JPH06505175A - Bio-based medical adhesives and their uses - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Background of the invention of biologically derived medical adhesives and their use This application is filed by applicants Barry L., Bowyer and Jeffrey Ro. No. 549.797 filed on July 9, 1990 by Bin. This is a continuation application.

Adhesives that can be used in surgical applications have been taught since the late 1940's. surgery The first report on adhesives for corneal transplantation was published in 1949, and was used to fix corneal transplant wounds. Tassman for maintaining cataract surgical incisions and repairing corneal tears on the use of fibrin clots. This adhesive is suitable for in vitro surgical applications. It was not successful due to its susceptibility to enzymatic degradation.

Fibrin as a surgical adhesive was almost completely abandoned by the early 1950s. It was done.

In the early 1960s, National Health and Battelle Memorial are resorcinol-crosslinked gelatin (especially , a mixture of gelatin, resorcinol, and formaldehyde, sometimes We have developed an adhesive based on GRFJ (called GRFJ). Tissues with a lot of gelatin while other additives in this mixture may be considered cytotoxic. This gives rise to serious concerns. Furthermore, adhesives using this chemical are difficult to prepare. It was found that the method was complicated and did not provide stable adhesion. For application to the heart The required adhesion ability could be achieved, but not in all cases. It wasn't.

At the same time as the GRF research, cyanoacrylates became available and were used for surgical applications. Their application to was studied. These substances have excellent adhesive properties. But this These materials are generally very hard and impermeable to nutrients essential for tissue healing. , its byproducts formaldehyde and cyanide are toxic to tissue cells. be. Furthermore, this material is not eroded by living organisms, so it must be removed afterwards. obtain. This substance is used in a small number of surgical procedures, for example to close small perforations. However, the US Federal Food and Drug Administration has not approved their use. Furthermore, these Because of its essentially plastic-like properties, it cannot be used to close incisions. do not have.

In the 1970s, European researchers discovered that human fibrinogen and bovine We have developed an adhesive made of thrombin. This is available in Europe as Ti5seel'. (In+muno Ag1 from Vienna, Austria).

This commercially available product is obtained from pooled human serum, so there is a possibility of viral infection. , which limits the desirability of adhesives. This adhesive is multi-component and safe. It is difficult to prepare it to have a certain adhesive property, and one of its components is When fibrinogen is used to bond living tissues together, it quickly Decompose into crabs.

In recent years, polyphenolic protein-like adhesives derived from molluscs have been developed. child Adhesives are two-component systems, difficult to prepare stably, and the resulting adhesive Gender fluctuates greatly.

Other surgical or medical adhesives have been reported in the patent literature. For example, US patent No. 4.035.334 contains two epoxyethyl-alphasia/acrylic poly-N-vinyl ether and 1-4, bis(p-toluidino)-a Medical adhesives consisting of intraquinone have been described. This medical adhesive is first Although an improvement on the cyanoacrylates mentioned, they still require Requires the use of diisocyanate chemicals, which are mild to the tissue being joined. Acupuncture provides potentially toxic chemicals. Additionally, this polymeric material is eroded. It doesn't exist, so it has to be removed at some point. Furthermore, containing this adhesive Substances can chemically bind to tissue and cause damage to that tissue.

Collagen materials are widely considered to be useful for medical applications. For example, No. 4,760,131 describes fibrous collagen, heparin, and granulated blood. Wound healing compositions containing platelet or platelet release is listed.

However, this composition is intended to act as a wound dressing. In other words, this The composition has no adhesive properties and cannot be considered a wound or incision occlusive agent. Information The reported medical adhesive contains chemically crosslinked gelatin. This is 1 It was extensively studied in the mid to late 1960s. For example, October 1966 "Using Cross-Linked Gelatin - Liver" in Futae, pp. 857-861. Tissue Adhesives for Controlling Bleeding from the Viscera and Kidneys” Yo. It should be noted that this material is not intended for wound closure. difference Furthermore, the reported method uses gelatin-resol cross-linked with formaldehyde. A nol mixture is used as an adhesive.

The use of medical substances containing or producing formaldehyde is impractical.

The purpose of the invention is to enable closure of wounds or surgical incisions and augmentation of sutures. Or to provide a medical adhesive that enables an alternative. Furthermore, the present invention The purpose is to promote wound healing and not create local pressure on the incision or wound It is to provide adhesive. A further purpose is that its adhesive strength decreases rapidly so rapidly that the tissue to be joined cannot be manipulated into the desired shape without It does not harden and does not require complicated preparation immediately before its use. Our goal is to provide the best adhesives. Furthermore, it is an object of the present invention to The objective is to provide an adhesive through which nutrients essential for healing can pass.

Nona: 8 Figure 1 shows an electron scan of a cross-section of a rabbit corneal tissue sample bonded with the adhesive of the present invention. This is a microscopic photograph.

Figure 2 shows rabbit horn bonded with the adhesive of the invention containing 12.5% by weight of collagen. 1 is a cross-sectional scanning electron micrograph of a membrane tissue sample after separation.

Figure 3 shows a cross section of a rabbit corneal tissue sample adhered with a 20 wt% collagen solution. This is a scanning electron micrograph.

Five days gone! And The present invention can be used as a material useful for sealing wounds and/or surgical incisions. The present invention relates to medical adhesives that can be used as adhesives. The composition essentially consists of collagen or gelatin. consists of an aqueous solution of This aqueous solution has: 1) a melt index of 33°C to 60°C; 2) when heated to a temperature higher than its melt index temperature. 3) the material flows easily, has a viscosity that allows for easy handling, and 3) adheres to tissue.

In general, one way in which these properties can be achieved is by using collagen/gelatin. One method is by adjusting the crosslink density of chin. collagen in aqueous solution or By varying the concentration of the total amount of gelatin, the viscosity can be adjusted to some extent. General In general, this concentration is in the range of 5 to 30% by weight.

The present invention provides adhesive compositions with a set of properties that can be uniquely applied to particular medical procedures. provide something. Because cross-linked and non-cross-linked collagen or gelatin By blending, specific viscosity, adhesion, melt index temperature, and hardness can be achieved. temperature, and a substance with permeability can be supplied. The present invention is a medical adhesive useful for closing wounds or surgical incisions. Main group The composition is essentially an aqueous solution of naturally occurring collagen or purified gelatin. It will be. This aqueous solution has the properties described below. That is, 1) melt index The temperature range is from 33°C to 60°C, preferably from 35°C to 45°C. The temperature is preferably within the range of 40°C to 45°C. 2) The melt A substance that has a viscosity that allows it to flow easily when heated above its index temperature. do. and 3) can adhere to tissue. These properties vary to a certain extent at a given concentration. Obtained by cross-linking natural collagen to the highest degree.

The degree of crosslinking can be adjusted by adjusting the crosslinked collagen or gelatin solution and the relatively crosslinked collagen or gelatin solution. Natural collagen or gelatin (a process that increases the crosslinking density of the material) By mixing with a solution of collagen (extracted and purified without going through the process) or gelatin This can be best achieved by:

Increasing the crosslink density of collagen or gelatin can be achieved in many ways. Ru. For example, UV irradiation increases the crosslink density of collagen or gelatin. It can be done. It can also be crosslinked by a thermal crosslinking method. For example, dry collagen solution and then at a specific temperature above 100° C. to produce a specific crosslinking density. It can be heated for a certain period of time. After this step, cross-linked collagen is then added to the solution. I can do it. This solution has a higher melt index than non-crosslinked collagen; Its viscosity at temperatures higher than its melt index temperature is slightly higher than that of non-crosslinked collagen. It exhibits the same properties as a non-crosslinked natural collagen solution, except for being higher.

For the purpose of this application, melt index temperature is defined as collagen or gelatin temperature. Defined as the midpoint temperature at which a solution changes from a relatively non-fluid state to a fluid state . In reality, this solution flows very easily from a very thick, non-flowable substance. (Typically, the solution is heated 10° below its melt index/ex temperature. When heated at °C, the viscosity of the solution is 50,000 cm ).

This transition occurs over a relatively narrow temperature band (typically less than about 8 to 10°C).

This phenomenon in collagen solutions is due to the fact that when the solution temperature increases, the triple layer of collagen This is thought to occur because the internal hydrogen bonds of the molecule are reduced, causing the molecule to unwind. . Therefore, the collagen molecule loses many of its secondary structural properties and becomes more fluid. . By increasing the density of covalent crosslinks between strands, triple The integrity of the wax can be increased and its melt index can be raised.

The collagen material used in the present invention can be purified from any source. death However, it is preferred that the collagen material is type I collagen. collagen A preferred source of is porcine sclera. Similarly, gelatin comes from many sources. I can do it.

A typical method of obtaining such materials is by processing the sclera of animal eyes. . The eye is completely stripped of its lining, residual tissue is removed, and the sclera is cleaned and separated.

The separated sclera was then cut into small pieces, further rinsed with distilled water, and washed with saturated sodium sulfate. Transfer to a solution of alkali hydroxide in lium solution. This solution typically removes the sclera. Digests over a long period of time (typically 48 hours). This solution is then decanted The tissue is washed with water to within a range of 6.0 to 7.0 (typically with boric acid). Neutralize. The scleral tissue is then washed with diluted water to remove acid counterions. Ru. This tissue is then added to a solution of a 0.5 to 1.0 molar organic acid and allowed to cool. Leave it undisturbed for up to 3 days. This solution was homogenized, centrifuged, and then The mixture is allowed to stand at a low temperature for several days, and then the remaining particulate matter is removed by filtration. Then the solution The sample is dialyzed against a buffer system that brings the pH between 4.5 and 7.5.

Adhesive properties: its adhesive strength, viscosity, melt index temperature, and transparency. Transactivity can be tuned by adjusting adhesive crosslink density, concentration, and tissue source. It can be saved. According to the invention, therefore, specific further properties for specific medical procedures are provided. An adhesive having the following properties may be provided.

One way to control the crosslink density of adhesives is to use densely crosslinked collagen or Blend a solution of gelatin with a solution of uncrosslinked collagen or gelatin. One way to do this is to Typically, collagen or enzymes in medical adhesives The total amount of latin ranges from 5 to 35% by weight of the total solution.

The ratio of densely crosslinked material to relatively uncrosslinked material is between 10:1 and 1. : It can vary up to 1. In thermal theory, this ratio depends on the degree of crosslink density in a densely crosslinked material. Dependence is likewise recognized.

The starting purified collagen solution material is in a somewhat cross-linked state. However, it can be used as a relatively uncrosslinked collagen solution. Basic The concept is to blend two solutions to determine their viscosity and melt index temperature. to obtain two solutions with different crosslink densities in order to obtain exact solution properties. It is in.

The medical adhesive of the present invention also comprises cross-linking of a single collagen or gelatin solution. It can also be obtained by controlling the degree of and using this solution as a medical adhesive. Can be done. Currently, the most convenient approaches are collagen or gelatin The solution is to blend it. In either case, the melt index temperature Final adhesion to ensure invariance from one sample to the next. It is critical to homogenize the composition.

The present invention is useful as a medical adhesive in a wide variety of surgical procedures. this surgery Treatments include, for example, cataract surgery, epikeratophore surgery, corneal trepanation, corneal transplantation, and and other ophthalmic surgical procedures.

In particular, the adhesive is believed to be useful for removing cataracts.

Recent trends in cataract surgery, especially the incisions used, are smaller than ever before. The use of adhesive may be more effective if the tilt is performed more posteriorly than previously. Seem. These techniques provide an incision that is shaped like the one on the left and is loose to close. No compression force is required. This adhesive also helps prevent tears or lacerations in the posterior capsule. It can be used intraocularly in the extraction of cataracts with complex coloration.

The adhesive is also useful in corneal transplants. The standard methods currently used are Up to 16 sutures are used. This adhesive reduces the number of sutures. This may reduce the degree of post-operative astigmatism and enable faster visual recovery.

Lamellar keratoplasty is performed to treat certain eye conditions for which a full-thickness corneal transplant is not indicated. This is a partial-thickness corneal transplant, in which the use of this adhesive may be effective. layered excision By layering this adhesive along the area, it is possible to close the wound better than currently possible. It may become possible to do so. The advantages of the adhesive described above also apply to retinopexy and ocular It can also be used in other surgical procedures such as plastic surgery.

This adhesive is first developed at a melt index temperature that allows the adhesive to flow easily. It is used by heating to .

This material is then placed on the surface of the tissue to be adhered, and the tissue is then positioned appropriately. let When this adhesive cools to body temperature, it thickens and becomes an effective adhesive.

In addition to acting as an adhesive, this substance can also be used to deliver drugs. Ru. Drugs are incorporated into formulations to help regulate the rate of healing at the wound site. It can be done. For example, growth factors can be added to the adhesive to accelerate healing.

Alternatively, cortistearoids or antimetabolites Factors such as antibiotics can be added to the adhesive to slow wound healing. anti Biological substances can be added to the adhesive as well. By using this adhesive with drugs, The drug can be precisely delivered to the wound site. Therefore, use the drug in lower doses obtain.

Adhesives of the invention may also contain small amounts of other biopolymers. living organisms like this Polymers include, for example, chondroitin (1ns), luronic acid, and glycosaminoglycans such as keratin sulfate, or dext Synthetic analogs such as orchids may be mentioned.

Although the following examples illustrate certain aspects of the invention, It does not fully explain the scope.

110° A 10% by weight solution was prepared from porcine sclera collagen. Dry some of the solution, Heating at 145° C. for 60 minutes produced a densely crosslinked material. similar to another part The sample was treated at 145°C for 15 minutes to provide a relatively uncrosslinked sample. did.

5% by weight of relatively uncrosslinked material and 95% by weight of densely crosslinked material. The mixture was prepared at various total solids concentrations (12.5 wt.% colloid). -gen, 15 wt% collagen, 20 wt% collagen, and 30 wt% collagen -gen).

Cut the rabbit corneal tissue immediately after collection to make a standard size sample (approximately 5 mm x lo ++m) and then these were preheated from about 38°C to above 45°C. The adhesive composition was used to bond and then cooled. The bond strength of the sample is determined using this set. Durham measurements were taken at specified times after the woven samples were first bonded with the adhesive.

As shown in Table 1, the following results were obtained. This result is based on the standard area of the sample. Recorded in Durham.

Table”- Bond strength (ream/standard membrane) 30.8 6.10.

Me L friend [ri1] L The medical adhesive described in Example 1 with a total solid weight of 12.5% was applied to a rabbit corneal tissue sample. used for gluing samples. Adhesive ability of adhesives using scanning electron microscopy Photographs of the samples were taken at various stages of testing. Figure 1 shows the adhesive 2 of the present invention. Bonded tissue sample 1.3 is shown.

For samples adhered with 15 wt% collagen adhesive, the attached tissue was All I could see was a kana split. This means that the strength of the tissue is greater than the strength of adhesive bonds. Show that you listened.

Samples bonded with 20% collagen adhesive showed that the adhesive failure of the sample was At the time, significant tissue damage occurred.

Figures 2 and 3 show 12.5 wt% collagen and 20 wt% collagen, respectively. SEM of a fractured sample using a gen. According to Figure 2, the adhesive failure point was found in adhesive layer 4, and tissue 5 showed only slight division. Ru. The magnification of Figures 2 and 3 is 0, which is higher than the magnification used to create Figure 1. According to FIG. 3, when a 20% by weight collagen adhesive is used, the adhesive failure point 8 is in the tissue area. It can be seen that it was in the sample 4 and 6. These results are based on the 20 wt. When using Lagen adhesive, the strength of the adhesive bond was higher than that of the tissue. show.

These results indicate that adhesive strength can be engineered for specific medical applications. it is obvious.

K plate owner Dried collagen made from a 1% by weight solution of porcine scleral collagen as described in Example 1 The film was cut into small pieces and heated at 60°C for 60 minutes without stirring. was used to prepare a 10% by weight collagen solution in distilled water. This solution After casting and drying, the resulting film was heated at 145°C for 80 minutes to induce crosslinking. I let it happen. Next, the crosslinked film was crushed into a coarse powder and further heated to 65°C. A 27% dry weight solution was prepared by heating and homogenizing in a tissue grinder. The molten solution was then kept above its melting temperature. However, it was degassed by centrifugation and packed into an LCC syringe.

Once placed in the syringe, the adhesive cools and becomes solid, allowing it to be reheated and used as a surgical adhesive. Can be used as an adhesive.

Good supervisor soil The adhesive packed in the syringe prepared in Example 3 was heated to 50°C for 30 minutes in a water bath. Ru. This adhesive is then used to repair the cataract extraction done below the flap of the scleral tissue. Seal the posterior incision. Push the molten glue into the incision, then glue and position the valve over the incision. Furthermore, this adhesive is cooled and solidified. until it solidifies or has a curing temperature below its melt index temperature. Manipulate the valve placement with forceps.

11ti Commercially available 300 bloom gelatin derived from pig skin was mixed with water and gelatin. Add to distilled water in an amount of 10% based on the total weight of the sample.

This is heated at 60°C with stirring to form a solution, which is then poured into a cast iron. Dry. The resulting film was then heated to 145°C for 80 minutes to effect crosslinking. The film is cooled and ground into a coarse powder. crosslinked ze By heating the latin powder to 65°C with stirring, Used to prepare 0% by weight gelatin solution. The resulting solution was prepared as described in Example 4. The sea urchin is degassed, packed into a syringe, and used as a surgical adhesive. final sterile organism Two methods are used to generate adhesive products. Both procedures require sterile product production. A series of aseptic processes are used to prevent the introduction of any viable microorganisms. I will do it. The first method is intermittent sterilization.

Producing bioadhesive formulations by reconstituting thermally crosslinked powders at 145 °C using sterile filtered water After brewing, fill it into a sterilized syringe and put it in a beer pouch. hes). All steps are carried out under aseptic conditions in a laminar flow hood. Performed by gloved and gowned personnel. This method works best for 3 consecutive days. Involves exposing the final product to heat from 80°C to 100°C for 30 minutes in humid conditions. It is a partial method of sterilization.

dish with salt Using the adhesive obtained in the present invention, tissue samples were prepared by the method used in Example 1. combined. The adhesive has a solids content of 20% by weight and a melt index temperature of The temperature is 35°C. Heat this adhesive to approximately 50°C and apply it to the surface of the tissue to be bonded. application and then contacting the tissue sample. The sample is also Ti5see1r Coupling was carried out using a method according to the instructions indicated by the manufacturer. Then, connect By applying a load to the sample that causes displacement at the attachment site, Adhesive bond strength was assayed. The bond strength is the weight required to break the sample. Ta. The binding strength of a sample is measured at a fixed time after its preparation and is expressed in Durham. Ta. The results are shown in Table 2.

Master of costumes Comparative bonding strength (reram/marker $ chimple) From this result, the bonding strength of this adhesive It can be seen that the strength is significantly higher than that of the commercially available Ti5seel' medical adhesive.

Copy and translation of written amendment) Submission (Article 184-7, Paragraph 1 of the Patent Law)

Claims (16)

[Claims] 1. Adhesive compositions suitable for surgical applications, consisting essentially of the following components: A biopolymer selected from the group of biopolymers consisting of collagen and gelatin. - an aqueous solution with a melt index temperature in the range of 33°C to 60°C Aqueous solution. 2. 50,000 centipots at a temperature 10°C above the melt index temperature. 2. The adhesive composition of claim 1, having a viscosity lower than that of azu. 3. The melt index temperature of the aqueous solution is in the range of 35°C to 45°C. The adhesive composition according to claim 1. 4. The critical melt index temperature properties of the composition polymer and a non-crosslinked biopolymer. The adhesive composition according to claim 1. 5. According to claim 4, the densely crosslinked biopolymer is obtained by a thermal crosslinking method. Adhesive composition as described. 6. The non-crosslinked biopolymer comprises 50% by weight of the total solids content of the composition. The adhesive composition according to claim 4. 7. Claimed that the non-crosslinked biopolymer comprises 25% by weight of the total solids content of the composition. The adhesive composition according to claim 4. 8. wherein said non-crosslinked biopolymer comprises 20% by weight of the total solids content of said composition. The adhesive composition according to claim 4. 9. The non-crosslinked biopolymer comprises 15% by weight of the total solids content of the composition. The adhesive composition according to claim 4. 10. The non-crosslinked biopolymer comprises 5% by weight of the total solids content of the composition. The adhesive composition according to claim 4. 11. The critical melt index temperature characteristic is similar to that of densely cross-linked gelatin. Claimed to be obtained by blending with relatively uncrosslinked gelatin. Item 1. Adhesive composition according to item 1. 12. Claims wherein the total biopolymer content in the solution ranges from 5 to 30% by weight. Item 1. Adhesive composition according to item 1. 13. The total biopolymer content in said solution is in the range of 20 to 30% by weight. The adhesive composition according to claim 1. 14. contacting the adhesive composition with at least one surface of the wound; A method of closing a wound, the adhesive composition comprising purified naturally derived collagen or is an aqueous solution consisting essentially of a biopolymer selected from polyester and gelatin and water. The solution has a melt index temperature between 35°C and 45°C, and the melt Viscosity is less than 50,000 centipoise when heated 10°C above index temperature Low, way. 15. Wound treatment comprising contacting at least one surface of a wound with a composition A method for promoting a biopolymer collagen of natural origin in water, the composition comprising: The composition consists essentially of a solution in which cultured epithelial cells are dispersed. The melt index is between 35°C and 45°C, and the temperature is 10° below the melt index temperature. A method in which the viscosity is less than 50,000 centipoise when heated at °C. 16. a wound comprising contacting a composition with at least one surface of the wound. A method of promoting healing, the composition comprising: a purified naturally derived biopolymer; an aqueous solution consisting essentially of , water, and growth factors; The temperature is between 35℃ and 45℃, and the temperature is 10℃ above the melt index temperature. a method in which the viscosity is less than 50,000 centipoise when