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WO1997029715A1 - Compositions et procedes permettant de fermer les tissus et de prevenir les adherences postoperatoires - Google Patents

Compositions et procedes permettant de fermer les tissus et de prevenir les adherences postoperatoires Download PDF

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Publication number
WO1997029715A1
WO1997029715A1 PCT/US1997/002542 US9702542W WO9729715A1 WO 1997029715 A1 WO1997029715 A1 WO 1997029715A1 US 9702542 W US9702542 W US 9702542W WO 9729715 A1 WO9729715 A1 WO 9729715A1
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WO
WIPO (PCT)
Prior art keywords
crosslinking agent
gelatin
composition
collagen
sealant
Prior art date
Application number
PCT/US1997/002542
Other languages
English (en)
Inventor
Cary J. Reich
Donald Wallace
Shekharam Tammishetti
Original Assignee
Fusion Medical Technologies, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fusion Medical Technologies, Inc. filed Critical Fusion Medical Technologies, Inc.
Priority to AU20521/97A priority Critical patent/AU2052197A/en
Publication of WO1997029715A1 publication Critical patent/WO1997029715A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/10—Polypeptides; Proteins
    • A61L24/102—Collagen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/10—Polypeptides; Proteins
    • A61L24/104—Gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/043—Proteins; Polypeptides; Degradation products thereof
    • A61L31/044—Collagen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/043—Proteins; Polypeptides; Degradation products thereof
    • A61L31/045—Gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/141—Plasticizers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods
    • A61B17/00491—Surgical glue applicators
    • A61B2017/00495—Surgical glue applicators for two-component glue

Definitions

  • the present invention relates generally to compositions and surgical methods for effecting and enhancing wound closure in tissue and compositions and methods for preventing post- surgical adhesions. More particularly, the present invention relates to compositions and methods for applying these compositions to tissue to close wounds and seal severed vessels and to provide a barrier between healing tissue planes.
  • Tissue damage can be the result of direct trauma to the body or as part of a surgical procedure in which there is a separation of normally continuous tissue such as blood vessels.
  • suturing has been the accepted technique for rejoining severed tissues and closing wounds. To suture a wound, the surgeon manually stitches the surrounding tissues with a surgical needle and suturing thread, and more recently, with a variety of polymeric or metallic staples.
  • suturing and stapling techniques are often successful, there are a number of limitations inherent in such mechanical approaches .
  • the practice of suturing or stapling tissue together not only requires significant skill, but is a relatively slow process, particularly when extensive repair is required or when anastomosing tiny biological structures. Even when suturing is properly performed, however, this technique can be less than satisfactory because of the gaps which are left between the stitches and the possibility of progressive structural weakening over time. For example, the gaps leave the wound open to bacteria, producing a risk of infection.
  • the suture needle or staples puncture the tissue, producing holes through which biological fluid may leak.
  • tissue adhesives In an effort to overcome the difficulties associated with conventional suturing techniques, sutureless repairs using surgical adhesives or glues have been developed. These surgical adhesives adhere to tissue surfaces and form a bond until the tissue heals.
  • one common tissue adhesive comprises fibrin and typically contains fibrinogen and thrombin. These agents are mixed together to form an adhesive capable of joining separated tissues.
  • Fibrin adhesive is usually obtained from pooled human plasma and the threat of infection from agents such as Hepatitis "B", HIV or others has outweighed the benefits of obtaining commercial quantities of fibrin adhesive.
  • other disadvantages of fibrin adhesives include its relatively slow set up time (>5 minutes) .
  • Non-biological materials such as cyanoacrylates including isobutyl-2-cyanoacrylate, have also been examined as potential surgical adhesives. These materials, however, are generally irritating to tissues, difficult to apply because they require a dry field and often fail to form a permanent closure. (Tatooles et al . (1966) Surgery 50 (4) : 857-861) .
  • Glues based on gelatin-resorcinol crosslinked with formaldehyde have been used experimentally.
  • gelatin-resorcinol- formaldehyde "GRF” gelatin-resorcinol- formaldehyde
  • Warm solutions of gelatin- resorcinol are mixed in situ with a curing agent consisting primarily of a formaldehyde solution.
  • the sealant rapidly sets to a solid which adheres to tissue.
  • the main disadvantage has been the required use of both formaldehyde and resorcinol, known hazardous materials. (Tatooles, et al . , supra) .
  • Ennker et al evaluated substitute crosslinking agents. (Ennker et al . (1994) Ann. Thoracic Surgeons 57:1622- 1627) . Pentane 1,5 dial (glutaraldehyde) and ethanedial in combination with gelatin-resorcinol were evaluated and found to be less toxic than formaldehyde. However, Ennker also teaches that extensive toxicity studies including resorption kinetics will be necessary to determine utility. In addition, the compositions taught by Ennker continue to contain resorcinol, a known hazardous material.
  • Gelatin-based adhesive agents have been used in a non- biological setting as book-binding agents (see Japanese patent (Kokai) No. 3-239781) .
  • the disclosed book-binding agent consists of a "glue-gelatin” that comprises a principal agent and a setting agent.
  • the principal agent is described as either a gelatin-based material, vinyl acetate resin, ethylene resin, acrylic resin or acrylic-styrene resin.
  • the setting agent is described as an aldehyde compound, tannin, epoxy compound, isocyanate compound or alum containing trivalent chromium and zirconium salts.
  • HSA human serum albumin
  • BSA bovine serum albumin
  • glutaraldehyde glutaraldehyde
  • An adhesive composition comprising non-crosslinked collagen or gelatin mixed with collagen crosslinked by either
  • UV or thermal means is also disclosed for wound closure (EP 466383) .
  • the composition is deficient as an adhesive because the integrity of the bond is relatively low and the sealant, upon insertion into the body cavity, will disintegrate rapidly prior to wound healing.
  • Post-surgical adhesion formation occurs frequently and may contribute to or cause compromised surgical results and post-surgical complications.
  • Surgical adhesions may occur in various areas: pelvic, abdominal, spinal, tendon, ophthalmic, urinary, thoracic and cardiovascular, and are formed when normal tissue bonds to the surfaces of internal organs which have been traumatized or damaged during surgery. Such adhesions may join organs or other body tissues that normally are separate. Treating adhesions may necessitate additional surgery with additional costs, danger and/or discomfort to the patient.
  • Several previous attempts have been made to minimize or eliminate post-surgical adhesions.
  • WO 9515747 discloses a method of preventing adhesions by topical administration of fibrinolysis enhancing agents, especially urokinase. However, the addition of pharmaceutical agents may adversely affect wound healing at the surgical site.
  • Other barrier devices have been used to prevent post ⁇ operative adhesions including sheets of a warped knit fabric of oxidized regenerated cellulose (Interceed, see US patent No. 5,007,916 and US patent No.
  • WO 9221354 describes the use of dextran sulfate, with a sulfur content greater than 10% by weight, for inhibiting fibrosis, granulation or scar formation of a surgical lesion. This material does not adhere to the underlying tissue.
  • hyaluronic acid HA
  • US patent No. 5,017,229 describes a novel composition comprising HA, a polyanionic polysaccharide like carboxymethylcellulose (CMC) and an activating agent to prevent surgical adhesions . This method also has limited success because the HA composite material is not secured to the underlying tissue and, therefore, does not provide an immobilized barrier between the tissues.
  • WO 86/00912 describes a slowly-degradable gel for preventing tissue adhesions following surgery prepared by cross-linking a carboxy-containing polysaccharide with a bi- or poly-functional epoxide. This gel does not adhere to the underlying tissue.
  • US patent No. 5,135,751 discloses an aqueous composition for reducing post-surgical formation comprising a polyoxyalkalene block copolymer.
  • US patents Nos. 5,080,893, 5,140,016 and 5,350,173 describe methods of preventing adhesions during surgery by applying a hydrophilic, polymeric substance prior to surgery. None of these methods provide a means for securing the material to the tissue to insure lasting separation of the tissue planes.
  • compositions and methods for effectively sealing damaged tissue structures such as torn vessels or open wounds.
  • These compositions and methods should be capable of forming an immediate closure of the damaged tissue to prevent further gas, fluid or blood leakage, and creating a permanent seal around the wound, while minimizing damage or destruction of surrounding tissue.
  • the compositions and methods should also minimize or prevent the occurrence of post-surgical adhesions .
  • the present invention relates to compositions and methods of sealing tissue and preventing post-surgical adhesions comprising preparing a composition comprising a solution or suspension of a proteinaceous material such as collagen or gelatin and a solution of one or more protein crosslinking agents, optionally comprising a plasticizer, that has been heated to an elevated temperature to form a flowable sealant; applying the flowable sealant to the tissue to form a continuous layer of the sealant on the tissue; allowing the layer to continue crosslinking on the tissue to form a cured layer of the proteinaceous material adhered to the underlying tissue that degrades in at least about 2-120 days, preferably 2-90 days, more preferably 2-30 days.
  • the proteinaceous solution or suspension preferably consists of about 5-60%, more preferably about 30-55%, even more preferably 40-50% collagen or gelatin. If the sealant is applied by spraying, the concentration of the proteinaceous material is preferably about 10-40%, more preferably about 25-35%.
  • the crosslinking agent (s) are preferably aldehydes, preferably di- or polyaldehydes, more preferably a glutaraldehyde, glyoxal or a dialdehyde starch. Crosslinking agents also comprise oxidized carbohydrates, preferably malto-dextrins.
  • Crosslinking agents also comprise epoxy compounds, preferably polymers with 2 or more pendant epoxy groups, more preferably a polyethylene glycol ether or a diglycidyl ether.
  • the crosslinking agents effect a complete cure of the sealant in about 30 seconds to about 24 hours, preferably less than 5 minutes.
  • the crosslinking agent (s) is present in an amount of about 0.01- 35%, preferably 0.1-5%, more preferably 0.6-1.2%.
  • the plasticizers comprise polymers, preferably polyethylene glycol having a molecular weight of 200 to 1000 Daltons, more preferably 400 Daltons. Plasticizers are present in an amount of about 1-30%, preferably 5-10%.
  • Figure 1 shows the viscosity of gelatin solutions at various temperatures.
  • the plot for the 50% gelatin solution shows that the viscosity of the material is approximately 30,000 centipose (cP) at 50°C.
  • Viscosity measurements for more dilute solutions, e.g., concentrations which are appropriate for spray delivery, are also shown.
  • Figure 2 shows the change in elastic modulus of an adhesive formulation over various cure times.
  • the viscosity initially decreases due to dilution of the gelatin solution.
  • the dialdehyde starch crosslinks the gelatin, the solution becomes a gel due to the formation of Schiff bases between the oxidized starch and amino groups on gelatin.
  • the strength of the gel may then be measured by elastic modulus as shown.
  • 50% gelatin mixed with water in a 4:1 ratio demonstrating that the addition of dialdehyde starch hastens curing of the gelatin and strengthens the final sealant composition.
  • Figure 3 illustrates the behavior of the cured sealant composition in physiological saline solution at 37°C.
  • Gelatin 50% aq. solution
  • dialdehyde starch 3% aq. solution
  • Gelatin mixed with water in the same manner dissolved in approximately 1 day.
  • the present invention relates generally to compositions and surgical methods for effecting and enhancing wound closure in tissue and compositions and methods for preventing post- surgical adhesions. More particularly, the present invention relates to a composition comprising a sealant which is heated in order to allow it to be applied as a flowable substance to close wounds and seal severed vessels and methods of sealing tissue utilizing the composition.
  • the heated sealant comprises two or more components; the required components are a proteinaceous material such as collagen or gelatin, preferably gelatin, and a protein crosslinking agent.
  • the crosslinking agent is preferably an aldehyde, more preferably, a di-or polyaldehyde, even more preferably di-aldehyde starch or glutaraldehyde.
  • the sealant may also comprise a plasticizer.
  • the plasticizer increases the malleability, flexibility and the rate of degradation of the sealant.
  • the plasticizer is an alcohol, more preferably a polyethylene glycol (PEG) , more preferably PEG with a molecular weight ranging from about 200 to about 1,000 Daltons, more preferably about 400 Daltons.
  • compositions of the sealant are generally prepared as follows.
  • a sample of at least about 5-60% (w/w) solution or suspension of a proteinaceous material such as collagen or gelatin and at least about 0.01-35.0% of a protein crosslinking agent are mixed together to form a crosslinked, cured sealant.
  • the composition may include a plasticizer, such as PEG, in an aqueous solution or suspension of at least about 1-30%, preferably 5-10%.
  • a plasticizer may be added to the proteinaceous material, the crosslinker or both.
  • the composition may also contain a viscosity enhancer such as a biocompatible polymer or sugar, such as maltose, glycol or PEG.
  • the compositions may also contain a solvent such as water, dilute buffered saline solution, phosphate buffer and the like.
  • compositions within the present invention can be made using protocols that are within the present invention but differ somewhat from those described herein.
  • a sample of proteinaceous material such as gelatin or collagen in a phosphate or other biocompatible buffer is combined with a protein crosslinking agent.
  • the pH of the gelatin solution or suspension is related to the crosslinking agent employed.
  • crosslinking with Schiff base formation i.e., with aldehydes
  • crosslinking with other agents will require different pH ranges which can be determined without undue experimentation by one of skill in the art.
  • Compositions of the present invention bond to various organs and tissue, such as muscle, skin, epithelial tissue, connective or supporting tissue, nerve tissue, ophthalmic and other sense organ tissue, vascular and cardiac tissues, gastrointestinal organs and tissue, pleura and other pulmonary tissue, kidney, endocrine glands, male and female reproductive organs, adipose tissue, liver, pancreas, lymph, cartilage, bone, oral tissue, mucosal tissue and the like.
  • organs and tissue such as muscle, skin, epithelial tissue, connective or supporting tissue, nerve tissue, ophthalmic and other sense organ tissue, vascular and cardiac tissues, gastrointestinal organs and tissue, pleura and other pulmonary tissue, kidney, endocrine glands, male and female reproductive organs, adipose tissue, liver, pancreas, lymph, cartilage, bone, oral tissue, mucosal tissue and the like.
  • the sealants may also provide strong and rapid bonding to either natural or synthetic materials, including Dacron ® , nylon, polypropylene and silicone in various forms including mesh.
  • the sealants may also bond to Teflon ® -coated materials, cellulose materials such as paper, cardboard and the like and metals including stainless steel, titanium and the like.
  • Compositions of the present invention are also useful for sealing tissue by attachment of a patch as described in co- owned and co-pending applications, U.S. serial nos.
  • Composition of the present invention may also be useful in the attachment of surgical devices and prosthetics as well as for wound closure, trauma repair and the like.
  • compositions of the present invention When employed as surgical adhesives, compositions of the present invention are flowable at the time of delivery and have a peel bond strength to the underlying tissue of at least about 3.0 N/m. Peel bond strengths higher than about 3.0 N/m are acceptable.
  • Compositions of the present invention are biocompatible and remain immobile until the tissue is satisfactorily sealed and preferably will resorb by biodegrading in about 2-120 days, preferably 2-90 days, more preferably 2-30 days following application.
  • Compositions of the present invention also prevent post-surgical adhesions by providing a barrier between opposing healing tissue planes.
  • compositions of the present invention may be applied to tissue in any "flowable" state including a gel, paste, foam, sol, liquid, spray or the like. If the sealant composition is sprayed it may be sprayed as an aerosol and the like.
  • concentration of the components of the inventive compositions will vary depending upon the preferred form of delivery. One skilled in the art will be readily able to determine from the formulations of the compositions disclosed herein the concentrations of the various components of the inventive compositions necessary to achieve the desired consistency.
  • the sealant Upon contacting the tissue, the sealant should be sufficiently fluid to flow into surface tissue irregularities. This provides good apposition of tissue and sealant.
  • Viscosities less than about 80,000 cP are adequate, however, a viscosity of less than about 20,000 cP is preferable, and a viscosity of less than about 4,000 cP is even more preferable.
  • the sealant In addition to the need for the sealant to be fluid upon application, the sealant must also be of a sufficient viscosity to coat the desired tissue site but not so fluid as to flow away from the desired tissue site to other tissue regions. To maintain placement of the sealant, the minimum viscosity must be at least 1000 cP, and more preferably, 2000-4000 cP.
  • the desired viscosity of the sealant is related to the time required for curing. For example, the viscosity of a fast-curing sealant can be lower than that of a slow-curing sealant because rapid curing will cause the sealant to remain in place.
  • sealant is applied as a spray or foam, lower viscosities may be preferred; however, a minimum peel bond strength to the underlying tissue of at least about 3 N/m is required. In addition, a minimum elastic modulus of about lxlO 5 N/m 2 is also required in order for the sealant to provide adequate closure of the wound, incision or defect and form an immobilized continuous barrier layer to prevent post ⁇ operative adhesions.
  • Such formulations are particularly useful for wound closure.
  • the sealant components crosslink to become an elastic solid that is very soft initially, but within minutes becomes a non-tacky, rubbery elastic solid useful for closing various forms of wounds including surgical incisions, wounds caused by trauma and other defects.
  • the sealant composition in addition to its utility for wound closure also provides a method to prevent and/or reduce post ⁇ operative adhesions.
  • the superior results obtained by the compositions of the present invention are noted in Figures 2 and 3. These figures illustrate that the addition of a protein crosslinking agent to collagen or gelatin produced far better results that those obtained with gelatin alone.
  • compositions within the present invention are superior sealants because they exhibit excellent peel bond strength, elastic modulus, survival (persistence) , are biocompatible and also prevent or reduce the occurrence of post-operative adhesions.
  • Exemplary delivery systems that may be used in conjunction with compositions within the present invention include the following criteria: a) a cartridge to hold and dispense sealant .
  • the cartridge may have a single or double barrel, available from Mixpac; Conprotec, Inc., Salem, NH and the like; b) a pump or dispense actuation mechanism such as a pressure pump available from Johnson Medical Devices, Milford, NH, or a pneumatic dispense pump available from I.J. Fisnar,
  • a dispensing nozzle capable of mixing and dispensing sealant to the target site
  • a heating element that may be incorporated as a part of the apparatus or may stand alone such as a heating block or water bath.
  • proteinaceous material includes fibrin, fibrinogen, thrombin, albumin of human or animal origin, Factor VIII and elastin.
  • collagen includes various types of native and denatured collagen including type I collagen, type III collagen, type IV collagen, collagen rich tissue, atelopeptide collagen and the like , or a combination thereof.
  • Bovine, porcine or any other appropriate vertebrate collagen are all exemplary tissue sources of collagen.
  • gelatin is the well-known denatured form of collagen as defined above. Gelatin may be produced from bovine or porcine hide or bone, or may be produced by denaturing collagen using heat or other methods known in the art .
  • biocompatible means the sealant composition of the present invention meets the criteria outlined in the current North American Science Associates, Inc. (NAmSA ® ) guidelines for evaluating biomaterial and devices as defined by committees of the Tripartite Biocompatibility Guidance and the International Organization for Standardization (ISO) (NAmSA, Northwood, OH)
  • protein crosslinking agent means an agent that is capable of bonding or causing bonds to form between at least two functional groups of a protein.
  • exemplary crosslinking agents include, but are not limited to: epoxy compounds, such as polymers with 2 or more pendant epoxy groups, polyethylene glycol di-glycidyl ethers, preferably having a molecular weight of about 200 to about 3400D; N- hydroxysuccinimidyl compounds, such as di-N-hydroxy- succinimidyl-polyethylene glycol, preferably having a molecular weight, of about 200 to about 3400D and di-N- hydroxy-succinimidyl-suberate; carbodiimide compounds, such as l-ethyl-3- (3-dimethylaminopropyl) carbodiimide; imidate compounds, such as dimethylsuberimidate; carbonyl-imidazoles, such as di-carbonyl-imidazole-polyethylene glycol, molecular weight.
  • tresylates such as -OS02CH2CF3 , such as di-tresyl- polyethylene glycol, molecular weight. 200-3400D; di- isocyanates, such as hexamethylene-diisocyanate; acid anhydride compounds, such as co-polymers of polyethylene oxide allyl ether and maleic acid anhydride; di-cyanuric chloride compounds, such as di-cyanuric chloride derivatives of polyethylene glycol, molecular weight, of at least about 200 to about 3400D; bisiodoacetamide, such as N,N' ethylene bisiodoacetamide; methylene bibromide and related compounds; hydrazine and related compounds, oxidized carbohydrates such as maltodextrins, polysaccharides such as carboxymethyl cellulose and the like and combinations thereof.
  • di- isocyanates such as hexamethylene-diisocyanate
  • acid anhydride compounds such as co-polymers of polyethylene
  • Aldehydes obtained by oxidative cleavage of carbohydrates and their derivatives such as oxidized oligosaccharides, e . g. , malto-dextrins and cellulose derivatives of various molecular weights are preferred crosslinking agents, while poly- or di-aldehydes are more preferable and dialdehyde starch is even more preferable.
  • elevated temperature means a temperature at which the protein component of the sealant remains in a fluid state, but that does not cause an extensive cauterizing or damaging effect to the underlying tissue. Exemplary temperatures are about 50-80°C.
  • the sealant may be heated to higher temperatures, however, at delivery, the sealant is preferably at a temperature of about 50 to about 70°C when it contacts the tissue.
  • flowable means a fluid state wherein the viscosity of the composition is about 80,000cP or less; preferably about 20,000 or less; more preferably about 2,000cP.
  • cured means sufficient cross-linking has occurred to achieve the desired mechanical strength and stability to dissolution at 37-40°C. Crosslinking may be measured by elastic modulus. A cured composition will exhibit a plateau elastic modulus of about 1X10 6 N/m 2 and will remain solid or gelatinous (will not re-melt or dissolve) at 37-40°C.
  • continuous layer means an uninterrupted, smooth, even surface layer that fills inconsistencies, crevices, divots and/or gaps in the underlying tissue. The amount of sealant required to achieve a continuous layer will depend on the type of underlying tissue and the pressure, if any, present in the organ being sealed.
  • adhere means having a peel bond strength of at least about 3.0 N/m.
  • persistence means the sealant remains intact and immobilized for at least about 2-120 days, preferably 2-90 days, and more preferably 2-30 days. Following such time period, the material will biodegrade.
  • intact means that the sealant remains in one piece and does not disintegrate for at least about 2- 120 days, preferably 2-90 days, and more preferably 2-30 days.
  • stress modulus means the stress divided by the strain.
  • stress and strain are defined in any text on rheology, such as VISCOE ASTIC PROPERTIES OF
  • the final components of the inventive compositions include an aqueous solution or suspension of at least about 5- 60% proteinaceous material, preferably collagen or gelatin, preferably in the range of 30-55%, more preferably in the range of 40-50% or, if applied by spraying, in the range of 10-40%, preferably in the range of 25-35%, and at least about 0.01%-35% of a protein crosslinking agent, preferably in the range of 0.1- 5%, more preferably in the range of 0.6-1.2%.
  • the gelatin or collagen and protein crosslinking agent are in a final weight ratio of 2:1 to 500:1.
  • Various solvents may be used including water, dilute buffer saline solution, phosphate buffer and the like.
  • the compositions of the present invention may also include a plasticizer such as PEG in a final amount of about 1-30%, preferably 5-10%.
  • the molecular weight of the PEG may be in the range of about 200 to 1000 Daltons, preferably 400 Daltons.
  • the components of the inventive compositions may be combined after they are heated separately at 70°C.
  • the sealant components may be heated prior to delivery, for example, in a heat block or hot water bath, and/or may be placed into a heated device for delivery, for example, an epoxy glue gun or heated dual syringe with a heat source .
  • the material may be heated to about 50-100°C prior to application. However, upon application, the temperature of the sealant will rapidly decrease until reaching body or ambient temperature.
  • crosslinking immediately commences and continues until maximum crosslinking is achieved. The degree of the crosslinking achieved depends on the ratio of protein to crosslinker.
  • the degree of crosslinking is measured by assaying for free functional groups on the protein or by elastic modulus (see Figure 2) .
  • Crosslinking of the sealant may occur over a period of about 30 seconds to about 24 hours at 37°C depending on the crosslinking agent used.
  • Exemplary embodiments of the inventive sealant may include mixtures of more than one crosslinking agent .
  • the cure time for a "fast-curing" crosslinking agent is less than or equal to 5 minutes, while the cure time for a "slow-curing" crosslinker is from about 5 minutes to 24 hours. If two or more "fast-curing" agents are employed, the cure time will remain less than or equal to 5 minutes, but the resulting sealant will exhibit superior mechanical strength. If a "fast-curing" and a "slow-curing” agent are employed, the resulting sealant will exhibit superior strength and persistence.
  • a "fast-curing" crosslinking agent for example, a dialdehyde, carbodiimide or di-isocyanate, is preferred for indications such as wound or incision closure or organ tissue repair that requires rapid curing of sealant to insure integrity of seal, e . g. , sealing air leaks in lung tissue such that gas, fluid or blood leakage is prevented.
  • "Slow-curing" agents such as epoxy compounds, are preferred for applications such as securing a prosthetic device, shunt or other implantable device.
  • the combination of a slow-curing crosslinking agent and a fast- curing crosslinking agent may be preferred.
  • sealant compositions described herein are also useful for the prevention or reduction of post-surgical adhesions.
  • Methods for preventing post-surgical adhesions comprise coating tissue surfaces in a patient with the compositions described herein. Tissue surfaces can be coated either during or after a surgical procedure, but prior to final closure of the patient.
  • the sealant compositions may be placed on the target tissue as the final step of any surgical procedure, i.e., immediately prior to closing the surgical wound. The sites furthest away from the surgical incision are treated with the sealant compositions first, followed by sites that are closer to the incision site. This will minimize excessive manipulation of the previously placed sealant material.
  • the sealant may be applied to any site that has been manipulated surgically or damaged by any other means, including but not limited to, areas such as suture or staple lines, areas of resection, areas of tissue denudation, areas of serosal damage, or areas where formation of adhesions is anticipated , such as sites of tissue trauma, areas of cautery or other types of manipulation.
  • the sealant is applied to areas that are dry or as free of pooled blood or fluid as possible.
  • the site may be dried using cautery, direct pressure, suction or any other standard means.
  • the sealant compositions should be applied in such a manner that the entire area of interest is covered with a continuous layer of the sealant composition. Accordingly the sealant should completely fill and coat any divots, creases, or other defects in the target tissue and should complete cover the entire defect. When applied correctly, the sealant compositions should extend at least 5 mm beyond the perimeter of the target area.
  • the sealant compositions described herein are also useful for local delivery of biologically active substances to tissue surfaces of a patient.
  • Methods of local delivery of biological substances comprise the steps of mixing a biological substance with the inventive composition and then applying the resulting mixture to the target tissue.
  • Biologically active substances include, but are not limited to, proteins, carbohydrates, nucleic acids, and inorganic and organic biologically active molecules such as enzymes, antibiotics, antineoplastic agents, local anesthetics, anti- inflammatory agents, hormones, antiangiogenic agents, antibodies, neurotransmitters, psychoactive drugs, drugs affecting reproductive organs and oligonucleotides such as antisense oligonucleotides.
  • Example 2 Sealant formulations prepared with non-aldeh de crosslinking agents:
  • Example 4- Preparation of a gelatin sealant A gelatin formulation of the present invention was initially prepared as a 50% (wt/wt) gelatin solution which was then mixed in a 4:1 ratio with the aqueous 3% DAS solution described in Example 3.
  • Example 5- Viscosity Measurement Viscosity measurements were used to determine concentrations of sealant components suitable for application. Preferred concentrations for applications of the collagen or gelatin component of the sealant by spraying or painting were determined to be in the range of about 5 to about 30%.
  • cyanoacrylate Super Glue ®
  • Example 7 Sealant In Vi tro Stability 1.0 mL gelatin, 300 Bloom, 50% (w/v) in 0.2M sodium phosphate, pH 8, was heated to 65-70°C for 10-30 minutes, and then mixed rapidly with 0.25 mL of 3% (w/v) aq.
  • di-aldehyde starch DAS (75% degree of oxidation) prepared from potato starch by periodate oxidation, according to METHODS IN CARBOHYDRATE CHEMISTRY, Vol. 4 (Whistler, R. , et al., eds., 1964) .
  • the mixture was extruded into tared vials at 37°C, incubated for 10 minutes, and then covered with a solution of 0.9% sodium chloride and held at 37°C. At intervals, the buffer was poured off the gel, and excess buffer drained from the gel with an absorbent tissue. The vial and gel were weighed. The gel weight was a measure of gel plus absorbed buffer.
  • Example 8 - Elastic Modulus Figure 2 illustrates the curing of the sealant by measuring its elastic modulus as defined above. As the sealant was curing to become an elastic solid, increasing modulus values were observed and on completion of curing, the elastic modulus remained constant. Measurements of the elastic modulus as shown in Figure 2 were made by measuring the force required to compress a curing sealant under small strain, i.e., strains less than 0.1.
  • the formulation of the sealant was approximately 2mL of 50% (w/w) Woburn gelatin in 0.2 M phosphate buffer , pH 8.0, mixed with 0.6mL of 3% DAS oxidized to 75%. The sealant was mixed at 70 ° C and maintained at 37°C for the duration of the curing process.
  • EXAMPLE 9 Antiadhesion Animal Study
  • a standard animal model for evaluating surgical adhesions has been developed using the Sprague Dawley rat (Harris, E.S. (1995) "Analysis of the kinetics of peritoneal adhesion formation in the rat and evaluation of potential anti-adhesive agents," Surgery 117:663-669) .
  • Anesthesia was induced with an intramuscular injection of ketamine hydrochloride in combination with xylazine in 21 animals.
  • the abdomen was clipped with electric clippers and the skin prepared with an iodophor scrub and rinsed with 70% alcohol.
  • a 6 cm midline skin incision was made at the abdomen, and the skin retracted. A 4 cm incision was made through the abdominal wall. The abdominal wall was also reflected. A defect in the abdominal wall was created approximately 1 cm lateral to the midline incision. This defect was created by excising a 1 x 2 cm segment of parietal peritoneum, including a superficial layer of muscle. The cecum was then elevated and positioned so that at closure, the cecum contacted the abdominal wall defect. A 1 x 2 cm defect was then created on the serosal surface of the cecum. The cecum was abraded by scraping with a scalpel blade so that a homogenous surface of petechial hemorrhage was created over the abraded area. Both areas of defect (the cecum and body wall) were exposed to air for 10 minutes. The animals were grouped for further manipulation as follows:
  • the sealant-covered peritoneal defect was placed into contact with the abraded, air-dried abdominal wall defect, and the midline incision was closed with a 4-0 absorbable suture in a continuous pattern.
  • the skin was closed with 4-0 absorbable Maxon ® suture in a continuous pattern.
  • the skin was closed with a 9 mm Autoclip ® .
  • Sealant C (a final composition of 21.5% gelatin mixed with 1.5% DAS) was applied. After air drying for ten minutes, the cecal defect was covered with Sealant C and allowed to cure for approximately 4 minutes.
  • Sealant D (a final composition of 32.0% gelatin mixed with 0.42% DAS) was applied. After air drying for ten minutes, the abdominal wall defect was covered with Sealant D and allowed to cure for approximately 4 minutes. The sealant-covered peritoneal defect was placed into contact with the abraded, air-dried abdominal wall defect, and the midline incision was closed with a 4-0 absorbable Maxon ® suture in a continuous pattern. The skin was closed with a 9 mm Autoclip ® .
  • Example 10 Evaluation of Various Sealant Compositions Using a farm grade Hampshire/Yorkshire cross pig (Pork Power Farms, Turlock, CA) various sealant compositions were applied during non-survival surgeries to evaluate adherence and bonding of the sealant compositions to the underlying tissue. The results are shown in Table 6.

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  • Animal Behavior & Ethology (AREA)
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  • Heart & Thoracic Surgery (AREA)
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Abstract

L'invention concerne des compositions et procédés permettant de fermer les tissus et de prévenir les adhérences postopératoires. Les compositions qui sont l'objet de la présente invention comprennent un composant à base de collagène ou de gélatine, un ou plusieurs agents de réticulation, et, de manière facultative, un plastifiant. Les procédés de fermeture des tissus consistent à appliquer sur les tissus lesdites compositions réchauffées afin de former une couche continue sur le tissu, et de permettre ensuite au produit de fermeture de se durcir afin de former une couche biocompatible qui adhère au tissu et se dégrade sur une période qui va au moins de 2 à 120 jours environ.
PCT/US1997/002542 1996-02-20 1997-02-19 Compositions et procedes permettant de fermer les tissus et de prevenir les adherences postoperatoires WO1997029715A1 (fr)

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US1189896P 1996-02-20 1996-02-20
US60/011,898 1996-02-20
US78298297A 1997-01-14 1997-01-14
US08/782,982 1997-01-14

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EP0959795A4 (fr) * 1996-10-16 2000-01-19 Fusion Medical Technologies Films possedant des caracteristiques ameliorees et procedes pour leur preparation et de leur utilisation
WO2000016698A1 (fr) * 1998-09-18 2000-03-30 Imedex Biomateriaux Dispositif pour la formation et la delivrance d'un melange
AU721494B2 (en) * 1996-10-07 2000-07-06 Imedex Biomateriaux Adhesive composition with macromolecular polyaldehyde base and method for cross-linking collagen
EP0898973A3 (fr) * 1997-08-18 2000-09-27 Medtronic, Inc. Procédé de préparation d'un matériau à base de collagene réticule et dispositifs bioprothétiques ainsi produits
WO2001030410A1 (fr) * 1999-10-28 2001-05-03 Tissuemed Ltd. Utilisation medicale
EP1018944A4 (fr) * 1997-09-26 2001-08-22 Cryolife Inc Technique anastomotique sans suture dans laquelle on utilise un bioadhesif et dispositif associe
WO2004028404A3 (fr) * 2002-09-30 2006-01-05 Fibrogen Inc Compositions seches scellant les tissus
DE102006033168A1 (de) * 2006-07-10 2008-01-17 Gelita Ag Verwendung von Gelatine und einem Vernetzungsmittel zur Herstellung einer vernetzenden therapeutischen Zusammensetzung
WO2008006545A3 (fr) * 2006-07-10 2008-12-04 Gelita Ag Utilisation de gélatine et d'un agent réticulant pour produire un adhésif médical à réticulation
WO2009030867A1 (fr) * 2007-09-07 2009-03-12 Cousin Biotech Implant textile, notamment pour la refection des hernies
WO2011132153A3 (fr) * 2010-04-20 2012-01-19 Lifebond Ltd. Procédés et dispositifs pour l'application de produits d'étanchéité et d'adhésifs de tissu
US8703117B2 (en) 2008-06-18 2014-04-22 Lifebond Ltd. Cross-linked compositions
US8722039B2 (en) 2006-12-15 2014-05-13 Lifebond Ltd. Gelatin-transglutaminase hemostatic dressings and sealants
WO2014195618A1 (fr) 2013-06-03 2014-12-11 Universite De Picardie Jules Verne Procédé de préparation d'un polyamide ester de gélatine
US8961544B2 (en) 2010-08-05 2015-02-24 Lifebond Ltd. Dry composition wound dressings and adhesives comprising gelatin and transglutaminase in a cross-linked matrix
US9066991B2 (en) 2009-12-22 2015-06-30 Lifebond Ltd. Modification of enzymatic crosslinkers for controlling properties of crosslinked matrices
US9701940B2 (en) 2005-09-19 2017-07-11 Histogenics Corporation Cell-support matrix having narrowly defined uniformly vertically and non-randomly organized porosity and pore density and a method for preparation thereof
EP3281605A1 (fr) 2003-08-20 2018-02-14 Histogenics Corporation Implants de matrice acellulaire pour le traitement de défauts et de lésions ostéochondrales, d'un cartilage articulaire, d'un os ou et leurs procédé d'utilisation
US10077420B2 (en) 2014-12-02 2018-09-18 Histogenics Corporation Cell and tissue culture container
WO2019003206A1 (fr) 2017-06-30 2019-01-03 Universidad De Los Andes Biomatières comprenant de la gélatine dérivée d'espèces aquatiques adaptées au froid
US10549015B2 (en) 2014-09-24 2020-02-04 Sofradim Production Method for preparing an anti-adhesion barrier film
WO2020156968A2 (fr) 2019-01-30 2020-08-06 Ventana Medical Systems, Inc. Lames d'étalonnage pour pathologie numérique
CN115785478A (zh) * 2022-10-12 2023-03-14 浙江大学 一种双网络纤维蛋白凝胶及其制备方法和应用
US11739166B2 (en) 2020-07-02 2023-08-29 Davol Inc. Reactive polysaccharide-based hemostatic agent
US11998654B2 (en) 2018-07-12 2024-06-04 Bard Shannon Limited Securing implants and medical devices
US12151045B2 (en) 2020-12-28 2024-11-26 Davol Inc. Reactive dry powdered hemostatic materials comprising a protein and a multifunctionalized modified polyethylene glycol based crosslinking agent
US12161777B2 (en) 2020-07-02 2024-12-10 Davol Inc. Flowable hemostatic suspension

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Cited By (45)

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Publication number Priority date Publication date Assignee Title
AU721494B2 (en) * 1996-10-07 2000-07-06 Imedex Biomateriaux Adhesive composition with macromolecular polyaldehyde base and method for cross-linking collagen
EP0959795A4 (fr) * 1996-10-16 2000-01-19 Fusion Medical Technologies Films possedant des caracteristiques ameliorees et procedes pour leur preparation et de leur utilisation
EP0898973A3 (fr) * 1997-08-18 2000-09-27 Medtronic, Inc. Procédé de préparation d'un matériau à base de collagene réticule et dispositifs bioprothétiques ainsi produits
US6685726B2 (en) 1997-09-26 2004-02-03 Cryolife, Inc. Sutureless anastomotic technique using a bioadhesive and device therefor
EP1018944A4 (fr) * 1997-09-26 2001-08-22 Cryolife Inc Technique anastomotique sans suture dans laquelle on utilise un bioadhesif et dispositif associe
AU747254B2 (en) * 1998-09-18 2002-05-09 Imedex Biomateriaux Device for forming and delivering a mixture
WO2000016698A1 (fr) * 1998-09-18 2000-03-30 Imedex Biomateriaux Dispositif pour la formation et la delivrance d'un melange
FR2784296A1 (fr) 1998-09-18 2000-04-14 Imedex Biomateriaux Dispositif pour la formulation et la delivrance d'un melange, notamment pour l'application chirurgicale de ce melange
WO2001030410A1 (fr) * 1999-10-28 2001-05-03 Tissuemed Ltd. Utilisation medicale
WO2004028404A3 (fr) * 2002-09-30 2006-01-05 Fibrogen Inc Compositions seches scellant les tissus
EP3281605A1 (fr) 2003-08-20 2018-02-14 Histogenics Corporation Implants de matrice acellulaire pour le traitement de défauts et de lésions ostéochondrales, d'un cartilage articulaire, d'un os ou et leurs procédé d'utilisation
US9701940B2 (en) 2005-09-19 2017-07-11 Histogenics Corporation Cell-support matrix having narrowly defined uniformly vertically and non-randomly organized porosity and pore density and a method for preparation thereof
DE102006033168A1 (de) * 2006-07-10 2008-01-17 Gelita Ag Verwendung von Gelatine und einem Vernetzungsmittel zur Herstellung einer vernetzenden therapeutischen Zusammensetzung
US9744218B2 (en) 2006-07-10 2017-08-29 Tetec Tissue Engineerging Technologies Ag Multi-chamber applicator for gelatin solution
JP2009542384A (ja) * 2006-07-10 2009-12-03 ゲリタ アクチェンゲゼルシャフト 架橋医療用膠剤を製造するためのゼラチンおよび架橋剤の使用
WO2008006545A3 (fr) * 2006-07-10 2008-12-04 Gelita Ag Utilisation de gélatine et d'un agent réticulant pour produire un adhésif médical à réticulation
US9295751B2 (en) 2006-07-10 2016-03-29 Gelita Ag Use of gelatin and a cross-linking agent for producing cross-linking medical glues
US8637081B2 (en) 2006-07-10 2014-01-28 Tetec Tissue Engineering Technologies Ag Use of gelatin and a cross-linking agent for producing a cross-linking therapeutic composition
US9017664B2 (en) 2006-12-15 2015-04-28 Lifebond Ltd. Gelatin-transglutaminase hemostatic dressings and sealants
US9636433B2 (en) 2006-12-15 2017-05-02 Lifebond Ltd Gelatin-transglutaminase hemostatic dressings and sealants
US8722039B2 (en) 2006-12-15 2014-05-13 Lifebond Ltd. Gelatin-transglutaminase hemostatic dressings and sealants
US9655988B2 (en) 2006-12-15 2017-05-23 Lifebond Ltd Gelatin-transglutaminase hemostatic dressings and sealants
WO2009030867A1 (fr) * 2007-09-07 2009-03-12 Cousin Biotech Implant textile, notamment pour la refection des hernies
FR2920671A1 (fr) * 2007-09-07 2009-03-13 Cousin Biotech Soc Par Actions Implant textile, notamment pour la refection des hernies
EP2556845A1 (fr) * 2007-09-07 2013-02-13 Cousin Biotech Implant textile, notamment pour la refection des hernies
US9427298B2 (en) 2007-09-07 2016-08-30 Bard Shannon Limited Textile implant, in particular for repairing hernias
US8703117B2 (en) 2008-06-18 2014-04-22 Lifebond Ltd. Cross-linked compositions
US9044456B2 (en) 2008-06-18 2015-06-02 Lifebond Ltd. Cross-linked compositions
US9066991B2 (en) 2009-12-22 2015-06-30 Lifebond Ltd. Modification of enzymatic crosslinkers for controlling properties of crosslinked matrices
US10202585B2 (en) 2009-12-22 2019-02-12 Lifebond Ltd Modification of enzymatic crosslinkers for controlling properties of crosslinked matrices
WO2011132153A3 (fr) * 2010-04-20 2012-01-19 Lifebond Ltd. Procédés et dispositifs pour l'application de produits d'étanchéité et d'adhésifs de tissu
US8961544B2 (en) 2010-08-05 2015-02-24 Lifebond Ltd. Dry composition wound dressings and adhesives comprising gelatin and transglutaminase in a cross-linked matrix
WO2014195618A1 (fr) 2013-06-03 2014-12-11 Universite De Picardie Jules Verne Procédé de préparation d'un polyamide ester de gélatine
US10549015B2 (en) 2014-09-24 2020-02-04 Sofradim Production Method for preparing an anti-adhesion barrier film
US12070534B2 (en) 2014-09-24 2024-08-27 Sofradim Production Method for preparing an anti-adhesion barrier film
US10077420B2 (en) 2014-12-02 2018-09-18 Histogenics Corporation Cell and tissue culture container
US11555172B2 (en) 2014-12-02 2023-01-17 Ocugen, Inc. Cell and tissue culture container
WO2019003206A1 (fr) 2017-06-30 2019-01-03 Universidad De Los Andes Biomatières comprenant de la gélatine dérivée d'espèces aquatiques adaptées au froid
US11998654B2 (en) 2018-07-12 2024-06-04 Bard Shannon Limited Securing implants and medical devices
WO2020156968A2 (fr) 2019-01-30 2020-08-06 Ventana Medical Systems, Inc. Lames d'étalonnage pour pathologie numérique
US11739166B2 (en) 2020-07-02 2023-08-29 Davol Inc. Reactive polysaccharide-based hemostatic agent
US12161777B2 (en) 2020-07-02 2024-12-10 Davol Inc. Flowable hemostatic suspension
US12151045B2 (en) 2020-12-28 2024-11-26 Davol Inc. Reactive dry powdered hemostatic materials comprising a protein and a multifunctionalized modified polyethylene glycol based crosslinking agent
CN115785478A (zh) * 2022-10-12 2023-03-14 浙江大学 一种双网络纤维蛋白凝胶及其制备方法和应用
CN115785478B (zh) * 2022-10-12 2023-08-22 浙江大学 一种双网络纤维蛋白凝胶及其制备方法和应用

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