JP2008500095A - Medical adhesive and tissue bonding method - Google Patents

Abstract

  An isocyanate-capped molecule formed by reacting a polyisocyanate functional molecule with a polyfunctional precursor molecule containing a terminal functional group selected from the group consisting of a hydroxyl group, a primary amino group and a secondary amino group Adhesive containing a mixture of. Preferably, the terminal functional group is a hydroxyl group. The polyfunctional precursor compound is biocompatible. Multi-amine functional precursors of multi-isocyanate functional molecules are also biocompatible. As mentioned above, the molecular mixture preferably has an average isocyanate functionality of at least 2.1, more preferably an average isocyanate functionality of at least 2.5. Also, as noted above, the molecular mixture preferably has a viscosity in the range of about 1 to about 100 centipoise. The molecular mixture forms a crosslinked polymer network upon contact with organic tissue in the presence of water. The crosslinked polymer network is biocompatible and biodegradable. The crosslinked polymer network degrades into degradation products comprising the precursor molecule and the multi-amine functional precursor.

Description

(Background of the Invention)
The present invention relates generally to medical adhesives and tissue closure methods, and more particularly to tissue adhesive methods in which a mixture of medical adhesives and molecules or prepolymers having isocyanate functional groups is applied to tissue.

Each year about 11,000,000 trauma wounds are treated by emergency physicians in the United States. Traumatic wounds are comparable to respiratory tract infections as the most common reason people get medical attention. Traditional methods of tissue closure (eg, sutures and staples) cannot produce a fluid tight closure, are not suitable for microsurgical applications, and require a second surgery for removal Have some substantial limitations, such as increased probability of inflammation and infection, and obvious wounds and tissue damage during insertion. Medical tape is used in several applications, but medical tape is limited due to its low strength and has problems with tissue adhesion. Treatment of lacerations with sutures often involves local anesthesia injections and the use of needles, which can afflict already frightened patients. 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 Pain, Boston, Mass: Little Brown & Co., 1997 453-473, and suture wound repair is painful and time consuming. They were looking for a wound repair method that required and did not require additional surgery, minimizing the patient's discomfort and making it look good.
In an effort to achieve that goal, biological and synthetic tissue adhesives have been developed. The application of adhesives to biological tissues varies from soft (bonded) tissue adhesives to hard (calcified) tissue adhesives. Soft tissue adhesives are used externally and internally, for example for wound closure and closure. Hard tissue adhesives are used, for example, to bond prosthetic materials to teeth and bones. Four main mechanisms of adhesives have been proposed for such tissue adhesives, including mechanical interlocking, adsorption, diffusion theory and electronic theory. Mechanical bonding includes the bonding agent penetrating into the surface irregularities or pores of the substrate surface as an adhesive means. Adsorption theory relies on the fact that establishing close interatomic and intermolecular forces when close contact of interfacial molecules is achieved. Diffusion theory states that the polymer adhering to the substrate and to each other requires that the polymer molecules or parts thereof cross-diffuse across the interface. Finally, electronic theory suggests that electron transfer between the adhesive and the adherend can result in electrostatic forces that result in high intrinsic adhesion.

Unfortunately, currently available tissue adhesives have significant limitations. For example, biological tissue adhesives such as fibrin glue are effective in some applications, but are very expensive because they originate from self tissue. Fibrin glue is relatively weak in tensile strength and involves production means that require a lot of work. Furthermore, fibrinogen and thrombin obtained from human blood pose a risk of viral infection, for example acquired immune deficiency syndrome and / or hepatitis. For example, Spotniz WD, "History of Tissue Adhesives," in Sierra D, Saits R, editors, Surgical Adhesives and Sealants, Current Technology and Applications , USA: Technomic, 1996; and Borst AH, et al., "Fibrin Adhesive: An Important Hemostatic Adjunct in Cardiovascular Operations, " J. Thorac. Cardiovasc. Surg. , 1982, 84, 548-553.
Synthetic and semi-synthetic surgical adhesives such as cyanoacrylates, urethane prepolymers and gelatin-resorcinol-formaldehyde have also been proposed. For example, Tseng YC, et al., "In Vivo Evaluation of 2-cyanoacrylates as Surgical Adhesives," J. Appl. Biomater , 1990, 1, 11-22; Kobayashi H., et al., "Water-curable and Biodegradable Prepolymer, J. Biomed. Mater. Res. , 1991, 25, 1481-1494; Matsuda T, et al., "A Novel Elastic Surgical Adhesive, Design Properties and In Vivo Performance," Trans. Am. Soc. Artif. Intern Organ , 1986, 32, 151-156; and Matsuda T, et al., Department of a Compliant Surgical Adhesive Derived from Novel Flurinated Hexamethyiene Diisocyanate, " Trans. Am. Soc. Artif. Intern. Organ , 1989, 35, 381 See -383. However, these synthetic glues are due to the cytotoxicity, low degradation rate and the sustained release of their degradation products (eg cyanoacrylate polymers and gelatin-resorcinol-formaldehyde-derived formaldehyde and polyurethane-derived aromatic diamines). Has some disadvantages such as the resulting chronic inflammation. 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, "Surgical Tissue Adhesive: Host Tissue Response, See Adhesive Strength and Clinical Performance, "in Sierra D and Saits, R, ed. Surgical Adhesives and Sealants Current Technology and Applications , USA: Technomic, 1996: 61-69. Typically, synthetic glues are not suitable for internal use.

Cyanoacrylate macromonomers polymerize upon contact with water by a chemistry similar to that used in the well-known “super glue”. However, in addition to the above problems, the use of cyanoacrylate groups in cyanoacrylate polymers limits the versatility of the formulation, and other functional groups in the material can react when mixed with highly sensitive cyanoacrylates. It must not be. The use of polyethylene glycol with acrylate functionality allows for blocking and degradation (by incorporating lactic acid or glycolic acid repeat units in the polyethylene glycol precursor). However, curing requires the use of UV or other radiation. Given the light penetration length limit, radiation curing limits the use of this technique to thin films that can be easily approached to a light source.
Accordingly, it is desirable to develop improved adhesives and tissue bonding methods for use with living tissue.

(Summary of the Invention)
In one aspect, the present invention provides a method of applying an adhesive to organic tissue. The method includes applying a mixture of molecules to an organic tissue. The molecular mixture includes molecules having terminal isocyanate functional groups. The molecular mixture has an average isocyanate functionality of at least 2.1 so that it can be crosslinked (or cured). More preferably, the average isocyanate functionality of the mixture is at least 2.5. The molecular mixture has a viscosity in the range of about 1 to about 100 centipoise, for example, to allow easy application to tissue over the temperature range used (typically about 0 ° C. to about 40 ° C.). Have. More preferably, the viscosity is in the range of about 1 to about 50 centipoise over the temperature range used. In general, the molecular mixture must be able to be applied or extended at the temperature used.
The molecular mixture forms and cures a crosslinked polymer network upon contact with organic tissue in the presence of water. Sufficient water is generally present on or in the organic tissue and the addition of water is typically not necessary for hardening. The crosslinked polymer network is biocompatible and biodegradable. The crosslinked polymer network biodegrades into molecules or degradation products that are biocompatible.
Not all of the molecular mixture need be stored in mixed form. For example, the mixing of molecules may occur immediately before or during application.
In one embodiment, the molecular mixture comprises lysine triisocyanate or a lysine triisocyanate derivative (eg, lysine triisocyanate ethyl ester).

Preferably, the molecular mixture is obtained by reacting a polyisocyanate functional molecule with a polyfunctional precursor molecule comprising a terminal functional group selected from the group consisting of a hydroxyl group, a primary amino group and a secondary amino group. Contains the isocyanate-capped molecule that is formed. As used herein, the term “polyfunctional” means a compound having two (bifunctional) or higher functionalities. Thus, a polyurethane prepolymer can be formed. The polyfunctional precursor compound is biocompatible. In addition, multi-amine functional precursors of multi-isocyanate functional molecules are also biocompatible. The multi-amine functional precursor of the multi-isocyanate functional molecule may be, for example, a biocompatible amino acid or a biocompatible derivative of an amino acid. Polyfunctional precursor molecules include, for example, polyethylene glycol, polyamino acids (typically more than 50 linked amino acids and, for example, proteins and / or polypeptides), aliphatic polyesters (eg, polylactic acid, polyglycolic acid and / Or polycaprolactone, etc.), saccharides (eg, sugars), polysaccharides (eg, starch), aliphatic polycarbonates, polyanhydrides, steroids (eg, hydrocortisone), glycerol, ascorbic acid, amino acids (eg, lysine) , Tyrosine, serine and / or tryptophan), or peptide (typically 2-50 linked amino acids).
In one embodiment, the polyfunctional precursor molecule comprises polyethylene glycol and the polyisocyanate functional molecule comprises at least one of lysine diisocyanate ethyl ester or lysine triisocyanate ethyl ester. The polyfunctional precursor molecule can further include a sugar such as glucose.

When the polyfunctional precursor molecule contains polyethylene glycol, the number average molecular weight of polyethylene glycol is preferably less than 10,000. More preferably, the polyethylene glycol has a number average molecular weight of less than 2,000. Most preferably, the polyethylene glycol has a number average molecular weight of less than 1,000. In some embodiments of the present invention, the number average molecular weight of the polyethylene glycol ranges from about 50 to about 1000.
Preferably, the molecular mixture of the present invention forms a crosslinked polymer network within 2 minutes. More preferably, the molecular mixture forms a crosslinked polymer network within 1 minute. The cross-linked polymer network resulting from curing of the molecular mixture of the present invention upon contact with an organic tissue preferably biodegrades during the period of healing. For example, the cross-linked polymer network is preferably held as it is to adhere the lacerated or incised tissue until healing is sufficiently advanced with the wound or incision closed. In one embodiment, for example, the crosslinked polymer network biodegrades to the extent that it loses at least about 2/3 of its material in about 7 to about 30 days, more preferably in about 7 to about 14 days.

  In another aspect, the present invention reacts a polyisocyanate functional molecule with a polyfunctional precursor molecule comprising a terminal functional group selected from the group consisting of a hydroxyl group, a primary amino group, and a secondary amino group. An adhesive comprising a mixture of isocyanate-capped molecules formed by Preferably, the terminal functional group is a hydroxyl group. The polyfunctional precursor compound is biocompatible. Multi-amine functional precursors of multi-isocyanate functional molecules are also biocompatible. As mentioned above, the molecular mixture preferably has an average isocyanate functionality of at least 2.1, more preferably an average isocyanate functionality of at least 2.5. Also, as noted above, the molecular mixture preferably has a viscosity in the range of about 1 to about 100 centipoise. The molecular mixture forms a crosslinked polymer network upon contact with organic tissue in the presence of water. The crosslinked polymer network is biocompatible and biodegradable. The crosslinked polymer network degrades into degradation products comprising the precursor molecule and the multi-amine functional precursor.

  In yet another aspect, the present invention reacts a polyisocyanate functional molecule with a polyfunctional precursor molecule comprising a terminal functional group selected from the group consisting of a hydroxyl group, a primary amino group, and a secondary amino group. An adhesive comprising a mixture of isocyanate capped prepolymers is formed. As before, the polyfunctional precursor compound is biocompatible. Multi-amine functional precursors of multi-isocyanate functional molecules are also biocompatible. At least one of the polyfunctional precursors is a plastic biocompatible polymer having a number average molecular weight of at least 50. As mentioned above, the prepolymer mixture has an average isocyanate functionality of at least 2.1. The prepolymer mixture is preferably a non-solid that can be extended for application to tissue over the temperature range used. The prepolymer mixture forms a crosslinked polymer network upon contact with organic tissue in the presence of water. The crosslinked polymer network is biocompatible and biodegradable. The crosslinked polymer network degrades into degradation products that include the precursor molecules and the multi-amine functional precursor.

As noted above, in addition to other mechanisms for binding to tissue, the adhesives of the present invention may chemically bond (covalently bond) to tissue. For example, the reactive isocyanate groups of the adhesive can react with reactive groups such as hydroxyl groups or free amine groups in the tissue to form covalent bonds (ie, urethane bonds or urea bonds). The isocyanate groups also form a crosslinked polymer network in the presence of moisture that is essentially present in and on the tissue.
As mentioned above, the adhesive of the present invention, the biodegradable crosslinked polymer network formed therefrom and the biodegradation product of the polymer network are preferably biocompatible. The term “biodegradable” as used herein generally means that the adhesive can be broken down (especially into harmless degradation products) over time in the environment of use. As used herein, the term “biocompatible” generally refers to compatibility with living tissue or living systems. In that regard, the adhesives, polymer networks and degradation products of the present invention are substantially non-toxic and / or non-toxic to living tissue or living systems, preferably in the amount required over the contact / exposure period. Or substantially non-harmful. Furthermore, such materials preferably do not produce a substantial immune response or rejection in the amount required over the contact / exposure period.
Unlike many currently available adhesives used in medicine for tissue closure and other applications, the adhesives of the present invention have a relatively strong tensile strength and a relatively strong tissue. But reduces or eliminates problems such as cytotoxicity, low degradation rate and inflammation associated with many current adhesives. The adhesives and methods of the present invention provide a minimally invasive means for tissue closure, for example, generally without mechanical damage to the tissue and with a low probability of infection. The adhesive of the present invention is relatively easy to synthesize and does not require the use of solvents that may be harmful.

In one embodiment, the present invention provides a biocompatible and biodegradable lysine diisocyanate- (LDI-) or lysine triisocyanate- (LTI-) based urethane polymer suitable for use as a tissue adhesive. A prepolymer is provided. LDI-polyurethane adhesives or glues are easily synthesized without solvents from, for example, LDI, polyethylene glycol (also called PEG) and glucose. The degradation products are lysine, PEG, glucose and ethanol. The LDI-polyurethane tissue adhesives and other adhesives of the present invention reduce the time required for wound treatment, provide a plastic water-resistant protective coating, and eliminate the need for thread removal. The LDI-polyurethane tissue adhesives and other tissue adhesives of the present invention are relatively easy to use later suitable general wound formulations compared to currently available skin adhesives . The adhesive of the present invention is more convenient to use than conventional treatment methods such as suturing. This is because, for example, patients, especially children, are more likely to accept the idea of being “adhered” than such traditional or traditional treatment methods.
Furthermore, the modulus of elasticity and stiffness of the LDI-based polyurethane tissue adhesives and other tissue adhesives of the present invention is determined by both soft (bonding) tissue adhesives (eg, certain lacerations and / or incisions) in both humans and animals. It can be easily adjusted for use as a skin adhesive to replace closure sutures and staples) and as a hard (calcified) tissue adhesive (eg, bone or tooth adhesive).

(Detailed description of the invention)
The tissue adhesive is preferably in a liquid or another form that can be extended (eg, a fluid-like gel) for application to tissue. Also, the adhesive preferably sets relatively quickly upon application and binds to living tissue in the presence of moisture. Also, the tissue adhesive is preferably locally non-irritating and systematically non-toxic in the amount necessary to achieve effective tissue adhesion. Furthermore, suitable plasticity and degradability is necessary for the cured adhesive, for example in wound closure, so that the adhesive does not interfere with healing. The tissue adhesive of the present invention meets such criteria.
In general, the adhesive of the present invention comprises a mixture of molecules having terminal isocyanate functional groups. The molecular mixture has an average isocyanate functionality of greater than 2 (per molecule or chain), preferably greater than 2.1, so that it can be crosslinked (or cured). More preferably, the average isocyanate functionality of the mixture is at least 2.5. As the adhesive of the present invention, a relatively low molecular weight molecule such as lysine triisocyanate or a combination of lysine diisocyanate and triisocyanate can be used, but the adhesive of the present invention is preferably an isocyanate. Applied as a capped polymer / prepolymer mixture. A general description of examples of such molecules is shown in FIG. Such a prepolymer is obtained, for example, by reacting a polyisocyanate functional molecule with a polyfunctional precursor molecule comprising a terminal functional group selected from the group consisting of a hydroxyl group, a primary amino group and a secondary amino group. Can be formed. Preferably, the terminal functional group is a hydroxyl group.

As described above, the isocyanate cap of a molecule as represented in FIG. 1 is crosslinkable and can be strongly bonded to tissue by covalently bonding to the hydroxyl and amine groups of the tissue. Precursor compounds that react with multi-isocyanate functional molecules to form “intermediate” or internal chain moieties of such molecules preferably control physical properties such as adhesive viscosity and cured polymer network elasticity. Chosen to allow.
For example, the physical properties of the cured polymer network are the total or average functionality of the adhesive (average number of isocyanate end groups per chain), the molecular weight between crosslinks (ie, the molecular weight between the isocyanate groups of the prepolymer) ), For certain prepolymers containing aromatic groups, the aromatic content of the prepolymer (eg, incorporated through the addition of a biocompatible amino acid tyrosine) and the hydrogen bonding groups of the prepolymer (eg, urea groups and urethane groups) Can be controlled by the number of. For example, increased functionality (eg, the use of a higher amount of isocyanate-capped sugar in the precursor) results in a crosslinked polymer network having a relatively high modulus of elasticity (stiffness). Increased molecular weight between cross-linking points (eg, by incorporating higher molecular weight PEG “spacers”), decreased number of hydrogen bonding groups, or decreased aromatic content is formed by the adhesives of the present invention. Reduce the elastic modulus of the crosslinked polymer network. Therefore, the properties of the adhesive bond can be controlled over a wide range by known modifications to the original formulation.

Also, the biocompatible compound or molecule selected for the intermediate or internal chain moiety can be selected to provide other desired properties to the adhesive. For example, active enzymes (proteins) may be incorporated, for example, to inhibit certain bacteria or enhance certain biological functions. By adding an aqueous protein solution to the urethane prepolymer, the incorporation (covalent) of the protein into the polyurethane network (through the reaction of the protein having a terminal isocyanate group with a free amine) is promoted, Already shown. Such incorporation maintains protein activity and increases stability by several orders of magnitude. Similarly, steroids such as hydrocortisone (incorporated into the adhesive of the present invention) can be incorporated, for example, to act as anti-inflammatory agents.
To illustrate the present invention, a study of a representative adhesive comprising an isocyanate functional prepolymer generated from the following molecules or building blocks is shown: lysine diisocyanate ethyl ester, ie LDI (of lysine ethyl ester Synthesized by phosgenation) or lysine triisocyanate (LTI); glucose (containing 5 hydroxyl functions) and polyethylene glycol, ie PEG (containing 2 hydroxyl functions). The isocyanate group of LDI or LTI forms a prepolymer chain by reaction with glucose and the hydroxyl group of PEG. The use of excess LDI or LTI ensures that substantially all or all hydroxyl groups react with the isocyanate to yield the isocyanate capped prepolymer. The chemical structure of the molecular building blocks used in the study of the present invention is shown in FIG. FIG. 3 shows representative examples of isocyanate- (LDI-) capped glucose, isocyanate- (LDI-) capped PEG and isocyanate- (LDI-) capped PEG-glucose-LDI prepolymer molecules. . Lysine diisocyanate (which is a volatile compound) becomes non-volatile by incorporation into the polymer precursor of the present invention (therefore LDI is not present, but rather is incorporated into the macromonomer).

Thus, the adhesive of the present invention is simply a polyurethane prepolymer, ie, a polyurethane precursor in which all reactive end groups (amine and hydroxyl) are capped, for example by lysine diisocyanate, It leaves a terminal isocyanate group, but preferably leaves only a small amount of free hydroxyl or amine groups (to prevent further reaction) or no free hydroxyl or amine groups. By contacting such a prepolymer with tissue, the polymer can be covalently bound to the tissue by reaction with isocyanate groups in the prepolymer of free amine groups or hydroxyl groups. In addition, water also reacts with isocyanate groups, releasing CO ₂ and further forming free amine groups (which eventually react with isocyanates to form cross-linking points).
In general, many cross-linking points are controlled primarily by the concentration of glucose (containing 5 hydroxyl groups). By using a relatively high concentration of glucose, the cross-linking points increase and the elastic modulus of the cross-linked polymer network increases. A polymer that is biocompatible and generally plastic, such as PEG, functions to some extent as a spacer. Increasing the molecular weight of PEG used in the adhesive of the present invention increases the distance between cross-linking points and decreases the elastic modulus of the cross-linked polymer network.
Unlike the adhesives of the present invention, commercially available polyurethanes (including adhesives) are produced from aromatic isocyanates. Its degradation rate is not fast enough for in vivo use (as a biodegradable adhesive), and the degradation by-products of commercially available polyurethane adhesives contain toxic aromatic diamines.
Lysine diisocyanate was produced by phosgenating the ethyl ester of lysine in the presence of pyridine. Unlike lysine or its ethyl ester, LDI is volatile and is therefore easily purified by vacuum distillation.

Several studies have shown the biocompatibility and biodegradability of LDI-based polymers. For example, polymer foams were generated by adding water to the glycerol / LDI prepolymer. The prepolymer was produced by capping by LDI of each of the three hydroxyl groups in glycerol. Foam degradation occurred over a period of weeks, with 2/3 of the material disappearing after 60 days. The degradation products were measured mainly as lysine and glycerol. Thus, the material degraded significantly faster than conventional polyurethane. Presumably, ester groups (derived from lysine) activate urethane linkages and hydrolyze. Furthermore, the ester group hydrolyzed once acts as an in situ acid catalyst to promote hydrolysis of urethane bonds. Bone marrow stromal cells (BSMC's) from New Zealand white rabbits were seeded in glycerol / LDI foam and observed for adhesion and spreading. BMSC's produced collagen (as determined by measurement of hydroxylproline) at a level commensurate with control cells.
In addition, studies were conducted using glucose / LDI foam. In such studies, LDI was added to glucose in a 5: 2 ratio. The addition of water produced a hard (high modulus of elasticity) foam material. By taking a prepolymer sample prior to completion of the LDI + glucose reaction, it was possible to produce a foam that was soft and plastic. BMSC's were seeded into these foams as in previous studies. Both BMSC's adhered to the foam and spread on it. The glucose-LDI foam degraded to sugar and lysine over a period of 2-3 months depending on the crosslink density of the material (i.e., the soft foam degraded faster than the hard foam). In addition, a small sample of glucose-LDI foam was implanted into White Rabbit, New Zealand. Samples of material surrounding the tissue were removed after 2 months. For example, fewer giant cells were observed in these samples than control samples using polylactic acid / glycolic acid copolymers.

The polymer foam described above was generally a highly crosslinked material. Once formed, these materials could not be reworked. Linear polymers obtained from LDI and bifunctional polyethylene glycols (200-8000 molecular weight) were also synthesized. Such polymers can be processed but dissolved in water. By using tyrosine, lysine or tryptophan as the chain extender, the “hard” portion of the polyurethane could be extended to produce a thermoplastic elastomer (ie, a processable water-insoluble polymer). In such studies, excess LDI was added to other amino acids. The resulting LDI-amino acid-LDI compound was then reacted with polyethylene glycol. The use of hardened parts with increased chain lengths allowed the production of processable polyurethanes from LDI that did not dissolve in water.
The cross-linking materials described above can be applied per se as described with respect to FIG. 4B below, but are generally not preferred for use as adhesives. Nevertheless, the above study shows that (a) the isocyanate-terminated prepolymer is easily synthesized and (b) the polymer foam produced from LDI and either glucose or glycerol has been degraded over a period of 2-3 months. Mainly produces lysine and hydroxy functional precursors, (c) bone marrow stromal cells readily adhere and grow on polymer foams generated from LDI, and (d) LDI-glucose polymer has a slow immune response in vivo It was shown to generate.

A preferred embodiment of the adhesive of the present invention includes a mixture of isocyanate capped prepolymers with functionality suitable for crosslinking by application to the tissue described above. In order to achieve a water-resistant biodegradable and biocompatible polymer network that can be stretched adhesives, the prepolymer generates cross-linking points, such as the above-mentioned LDI or LTI polyisocyanate functional molecules In order to incorporate a relatively high functionality molecule (such as glycerol or sugar) with at least 3 reactive functional groups, and a PEG that must be at least bifunctional to be incorporated into the internal chain of the prepolymer Such spacer molecules / groups can be incorporated. The spacer preferably has a number average molecular weight of at least 50 which acts to reduce the viscosity of the adhesive and / or reduce the elastic modulus of the cured polymer network when the concentration is high compared to other components of the prepolymer The polymer.
Preferably, substantially all or all functional groups of the adhesive molecule are capped / functionalized with isocyanate functional groups to prevent further reaction. In that regard, at least a stoichiometric amount of isocyanate functionality, preferably an excess of isocyanate functionality, is used in the synthesis. As shown in FIG. 4A, such an adhesive of the present invention (substantially all or all functional groups of the adhesive molecule are capped by isocyanate functional groups) is long until applied. Can be stored in a watertight container in the absence of period water. As shown in FIG. 4B, long-term storage also includes a molecule / prepolymer mixture where one compartment has excess hydroxyl (and / or amine) functionality and the other compartment contains excess isocyanate (− NCO) can be achieved using a two-compartment container containing a molecular / prepolymer mixture with functional groups. The container can include mixing units or elements known in the art to mix the contents of each compartment by applying to tissue to produce a crosslinked polymer network.

Example 1
A typical LDI polyurethane tissue adhesive or glue was synthesized using the procedure described below. To produce an adhesive, 0.5889 grams of glucose (3.27 mmol, -OH 16.36 mmol) was added to 5 ml PEG 400 (14.09 mmol, -OH 28.18 mmol) in a dry round bottom flask, flushed with nitrogen, 50 Heated at 0 ° C. to give a clear solution. PEG was a liquid at room temperature and increased glucose solubility without the need for additional solvents. Then 4.6 ml lysine diisocyanate (LDI, d 1.157, FW 226, 23.55 mmol, -NCO 47.10 mmol) was added and the flask was fitted with a rubber septa and sealed. The reaction mixture was stirred at 50 ° C. for 48 hours to obtain a viscous solution. The viscous solution was kept at room temperature under a nitrogen atmosphere until use. When the viscous liquid was spread over each of the two pieces of moist tissue and pressed together, it adhered firmly to each other after about 1-2 minutes.

(Example 2)
Another LDI-based polyurethane tissue was synthesized by the following procedure using PEG 200 instead of PEG 400 (finally producing a harder seal than the adhesive of Example 1 and greater strength than the adhesive of Example 1 Showing). In this procedure, 0.6 grams of glucose (3 mmol, —OH 15 mmol) was added to 5 ml PEG 200 (28.18 mmol, —OH 56.35 mmol) in a dry round bottom flask, flushed with nitrogen and heated at 50 ° C. A clear solution was obtained. Then 7 ml LDI (d 1.157, FW 226, 35.83 mmol, -NCO 71.67 mmol) was added and the flask was fitted with a rubber membrane and sealed. The reaction mixture was stirred at 50 ° C. for 48 hours to obtain a viscous solution. The glue was kept at room temperature under a nitrogen atmosphere until use. When the viscous liquid was spread over each of the two pieces of wet tissue and pressed together, it adhered firmly to each other after 1-2 minutes.

(Example 3)
Example 3 showed that some of the glucose increased in the reaction mixture, the time required to close the wound was shorter, the bond strength increased, and the final material was harder. In this example, 1.8 grams of glucose (10 mmol, -OH 50 mmol) was added to 5 ml PEG 200 (28.18 mmol, -OH 56.35 mmol) in a dry round bottom flask, flushed with nitrogen and heated at 50 ° C. A clear solution was obtained. 10 ml of LDI (d 1.157, FW 226, 51.19 mmol, -NCO 102.02 mmol) was then added. The flask was fitted with a rubber membrane and sealed. The reaction mixture was stirred at 50 ° C. for 48 hours to obtain a viscous solution. The glue was kept at room temperature under a nitrogen atmosphere until use. When the viscous liquid was spread over each of the two pieces of wet tissue and pressed together, it adhered firmly to each other after about 1 minute.

Example 4
In this example, the procedure of Example 3 was generally followed except that PEG 200 was replaced with PEG 400. In this example, 1.8 grams of glucose (10 mmol, -OH 50 mmol) was added to 10 ml PEG 400 (28.18 mmol, -OH 56.35 mmol) in a dry round bottom flask, flushed with nitrogen and heated at 50 ° C. A clear solution was obtained. 10 ml of LDI (d 1.157, FW 226, 51.19 mmol, -NCO 102.39 mmol) was then added and the flask was fitted with a rubber membrane and sealed. The reaction mixture was stirred at 50 ° C. for 48 hours to obtain a viscous solution. The solution was kept at room temperature under a nitrogen atmosphere until use. When the viscous liquid was spread over each of the two pieces of wet tissue and pressed together, it adhered firmly to each other after about 1 minute.

(Example 5)
In this example, lysine triisocyanate was used instead of lysine diisocyanate. Lysine triisocyanates can be obtained commercially, or (a) using any one of a number of carbodiimides to produce an aminoamide derivative of lysine by coupling ethylenediamine (a significant excess) to lysine; Subsequently, it can be synthesized by (b) phosgenation. When LTI (lysine triisocyanate) was reacted with glucose and PEG instead of LDI, the curing time of the material was much shorter (30 seconds) and the bond strength was much stronger. In this example, 0.6 grams of glucose (3.33 mmol, —OH 16.67 mmol) was added to 5 ml of PEG 200 (28.18 mmol, —OH 56.35 mmol) in a dry round bottom flask, flushed with nitrogen and heated at 50 ° C. A clear solution was obtained. 5 ml of LTI (d 1.231, FW 267.25, 23.05 mmol, -NCO 69.15 mmol) was then added and a rubber membrane was attached to the flask and sealed. The reaction mixture was stirred at 50 ° C. for 48 hours to obtain a viscous solution. The solution was kept at room temperature under a nitrogen atmosphere until use. When the viscous liquid was spread over each of the two pieces of wet tissue and pressed together, it adhered firmly to each other after about 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 TLI. In this example, the curing time of the material was the same as LTI-glucose-PEG 200. 0.229 grams of glucose (1.27 mmol, -OH 6.36 mmol) was added to 5 ml of PEG 400 (14.1 mmol, -OH 29.2 mmol) in a dry round bottom flask, flushed with nitrogen, heated at 50 ° C and clear. It was set as the solution. Then 2.5 ml LTI (d 1.231, FW 267.25, 11.52 mmol, -NCO 34.55 mmol) was added and the flask was fitted with a rubber membrane and sealed. The reaction mixture was stirred at 50 ° C. for 48 hours to obtain a viscous solution. The viscous solution was kept at room temperature under a nitrogen atmosphere until use. When the viscous liquid was spread over each of the two pieces of wet tissue and pressed together, it adhered firmly to each other after about 30 seconds.

(Example 7)
In this example, two precursor solutions were prepared and then mixed just prior to application to wet tissue. Solution A was made from 2.15 g PEG 200 (10.75 mmol, —OH 21.5 mmol) and 4.4 ml LDI (d 1.157, FW 226, 22.53 mmol, —NCO 45.05 mmol) after 48 hours of reaction. Solution B was prepared from 4.2 g PEG 200 (21 mmol, -OH 42 mmol) and 2.2 ml LDI (11.26 mmol, -NCO 22.52 mmol) after 48 hours of reaction. Since solution A has an excess of LDI in the reaction mixture and solution B has an excess of PEG 200 in the reaction mixture, both solutions A and B can be stored for long periods of time. The same amount of each solution was mixed well and used as glue. Solutions A and B were mixed well (1: 1 volume ratio) and the viscous liquid was spread over each of the two pieces of wet tissue. When pressed together, the tissue pieces adhered firmly to each other after 2 minutes.

(Example 8)
In this example, the two precursor solutions were prepared again and then mixed just prior to application to wet tissue. Solution A was prepared from 4 g of PEG 400 (10 mmol, —OH 20 mmol) and 4 ml of LDI (d 1.157, FW 226, 20.48 mmol, —NCO 40.96 mmol) after 48 hours of reaction. Solution B was made from 8 g PEG 400 (20 mmol, —OH 40 mmol) and 2 ml LDI (10.23 mmol, —NCO 20.48 mmol) after 48 hours of reaction. Since solution A has an excess of LDI in the reaction mixture and solution B has an excess of PEG 400 in the reaction mixture, both solutions A and B were easy to store for long periods. The same amount of each solution was mixed well and used as glue. Solutions A and B were mixed well (1: 1 volume ratio) and the viscous liquid was spread over each of the two pieces of wet tissue. When pressed together, the tissue pieces adhered firmly to each other after 2 minutes.

Example 9
In this example, the two precursor solutions were prepared again and then mixed just prior to application to wet tissue. Solution A was charged with 0.9 g glucose (5 mmol, 5 mmol, PEG 200 (28.18 mmol, -OH 56.35 mmol, total -OH 81.35 mmol) and 16 ml LDI (d 1.157, FW 226, 81.9 mmol, -NCO 163.82 mmol). -OH 25 mmol) and prepared after 48 hours of reaction. Solution B was transferred from 1.8 g glucose (5 mmol, -OH 25 mmol) in 10 ml PEG 200 (56.35 mmol, -OH 112.7 mmol, total -OH 162.7 mmol) and 8 ml LDI (40.96 mmol, -NCO 81.91 mmol) for 48 hours. It was prepared after the reaction. Since solution A has an excess of —NCO in the reaction mixture and solution B has an excess of —OH in the reaction mixture, both solutions A and B were easy to store for a long period of time. The same amount of each solution was mixed well and used as glue. Solutions A and B were mixed well (1: 1 volume ratio) and the viscous liquid was spread over each of the two pieces of wet tissue. When pressed together, the tissue pieces adhered firmly to each other after about 2 minutes.

(Example 10)
In this example, gelatin was used with the LDI-polyurethane adhesive of the present invention. The setting time was shorter than when the LDI polyurethane adhesive was used without gelatin. In this example, 100 μl of 0.1% gelatin (Type A: from porcine skin, 300 bloom, Sigma Co.) was mixed with 0.5 ml of the LDI polyurethane of Example 1. When the viscous liquid was spread over each of the two pieces of wet tissue and pressed together, the pieces of tissue adhered firmly to each other after about 10-30 seconds.
The foregoing description and accompanying drawings illustrate the presently preferred embodiments of the invention. Various modifications, additions and design alternatives will, of course, be apparent to those skilled in the art in light of the above teachings without departing from the scope of the invention. The scope of the invention is indicated by the appended claims rather than by the foregoing description. All changes and variations that come within the meaning and range of equivalency of the claims are to be embraced within their scope.

1 shows the general structure of an isocyanate capped prepolymer of the present invention. The chemical structures of lysine diisocyanate (LDI), lysine triisocyanate (LTI), polyethylene glycol (PEG) and glucose are shown. Examples of chemical structures of LDI capped glucose, LDI capped polyethylene glycol and LDI capped LID-PEG-glucose prepolymer are shown. Figure 3 shows a container containing an adhesive of the present invention wherein substantially all or all functional groups of the adhesive molecule are capped by isocyanate functional groups. One compartment contains a molecule / prepolymer mixture with excess hydroxyl (and / or amine) functionality and the other compartment contains a molecule / prepolymer mixture with excess isocyanate (-NCO) functionality A two-compartment container is shown.

Claims (31)

  A method of applying an adhesive to an organic tissue comprising the step of applying a mixture of molecules to an organic tissue, wherein the molecules have terminal isocyanate functional groups, and the average isocyanate functionality of the molecular mixture is at least 2.1. The viscosity of the molecular mixture is in the range of about 1 to about 100 centipoise, the molecular mixture forms a cross-linked polymer network upon contact with an organic tissue in the presence of water, and the cross-linked polymer network is biocompatible And the method wherein the crosslinked polymer network is biodegradable and biodegradable into biocompatible molecules.   The method of claim 1, wherein the average isocyanate functionality of the molecular mixture is at least 2.5.   The method of claim 1, wherein the molecular mixture comprises lysine triisocyanate or a lysine triisocyanate derivative.   The method of claim 1, wherein the molecular mixture comprises lysine triisocyanate ethyl ester.   The molecular mixture is formed by reacting a polyisocyanate functional molecule with a polyfunctional precursor molecule containing a terminal functional group selected from the group consisting of a hydroxyl group, a primary amino group and a secondary amino group. The method of claim 1, comprising a nato-capped molecule, wherein the polyfunctional precursor compound is biocompatible and the polyamine functional precursor of the polyisocyanate functional molecule is biocompatible.   6. The method of claim 5, wherein the multi-amine functional precursor of the multi-isocyanate functional molecule is a biocompatible amino acid or a biocompatible derivative of an amino acid.   The polyfunctional precursor molecule comprises at least one of polyethylene glycol, polyamino acid, aliphatic polyester, saccharide, polysaccharide, aliphatic polycarbonate, polyanhydride, steroid, glycerol, ascorbic acid, amino acid or peptide. 5. The method according to 5.   8. The method of claim 7, wherein the polyfunctional precursor molecule comprises polyethylene glycol and the polyisocyanate functional molecule comprises at least one of lysine diisocyanate ester or lysine triisocyanate ethyl ester.   9. The method of claim 8, wherein the polyfunctional precursor molecule further comprises glucose.   The method of claim 8, wherein the polyethylene glycol has a number average molecular weight of less than 10,000.   The method of claim 8, wherein the number average molecular weight of the polyethylene glycol is less than 2,000.   The method of claim 8, wherein the polyethylene glycol has a number average molecular weight of less than 1,000.   The method of claim 1, wherein the molecular mixture forms a crosslinked polymer network within 2 minutes.   The method of claim 1, wherein the crosslinked polymer network biodegrades in about 7 to about 14 days.   An isocyanate-capped molecule formed by reacting a polyisocyanate functional molecule with a polyfunctional precursor molecule containing a terminal functional group selected from the group consisting of a hydroxyl group, a primary amino group and a secondary amino group The polyfunctional precursor compound is biocompatible, the polyisocyanate functional precursor of the polyisocyanate functional molecule is also biocompatible, and the average isocyanate functionality of the molecular mixture is at least 2.1, the viscosity of the molecular mixture is in the range of about 1 to about 100 centipoise, the molecular mixture forms a cross-linked polymer network by contact with an organic tissue in the presence of water, and the cross-linked polymer network is biocompatible Biodegradable, wherein the crosslinked polymer network comprises the precursor molecule and the multi-amine functional precursor Decomposed at the object, the adhesive.   The adhesive of claim 15, wherein the average isocyanate functional group of the molecular mixture is at least 2.5.   The adhesive of claim 15, wherein the molecular mixture comprises lysine triisocyanate or a lysine triisocyanate derivative.   The adhesive of claim 15, wherein the molecular mixture comprises lysine triisocyanate ethyl ester.   The adhesive of claim 15, wherein the multi-amine functional precursor of the multi-isocyanate functional molecule is a biocompatible amino acid or a biocompatible derivative of an amino acid.   The polyfunctional precursor molecule comprises at least one of polyethylene glycol, polyamino acid, aliphatic polyester, saccharide, polysaccharide, aliphatic polycarbonate, polyanhydride, steroid, glycerol, ascorbic acid, amino acid or peptide. 15. The adhesive according to 15.   21. The adhesive of claim 20, wherein the polyfunctional precursor molecule comprises polyethylene glycol and the polyisocyanate functional molecule comprises at least one of lysine diisocyanate ester or lysine triisocyanate ethyl ester.   The adhesive of claim 21, wherein the multifunctional precursor molecule further comprises glucose.   The adhesive of claim 21, wherein the polyethylene glycol has a number average molecular weight of less than 10,000.   The adhesive of claim 21, wherein the polyethylene glycol has a number average molecular weight of less than 2,000.   The adhesive according to claim 21, wherein the number average molecular weight of polyethylene glycol is less than 1,000.   The adhesive of claim 21, wherein the molecular mixture forms a crosslinked polymer network within 2 minutes.   The adhesive of claim 21, wherein the crosslinked polymer network biodegrades in about 7 to about 14 days.   An isocyanate-capped prepolymer formed by reacting a polyisocyanate functional molecule with a polyfunctional precursor molecule containing a terminal functional group selected from the group consisting of a hydroxyl group, a primary amino group and a secondary amino group An adhesive comprising a mixture of polymers, wherein the polyfunctional precursor compound is biocompatible, the polyisocyanate functional molecule polyamine functional precursor is also biocompatible, and at least one of the polyfunctional precursors is at least one A plastic biocompatible polymer having a number average molecular weight of 50, wherein the average isocyanate functionality of the prepolymer mixture is at least 2.1, the prepolymer mixture can be extended, and the prepolymer mixture is in the presence of water. In this way, a crosslinked polymer network is formed by contact with an organic tissue. Is compatible and biodegradable, degrades the decomposition products the crosslinked polymer network containing the precursor molecules and the multi-amine functional precursor adhesive.   29. The adhesive of claim 28, wherein the at least one multifunctional polymer precursor is polyethylene glycol.   30. The adhesive of claim 28, wherein at least one other polyfunctional precursor is a molecule having three or more hydroxyl groups.   The adhesive of claim 30, wherein the at least one multifunctional polymer precursor is a sugar.

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