WO1999010019A2 - Composition heterofonctionnelle de reconstitution de tissus - Google Patents

Composition heterofonctionnelle de reconstitution de tissus Download PDF

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Publication number
WO1999010019A2
WO1999010019A2 PCT/US1998/017001 US9817001W WO9910019A2 WO 1999010019 A2 WO1999010019 A2 WO 1999010019A2 US 9817001 W US9817001 W US 9817001W WO 9910019 A2 WO9910019 A2 WO 9910019A2
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composition
tissue
binding component
ligand
functional group
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PCT/US1998/017001
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English (en)
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WO1999010019A3 (fr
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Carroll Eugene Jones
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Carroll Eugene Jones
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Publication of WO1999010019A3 publication Critical patent/WO1999010019A3/fr

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    • 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
    • A61L24/043—Mixtures of macromolecular materials

Definitions

  • This invention is in the field of tissue engineering products. More particularly, it concerns heterofunctional bioadhesive compositions that are designed to react with human or animal tissue via specific and non-specific interactions with sell surfaces.
  • Suturing involves stitching together the tissue on either side of an incision or wound to facilitate healing.
  • Stapling involves joining tissue by applying staples along the line of an incision or wound using a manually operated stapling device.
  • Sutures and staples are invaluable for closing surgical and traumatic wounds, they have a number of limitations in many cases. Sutures and staples do not have inherent adhesive capabilities, and as a result, cannot eliminate fluid or gas leakage at the wound site. Additionally, soft tissues, such as internal organs including the liver, spleen, and kidneys, lack the ability to support sutures or staples. This can cause further damage to the tissue or can cause post-surgical complications. Sutures and staples can also be very difficult and time consuming to put in place in endoscopic or minimally invasive surgeries, as well as in vessel or intestinal anastomoses.
  • Fibrin sealants are currently being developed in the U.S. for hemostasis and wound closure. They rely upon the blood derived raw materials thrombin and fibrinogen. Thrombin is mixed with and reacts with fibrinogen to form fibrin, the basis of a blood clot. However, fibrin sealants may be possible carriers of blood borne pathogens, require a relatively slow set-up time and are quite expensive. (In Vivo, March 1996).
  • PCT application WO 97/29792 describes compositions using thromboplastin and fibrinogen.
  • cyanoacrylates household adhesives commonly called “super glue”
  • super glue cyanoacrylates
  • They are both inexpensive and have a high tensile strength. However, they generally require a dry field, whereas most wounds are wet. Polymerization tends to be exothermic, causing tissue irritation. Because cyanoacrylates are non-absorbable, their use is limited to topical applications. Furthermore, they have a tendency to generate toxic formaldehyde during setting time which are suspected carcinogens.
  • Purified collagen derived from animals has been used for cosmetic purposes and as bandage components for a number of years. It is currently being tested as a wound closure material by using polyethylene glycol or aldehyde chemical cross-linkers to form a collagen gel. Collagen from either human or animal sources has good potential as a wound dressing material but is very expensive and the chemical cross-linkers may be somewhat toxic. Additionally, because collagen may be of animal origin, questions of long-term compatibility arise.
  • Hydrogels are specially treated hydrophilic polymers that have been used as wound dressings, sponges, and contact lenses for a number of years. Most of the hydrogels used in wound care are derived from polyurethane, polyvinylpirrolidone (PVP), or other polymers. Their use as wound covering material is well established, however, long term biocompatibility in internal applications such as sealants or adhesives may need additional study. Furthermore, certain hydrogels rely upon a light source for polymerization, which is inconvenient and may release free radicals.
  • U.S. Patent 5,583,114 describes a two part adhesive composition. The first part is a protein in an aqueous buffer and the second part is a water- compatible or water-soluble bifunctional cross-linking agent. Mixing the two parts results in a liquid which cures in vivo on the surface of the tissue.
  • U.S. Patent 5,583,114 describes a two part adhesive composition. The first part is a protein in an aqueous buffer and the second part is a water- compatible or water-soluble bifunctional cross-linking agent. Mixing the two parts results in a liquid which cures in vivo on the surface of the tissue.
  • Patent 5,385,606 describes a mixture of proteinaceous material and an aldehyde cross-linker.
  • cell adhesion is non-specific and requires only the adsorbtion of the protein.
  • Cell adhesion to materials is mediated by cell-surface receptors, interacting with cell adhesion proteins bound to the material surface (Biotechnology, Vol. 13, June 1995).
  • An important class of receptors are the integrins, a superfamily of related noncovalently linked heterodimers.
  • the heterodimers consist of an ⁇ subunit and a ⁇ subunit. There are known to be at least 15 ⁇ subunits, 8 ⁇ subunits, and 21 ⁇ combinations to form functional receptors, each binding to a slightly different set of adhesion protein ligands.
  • the integrin receptors bind to relatively small domains on their adhesion protein ligands. These domains can be mimicked by synthetic linear or cyclic oligopeptides.
  • the prototypical such oligopeptide is the three amino acid sequence arginine-glycine-aspartic acid (RGD), which is found in many adhesion proteins and binds to many integrin receptors.
  • RGD arginine-glycine-aspartic acid
  • Variations of the RGD sequence change the affinity of the oligopeptide for the receptor.
  • the RGD and many other oligopeptides have been incorporated into biomaterials to simulate cell adhesion. In these instances, cell adhesion is specific, not depending on the adsorption of an adhesion protein. See, for example, U.S. Patent 5,677,276, which describes a composition comprising RGD peptides and hyaluronic acid. Although the composition is cross-linked prior to administration, no further cross-linking with the tissues is described. U.S.
  • Patent 5,654,267 describes compositions comprising an RGD peptide and a growth factor incorporated into a matrix of biodegradable polymer.
  • Albumin conjugated with RGD has also been described as a bioadhesive (Biomaterials, 13(13):924-30 (1992)).
  • the RGD-albumin conjugate is prepared via a coupling reaction of albumin with pentapeptide glysine-RGD-serine by water-soluble carbodiimide (ASAIO J, 38(3):275-8 (July, 1992)).
  • the albumin is a vehicle for the specific binding of the oligopeptide, and no non-specific protein adsorption is identified.
  • tissue adhesive that provides a strong bond for either internal or external tissues, and displays rapid hemostatic control. It should be biocompatible with the host tissue, and not interfere with the healing process. It should not produce an allergic response, adverse tissue reaction, or systemic toxic effects.
  • the adhesive should be easy to use, be free of contaminants and side-effects, rapidly cure upon application, and remain pliable after curing. It should be inexpensive and should perform consistently upon each administration.
  • Figure 1 is a diagram which comparatively illustrates the methods of action involved in natural tissue bonding, specific receptor site bonding and bonding via non-specific cross-linking.
  • Figure 2 is a graph depicting the relative tensile strengths of three bioadhesive compositions. Summary of the Invention
  • the present invention is a non-toxic, biodegradable, absorbable, heterofunctional adhesive composition.
  • These compositions exhibit the target specificity involved in the interaction between circulating extracellular adhesion proteins and their associated cell surface receptors which cause cell-to-cell adhesion.
  • these compositions exhibit the stability and cross-linking efficiency characteristics of matrix components that non-specifically bind to cell surfaces.
  • an event such as cell disruption
  • an event triggers receptor exposure with subsequent recognition and adsorption of the protein by the cell surface receptor.
  • An example is the blood clotting mechanism where the cell (platelet) is disrupted by injury. The platelet disruption exposes a receptor which is recognized by and adsorbed to a circulating adhesion protein. A chain reaction occurs in which the platelet and adhesion protein interaction forms the basis of the blood clot.
  • the materials involved lack biological recognition. Instead, they form simple compounds with adhesive properties and can aid tissue regeneration by acting as a temporary matrix.
  • the adhesive composition is readily formed from at least a two-part mixture consisting of a first part which is a tissue binding member comprising at least one ligand that is specific for a cell surface receptor, and a second part which is a second tissue binding member comprising at least one functional group which reacts nonspecifically with cell surface molecules to form a stable bond with the tissue when mixed together.
  • a tissue binding member comprising at least one ligand that is specific for a cell surface receptor
  • a second part which is a second tissue binding member comprising at least one functional group which reacts nonspecifically with cell surface molecules to form a stable bond with the tissue when mixed together.
  • the first and second components may also be joined by at least one intermediary compound.
  • the first functional component which is specific for a cell surface receptor, can be any physiologically acceptable compound which binds to a receptor and may mimic the natural effect of extracellular adhesion proteins. This includes, for example, amino acid sequences or chemical compounds determined, for example, by combinatorial chemistry methods.
  • Extracellular adhesion proteins include bone sialoprotein, complement component C3bi, collagen, fibrinogen, fibronectin, intercellular adhesion molecule, laminin, thrombospondin, vitronectin, vascular cell adhesion molecule, and von Willebrand factor (vWF).
  • integrins a family of related heterodimers that consist of an ⁇ and a ⁇ subunit. These subunits form functional receptors, each binding to a slightly different set of adhesion protein ligands and to relatively small domains on the ligands.
  • adhesion protein binding domains contain the amino acid sequence arginine-glycine-aspartic acid (RGD) which binds to a large number of integrin receptors. This sequence can be mimicked by a linear or cyclic synthetic oligopeptide so that the very small peptide will behave similarly to the very large protein in its binding affinity for the receptor.
  • RGD cell binding sequence is common to fibronectin, fibrinogen, vitronectin, laminin, collagen, thrombospondin and vWF.
  • a linear or cyclic synthetic oligopeptide containing at least the RGD sequence is utilized for its affinity to the integrin receptors.
  • This oligopeptide may be flanked by residues, for example, RGDC, CRGDFPASSC, RGDS or GRGDSP, etc. See, for example, U.S. Patents 4,792,525, 4,614,517 and 5,695,997.
  • the oligopeptides are limited in design only by the cross-linking agent used in conjunction with it.
  • the cross-linking agent should be able to bind to the terminus of the oligopeptide as well as being able to bind to the second functional component of the composition or to a bridging compound between the two.
  • oligopeptide utilized is RGDC
  • non-specific binding component is albumin or another human plasma protein
  • preferred cross-linking agents are maleimidic, or carbodiimidic, for example, N-Maleimidocaproic acid-(2-nitro-4- sulfo)-phenyl ester (Bachem, Inc., Torrance, CA) or other similar peptide cross-linkers.
  • the specific sequences of the synthetic oligopeptide as well as the bifunctional cross-linking agents useful with them are readily apparent to any person having average skill in the art.
  • the second functional component of the composition is any physiologically acceptable compound which comprises a functional group capable of non-specifically reacting with cell sur ace molecules.
  • this component is a nonimmunogenic, water-soluble proteinaceous material, for example, a human plasma protein.
  • albumin is the non-specific binding component
  • the albumin may be any physiologically acceptable type, for example, animal serum albumin, human serum albumin (HSA) or recombinant albumin.
  • HSA human serum albumin
  • the protein is recombinant, it may be produced from any known recombinant means, including bacteria, yeast, animal cell culture and transgenic methods.
  • a cross-linking agent is used in order to activate cross-linking amongst the non-specific binding component as well as to the tissue.
  • the preferred cross-linker is a polyethylene glycol or polyoxyethylene type or other physiologically acceptable cross-linker. See, for example, U.S. Patent 5,583,114.
  • cross-linking agents can be readily determined by any person having average skill in the art.
  • the cross-linking agents can be prepared using known processes. See, for example, U.S. Patents 4,101 ,380 and 4,839,345.
  • the protein solutions should be buffered to a pH of about 8.5 to 11.
  • Suitable buffer systems include, but are not limited to carbonate or phosphate buffer systems, or other similar physiologically acceptable buffers.
  • the buffer system must not alter the protein cross-linking agent.
  • the heterofunctional biomaterial is the product of the mixture of an albumin based solution and an albumin cross- linking agent.
  • the albumin based solution is produced by cross-linking pharmaceutical grade peptides containing the RGD sequence to the human albumin protein in about 30% to 65% buffered solution having a pH of about 8.5 to 11 at a ratio of approximately 20-2000 parts protein to 1 part peptide by weight, using N-Maleimidocaproic acid-(2-nitro-4-sulfo)-phenyl ester (Bachem, Inc., Torrance, CA) or other similar peptide cross-linker. Unlinked peptides can be removed by dialysis and/or filtration.
  • the albumin cross-linking solution comprises a water-soluble cross-linking agent, preferably a 1 % to 15% solution of glutaraldehyde or a 1 % to 30% ethylene glycol di- succinimidylsuccinate solution.
  • the two solutions are mixed at the time of use, preferably at the site of application.
  • the albumin cross-linking solution provides for cross-linking of the albumin as well as for non-specific binding of the albumin to the tissue.
  • Other binding components may also be included in the composition, for example, additional human plasma proteins.
  • formulation factors to be considered are a) the pH of the solution; b) the concentration of the protein cross-linker; c) the concentration of the functional group capable of non-specifically reacting with cell surface molecules; and d) the concentration of the functional group capable of specifically reacting with the cell receptors.
  • the concentration of the albumin should be about 35% to 60%
  • the pH of the albumin solution should be about 8.5 to 10.0
  • the concentration of the SS2 cross-linker should be about 130 to 275 mg/ml.
  • the SS2 cross-linker must be freshly mixed and used within about 30 minutes. Optimal parameters will vary depending upon the desired effect and can be readily determined by any person having average skill in the art. These parameters also effect the curing rate of the end product, which may be an important characteristic when the composition is used for the prevention of tissue adhesion.
  • the composition of the present invention may be useful for many types of procedures, including promotion or inhibition of tissue adhesion. Tissue adhesion is promoted when the composition is used between tissues which are to be joined. Tissue adhesion is prevented when the composition is applied to one tissue and allowed to cure while other tissue is kept out of contact with the treated tissue.
  • the invention is also useful in conjunction with traditional sutures or staples in order to enhance their effect, for example, to reduce gas or fluid leaks.
  • the composition may be used to reduce the number of sutures or staples necessary for a procedure, or to eliminate their use entirely. Additionally, the product may be used to help reduce bleeding. It may be used on a wound during surgery or after injury. It is also useful for attachment of skin or bone grafts and other biocompatible materials or for plastic and reconstructive surgery.
  • the two components of the final composition should be mixed at the point of use. They can be premixed and then spread on to the wound site. Preferably, a double barrel syringe may be employed which mixes the components at the point of contact. The composition may then be spread or sprayed onto the site.
  • FibriJet® surgical sealant delivery systems (Micromedics, Inc., Eagan, MN) offer a controlled one-to-one delivery ratio of components by means of a dual cannula applicator tip. With a variety of tips and syringe sizes, the surgeon can conveniently apply the right amount of compound to the desired location with a simple one-handed operation. Tip and syringe sizes allow for micro, topical and endoscopic applications.
  • the cure rate may be also manipulated by formulation such that the product is cured more or less quickly, depending upon the need. Typically, fast cure rates are more widely desired, and the product can be formulated to cure in less than one minute. This rate can be adjusted by any person having average skill in the art.
  • the invention is further illustrated by the following example.
  • the example is not intended to limit the invention in any manner.
  • Example 20 ml of sodium chloride-sodium phosphate peptide buffer solution was prepared and the pH was adjusted to 6 using 1M NaOH. 0.1 M and 1.0M carbonate/bicarbonate buffers (Sigma catalog # C3041 ) were also prepared.
  • the peptide solution was prepared by dissolving 5.0 mg RGD peptides (RGDC Bachem catalog #H-3156) in 1.92 ml of the peptide buffer. Where necessary, the pH was adjusted to 6.0 using 1 M NaOH.
  • the peptide cross- linker solution was prepared by dissolving 50 mg Peptide HSA Cross-linker (mal-sac-HNSA Bachem catalog #Q-1615) in 5 ml peptide buffer solution.
  • the peptide cross-link mixture was prepared by mixing 2 ml peptide solution with 0.2 ml peptide cross-linker solution and the pH was adjusted to 7.4 using 0.1 M NaOH.
  • a 40% albumin solution was prepared by stirring 2.5 ml of 0.1 M albumin buffer into I gram of human serum albumin (Sigma catalog #A1887).
  • a 45% albumin solution was prepared by stirring 4.5 ml of 0.1 M albumin buffer into 2 grams of human serum albumin.
  • 0.14ml peptide crosslink mixture was added to 1.25 ml 40% albumin solution.
  • 0.28 ml of peptide cross-link mixture was added to 2.5 ml 45% albumin solution. Both were agitated gently at room temperature for about 1 hour.
  • the pH of each was adjusted to between 8.5 and 10.0 using 1 M albumin buffer.
  • the PEG cross-linker was prepared by mixing 3.85 ml distilled water with 1.0 gram of HSA Cross-linker (Shearwater catalog#SS-3400) to yield a concentration of 260 mg/ml.
  • SYN-A is the combination of the peptide cross-link 40% albumin solution and the PEG cross-linker
  • SYN-B is the combination of the peptide cross-link 45% albumin solution and the PEG cross-linker.
  • the peptide buffer was made up one week prior to testing. All other components were made 1 -2 days prior to use except the PEG cross-linker, which was made up immediately prior to use.
  • TISSEEL ® (Immuno AG, Vienna, Austria) was reconstituted a few hours before use according to the directions provided in the packaged kit, resulting in a fibrinogen solution (70- 100 mg/ml) and thrombin solution (4 units/ml).
  • the rectangular skin sections were sliced into 1 cm wide strips perpendicular to the spine using a multi-bladed cutter. Each strip was then bisected across its width and lines 1 cm back from the bisected ends drawn on the dermis. The strips were divided into 3 groups, one for each product tested, such that strips that were adjacent on the rabbit were not in the same group. All strips were kept covered with saline-soaked gauze. Immediately prior to application of the products, the gauze was peeled back from the strips. An aliquot of 0.01 ml of the appropriate proteinaceous solution was applied to the center of the 1 cm 2 end region of one strip in each pair.
  • the mean maximum shear strength of each of the three biodhesives tested was calculated, as was the standard deviation.
  • a one-way analysis of variance with Bonferroni posthoc test was performed to elucidate statistically significant differences in adhesive strength among the three bioadhesives.
  • a p-value of ⁇ 0.05 was considered statistically significant.
  • SYN-B provided better strength than did SYN-A. although the difference was not statistically significant (p>0.05) (Table and Figure).
  • the mean adhesive shear strength of SYN-B was not statistically different from that of TISSEEL.
  • the mean adhesive shear strength of SYN-A was significantly less than that of TISSEEL (p ⁇ 0.05).

Abstract

La présente invention concerne une composition hétérofonctionnelle destinée à être utilisée pour reconstituer des tissus. Ces compositions, qui sont conçues pour réagir avec des surfaces cellulaires par interaction spécifique ou non spécifique, présentent la spécificité cible liée aux interactions exercées par un récepteur cellulaire, et affichent les caractéristiques de stabilité et d'efficacité de réticulation qui sont celles des composantes matricielles non spécifiquement fixées aux surfaces cellulaires.
PCT/US1998/017001 1997-08-22 1998-08-17 Composition heterofonctionnelle de reconstitution de tissus WO1999010019A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US5666697P 1997-08-22 1997-08-22
US60/056,666 1997-08-22
US13487998A 1998-08-15 1998-08-15
US09/134,879 1998-08-15

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WO1999010019A2 true WO1999010019A2 (fr) 1999-03-04
WO1999010019A3 WO1999010019A3 (fr) 1999-06-10

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010095051A3 (fr) * 2009-02-21 2011-04-07 Sofradim Production Adhésifs chirurgicaux fonctionnalisés
WO2011117745A3 (fr) * 2010-03-25 2012-03-22 Sofradim Production Fixations chirurgicales et procédés pour fermer des plaies

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5583114A (en) * 1994-07-27 1996-12-10 Minnesota Mining And Manufacturing Company Adhesive sealant composition

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5583114A (en) * 1994-07-27 1996-12-10 Minnesota Mining And Manufacturing Company Adhesive sealant composition

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KISHIDA ET AL.: "RGD-Albumin conjugate: expression of tissue regeneration activity" BIOMATERIALS, vol. 13, no. 13, 1992, pages 924-930, XP002097467 cited in the application *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010095051A3 (fr) * 2009-02-21 2011-04-07 Sofradim Production Adhésifs chirurgicaux fonctionnalisés
US8968733B2 (en) 2009-02-21 2015-03-03 Sofradim Production Functionalized surgical adhesives
WO2011117745A3 (fr) * 2010-03-25 2012-03-22 Sofradim Production Fixations chirurgicales et procédés pour fermer des plaies
US9272074B2 (en) 2010-03-25 2016-03-01 Sofradim Production Surgical fasteners and methods for sealing wounds
US10143471B2 (en) 2010-03-25 2018-12-04 Sofradim Production Surgical fasteners and methods for sealing wounds

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