MEDICAL ADHESIVE AND TISSUE ADHESION METHODS BACKGROUND OF THE INVENTION The present invention relates generally to medical adhesives and tissue closure methods, and especially, to medical adhesives and tissue adhesion methods in which a mixture of isocyanate functional molecules or propolymers is applied to the fabric. Each year approximately eleven million traumatic injuries are treated by emergency physicians in the United States. Traumatic injuries rival respiratory tract infections as the most common reason people seek for medical care. Conventional methods of tissue closure (eg, sutures and staples) have several substantial limitations, including the inability to produce fluid tight closure, unsuitability for microsurgical applications, need for a second operation for removal, increased likelihood of inflammation. and infection, and significant scarring and tissue injury during insertion. Medical tapes have been used for some applications, but medical tapes are limited by weak resistance and problems with tissue adhesion. The treatment of lacerations with sutures often involves the injection of local anesthetic and the use of needles, which can afflict an already frightened patient. See, for example, McCaig LF, "National Hospital Ambulatory Medical Care Survey: 1992 Emergency Department Summary, Vital Health Stat. 1994, 245.1-12 and Eland JM, Anderson JE." The Experience of Pain in Children, "In: Jacox AK, ed Boston, Mass: Litle Brown &Co, 1997 453-473 Suture wound healing is also painful and time-consuming For some time, physicians have sought methods of wound healing that require little time, do not require additional surgery, minimize the discomfort of their patients and produce a good cosmetic effect In an attempt to achieve such goals, both biological and synthetic tissue adhesives have been developed.Applications of adhesives to biological tissue vary from soft tissue adhesion ( connective) to the adhesion of hard tissue (calcified) Soft tissue adhesives are, for example, used both externally and internally for the closure and sealing of wounds. Gone hard are used, for example, to attach prosthetic materials to the teeth and bones. Four main adhesion mechanisms have been proposed for such tissue adhesives, including, mechanical interfixing, adsorption, diffusion theory and electronic theory. The mechanical interfixation involves the penetration of the bonding agent into the irregularities of the surface or the porosity at the surface of the substrate as the means for adhesion. The theory of adsorption depends on the fact that if intimate interfacial molecular contact is achieved, the interatomic and intermolecular forces will establish a strong junction. The diffusion theory states that the adhesion of polymers to substrates and to each other requires the mutual diffusion of polymeric molecules or segments through the interfacial zone. Finally the electronic theory suggests that the electronic transfer between the adhesive and the adherent can lead to electrostatic forces that result in high intrinsic adhesion. Unfortunately, the currently available fabric adhesives have significant limitations. For example, biological tissue adhesives such as glues or glues of fibrins are effective in some applications, but are extremely expensive because they are derived from autologous tissue. The fibrin glue also suffers from relatively weak tensile strengths and a labor-intensive production medium. In addition, fibrinogen and thrombin obtained from human blood have the risk of viral infection with, for example, acquired immunodeficiency syndrome and / or hepatitis. See, for example Spotniz WD, "History of Tissue Adhesives," in Sierra D. Saits R, editors, Surgical Adhesives and Sealants. Current Tchnology and Applications, USA: Techno ic, 1996; and Borst AH et al., "Fibrin Adhesive: An Important He ostatic Adjunct in Cardiovascular Operations", J. Thorac. Cardiovasc. Surg. , 1982, 84, 548-553. Synthetic and semi-synthetic surgical adhesives, such as cyanoacrylate, urethane prepolymers, and gelatin-resorcinol-formaldehyde, have also been proposed. See, for example, Tseng Y-C et al., "Jn Vivo Evaluation of 2-cyanoacrylates as Surgical Adhesives," J. Appl. Bio ater, 1990, 1, 11-22; Kobayashi H, et al. "Water-curable and Biodegradable Prepolymer, y_ Biomed. Mater: Res, 1991, 25, 1481-1494; Matsuda T, and collaborators" A Novel Elastic Surgical Adhesive, Design Properties and In Vivo Perfomance, "Trans. Am. Soc. Artif. Intern. Organ, 1986, 32, 151-156 and Matsuda T, and collaborators, Department of a Compliant Surgical Adhesive Derive from Novel Flurinated Hexamethyiene Diisocyanate, "Trns. A.M. Soc. Artif. Intern. Organ. 1989, 35, 381-383. However, these synthetic glues have several disadvantages including cytotoxicity, low rates of degradation and chronic inflammation induced by sustained release of their degradation products (such as formaldehyde from cyanoacrylate and gelatin-resolcinol-formaldehyde polymers, and aromatic polyurethane diamine) . See, for example, Braumwald NS, et al. "Evaluation of Crosslinked Gelatin as a Tissue Adhesive and Hemostatic Agent: An Experimental Study," Surgery, 1966, 59, 1024-1030;
and Toriumi D, xvSurgical Tissue Adhesive: Host Tissue Response, Adhesive Strenghth and Clinical Performance, "in Sierra D and Sats R, ed Surgical Adhesive and Sealants Current Technology and Applications, USA: Technomic, 1996: 61-69. Synthetic glues are not suitable for internal use Cyanoacrylate macromonomers are polymerized on contact with water by the similar chemistry used in the well known "super glues." In addition to the problems described above, However, the use of the cyanoacrylate group in cyanoacrylate polymers limits the versatility of the formulation, and other functional groups in the material must be compatible with the hypersensitive cyanoacrylate.The use of functional acrylate polyethylene glycols allows sealing and degradation ( in the incorporation of repeating units of lactic acid or glycolic acid in the polyethylene glycol precursor.) However, curing requires l use of UV light or other radiation. Given the limitations of the penetration depth of light, curing with radiation limits the use of this technology to thin films that are easily accessible to the light source. Thus it is desirable to develop improved adhesives and tissue adhesion methods for use in relation to living tissue.
BRIEF DESCRIPTION OF THE INVENTION In one aspect, the present invention provides a method for applying an adhesive to organic tissue. The method includes the step of applying a mixture of molecules to the organic tissue. The mixture of molecules includes molecules having terminal isocyanic functional groups. The mixture of molecules has an average isocyanate functionality of at least 2.1 to allow crosslinking (or curing). More preferably, the average isocyanate functionality of the mixture is at least 2.5. The mixture of molecules preferably has a viscosity in the range of about 1 to about 100 centipoise to, for example, allow easy application to the tissue over a range of use temperature (typically, about 0 ° C to about 40 °. C). More preferably, the viscosity is in the range of about 1 to about 50 centipoise over a range of use temperature. In general, the mixture of molecules must be applicable or dispersible at the temperature of use. The mixture of molecules is formed of a crosslinked polymer network or is cured on contact with the organic tissue in the presence of water. Sufficient water is generally present in or within the organic tissue and the addition of water is not typically required for curing.
The crosslinked polymer network is biocompatible and biodegradable. The crosslinked polymer network is biodegraded into molecules or degradation products that are biocompatible. Not all molecules in the mixture need to be stored in a mixed form. For example, the mixing of molecules can occur precisely prior to application or during application. In one embodiment, the mixture of molecules includes lysine tri-isocyanate or a lysine tri-isocyanate derivative (e.g., ethyl ester of lysine tri-isocyanate). Preferably, the mixture of molecules includes isocyanate-terminated molecules formed by reacting multi-isocyanate functional molecules with multi-functional precursor molecules including terminal functional groups selected from the group consisting of a hydroxyl group, a primary amino group and an amino group secondary. As used herein, the term "multi-functional" refers to a compound that has two (di-functional) or more functionalities. In this way, polyurethane prepolymers can be formed. The multi-functional precursor compounds are biocompatible. In addition, the multi-amine functional precursors of the multi-isocyanate functional molecules are also biocompatible. The multi-amine functional precursors of the multi-isocyanate functional molecules can be, for example, biocompatible amino acids or biocompatible amino acid derivatives. The multi-functional precursor molecules may include, for example, at least one of polyethylene glycol, a polyamino acid (typically, greater than 50 linked amino acids and including, for example, proteins and / or polypeptides), an aliphatic polyester including, by example, polylactic acid, polyglycolic acid and / or polycaprolactone), a saccharide (including, for example, a sugar), a polysaccharide (eg, starch), an aliphatic polycarbonate, a polyanhydride, a steroid (eg, hydrocortisone), glycerol , ascorbic acid, an amino acid (for example lysine, tyrosine, serine and / or tryptophan), or a peptide (typically 2 to 50 linked amino acids) In one embodiment, the multifunctional precursor molecules include polyethylene glycol and the multi-isocyanate functional molecules include At least one of lysine di-isocyanate ethyl ester or lysine tri-isocyanate ethyl ester.The multifunctional precursor molecules In addition, they may include a sugar such as glucose. In the case where the multifunctional precursor molecule includes polyethylene glycol, the polyethylene glycol preferably has a number average molecular weight of less than 10,000. More preferably, polyethylene glycol has a number average molecular weight of less than 2,000. Much more preferably, polyethylene glycol has a number average molecular weight of less than 1,000. In various embodiments of the present invention, the polyethylene glycol has a number average molecular weight in the range of about 50 to about 1,000. Preferably, the mixture of molecules of the present invention forms a crosslinked polymer network in less than two minutes. More preferably, the mixture of molecules forms a crosslinked polymer network in less than one minute. The crosslinked polymer network resulting from curing the mixture of molecules of the present invention in contact with the organic tissue is preferably biodegraded in a period of time during which the cure occurs. For example, the reticulated polymer network is preferably retained intact to adhere to the tissue of a laceration or incision until healing has progressed sufficiently, so that the wound or incision remains closed. In one embodiment, for example, the crosslinked polymer network is biodegraded to lose at least about 2/3 of its material in about 7 to about 30 days, and more preferably in about 7 to about 14 days. In another aspect, the present invention provides an adhesive that includes a mixture of isocyanate-terminated molecules formed by reacting multi-isocyanate functional molecules with multi-functional precursor molecules including terminal functional groups selected from the group consisting of a hydroxyl group, a primary amino group and a secondary amino group. Preferably, the functional groups are hydroxyl groups. The multi-functional precursor compounds are biocompatible. The multi-amine functional precursors of the multi-isocyanate functional molecules are also biocompatible. As discussed, in the above, the mixture of molecules preferably has an average isocyanate functionality of at least 2.1 and, more preferably, has an average isocyanate functionality of at least 2.5. As also described above, the mixture of molecules preferably has a viscosity in the range of about 1 to about 100 centipoise. The mixture of molecules forms a crosslinked polymer network in contact with the organic tissue in the presence of water. The crosslinked polymer network is biocompatible and biodegradable. The crosslinked polymer network is degraded into degradation products including the precursor molecules and multi-amine functional precursors. In yet another aspect, the present invention provides an adhesive that includes a mixture of isocyanate-terminated prepolymers formed by reacting milti-isocyanate functional molecules with multi-functional precursor molecules including terminal functional groups selected from the group consisting of a hydroxyl group, a primary amino group and a secondary amino group. Once again, the multi-functional precursor compounds are biocompatible. Also, multi-amine multifunctional precursors of the multi-isocyanate functional molecules are biocompatible. At least one of the multi-functional precursors is a flexible biocompatible polymer having a number average molecular weight of at least 50. As described above, the mixture of prepolymers has an average isocyanate functionality of at least 2.1. The prepolymer mixture is a non-solid which is preferably dispersible for the applion of the fabric over the temperature range of use. The prepolymer mixture forms a crosslinked polymer network on contact with the organic tissue in the presence of water. The crosslinked polymer network is biocompatible and biodegradable. The crosslinked polymer network is degraded into degradation products including the precursor molecules and multi-amine functional precursors. In addition to other tissue binding mechanisms as described above, the adhesives of the present invention exhibit the possibility of chemly (covalently) binding to the tissue. For example, isocyanate groups reactive on the adhesive can react with reactive groups such as hydroxyl groups or free amine groups in the tissue to form a covalent bond (ie, a urethane linkage or a urea linkage). The isocyanate groups also form a crosslinked polymer network in the presence of moisture inherently present in and on the fabric. As discussed above, the adhesives of the present invention, the biodegradable crosslinked polymer network formed thereof and the biodegradation products of that polymer network are preferably biocompatible. As used herein, the term "biodegradable" generally refers to the ability of an adhesive to be decomposed (especially in harmless degradation products) over time in the environment of use. As used herein, the term "biocompatible" generally refers to compatibility with living tissue or a living system. In that regard, the adhesives, polymer networks and degradation products of the present invention are preferably substantially non-toxic and / or substantially non-detrimental to living tissue or the living system in the quantities required during the contact / exposure period. In addition, such materials preferably do not cause a substantial immunolog reaction or rejection in the quantities required during the contact / exposure period. Unlike many currently available adhesives used in med techniques for tissue closure and other uses, the adhesives of the present invention have relatively strong tensile strengths and form a relatively strong bond to tissue, while reducing or eliminating such problems. as cytotoxicity, low rates of degradation and inflammation associated with many current adhesives. The adhesives and methods of the present invention provide a minimally invasive route for, for example tissue closure, are generally no tissue damage and a decreased likelihood of infection. The adhesives of the present invention are relatively easy to synthesize and do not require the use of potentially hazardous solvents. In one embodiment, the present invention provides biocompatible and biodegradable lysine-di-isocyanate (LDI-) and lysine-tri-isocyanate (LTl) based urethane polymers / prepolymers suitable for use as a tissue adhesive. The adhesives or glues of LDI-polyurethane are, for example, easily synthesized LDL, polyethylene glycol (sometimes referred to as PEG) and glucose without solvent. The degradation products are lysine, PEG, glucose and ethanol. The LDI-polyurethane fabric adhesives and other adhesives of the present invention reduce the time required in wound healing, provide a flexible water-resistant protective coating and eliminate the need for suture removal. The LDI-polyurethane fabric adhesives and other fabric adhesives of the present invention are relatively easy to use following the proper and common wound preparation as compared to the currently available skin adhesives. The adhesives of the present invention are more convenient to use than conventional curing methods such as a suture because, for example, patients, and especially children, are more likely to accept the idea of being "glued" onto such methods. conventional or traditional healing. In addition, the modulus or stiffness of LDL-based polyurethane fabric adhesives and other fabric adhesives of the present invention can easily be adjusted for use as either soft tissue (connective) adhesives (e.g., as skin adhesives). replace sutures and staples for the closure of certain lacerations and / or incisions) and as hard tissue (calcified) adhesives (for example, as bone or dental adhesives) in both humans and animals. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 illustrates the general structure of an isocyanate-terminated prepolymer of the present invention. Figure 2 illustrates the chemical structures of lysine di-isocyanate (LD1), lysine tri-isocyanate (LT1), polyethylene glycol (PEG) and glucose. Figure 3 illustrates examples of the chemical structure of finished glucose in LD1, polyethylene glycol terminated in LD1, and a prepolymer of LID-PEG-glucose terminated in LD1. Figure 4A illustrates a container that includes an adhesive of the present invention in which substantially all or all of the functional groups of the adhesive molecules are terminated with isocyanate functionality. Figure 4B illustrates a double compartment container in which one compartment includes a mixture of molecules / prepolymers having an excess of hydroxyl functionality (and / or amines) and in another compartment includes a mixture of molecules / prepolymers having a excess isocyanate functionality (-NCO). DETAILED DESCRIPTION OF THE INVENTION An adhesive fabric is preferably as a liquid or in another dispersible form (eg, a fluid-like gel) for application to the fabric. The adhesive also preferably solidifies relatively quickly when applied and binds to living tissues in the presence of moisture. The tissue adhesive is also preferably non-irritating locally and non-toxic systematically in the amount required to achieve effective tissue adhesion. In addition, appropriate flexibility and degradability are required for the cured adhesive in, for example, wound closure so that the adhesive does not alter the cure. The tissue adhesives of the present invention meet those criteria. In general, the adhesives of the present invention include a mixture of molecules having terminal isocyanate functional groups. The mixture of molecules has an average isocyanate functionality greater than 2
(per molecule or chain) and preferably greater than 2.1 to allow crosslinking (or curing). More preferably, the average isocyanate functionality of the mixture is at least 2.5. Although it is possible to use relatively low molecular weight molecules such as lysine tri-isocyanate or a combination of lysine diisocyanate and triisocyanate as an adhesive of the present invention, the adhesives of the present invention are preferably applied as a mixture of polymers / isocyanate-terminated prepolymers. A general representation of an example of such a molecule is illustrated in Figure 1. Such prepolymers can be, for example, formed by reacting miluti-isocyanate functional molecules with multi-functional precursor molecules including terminal functional groups selected from the group consisting of a hydroxyl group, a primary amino group and a secondary amino group. Preferably, the functional groups are hydroxyl groups. As discussed above, the isocyanate terminations of a molecule as depicted in Figure 1 allow crosslinking which can increase tissue adhesion by covalently binding the hydroxyl groups and the amine groups in the tissue. The precursor compounds that react with the multi-isocyanate functional molecules, to form the section (s) of the "middle" or inner chain of such molecules, are preferably chosen to allow control of physical properties such as viscosity of the adhesive and the elasticity of the cured polymer network. For example, the physical properties of the cured polymer network can be controlled by the total or average functionality of the adhesive (average number of isocyanate end groups per chain), the molecular weight between the crosslinks (ie, the molecular weight between the groups). of isocyanate in the prepolymer), the aromatic content of the prepolymer for certain prepolymers including aromatic groups (incorporated, for example, through the addition of the biocompatible amino acid tyrosine) and the number of hydrogen bonding groups (e.g., urea groups) and urethane groups) in the prepolymer. For example, the increase in functionality (through the use, for example, of higher amounts of an isocyanate-terminated sugar in the precursor) leads to a relatively higher crosslinked polymer network with modules (rigidity). The increase in molecular weight between the crosslinking points (for example, by incorporating a "spacer" of higher molecular weight PEG), decreasing the number of linking groups and hydrogen, or decreasing the aromatic content decreases the modulus of the networks crosslinked polymers formed by the adhesives of the present invention. Accordingly, the properties of the adhesive bond over a wide range can be regulated through known modifications to the original formulation. The biocompatible compounds or molecules chosen for the middle or inner chain sections may also be chosen to impart other desirable properties to the adhesives. For example, an active enzyme (protein) can be incorporated, for example, to inhibit a particular bacterium or increase a particular biological function. It has previously been shown that the adhesion of an aqueous solution of protein to a urethane prepolymer speeds the incorporation of the protein (covalently) into the polyurethane network "(via the reaction of free amines on the protein with isocyanate groups). terminals.) Such incorporation preserves protein activity while increasing stability by several orders of magnitude.Similarly, a steroid such as hydrocortisone (which is incorporated in an adhesive of the present invention) can be incorporated to act as, for example, an anti-inflammatory To illustrate the present invention, studies of representative adhesives that include an isocyanate functional prepolymer generated from the following molecules or building blocks are disclosed: lysine ethyl ester di-isocyanate LD1 (synthesized via phosgenation of the ethyl ester of lysine) or lysine tri-isocyanate LTl; glucose (which includes five hydroxyl functional groups) and polyethylene glycol or PEG (which includes two hydroxyl functional groups). The isocyanate groups of LDl or LTl form the prepolymer chain via the reaction with the hydroxyl groups of glucose and PEG. The use of an excess of LDl or LTl helps to ensure that substantially all or all of the hydroxyl groups react with isocyanate resulting in an isocyanate-terminated prepolymer. The chemical structures of the molecular building blocks are used in the studies of the present invention as set forth in Figure 2. Figure 3 illustrates representative examples of isocyanate-terminated glucose (LD1), isocyanate-terminated PEG (LD1) and a PEG-glucose-LDI prepolymer molecule terminated in isocyanate LDl. The lysine di-isocyanate, which is a volatile compound, becomes non-volatile through incorporation into the polymer precursors of the present invention (therefore, LD1 is not present, but rather fixed in a macromonomer). The adhesive in this manner is simply a polyurethane prepolymer, that is, a polyurethane precursor where all the reactive end groups (hydroxyl amine) have been terminated with, for example, lysine diisocyanate, leaving numerous terminal isocyanate groups and preferably little or no hydroxyl groups or free amine (to prevent further reaction) in the prepolymer. Exposure of such a prepolymer to the tissue can result in the covalent attachment of the polymer to the tissue through the reaction of the amine groups or free hydroxyl groups with the isocyanate groups in the prepolymer. In addition, the water will also react with the isocyanate groups; releasing C0 and forming additional free amine groups, which finally react with isocyanate to form crosslinking points. In general, the number of crosslinking points was controlled mainly via the glucose concentration, which includes five hydroxyl groups. By using a relatively high concentration of glucose, the crosslinking points are increased and the modulus of the crosslinked polymer network is increased. A generally flexible, biocompatible polymer, such as PEG, acts, in part, as a spacer. The increase in molecular weight in PGE used in the adhesives of the present invention increases the distance between the crosslinking points and decreases the modulus of the crosslinked polymer network. Unlike the adhesives of the present invention, commercial polyurethanes (including adhesives) are generated from aromatic isocyanates. Their rate of degradation is not fast enough for in-vivo use (as biodegradable adhesives) and the commercially available polyurethane adhesive degradation by-products include toxic aromatic diamines. Lysine di-isocyanate was generated via the phosgenation of the ethyl ester of lysine in the presence of pyridine. Unlike lysine or its ethyl ester, LDl is volatile and therefore is easily purified by distillation at reduced pressure. Several studies have indicated the biocompatibility and biodegradability of LDL-based polymers. For example, polymeric foams were created by the addition of water to a glycerol / LDI prepolymer. The prepolymer was generated by terminating each of the three hydroxyl groups and glycerol with LDl. The degradation of the foams occurred over a period of weeks, with a loss of 2/3 of the material after 60 days. The degradation products were measured as mainly lysine and glycerol. Those materials thus degraded significantly faster than conventional polyurethanes. Possibly, the ester group (of lysine) activates the urethane linkage for hydrolysis. In addition, the ester group, once hydrolyzed, acts as an acid catalyst in situ to accelerate the hydrolysis of the urethane linkages. Bone marrow stromal cells (BSMC'S) from New Zealand white rabbits were seeded in glycerol / LDI foams, and they were observed to stick and disperse. The BMSC's produced collagens (as found through the measurement of hydroxy proline) at levels in proportion to the control cells. Additional studies were performed using glucose / LDI foams. In such studies, LDl was added to glucose in a ratio of 5: 2. The addition of water created a rigid foamed material (high modulus). By removing prepolymer samples before the completion of the LDl + glucose reaction, foams could be created that were soft and flexible. As in the previous studies, the BMSC's sowed on these foams. The BMSC's both adhered to the foam and dispersed over it. The glucose-LDI foams were degraded to sugar and lysine for a period of 2 to 3 months, depending on the cross-linking density of the materials (ie, the soft foams degrade more rapidly than the more rigid foams). In addition, small samples of glucose-LDI foam were implanted in New Zealand white rabbits. Samples of the material and the surrounding tissue were removed after two months. Fewer giant cells, for example, were observed in these samples than in the control samples using polylactic acid / glycolic acid copolymers. The polymeric foams described in the above were generally highly crosslinked materials. Once formed, these materials could not be reprocessed. Linear polymers of LDL and di-functional polyethylene glycols
(molecular weights of 200 to 8000) were also synthesized. While such polymers were processable, the polymers were dissolved in water. The extension of the "hard" segment of those polyurethanes to produce thermoplastic elastomers (ie processable but water-insoluble polymers) was carried out via the use of tyrosine, lysine or tryptophan, as chain extenders. In such studies, an excess < of LDl was added to the other amino acid. The resulting LDI-amino acid-LDI compound was then reacted with the polyethylene glycol). The use of the extended hard segment in the chain allowed the generation of processable polyurethanes from LDL that did not dissolve in water. The crosslinked materials described in the foregoing are generally not preferred for use as adhesives although they may be applied as such in the manner described in relation to Figure 4B below. However, previous studies indicated that (a) the isocyanate terminal prepolymers are easily synthesized, (b) the polymer foams generated from LDL and either glucose or glycerol are degraded over a period of 2-3 months, generating mainly lysine and the hydroxy-functional precursor, (c) the bone marrow stromal cells easily bind and thrive in the polymeric foams generated from LDL, (d) the LDI-glucose polymers produce a mild in-vivo immune reaction. Preferred embodiments of the adhesives of the present invention include isocyanate-terminated prepolymer blends that are suitably functionalized to crosslink in the application to the fabric as described above. To achieve a dispersible adhesive that is cured to a biodegradable, biocompatible, water resistant polymer network, a prepolymer may incorporate a multi-isocyanate functional molecule such as LD1 and LT1 as described above, a molecule such as glycerol or a sugar which is relatively highly functionalized (having at least three reactive functional groups) to create crosslinking points, and a molecule / spacer group such as PGE that must be at least di-functional for incorporation into the inner chain of the prepolymer The spacer is preferably a polymer with an average molecular weight of at least 50 which, when increased in concentration relative to the other components of the prepolymer, acts to lower the viscosity of the adhesive and / or decrease the modulus of the polymer network healed Preferably, substantially all or all of the functional groups of the adhesive molecules are terminated / functionalized with isocyanate functionality to prevent further reaction. In this regard, at least a stoichiometric amount of isocyanate functionality and preferably an excess of isocyanate functionality is used during the synthesis. As illustrated in Figure 4A, such an adhesive of the present invention (in which substantially all or all of the functional groups of the adhesive molecules are terminated with isocyanate functionality) can be stored in a water-tight container in the absence of water for extended periods of time until the application. As illustrated in Figure 4B, prolonged storage can also be achieved using a double-compartment container in which one compartment includes a mixture of molecules / prepolymers that have an excess of hydroxyl (and / or amine) functionality and the other compartment includes a mixture of molecules / prepolymers having an excess of isocyanate functionality (-NCO). The container may include a mixing unit or element as is known in the art for mixing the contents of each compartment in the application to the fabric to create a crosslinked polymer network. Example 1 A polyurethane tissue adhesive or adhesive based on representative LDl was synthesized using the procedure described below. To generate the adhesive, 0.5889 grams of glucose (3.27 mmol, -OH 16.36 mmol) was added to 5 ml of PEG 400 (14.09 mmol, -OH 28.18 mmol) in a dry round-bottomed flask, flushed with nitrogen and heated to 50 ° C. to make a clear solution. PEG is a liquid at room temperature and solubilized glucose without the need for additional solvent. Subsequently, 4.6 ml of lysine diisocyanate (LDl, d 1157, FW 226, 23.55 mmol, -NCO 47.10 mmol) was added, and the flask was fitted with a rubber septum and sealed. The reaction mixture was stirred at 50 ° C for 48 hours, and a viscous solution was obtained. The viscous solution was stored at room temperature under nitrogen until use. The viscous liquid was spread over each of two pieces of wet tissue, which when pressed together adhered firmly to each other after about 1-2 minutes. Example 2 Another polyurethane fabric based on LDl was synthesized by the following procedure using PEG 200 before PEG 400, which finally generated a seal that was stiffer and exhibited greater strength than the adhesive of Example 1. In this procedure, 0.6 grams of glucose (3 mmol, -OH 15 mmol) was added to 5 ml of PGE 200 (28.18 mmol, -OH 56.35 mmol) in a dry round bottom flask, flushed with nitrogen and heated to 50 ° C to make a clear solution. Subsequently 7 ml of LDl (d 1157, FW 226, 35.83 mmol, -NCO 71.67 mmol) was added, and the flask was fitted with rubber septum and sealed. The reaction mixture was stirred at 50 ° C for 48 hours, and a viscous solution was obtained. The glue was kept at room temperature under nitrogen until use. The viscous liquid was spread over each of two pieces of wet tissue, which when pressed together adhered firmly to each other after 1-2 minutes. Example 3 Example 3 illustrated that when the glucose portion was increased in the reaction mixture, the time needed to close the wound was shorter, the bond strength increased and the final material was stiffer. In this study, 1.8 grams of glucose (10 mmol, -OH 50 mmol) was added to 5 ml of PEG 200 (28.18 mmol, -OH 56.35 mmol) in a dry round-bottomed flask, flushed with nitrogen and heated to 50 ° C to make a clear solution. Subsequently, 10 ml of LDl (d 1157, FW 226, 51.19 mmol, -NCO 102.02 mmol) was added. The flask was fitted with a rubber septum and sealed. The reaction mixture was stirred at 50 ° C for 48 hours, and a viscous solution was obtained. The glue was kept at room temperature under nitrogen until use. The viscous liquid was spread on each of two pieces of wet fabric, which when pressed together adhered firmly to each other after about 1 minute. Example 4 In this study, the procedure of Example 3 was generally followed, except that the study replaced PEG 200 with PEG 400. In this study, 1.8 grams of glucose (10 mmol, -OH 50 mmol) was added to 10 ml of PEG 400 (28.18 mmol, -OH 56.35 mmol) in a dry round-bottomed flask was flushed with nitrogen and heated to 50 ° C to make a clear solution. Subsequently, 10 ml of LDL (d 1157, FW 226, 51.19 mmol, -NCO 102.39 mmol) was added and the flask was fitted with a rubber septum and sealed. The reaction mixture was stirred at 50 ° C for 48 hours and a viscous solution was obtained. The solution was stored at room temperature under nitrogen until use. The viscous liquid was spread on each of two pieces of wet fabric, which when pressed together adhered firmly to each other after about 1 minute. Example 5 In this study, lysine tri-isocyanate was replaced by glycine diisocyanate. Lysine tri-isocyanate can be obtained commercially, or it can be synthesized via
(a) the generation of the lysine aminoamide derivative via the coupling of ethylene diamine (large excess) to lysine using any of a number of carbodiimides, followed by (b) phosgenation. When LTl (lysine triisocyanate) instead of LDl is reacted with glucose and PEG, the time of constitution of the material was much shorter (only 30 seconds) and the binding strength was much stronger. In the study of this Example, 0.6 grams of glucose (3.33 mmol, -OH 16.67 mmol) was added to 5 mL in PEG 200 (28.18 mmol, -OH 56.35 mmol) in a dry round-bottomed flask, flushed with nitrogen and it was heated to 50 ° C to make a clear solution. Subsequently, 5 ml of LDl
(d 1.231, FW 267.25, 23.05 mmol, -NCO 69.15 mmol) was added and the mixture was adjusted with a rubber septum and sealed. The reaction mixture was stirred at 50 ° C for 48 hours and a viscous solution was obtained. The solution was stored at room temperature under nitrogen until use. The viscous liquid was spread on each of two pieces of wet fabric, which when pressed together adhered firmly to each other after 30 seconds. Example 6 In this example, the procedure of Example 5 was generally followed, except that PEG 400 (instead of PEG 200) was reacted with LTl. In this study, the time of constitution of the material was the same as that of LTI-glucose-PEG 200. Here, 0.229 grams of glucose (1.27 mmol, -OH 6.36 mmol) was added to 5 ml of PEG 400 (14.1 mmol, -OH 28.2 mmol) in a dry round bottom flask was flushed with nitrogen and heated to 50 ° C to make a clear solution. Subsequently, 2.5 ml of LDl (d 1.231, FW 267.25, 11.52 mmol, -NCO 34.55 mmol) was added and the flask was fitted with a rubber septum and sealed. The reaction mixture was added at 50 ° C for 48 hours and a viscous solution was obtained. The viscous solution was stored at room temperature under nitrogen until use. The viscous liquid was spread over each of two pieces of wet fabric, which when pressed together adhered firmly to each other after 30 seconds. Example 7 In this example, two precursor solutions were prepared, then mixed just before application to the wet tissue. Solution A was made of 2.15 g of PEG 200 (10.75 mmol, -OH 21.5 mmol) and 4.4 ml of LDL (d 1.157, FW 226, 22.53 mmol, -NCO 45.05 mmol) after 48 hours of reaction. Solution B was made of 4.2 g of PEG 200 (21 mmol, -OH 42 mmol) and 2.2 ml of LDL (11.26 mmol, -NCO 22.52 mmol) after 48 hours of reaction. Because solution A had excess LDl in the reaction mixture, and solution B had excess PEG 200 in the reaction mixture, both solutions A and B could be stored for long periods of time. The same volume of each solution was mixed well for use as a glue. Once the solutions A and B were completely mixed (ratio 1: 1 by volume) the viscous liquid was spread on each of two pieces of wet tissue. When pressed together, the woven pieces adhered firmly to each other after 2 minutes. Example 8 In this example two precursor solutions were prepared again, then mixed just before application to the wet tissue. Solution A was made of 4 g of PEG 400 (10 mmol, -OH 20 mmol) and 4 ml of LDl (d 1.157, FW 226, 20.48 mmol, -NCO 40.96 mmol) after 48 hours of reaction. Solution B was made of 8 g of PEG 400 (20 mmol, -OH 40 mmol) and 2 ml of LDl (10.23 mmol -NCO 20.48 mmol) after 48 hours of reaction. Because solution A had excess LDl in the reaction mixture, and solution B had excess PEG 400 in the reaction mixture, both solutions A and B were easy to store for long periods of time. The same volume of each solution was mixed well for use as a glue. Once solutions A and B were completely mixed (1: 1 ratio by volume) the viscous liquid was spread over each of two pieces of wet tissue. When pressed together, the tissue pieces adhered firmly to each other after 2 minutes. Example 9 In this example, two precursor solutions were prepared again, then mixed just before application to the wet tissue. Solution A was made from 0.9 g of glucose (5 mmol, 25 mmol -OH) to 5 ml of PEG 200 (28.18 mmol, -OH 56.35 mmol, total -OH 81.35 mmol) and 16 ml of LDL (d
1. 157, FW 226, 81.9 mmol, -NCO 163.82 mmol) after 48 hours of reaction. Solution B was made of 1.8 g of glucose
(10 mmol, -OH 50 mmol) in 10 ml of PEG 200 (56.35 mmol, -OH 112.7 mmol, total -OH 162.7 mmol) and 8 ml of LDL (40.96 mmol-NCO 81.91 mmol) after 48 hours of reaction. Because solution A had -NCO in excess in the reaction mixture, and solution B had excess -OH in the reaction mixture, both solutions A and B were easy to store for long periods of time. The same volume of each solution was mixed well for use as a glue for the skin. Once solutions A and B were thoroughly mixed (1: 1 volume ratio) the viscous liquid was spread over each of two pieces of wet tissue. When pressed together, the tissue pieces adhered firmly to each other after approximately 2 minutes. Example 10 In this example, gelatin was used with an LDI-polyurethane adhesive of the present invention. The constitution or curing time was found to be shorter than when polyurethane adhesive based on LD1 without gelatine was used. In this study, 100 μl of 0.1% gelatin (type A: porcine skin, 300 bloom, Sigma Co) was mixed with 0.5 ml of the LDL-based polyurethane of Example 1. This viscous liquid was spread over each of two pieces of wet tissue, which when pressed together firmly adhered to each other after about 10-30 seconds. The foregoing description and the accompanying drawings set forth preferred embodiments of the invention at the present time. Various modifications, additions and alternative designs, of course, will become apparent to those skilled in the art in view of the above teachings without departing from the scope of the invention. The scope of the invention is indicated by the following claims before the above description. All changes and variations that fall within the meaning and range of equivalency of the claims will be encompassed within its scope.