. The micromembrane system of claim 3, wherein the single layer of resorbable polymer based material is fluid impermeable. 4. The method of claim 3, wherein the single layer of resorbable polymer based material is a chemotactic material for affecting cell migration, an inhibitory material for affecting cell migration, mitotic promoting growth for affecting cell proliferation. A retinable micro-membrane system for reducing scar tissue, comprising at least one of a factor, a growth factor for affecting cell differentiation, and a factor for promoting neovascularization. 4. The micromembrane system of claim 3, wherein the resorbable scar-tissue reduction is sealed in a sterile package. 4. The resorbable scar-tissue reducing microstructure according to claim 3, wherein the single layer of resorbable polymer based material comprises a plurality of holes disposed along an edge of a single layer of resorbable polymer based material. Membrane system. 4. The resorbable scar-tissue reducing microstructure according to claim 3, wherein the single layer of resorbable polymer based material does not contain any pores away from the edge of the single layer of resorbable polymer based material. Membrane system. 18. The micromembrane system of claim 17, wherein said edge extends around a single layer of said resorbable polymer based material. 18. The micromembrane system of claim 17, wherein a slit is formed at the periphery of the single layer of resorbable polymer base material such that the edge extends along the slit. The method of claim 3,
The single layer of resorbable polymer based material further comprises a plurality of holes disposed away from an edge;
Each of the holes near the periphery has a first diameter;
Each of the holes near the center has a second diameter;
The first diameter is greater than the second diameter
Micromembrane system for resorption of scar-tissue reduction. delete 4. The micromembrane system of claim 3, wherein the single layer of resorbable polymeric base material comprises slits disposed in a non-porous base material. 4. The method of claim 3, wherein the single layer of resorbable polymer based material is cut to have a comfortable and anatomically fit size and shape on the anatomical structure to form scar-tissue between the anatomical structure and surrounding tissue. A micromembrane system for reducing resorptive scar-tissue reduction, wherein the membrane is attenuated or prevented and sealed in a sterile package. 4. The micromembrane system of claim 3, wherein the single layer of resorbable polymer based material is cut into tabs and folded onto or around the anatomical structure. The microfilm system of claim 3, wherein the single layer of resorbable polymer based material comprises one or more notches disposed in the non-porous substrate material. 4. The micromembrane system of claim 3, wherein the single layer of resorbable polymer base material comprises a plurality of notches disposed in the non-porous base material. 4. The micromembrane system of claim 3, wherein the single layer of resorbable polymer based material is cut to have a non-rectangular and non-circular shape and sealed in a sterile package. . The micromembrane system of claim 3, further comprising another membrane that is permeable and has a maximum thickness of less than 2000 micrometers. 30. The micromembrane system of claim 29, wherein said other membrane is a crosslinked membrane. 30. The micromembrane system of claim 29, wherein said other membrane is fluid permeable. 30. The micromembrane system of claim 29, wherein said other membrane is cell permeable. 30. The micromembrane system of claim 29, wherein said other membrane is vascular permeable. 30. The micromembrane system of claim 29, wherein said other membrane comprises a thickness of 500 micrometers to 2000 micrometers.

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