CN1968718B - Use of isocyanate functional composition in preparing adhesive for tissue adhesion - Google Patents
Use of isocyanate functional composition in preparing adhesive for tissue adhesion Download PDFInfo
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- CN1968718B CN1968718B CN200480043348.3A CN200480043348A CN1968718B CN 1968718 B CN1968718 B CN 1968718B CN 200480043348 A CN200480043348 A CN 200480043348A CN 1968718 B CN1968718 B CN 1968718B
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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
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0026—Sprayable compositions
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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
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0042—Materials resorbable by the body
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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
Abstract
An adhesive including a mixture of isocyanate capped 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. Multiamine functional precursors of the multi-isocyanate functional molecules are also biocompatible. As discussed, 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 approximately 1 to approximately 100 centipoise. The mixture of molecules forms a crosslinked polymer network upon contact with the organic tissue in the presence of water. The crosslinked polymer network is biocompatible and biodegradable. The crosslinked polymer network degrades into degradation products including the precursor molecules and the multi-amine functional precursors.
Description
Technical field
The present invention relates generally to adhesive of medical and methods of tissue closure, more specifically relate to adhesive of medical and methods of tissue adhesion, wherein the mixture of isocyanate-functional molecule or prepolymer is applied to tissue.
Background technology
Annual emergency treatment doctor need handle nearly 11,000,000 traumatic wound in the U.S..The two is the common cause that people seek medical rescue for traumatic wound and respiratory tract infection.The conventional method of tissue closure (for example, sew up and stapler) several serious limitation are arranged, comprise can not form the fluid sealability closure, be unsuitable for that microsurgery uses, need carry out that second operation removes, inflammation and possibility of infection increases and produce obvious cicatrix and tissue injury in intervention procedure.Medical adhesive tape has been used to during some uses, but the limitation of medical adhesive tape is weak strength and with tissue adhesion problem is arranged.Handle cut with stitching thread and often relate to injection site anesthetis and use pin, this causes anxiety can for the patient who has been in the fear.Referring to, McCaig LF for example, " National Hospital Ambulatory Medical Care Survey:1992Emergency Department Summary,
Vital Health Stat., 1994,245,1-12; And ElandJM, Anderson JE, " The Experience of Pain in Children, " Jacox AK version,
Pain, Boston, Mass:Little Brown ﹠amp; Co., 1997453-473.Suture wound repair is pain and time-consuming very also.For a comparatively long period of time, the doctor is seeking and is taking seldom, do not need extra operation, the uncomfortable minimum of patient and have the wound repair methods of well covering up effect.
Realize in the process of this target attempting, researched and developed biological and synthetic tissue adhesive.The biological tissue of applying adhesive can be that soft (knot is formed) tissue adhesion is to hard (calcification) tissue adhesion.Soft tissue adhesives for example is used for outside and internal wounds is closed and sealing.Hard tissue adhesive for example is used for bond prosthetic materials to tooth and bone.Propose four kinds of main adhesion mechanisms for this tissue adhesive, comprised mechanical interconnection, absorption, diffusion theory and electron theory.Mechanical interconnection relates to adhesive permeation in the hole as the irregular portion on the surface of adhesive means or substrate surface.The fact that adsorption theory relied on is, if realized the molecule contact at tight interface, will set up by force with molecular separating force between atom and be connected.Bonding polymer molecule or the segment of requiring that diffusion theory is set forth between to be polymer with substrate and polymer mutual passes the interfacial phase counterdiffusion.At last, the electron transfer between electron theory suggestion binding agent and bur can cause forming high intrinsic adherent electrostatic force.
Unfortunately, existing available tissue adhesive all has tangible limitation.For example, biological tissue adhesives such as fibrin sicker (glue) are very effective in some applications, but extremely expensive, because they are taken from autologous tissue.The hot strength of fibrin sicker also relatively a little less than, need a large amount of work to produce.In addition, Fibrinogen that obtains from human blood and thrombin may be for example cause viral infection because of acquired immunity deficiency syndrome and/or hepatitis.Referring to, Spotniz WD for example, " History ofTissue Adhesives, " Sierra D, Saits R edits,
Surgical Adhesives and Sealants, Current Technology and Applications, USA:Technomic, 1996; With people such as Borst AH, " Fibrin Adhesive:An Important Hemostatic Adjunct in CardiovascularOperations, "
J.Thorac.Cardiovasc.Surg., 1982,84,548-553.
Synthetic and semisynthetic surgical adhesive have been proposed, as cyanoacrylate, polyurethane prepolymer and gelatin-resorcine-formadehyde composition.Referring to, people such as Tseng Y-C for example, " In Vivo Evaluation of2-cyanoacrylate as Surgical Adhesives, "
J.Appl.Biomater, 1990,1,11-22; People such as Kobayashi H., " Water-curable and Biodegradable Prepolymer,
J.Biomed. Mater.Res., 1991,25,1481-1494; People such as Matsuda T, " A Novel Elastic SurgicalAdhesive, Design Properties and In Vivo Performance, "
Trans.Am.Soc.Artif. Intern.Organ, 1986,32,151-156; With people such as Matsuda T, Department of a CompliantSurgical Adhesive Derived from Novel Flurinated Hexamethylene Diisocyanate, "
Trans.Am.Soc.Artif.Intern.Organ, 1989,35,381-383.Yet, these synthetic sickers all have several shortcomings, comprise cytotoxicity, degradation rate is low and the chronic inflammatory disease that causes because of the lasting release of its catabolite (for example formaldehyde that discharges from cyanoacrylate polymer and gelatin-resorcine-formadehyde composition and the aromatic diamines that discharges from polyurethane).Referring to, people such as Braumwald NS for example, " Evaluation of Crosslinked Gelatin as a Tissue Adhesive and Hemostatic Agent:AnExperimental Study "
Surgery, 1966,59,1024-1030; With Toriumi D, Sierra D and Saits R edit " Surgical TissueAdhesive:Host Tissue Response, Adhesive Strength and Clinical Performance ",
Surgical Adhesives and Sealants Current Technology and Applications, USA:Technomic, 1996; 61-69.Usually, synthetic sicker is unsuitable for using in the body.
The big monomer of cyanoacrylate by with known " superpower sicker " in used quasi-chemical method mutually through contacting and polymerization with water.Yet except the problems referred to above, use alpha-cyanoacrylate ester group has limited the multifunctionality of preparation in cyanoacrylate polymer, and other functional group in the material must be compatible with the cyanoacrylate of hypersensitization.Use the Polyethylene Glycol of acrylate-functional to seal and to degrade (by in polyethylene glycol precursor, introducing lactic acid or hydroxyacetic acid repetitive).Yet solidifying needs to use UV ray or other irradiation.The length of penetration of supposing light is restricted, and actinic radiation-curable has just limited this technology and is applied to and is easy to be subjected on the thin film that light source influences so.
Therefore, need a kind of improved binding agent that is connected with biological tissue and method of tissue adhesion of being used for of exploitation.
Summary of the invention
In one aspect, the invention provides and a kind of binding agent is coated to method in the organic organization.This method comprises molecule mixture is coated to step in the organic organization.Described molecule mixture comprises the molecule with terminal isocyanate functional groups.The average isocyanate functionality of this molecule mixture is at least 2.1, so as can be crosslinked (or curing).More preferably the average isocyanate functionality of described mixture is at least 2.5.The viscosity of preferred described molecule mixture is about 1～about 100 centipoises, so that (about 0 ℃～about 40 ℃ usually) easily are coated to tissue in the scope of for example serviceability temperature.More preferably, described viscosity is about 1～about 50 centipoises in the serviceability temperature scope.Usually, molecule mixture must can apply maybe and can sprawl under serviceability temperature.
Molecule mixture forms crosslinked polymer network or firming body by contacting with organic organization under water exists.The water of capacity is present in the organic organization usually or wherein, therefore solidifying does not need to add entry usually.Crosslinked polymer network is biocompatible and biodegradable.Crosslinked polymer network biodegradation becomes biocompatible molecule or catabolite.
Not all mixture molecule all need be placed with blended form.For example, can be before applying or among applying mixed molecules.
In one embodiment, molecule mixture comprises lysine tri-isocyanate or lysine tri-isocyanate derivant (for example, lysine tri-isocyanate ethyl ester).
Preferably, described molecule mixture comprises the isocyanate-terminated molecule by polyisocyanates functional molecules and the multifunctional precursor molecule reaction that comprises the functional end-group that is selected from following group are formed: hydroxyl, primary amino radical and secondary amino group.In this description, term " multifunctional " refers to have the chemical compound of two (two is functional) or more a plurality of functional groups.Polyurethane prepolymer can form therefrom.Multifunctional precursor compound is biocompatible.In addition, the functional precursor of the polyamines of polyisocyanates functional molecules also is biocompatible.The polyamines official of polyisocyanates functional molecules can precursor can for example be biocompatible aminoacid, or biocompatible amino acid whose derivant.Multifunctional precursor molecule for example can comprise following at least a: Polyethylene Glycol, polyamino acid (common aminoacid greater than 50 connections, and comprise for example albumen and/or polypeptide), aliphatic polyester (comprises for example polylactic acid, polyglycolic acid and/or polycaprolactone), sugar (comprising for example sucrose), polysaccharide (for example starch), fatty poly-ester carbonate, poly-anhydride, steroid (for example hydrocortisone), glycerol, ascorbic acid, aminoacid (lysine for example, tyrosine, serine and/or tryptophan), or peptide (aminoacid of 2～50 connections usually).
In one embodiment, described multifunctional precursor molecule comprises Polyethylene Glycol, and the polyisocyanates functional molecules comprises at least a of lysine di-isocyanate ethyl ester or lysine tri-isocyanate ethyl ester.Multifunctional precursor molecule can also comprise sugar, as glucose.
Comprise at multifunctional precursor molecule under the situation of Polyethylene Glycol that described Polyethylene Glycol preferred number average molecular weight is less than 10,000.More preferably, the number-average molecular weight of described Polyethylene Glycol is less than 2,000.Most preferably, described Polyethylene Glycol number-average molecular weight is less than 1,000.In several embodiments of the present invention, the number-average molecular weight of Polyethylene Glycol is about 50～about 1000.
Preferably, molecule mixture of the present invention forms crosslinked polymer network in less than 2 minutes.More preferably, molecule mixture forms crosslinked polymer network in less than 1 minute.For solidifying resulting crosslinking polymer network by molecule mixture of the present invention, preferred described polymer network warp in the time that healing takes place contacts and biodegradation with organic organization.For example, crosslinked polymer network preferably be kept perfectly with the tissue adhesion of cut or otch, proceeded to fully up to healing and to have made wound or cut closure.In one embodiment, for example, crosslinked polymer network biodegradation to its material about 7～about 30 days, more preferably in about 7～about 14 days, lose at least about 2/3.
In one aspect of the method, the invention provides a kind of binding agent that comprises isocyanate-terminated molecule mixture, this isocyanate-terminated molecule forms by making polyisocyanates functional molecules and the multifunctional precursor molecule reaction that comprises the functional end-group that is selected from following group: hydroxyl, primary amino radical and secondary amino group.Preferred described functional group is a hydroxyl.Multifunctional precursor compound is biocompatible.The polyamines official of polyisocyanates functional molecules can precursor also be biocompatible.As mentioned above, the preferred average isocyanate functionality of described molecule mixture is at least 2.1, and more preferably, its average isocyanate functionality is at least 2.5.As mentioned above, this molecule mixture preferred viscosities is about 1～about 100 centipoises.Described molecule mixture forms crosslinked polymer network by contacting with organic organization under water exists.Crosslinked polymer network is biocompatible and biodegradable.Crosslinked polymer network is degraded into the catabolite that comprises precursor molecule and polyamines official energy precursor.
In aspect going back another, the invention provides a kind of binding agent that comprises the mixture of isocyanate-terminated prepolymer, this isocyanate-terminated prepolymer forms by making polyisocyanates functional molecules and the multifunctional precursor molecule reaction that comprises the functional end-group that is selected from following group: hydroxyl, primary amino radical and secondary amino group.Equally, multifunctional precursor compound is biocompatible.Also have, the polyamines official of polyisocyanates functional molecules can precursor be biocompatible.At least a multifunctional precursor is that number-average molecular weight is the biocompatible polymer of at least 50 compliance.As mentioned above, the average isocyanate functionality of described pre-polymer mixture is at least 2.1.The mixture of prepolymer is not solid, preferably can sprawl in the scope of serviceability temperature and be coated to tissue.The mixture of prepolymer forms crosslinked polymer network by contacting with organic organization under water exists.Crosslinked polymer network is biocompatible and biodegradable.Crosslinked polymer network is degraded into the catabolite that comprises precursor molecule and polyamines official energy precursor.
Be adhered to structural other mechanism except above-mentioned, binding agent of the present invention can to carry out chemistry (covalency) bonding with tissue.For example, the reactive isocyanate group on the binding agent can form covalent bond (that is, amino-formate bond or urea key) with reactive group such as the reaction of hydroxyl or free amino in the tissue.Isocyanate groups also forms crosslinked polymer network in the presence of the moisture of tissue neutralization intrinsic existence on it.
As mentioned above, binding agent of the present invention, preferably biocompatible by the biodegradable product of its biodegradable crosslinked polymer network that forms and described polymer network.In this description, term " biodegradable " is often referred to the ability (especially resolving into nontoxic catabolite) that binding agent decomposes in time in environment for use.In this description, term " biocompatible " is often referred to the compatible ability with biological tissue or living systems.In this regard, binding agent of the present invention, polymer network and catabolite contacting/aequum in open-assembly time under preferably to biological tissue or living systems is nontoxic basically and/or not injury basically.In addition, preferably can not cause a large amount of immunoreation or repulsion under the aequum of this material in contact/open-assembly time.
With in the medical field of tissue closure and other purposes used multiple now with binding agent different be, binding agent of the present invention has stronger hot strength relatively, and with tissue form relative stronger bonding, can reduce or eradicate simultaneously such as with multiplely show with the relevant cytotoxicity of binding agent, degradation rate is low and problem such as inflammation.Binding agent of the present invention and method provide minimum invasive channel to for example tissue closure, usually tissue are not had mechanical damage, and possibility of infection descends.Binding agent of the present invention is easy to synthesize relatively, and does not need to use the deleterious solvent of possibility.
In one embodiment, the invention provides the urethane polymer/prepolymer of the bio-compatible that is suitable for use as tissue adhesive and biodegradable lysine-di-isocyanate-(LDI-) or lysine-tri-isocyanate-(LTI-).For instance, LDI-polyurethane binder or sicker be easy to do not have under the solvent by LDI, Polyethylene Glycol (being called PEG sometimes) and glucose synthetic.Catabolite is lysine, PEG, glucose and ethanol.LDI-polyurethane tissue adhesives of the present invention and other binding agent can reduce the required time of wound repair, flexible anti aqueous protective finish is provided, and does not need to remove stitching thread.Compare with surgical appliance adhesive with existing, LDI-polyurethane tissue adhesives of the present invention and other tissue adhesive are relatively easy to be used following being fit to and wound preparation commonly used.Compare with conventional restorative procedure such as stitching thread, binding agent of the present invention is more convenient for using, because compare with conventional or traditional restorative procedure, for example, especially child's patient is easier to accept by this idea of " gluing ".
In addition, LDI-of the present invention is that the modulus or the rigidity of polyurethane tissue adhesives and other tissue adhesive can easily be regulated, (for example in humans and animals, to be used as soft (knot is formed) tissue adhesive, replace stitching thread and fiber as the surgical appliance adhesive that is used for closed some cut and/or otch), and as hard (calcification) tissue adhesive (for example, as bone or adhesive of tooth).
Description of drawings
Figure 1 shows that the common structure of bright isocyanate-terminated prepolymer of the present invention.
Figure 2 shows that the chemical constitution of lysine di-isocyanate (LDI), lysine tri-isocyanate (LTI), Polyethylene Glycol (PEG) and glucose.
Figure 3 shows that the chemical constitution example of the end capped glucose of LDI, the end capped Polyethylene Glycol of LDI and the end capped LID-PEG-glucose prepolymer of LDI.
Fig. 4 A is depicted as the container that comprises binding agent of the present invention, wherein basically the functional group of all or all binder molecule all by the isocyanate-functional end-blocking.
Fig. 4 B is depicted as two chambers container, and one of them chamber comprises the mixture of the molecule/prepolymer of (and/or amine) functional group that has excess of hydroxyl, and another chamber comprises the (NCO) mixture of the molecule/prepolymer of functional group that has excess isocyanate.
The specific embodiment
For being coated to tissue, tissue adhesive is liquid or the another kind of form (for example, flow-like gel) that can sprawl preferably.Preferred described binding agent apply be bonded to moisture in the presence of biological tissue the time can solidify quickly relatively.Realizing that preferred described tissue adhesive does not have local irritation and general toxicity yet under the required amount of effective tissue adhesion.In addition, for the cure adhesive of using in wound closure for example, the flexibility and the degradability that are fit to are needs, so that binding agent does not disturb healing.Tissue adhesive of the present invention has satisfied these standards.
In general, binding agent of the present invention comprises the molecule mixture with terminal isocyanate functional groups.The average isocyanate functionality of this molecule mixture is greater than 2 (each molecule or keys), is preferably greater than 2.1, thus can be crosslinked (or curing).More preferably, the average isocyanate functionality of mixture is at least 2.5.Although the molecule that can use relatively low molecular weight is as binding agent of the present invention, as the combination of lysine tri-isocyanate or lysine di-isocyanate and tri-isocyanate, but binding agent of the present invention preferably applies with the mixture of isocyanate-terminated polymer/prepolymer.The generality of this minute sub-instance is described and is shown among Fig. 1.This prepolymer for example can form by making polyisocyanates functional molecules and the multifunctional precursor molecule reaction that comprises the functional end-group that is selected from following group: hydroxyl, primary amino radical and secondary amino group.Preferred described functional group is a hydroxyl.
As mentioned above, for example among Fig. 1 represented isocyanate-terminated molecule make can be crosslinked, and can by with tissue in the hydroxyl and the covalent bond of amido strengthen bonding with tissue.Preferred " centre " or the precursor compound of interior chain of selecting to form with the reaction of polyisocyanates functional molecules this molecule makes thus and can control physical property, as the viscosity of binding agent and the elasticity of cured polymer network.
For example, by the whole or average functionality (average of isocyanate end/chain) of binding agent, between cross-bond molecular weight (promptly, molecular weight in the prepolymer between isocyanate groups), comprise in some prepolymer of aryl the prepolymer aromatics content (for example, introduce by adding biocompatible amino acid tyrosine) and prepolymer in the hydrogen bond group amount (for example, urea groups and carbamate groups), can control the physical property of cured polymer network.For example, increasing degree of functionality (for example, by use a large amount of isocyanate-terminated sucrose in precursor) makes crosslinked polymer network have relative higher modulus (rigidity).Increase molecular weight (for example) between crosslinking points, reduce the hydrogen bond group number or reduce aromatics content, can reduce the modulus of the crosslinking polymer network that forms by binding agent of the present invention by adding high-molecular weight PEG " sept ".Therefore, by the known variant that original formulation is carried out, can in wide range, regulate the binding agent bond properties.
Also can select biocompatible chemical compound or molecule middle or that interior chain is used, so that binding agent has other desired properties.For example, can add organized enzyme (albumen), for example be used to suppress specific antibacterial or strengthen specific biological function.Show before, can promote albumen (covalency) to be incorporated into (by the reaction of unhindered amina on the albumen and isocyanate end) in the polyurethane network by proteic aqueous solution is added in the polyurethane prepolymer.This combination has kept proteic activity, makes stability increase several magnitude simultaneously.Equally, can add steroid such as hydrocortisone (being incorporated in the binding agent of the present invention), for example to be used for anti-inflammatory.
In order to illustrate the present invention, the research of the representative adhesives that comprises the isocyanate-functional prepolymer that produces from following molecule or structure block is presented below: lysine di-isocyanate ethyl ester or LDI (light phosgenation by ethyl ester of lysine is synthetic) or lysine tri-isocyanate LTI; Glucose (comprising 5 hydroxy functional groups) and Polyethylene Glycol or PEG (comprising 2 hydroxy functional groups).The isocyanate groups of LDI or LTI forms prepolymer chain by the hydroxyl reaction with glucose and PEG.Use excess of LDI or LTI to help to guarantee basically all or all hydroxyl and the reaction of isocyanates, thereby form isocyanate-terminated prepolymer.The chemical constitution of used molecular structure block is shown among Fig. 2 in the present invention's research.Figure 3 shows that the representative example of end capped PEG-glucose-LDI prepolymer molecule of end capped PEG of the end capped glucose of isocyanates-(LDI-), isocyanates-(LDI-) and isocyanates-(LDI-).Lysine di-isocyanate is a kind of volatile compound, is non-volatile (therefore, LDI does not exist, but is advanced in the big monomer by lock) by adding to become in the polymer precursor of the present invention.
Thereby, described binding agent briefly is a polyurethane prepolymer, promptly, wherein all reactive terminal groups (amine and hydroxyl) are by the end capped polyurethane precursor of for example lysine di-isocyanate, in prepolymer, stay the end group of many isocyanates, and preferably seldom be with or without free hydroxyl group or amine groups (preventing further reaction).This prepolymer contact with tissue can cause polymer to react by the free amine in prepolymer or hydroxyl and isocyanate groups and with organize covalent bond.In addition, water also can react with isocyanate groups, discharges CO
2And forming extra free amine, final and isocyanate reaction forms crosslinking points.
Usually, mainly the concentration of the glucose by comprising 5 hydroxyls is controlled crosslinking points quantity.Use the glucose of relative higher concentration to increase crosslinking points, thereby increased the modulus of crosslinked polymer network.Polymer such as PEG biocompatible, common compliance can partly be used as sept.The molecular weight that increases used PEG in the binding agent of the present invention can increase the distance between crosslinking points, reduces the modulus of crosslinking polymer network.
Different with binding agent of the present invention is that commercially available polyurethane (comprising binding agent) is produced by aromatic isocyanate.Their degradation rate fast inadequately (as biodegradable binding agent) when in vivo using, and the degradation by-products of commercial polyurethane binding agent comprises the toxicity aromatic diamines.
Lysine di-isocyanate produces in the presence of pyridine by the phosgenation of ethyl ester of lysine.Different with lysine or its ethyl ester is that LDI is volatile, therefore is easy to by the distilling under reduced pressure purification.
Several researchs have illustrated the biocompatibility and the biological degradability of LDI-based polymer.For example, foam of polymers produces by water being added in glycerol/LDI prepolymer.And prepolymer is by producing each end-blocking of three hydroxyls in the glycerol with LDI.Foamy degraded takes several weeks, and material unaccounted-for (MUF) 2/3 after 60 days.Catabolite mainly is lysine and glycerol after measured.Therefore, the degraded of these materials is obviously fast than conventional polyurethanes.Possibly, ester group (being derived from lysine) activation amino-formate bond generation hydrolysis.In addition, in case hydrolysis, ester group will act as the hydrolysis that in-situ acid catalyst is accelerated amino-formate bond.The marrow stromal cell (BSMC) of New Zealand white rabbit is seeded on glycerol/LDI foam, observe its bonding with sprawl.BMSC produces the collagen suitable with control cells (finding by measuring hydroxyproline).
Use glucose/LDI foam further to study.In this research, LDI is added in the glucose with 5: 2 ratios.Add stiff (high-modulus) foamed materials of Aquatic product.By taking out prepolymer sample, the foam that can produce softness and deflect before finishing at the LDI+ glucose response.As described in the research of front, BMSC is seeded on these foams.BMSC is bonded on the foam, sprawls in the above simultaneously.Depend on the crosslink density of material, glucose-LDI foams is degraded into sucrose and lysine (that is, soft foam is faster than the rigid foam degraded) in 2～3 months time.In addition, the small sample of glucose-LDI foams is implanted in the New Zealand white rabbit.The sample of capturing material and surrounding tissue after 2 months.Compare with the control sample that uses the polylactic acid/hydroxy acetate multipolymer, in these samples, observe less giant cell for instance.
The material that above-mentioned foam of polymers is normally highly cross-linked.In case form, these materials just can not be reprocessed.Also synthesized the linear polymer that obtains from LDI and two-functionalized polyalkylene glycol (molecular weight 200～8000).Although this polymer is machinable, this polymer dissolves in water." " the segmental chain extension firmly of by using tyrosine, lysine or tryptophan, finishing those polyurethane of thermoplastic elastomer (TPE) to preparation (that is, can process but water-insoluble polymer) as chain extender.In this research, excessive LDI is added in other aminoacid.Then, LDI-aminoacid-LDI chemical compound that obtains and Polyethylene Glycol reaction.Use the hard segment of chain extension to be created in undissolved machinable polyurethane in the water by LDI.
Above-mentioned cross-linked material is not preferably used as binding agent usually, although they can apply by the mode shown in following Fig. 4 B.But, top studies show that, (a) isocyanate-terminated prepolymer is easy to synthesize, (b) degrade in 2-3 month from the foam of polymers of LDI and glucose or glycerol generation, producing mainly is the precursor of lysine and hydroxyl-functional, (c) marrow stromal cell is easy to adhere to and growth at the foam of polymers that produces from LDI, and (d) the LDI-glucose polymer produces slight immunoreation in vivo.
The preferred embodiment of binding agent of the present invention comprises the mixture of isocyanate-terminated prepolymer, through being coated to tissue as mentioned above, and can be suitably functionalized crosslinked to taking place.For obtaining through being solidified into the binding agent sprawled of the biodegradable and biocompatible polymer network of water proofing property, prepolymer can introduce aforesaid polyisocyanates functional molecules such as LDI or LTI, have relative higher functionality (having at least three reactive functional groups) and produce molecule such as the glycerol or the sugar of crosslinking points and must be at least two-functional sept molecule/group such as the PEG that is used for introducing the prepolymer internal chain.Described sept preferably number-average molecular weight is at least 50 polymer, when with respect to other component of prepolymer and concentration when increasing, and the modulus that described sept is used to reduce the viscosity of binding agent and/or is used to reduce the cure polymer network.
Preferably, functional group's isocyanate functional group's capped/functionalized of all or all binder molecules basically is to prevent further reaction.At this point, in synthetic, use the isocyanate functional group of stoichiometric at least amount, preferred excessive isocyanate functional group.As shown in Fig. 4 A, this binding agent of the present invention (wherein the functional group of all or all binder molecules by isocyanate functional group's end-blocking) basically can be stored considerable time in the water-proof container under the anhydrous condition, until application.Shown in Fig. 4 B, using two chambers container can realize prolonging stores, one of them chamber comprises the mixture of the molecule/prepolymer of (and/or amine) functional group that has excess of hydroxyl, and another chamber comprises the (NCO) mixture of the molecule/prepolymer of functional group that has excess isocyanate.This container can comprise mixed cell well known in the art or parts, is used for making when coating is organized the inclusions of each chamber to mix, and produces crosslinked polymer network.
Embodiment 1
Using the synthetic representational LDI of following process is polyurethane tissue adhesives or sicker.For preparing described binding agent, in the 5ml PEG 400 (14.09mmol ,-OH 28.18mmol) in the exsiccant round-bottomed flask of 0.5889 gram glucose (3.27mmol ,-OH 16.36mmol) adding,, make clear solution with nitrogen purging and 50 ℃ of heating down.PEG at room temperature is a liquid, solubilized glucose and do not need extra solvent.Then, 4.6ml lysine di-isocyanate (LDI, d 1.157, FW 226,23.55mmol ,-NCO 47.10mmol) is added, rubber septum and sealing are installed to flask.Reactant mixture is stirred 48hr down at 50 ℃, obtain viscosity solution.Viscosity solution at room temperature is kept in the nitrogen, up to use.Viscous liquid is spread on each piece of two moist tissues, when two block organizations force together, mutual good bond after about 1-2 minute.
Embodiment 2
Use PEG 200 rather than PEG 400, using the synthetic another kind of LDI of following process is polyurethane tissue adhesives, compares with the binding agent of embodiment 1, has finally produced seal harder, greater strength.In this process, in the 5ml PEG 200 (28.18mmol ,-OH 56.35mmol) in the round-bottomed flask of 0.6 gram glucose (3mmol ,-OH 15mmol) adding drying,, make clear solution with nitrogen purging and 50 ℃ of heating down.Then, add 7ml LDI (d 1.157, and FW 226,35.83mmol ,-NCO 71.67mmol), rubber septum and sealing are installed to flask.Reactant mixture is stirred 48hr down at 50 ℃, obtain viscosity solution.Sicker at room temperature is kept in the nitrogen, up to use.Viscous liquid is spread on each piece of two moist tissues, when two block organizations force together, mutual good bond after 1-2 minute.
Embodiment 3
Embodiment 3 shows when the glucose moiety in the reactant mixture increases, and required time of closure of wound is shorter, and bonding strength increases, and final material is harder.In this research, in the 5ml PEG 200 (28.18mmol ,-OH 56.35mmol) in the round-bottomed flask of 1.8 gram glucoses (10mmol ,-OH 50mmol) adding dryings,, make clear solution with nitrogen purging and 50 ℃ of heating down.Then, add 10ml LDI (d 1.157, and FW 226,51.19mmol ,-NCO 102.02mmol).To flask rubber septum and sealing are installed.At 50 ℃ of following stirred reaction mixture 48hr, obtain viscosity solution.This sicker at room temperature is kept in the nitrogen, up to use.Viscous liquid is spread on each piece of two moist tissues, when two block organizations force together, mutual good bond after about 1 minute.
Embodiment 4
In this research, generally speaking use the step of embodiment 3, except replacing PEG200 with PEG 400.In this research, in the 10ml PEG 400 (28.18mmol ,-OH 56.35mmol) in the round-bottomed flask of 1.8 gram glucoses (10mmol ,-OH 50mmol) adding dryings,, make clear solution with nitrogen purging and 50 ℃ of heating down.Then, add 10ml LDI (d 1.157, and FW 226,51.19mmol ,-NCO 102.39mmol), rubber septum and sealing are installed to flask.Reactant mixture is stirred 48hr down at 50 ℃, obtain viscosity solution.This sicker at room temperature is kept in the nitrogen, up to use.Viscous liquid is spread on each piece of two moist tissues, when two block organizations force together, mutual good bond after about 1 minute.
Embodiment 5
In this research, use lysine tri-isocyanate to replace lysine di-isocyanate.Lysine tri-isocyanate can be buied, or synthetic by following process: (a) by any one that uses multiple carbodiimide ethylenediamine (excessive greatly) is coupled to and produces lysine amino amide derivatives, (b) phosgenation then on the lysine.When LTI (lysine tri-isocyanate) replaced LDI and glucose and PEG reaction, opening of material glued the time shorter (only 30 seconds), and bonding strength is bigger.In the research of this embodiment, in the 5ml PEG 200 (28.18mmol ,-OH 56.35mmol) in the round-bottomed flask of 0.6 gram glucose (3.33mmol ,-OH 16.67mmol) adding drying,, make clear solution with nitrogen purging and 50 ℃ of heating down.Then, add 5ml LTI (d 1.231, and FW 267.25,23.05mmol ,-NCO 69.15mmol), rubber septum and sealing are installed to flask.Reactant mixture is stirred 48hr down at 50 ℃, obtain viscosity solution.Described solution at room temperature is kept in the nitrogen, up to use.Viscous liquid is spread on each piece of two moist tissues, when two block organizations force together, mutual good bond after 30 seconds.
Embodiment 6
In this embodiment, use the step of embodiment 5 usually, except reacting with LTI with PEG 400 (replacing PEG 200).In this research, material to open the sticking time identical with LTI-glucose-PEG 200.Here, in the 5ml PEG 400 (14.1mmol ,-OH 28.2mmol) in the round-bottomed flask of 0.229 gram glucose (1.27mmol ,-OH 6.36mmol) adding drying,, make clear solution with nitrogen purging and 50 ℃ of heating down.Add 2.5ml LTI (d 1.231, and FW 267.25,11.52mmol ,-NCO 34.55mmol) then, rubber septum and sealing are installed to flask.Reactant mixture is stirred 48hr down at 50 ℃, obtain viscosity solution.Viscosity solution at room temperature is kept in the nitrogen, up to use.Viscous liquid is spread on each piece of two moist tissues, when two block organizations force together, mutual good bond after 30 seconds.
Embodiment 7
In this embodiment, prepare two kinds of precursor solutions, before being coated to moist tissue, mix then.Solution A makes after reacting 48hr by 2.15g PEG 200 (10.75mmol ,-OH 21.5mmol) and 4.4ml LDI (d 1.157, and FW 226,22.53mmol ,-NCO 45.05mmol).Solution B makes after reacting 48hr by 4.2g PEG200 (21mmol ,-OH 42mmol) and 2.2ml LDI (11.26mmol-NCO 22.52mmol).Because solution A has excessive LDI in reactant mixture, solution B has excessive PEG 200 in reactant mixture, so A and B solution can both be long time stored.Each solution that fully mixes equal volume is to be used as sicker.In case A and B solution thoroughly mix (1: 1 volume ratio), just viscous liquid is spread on each piece of two moist tissues.When two block organizations force together, mutual good bond after 2 minutes.
Embodiment 8
In this embodiment, prepare two kinds of precursor solutions once more, before being coated to moist tissue, mix then.Solution A makes after reacting 48hr by 4g PEG 400 (10mmol ,-OH 20mmol) and 4ml LDI (d 1.157, and FW 226,20.48mmol ,-NCO 40.96mmol).Solution B makes after reacting 48hr by 8g PEG 400 (20mmol ,-OH 40mmol) and 2ml LDI (10.23mmol-NCO 20.48mmol).Because solution A has excessive LDI in reactant mixture, solution B has excessive PEG 400 in reactant mixture, so solution A and B can both be long time stored.Each solution that fully mixes equal volume is to be used as sicker.In case A and B solution thoroughly mix (1: 1 volume ratio), viscous liquid is spread on each piece of two moist tissues.When two block organizations force together, mutual good bond after 2 minutes.
Embodiment 9
In this embodiment, prepare two kinds of precursor solutions once more, before being coated to moist tissue, mix then.Solution A by the 0.9g glucose (5mmol, 25mmol-OH) and 5ml PEG 200 (28.18mmol ,-OH56.35mmol, total-OH 81.35mmol) and 16ml LDI (d 1.157, and FW 226,81.9mmol ,-NCO 163.82mmol) make after reacting 48hr.Solution B makes after reacting 48hr by 1.8g glucose (10mmol ,-OH 50mmol) among the 10ml PEG 200 (56.35mmol ,-OH 112.7mmol, total-OH 162.7mmol) and 8ml LDI (40.96mmol ,-NCO 81.91mmol).Because solution A has excessive-NCO in reactant mixture, solution B has in reactant mixture excessive-OH, so solution A and B can both be long time stored.Each solution that fully mixes equal volume is to be used as the skin sicker.In case A and B solution thoroughly mix (1: 1 volume ratio), viscous liquid is spread on each piece of two moist tissues.When two block organizations force together, mutual good bond after about 2 minutes.
Embodiment 10
In this embodiment, gelatin uses with LDI-polyurethane binder of the present invention.With using LDI is polyurethane binder and comparing when not using gelatin, and it is shorter to open sticking time or hardening time.In this research, be that polyurethane mixes with the LDI of 0.5ml embodiment 1 with the gelatin (A type: obtain 300bloom, Sigma Co. from Corii Sus domestica) of 100 μ l 0.1%.Viscous liquid is spread on each piece of two moist tissues, and when two block organizations forced together, about 10-30 is mutual good bond after second.
Above-mentioned description and annexed drawings set forth the present preferred embodiment of the invention.Certainly, those skilled in the art obviously can make various modifications, interpolation and alternative within the scope of the invention according to above-mentioned instruction.Scope of the present invention is shown by claims rather than above-mentioned description.The all changes and the modification that fall in claim equivalents and the scope are also included within its scope.
Claims (20)
1. the compositions of the isocyanate-functional of moisture curable is used for the purposes of the binding agent of adhesion organization in preparation, and the compositions of described isocyanate-functional comprises substantially the product of the reactant mixture of being made up of following material:
(a) the excessive functional molecule of the polyisocyanates derived from multifunctional amino acid precursor of stoichiometry; With
(b) be selected from multifunctional reactant in following group: sugar, polysaccharide, steroid, glycerol, ascorbic acid, aminoacid, and their combination, this multifunctional reactant has at least two isocyanate-reactive functional groups,
The average isocyanate functionality of wherein said product is at least 2.1.
2. the purposes of claim 1, wherein said multifunctional amino acid precursor comprises lysine.
3. the purposes of claim 2, wherein said polyisocyanates functional molecules is selected from following group: Lysine triisocyanate, lysinediisocyanate, lysinediisocyanate derivant or their combination.
4. the purposes of claim 2, wherein said polyisocyanates functional molecules is selected from following group: Lysine triisocyanate, lysinediisocyanate, lysinediisocyanate ethyl ester or their combination.
5. the purposes of claim 1, the average isocyanate functionality of wherein said product is at least 2.5.
6. the purposes of claim 1, wherein said multifunctional reactant comprises sugar, glycerol or ascorbic acid.
7. the purposes of claim 6, wherein said steamed bun stuffed with sugar is drawn together glucose.
8. the purposes of claim 6, wherein said multifunctional reactant comprises glycerol.
9. the purposes of claim 1, wherein said multifunctional reactant is selected from following group: sugar, glycerol, and their combination.
10. the purposes of claim 3, wherein make the excessive polyisocyanates functional molecules reaction of described multifunctional reactant and stoichiometry, so that an isocyanate groups reaction of each isocyanate-reactive group of described multifunctional reactant and described polyisocyanate compound.
11. the compositions of the isocyanate-functional of moisture curable is used for the purposes of the binding agent of adhesion organization in preparation, the compositions of described isocyanate-functional comprises following chemical compound, and this chemical compound is the product that is selected from the polyisocyanic acid ester functional compounds precursor compound of sugar, glycerol or ascorbic acid and at least a stoichiometry, that formed by the functional amino acid precursor of amino acids.
12. the purposes of claim 11, wherein said precursor compound are sugar or glycerol.
13. the purposes of claim 11, wherein said precursor compound is a glycerol.
14. the purposes of claim 11, wherein said precursor compound is a glucose.
15. the purposes of claim 11, wherein said amino acid precursor is a lysine.
16. the purposes of claim 15, wherein said polyisocyanic acid ester functional compounds is formed by lysine.
17. the purposes of claim 16, wherein said polyisocyanic acid ester functional compounds are lysinediisocyanate, lysinediisocyanate derivant, Lysine triisocyanate or their mixture.
18. the purposes of claim 17, wherein said polyisocyanic acid ester functional compounds are lysinediisocyanate, lysinediisocyanate ethyl ester, Lysine triisocyanate or their mixture.
19. the purposes of claim 17, wherein said precursor compound is a glycerol.
20. the purposes of claim 17, wherein said precursor compound is a glucose.
Applications Claiming Priority (1)
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| PCT/US2004/016767 WO2005118011A1 (en) | 2004-05-27 | 2004-05-27 | Medical adhesive and methods of tissue adhesion |
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| CN1968718A CN1968718A (en) | 2007-05-23 |
| CN1968718B true CN1968718B (en) | 2010-06-09 |
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| EP (1) | EP1755693A1 (en) |
| JP (1) | JP2008500095A (en) |
| CN (1) | CN1968718B (en) |
| AU (1) | AU2004320265B2 (en) |
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| RU (1) | RU2346704C2 (en) |
| WO (1) | WO2005118011A1 (en) |
| ZA (1) | ZA200609694B (en) |
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| US7264823B2 (en) | 2002-02-08 | 2007-09-04 | University Of Pittsburgh | Medical adhesive and methods of tissue adhesion |
| CA2613540A1 (en) * | 2005-07-01 | 2007-01-11 | University Of Pittsburgh | Wound healing polymeric networks |
| CA2638022A1 (en) * | 2006-01-27 | 2007-08-09 | Eric J. Beckman | Medical adhesive and methods of tissue adhesion |
| US7597882B2 (en) * | 2006-04-24 | 2009-10-06 | Incept Llc | Protein crosslinkers, crosslinking methods and applications thereof |
| DE102007038125A1 (en) | 2007-08-03 | 2009-02-05 | Aesculap Ag | Combination for bonding biological tissues |
| US8287566B2 (en) | 2007-10-26 | 2012-10-16 | Cohera Medical, Inc. | Spray devices and methods |
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| EP2987510B1 (en) | 2007-11-21 | 2020-10-28 | T.J. Smith & Nephew Limited | Suction device and dressing |
| GB0723875D0 (en) | 2007-12-06 | 2008-01-16 | Smith & Nephew | Wound management |
| US11253399B2 (en) | 2007-12-06 | 2022-02-22 | Smith & Nephew Plc | Wound filling apparatuses and methods |
| US20090192554A1 (en) * | 2008-01-29 | 2009-07-30 | Confluent Surgical, Inc. | Bioabsorbable block copolymer |
| GB0803564D0 (en) | 2008-02-27 | 2008-04-02 | Smith & Nephew | Fluid collection |
| WO2010111570A1 (en) * | 2009-03-27 | 2010-09-30 | E. I. Du Pont De Nemours And Company | Polyglycerol aldehydes |
| ITMI20100440A1 (en) * | 2010-03-18 | 2011-09-19 | Dow Global Technologies Inc | PROCESS FOR THE PREPARATION OF POLYURETHANE REINFORCED WITH LONG FIBERS CONTAINING PARTICULAR FILLERS |
| US9061095B2 (en) | 2010-04-27 | 2015-06-23 | Smith & Nephew Plc | Wound dressing and method of use |
| GB201011173D0 (en) | 2010-07-02 | 2010-08-18 | Smith & Nephew | Provision of wound filler |
| CA2817916C (en) | 2010-11-15 | 2019-02-12 | Cohera Medical, Inc. | Biodegradable compositions having pressure sensitive adhesive properties |
| CN107033596A (en) | 2010-11-25 | 2017-08-11 | 史密夫及内修公开有限公司 | Composition I-II and products thereof and purposes |
| GB201020005D0 (en) | 2010-11-25 | 2011-01-12 | Smith & Nephew | Composition 1-1 |
| US20150159066A1 (en) | 2011-11-25 | 2015-06-11 | Smith & Nephew Plc | Composition, apparatus, kit and method and uses thereof |
| US20160120706A1 (en) | 2013-03-15 | 2016-05-05 | Smith & Nephew Plc | Wound dressing sealant and use thereof |
| US9839222B2 (en) | 2014-08-28 | 2017-12-12 | Universidad Eafit | Process for increasing biomass and spores production of plant growth promoting bacteria of the bacillus genus |
| RU2597902C1 (en) * | 2015-05-06 | 2016-09-20 | Федеральное государственное бюджетное образовательное учреждение высшего профессионального образования "Чувашский государственный университет имени И.Н. Ульянова" | Polymer adhesive |
| CN106267324A (en) * | 2016-08-09 | 2017-01-04 | 西北师范大学 | A kind of temperature response type macromolecule bio-medical adhesive and synthetic method thereof |
| CN110832006B (en) * | 2017-04-28 | 2022-10-14 | 赢创运营有限公司 | Biodegradable bone glue |
| CN112807482B (en) * | 2018-08-20 | 2022-07-29 | 稳得希林(杭州)生物科技有限公司 | Polysaccharide-based tissue adhesive medical adhesive and application thereof |
| KR102190917B1 (en) * | 2018-08-31 | 2020-12-15 | 씨제이제일제당 주식회사 | An adhesive composition, and preparing method thereof |
| CN113150239A (en) * | 2021-04-09 | 2021-07-23 | 华南理工大学 | Preparation method of medical polyurethane adhesive with controllable curing time |
| CN113769153A (en) * | 2021-09-22 | 2021-12-10 | 华南理工大学 | Medical adhesive for repairing intestinal wounds and using method thereof |
| CN113925996A (en) * | 2021-09-22 | 2022-01-14 | 华南理工大学 | Medical adhesive for bone defect repair and using method thereof |
| CN114250057B (en) * | 2021-12-27 | 2022-09-02 | 四川大学 | Polyurethane adhesive containing catechol group and preparation method and application thereof |
| CN114832146A (en) * | 2022-04-06 | 2022-08-02 | 华南理工大学 | Medical adhesive for bone tissue wound repair and use method thereof |
| CN114907540A (en) * | 2022-05-17 | 2022-08-16 | 浙江欧鹿医疗器械有限公司 | Polyurethane high-molecular polymer and preparation method thereof, polyurethane high-molecular polymer hydrogel, kit and application thereof |
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- 2004-05-27 AU AU2004320265A patent/AU2004320265B2/en not_active Ceased
- 2004-05-27 CA CA2576223A patent/CA2576223C/en not_active Expired - Fee Related
- 2004-05-27 WO PCT/US2004/016767 patent/WO2005118011A1/en active Application Filing
- 2004-05-27 RU RU2006144819/15A patent/RU2346704C2/en not_active IP Right Cessation
- 2004-05-27 JP JP2007515009A patent/JP2008500095A/en active Pending
- 2004-05-27 BR BRPI0418804-7A patent/BRPI0418804A/en not_active Application Discontinuation
- 2004-05-27 CN CN200480043348.3A patent/CN1968718B/en not_active Expired - Fee Related
- 2004-05-27 MX MXPA06013721A patent/MXPA06013721A/en active IP Right Grant
- 2004-05-27 NZ NZ550970A patent/NZ550970A/en not_active IP Right Cessation
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2006
- 2006-11-17 ZA ZA200609694A patent/ZA200609694B/en unknown
- 2006-11-27 IL IL179643A patent/IL179643A0/en unknown
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Also Published As
| Publication number | Publication date |
|---|---|
| CA2576223C (en) | 2013-10-08 |
| CN1968718A (en) | 2007-05-23 |
| EP1755693A1 (en) | 2007-02-28 |
| AU2004320265A1 (en) | 2005-12-15 |
| RU2006144819A (en) | 2008-07-10 |
| WO2005118011A1 (en) | 2005-12-15 |
| JP2008500095A (en) | 2008-01-10 |
| NZ550970A (en) | 2010-01-29 |
| ZA200609694B (en) | 2008-04-30 |
| AU2004320265B2 (en) | 2011-03-03 |
| RU2346704C2 (en) | 2009-02-20 |
| IL179643A0 (en) | 2007-05-15 |
| BRPI0418804A (en) | 2007-10-16 |
| CA2576223A1 (en) | 2005-12-15 |
| MXPA06013721A (en) | 2007-04-17 |
| AU2004320265A2 (en) | 2005-12-15 |
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