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WO1997042986A1 - Procedes et produits permettant de bloquer de maniere etanche une fuite de fluide d'un tissu - Google Patents

Procedes et produits permettant de bloquer de maniere etanche une fuite de fluide d'un tissu Download PDF

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Publication number
WO1997042986A1
WO1997042986A1 PCT/US1997/008124 US9708124W WO9742986A1 WO 1997042986 A1 WO1997042986 A1 WO 1997042986A1 US 9708124 W US9708124 W US 9708124W WO 9742986 A1 WO9742986 A1 WO 9742986A1
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WIPO (PCT)
Prior art keywords
tissue
collagen
protein
polymerizable
covering
Prior art date
Application number
PCT/US1997/008124
Other languages
English (en)
Inventor
Dale P. Devore
Charles Putnam
James M. Pachence
Original Assignee
C. R. Bard, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by C. R. Bard, Inc. filed Critical C. R. Bard, Inc.
Priority to EP97925559A priority Critical patent/EP0901383A1/fr
Publication of WO1997042986A1 publication Critical patent/WO1997042986A1/fr

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Classifications

    • 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
    • A61L24/10—Polypeptides; Proteins

Definitions

  • Collagen the major connective tissue protein in animals, possesses numerous characteristics not seen in synthetic polymers. Characteristics of collagen often cited include good compatibility with living tissue, promotion of cell growth, and abso ⁇ tion and assimilation of implantations. Natural collagen fibers, however, are not very useful in their native form due to intermolecular crosslinking, insolubility, rigid triple-helical structure, and immunogenicity. Various methods and materials have been proposed for modifying collagen to render it more suitable as a biomedical adhesive. In many instances, the prior modified collagen-based adhesives suffer from various deficiencies which include crosslinking/polymerization reactions that generate exothermic heat, long reaction times, and reactions that are inoperative in the presence of oxygen and physiological pH ranges. Moreover, many of the prior art modified collagen-based adhesives contain toxic materials, hence rendering them unsuitable for biomedical use.
  • U.S. Patent No. 3,438,374 discloses a general matrix as a bioadhesive.
  • the material was useful in some applications, the material did not work very well or failed in applications where the material was subjected to substantial pressures or was used to fill a substantial gap in tissue (as opposed to adhering two pieces of tissue together).
  • the adhesive was found not to be effective in sealing divided bronchial stumps (which is characterized by large gaps in tissue) and also was not effective in sealing blood vessels (which involve elevated fluid flow at high pressures).
  • a more recent advance in the field is the use of collagen monomers derivatized with an acylating agent or a sulphonating agent and polymerized with an appropriate polymerization initiator such as a chemical oxidant, ultraviolet irradiation, a suitable oxidative enzyme or atmospheric oxygen.
  • an appropriate polymerization initiator such as a chemical oxidant, ultraviolet irradiation, a suitable oxidative enzyme or atmospheric oxygen.
  • these materials were shown to be biologically compatible, and their use was proposed for a number of biological applications. In particular, it was disclosed that these materials be used as adhesives to hold two tissues together or to hold a synthetic lenticule to an eye. They also were disclosed as useful in the formation of flexible films which could be used as a lap following surgery to prevent adhesion, as a synthetic tympanic membrane, as a substitute facial tissue, and as a wound dressing component. It was stated that the adhesive also may be used to seal an incision following cataract removal. The material was not proposed for use in sealing fluid leaks in
  • the invention provides methods and products for sealing a fluid leak in a tissue.
  • the various methods and products permit one or more of the following advantages: (1 ) the ability to seal quickly, in some instances under 30 seconds; (2) the ability to be immediately exposed to elevated pressures of at least 50 mm Hg, and in some instances, above 125 and even above 250 mm Hg; (3) the ability to be immediately exposed to pulsating fluid upon sealing, particularly at high pressures; (4) the ability to plug substantial gaps in tissue, as opposed to adhesively binding tissues in contact with one another, to one another; and (5) the ability to seal body fluids in bodily conduits.
  • a method for sealing a fluid leak in a tissue is provided.
  • a polymerizable protein is applied to the tissue to form a covering for an opening in the tissue, which opening creates a fluid leak in the tissue.
  • the covering then is exposed to a initiator so as to polymerize the covering in situ, so as to attach the covering to the tissue and so as to seal the opening from fluid leakage.
  • the invention is useful in connection with sealing anastomoses and suture lines for blood vessels.
  • the invention also is useful for sealing airholes in lung injuries, including injuries to parenchymal and bronchiole tissue (especially bronchiole stumps).
  • the foregoing are examples of tissues that act as conduits for fluid which pulses through the conduits at elevated pressures.
  • the polymerization can be carried out in less than 3 minutes. In certain embodiments, the polymerization preferably is carried out in less than 30 seconds, more preferably between about 10 and 30 seconds and most preferably in about 15 seconds.
  • the polymerizable protein is a viscous fluid, and the polymerization is carried out at between a pH of 6.0-9.0, more preferably 7.8-8.8, and most preferably between about 8.2 and 8.5.
  • the polymerizable protein is in a solvent which includes an initiator.
  • the initiator can be sodium persulfate, sodium thiosulfate, ferrouschloride tetrahydrate, sodium bisulfate or an oxidative enzyme.
  • the initiator is sodium persulfate, and the sodium persulfate is present in the solvent collagen mixture in a range of 0.01 M to 0.2M.
  • the initiator is a photochemical initiator. It is preferred that the irradiation used to initiate polymerization is a light band having a wavelength between about 250 and 550nm.
  • the polymerizable protein is selected from the group consisting of collagen, albumin, gelatin, elastin, and fibrinogen.
  • the protein is derivatized with an agent that enhances the solubility of the protein under physiological conditions.
  • the polymerizable protein is collagen derivatized with an acylating agent and/or a sulfonating agent.
  • the method also includes the step of applying a primer to the tissue surface prior to applying the polymerizable protein to the tissue.
  • the primer enhances the strength of the tissue seal.
  • the primer is a dilute solution of collagen having a concentration of 1-10 mg/ml. In a preferred embodiment the concentration of the dilute collagen solution is 4-8 mg/ml.
  • the primer has a pH of 6.0-9.0. In a preferred embodiment the pH is 8.2-8.5.
  • a method for sealing a fluid leak in a tissue is provided.
  • a primer is applied to the tissue to form a primer layer and then a polymerizable protein is applied to the primer layer to form a covering for an opening in the tissue, which opening creates a fluid leak in the tissue.
  • the covering then is exposed to a initiator so as to polymerize the covering in situ, so as to attach the covering to the tissue and so as to seal the opening from fluid leakage.
  • the polymerization can be carried out in less than 3 minutes. In certain embodiments, the polymerization preferably is carried out in 5 less than 30 seconds, more preferably between about 10 and 30 seconds and most preferably in about 15 seconds.
  • the polymerizable protein is a viscous fluid, and the polymerization is carried out at between a pH of 6.0-9.0, more preferably 7.8-8.8, and most preferably between about 8.2 and 8.5.
  • the polymerizable protein is in o a solvent which includes an initiator.
  • the initiator can be sodium persulfate, sodium thiosulfate, ferrouschloride tetrahydrate, sodium bisulfate or an oxidative enzyme.
  • the initiator is sodium persulfate, and the sodium persulfate is present in the solvent collagen mixture in a range of 0.01 M to 0.2M.
  • the initiator is a photochemical initiator. It is preferred that the irradiation used to initiate polymerization is a 5 light band having a wavelength between about 250 and 550nm.
  • the polymerizable protein is selected from the group consisting of collagen, albumin, gelatin, elastin, and fibrinogen.
  • the protein is derivatized with an agent that enhances the solubility of the protein under physiological conditions.
  • the polymerizable protein is collagen derivatized with an 0 acylating agent and/or a sulfonating agent.
  • the primer is a dilute solution of collagen having a concentration of 1-10 mg/ml. In a preferred embodiment the concentration of the dilute collagen solution is 4-8 mg/ml. In another embodiment the primer has a pH of 6.0-9.0. In a preferred embodiment the pH is 8.2-8.5. 5 According to another aspect of the invention, a biosealant is provided.
  • the biosealant is a polymerizable protein containing an initiator in an amount so that the polymerizable protein can be polymerized in less than 30 seconds when exposed to an appropriate light source.
  • biosealant is provided.
  • This biosealant is a polymerizable protein containing an initiator and that can be light polymerized in 0 less than 3 minutes and that after exposure to light for between 15 and 180 seconds, withstands at least 300 mm Hg when applied to and polymerized upon a blood vessel.
  • biosealant is a polymerizable protein in a solvent containing an acylating initiator in an amount of at least 0.1M, and preferably between about 0.05M and 0.2M sodium persulfate.
  • a primer is provided.
  • the primer is an adhesive protein in a dilute solution.
  • the adhesive protein is collagen and the collagen is diluted in a solution of 0.1 M phosphate buffer at a concentration of 1 -10 mg/ml.
  • concentration of the dilute collagen solution is 4-8 mg/ml.
  • the primer has a pH of 6.0-9-0.
  • the pH is 8.2-8.5.
  • the invention also includes kits which include two or more of any of the foregoing elements of the tissue sealing compositions of the invention.
  • derivatized collagen may be provided in one container and sodium persulfate can be provided in another container, both present in amounts whereby upon mixing, a polymerizable protein useful according to the invention is provided.
  • both the derivatized protein and the sodium persulfate could be provided as lyophilized preparations in one or more containers, and a solvent in another container whereby the polymerizable protein solutions of the invention can be reconstituted upon mixing.
  • a protein derivatized with an agent that results in the collagen being soluble under physiological conditions can be supplied in one container and an initiator such as sodium persulfate in a buffered solution can be provided in another container, wherein the materials are present in relative amounts such that when mixed according to the instructions the sodium persulfate is present in an amount of between 0.05M and 0.2M and the final pH of the mixture is between 8.2 and 8.5.
  • the kit may also include a primer in a syringe or other container.
  • a method for sealing tissue leaks involves the steps of applying a primer to the tissue and applying a protein based adhesive on top of the primer.
  • the primer is a dilute solution of collagen.
  • the protein based adhesive is a polymerizable protein and the method further includes the step of exposing the polymerizable protein to an intiator in situ to polymerize the proteins.
  • the protein based adhesive is selected from the group consisting of fibrin glue and modified collagen based adhesives.
  • the invention involves the use of polymerizable proteins.
  • the proteins useful in the invention include collagen, albumin, gelatin, elastin and fibrinogen.
  • the foregoing materials, particularly when prepared according to the preferred embodiments of the invention, are biologically compatible.
  • biologically compatible refers to polymerizable protein and polymerized products which are incorporated or implanted into or placed adjacent to the biological tissue of a subject and, more particularly, remain intact for a sufficient period of time to permit healing and do not induce an immune response or deleterious tissue reaction after such incorporation or implantation or placement.
  • the protein may be derived from virtually any source, including purified from natural sources, produced recombinately, etc.
  • the polymerizable protein is applied to tissues in situ to form a covering over an opening which creates a fluid leak in the tissue.
  • the tissue includes vascular tissue, lung tissue, bladder tissue, bowel tissue and dura mater.
  • the tissue is a soft tissue within the body, not normally exposed, and which is subjected to pulsating fluid pressures such as vascular tissue and lung tissue.
  • the tissue is characterized by an opening that forms a substantial gap.
  • the pressure of the blood on the artery is about 120 mm Hg in a normal individual. This may be higher or lower, depending upon the individual and the circumstances of the individual.
  • a vascular artery requires a seal resulting from a suture line or an anastomosis, it is believed that the seal must be capable of withstanding about 250 mm Hg pressure.
  • the sealant material Upon forming the seal, the sealant material will be exposed immediately to pulsating, fluid flow which will exert forces both on the bond between the sealant material and the tissue and on the sealant material itself. The sealant material, therefore, must be able to withstand such forces immediately and for an extended period of time (that is, long enough for normal healing to take place).
  • the materials of the present invention have demonstrated the ability to seal vascular tissue immediately upon polymerization without leakage when subjected to pressures in excess of 250 mm Hg, in excess of 300 mm Hg and even up to 500 mm Hg.
  • parenchymal tissue and bronchiole tissue can be sealed with the methods and products of the invention.
  • Parenchymal tissue repair typically involves sealing relatively small openings, whereas bronchiole tissue repair can involve sealing of substantial openings in tissue.
  • the materials of the invention, immediately upon polymerization can seal both parenchymal tissue injury and bronchiole stumps, which are exposed to immediate and pulsating pressures on the order of 45 mm Hg. Sealants used in repairing the lung also must last for periods of weeks to permit proper healing of lung tissue. Again, the materials and methods of the invention work to form seals which permit adequate healing without leakage.
  • the polymerizable proteins of the invention typically are applied as a viscous fluid. Particularly in connection with soft tissue and tissue with interstices, it is preferable to massage the viscous fluid onto the surface of the tissue to ensure adequate coverage of the surfaces of the tissue surrounding the openings being covered and to ensure covering the openings, thereby permitting solid, leak proof attachment of the covers to the tissue.
  • the gel containing the polymerizable protein may include an initiator for polymerization.
  • the initiator is unable to cause polymerization of the polymerizable protein to any meaningful extent until activated by an initiator-activating agent (e.g. sodium persulfate activated by UV light).
  • the polymerizable protein may be derivatized to enhance solubilization at physiological conditions, as mentioned above.
  • the polymerizable proteins also can be derivatized to enhance polymerization.
  • Suitable derivatives for enhancing solubilization are acylating agents and sulfonating agents.
  • the preferred polymerized protein is collagen derivatized with such agents.
  • the solution, suspension, or viscous fluid containing the polymerizable protein may also contain native insoluble fibers such as insoluble collagen fibers. Such fibers can enhance the strength of the material, can effect cell growth on to the material and can effect the hemostatic properties of the material.
  • the preferred protein is collagen.
  • the type of collagen useful to form a biologically compatible collagenous reaction product with the sealant properties of this invention is selected preferably from the following groups: purified Type I collagen, Type IV collagen and Type III collagen, or a combination of any of the foregoing.
  • Preferred as a collagen starting material is purified Type I collagen.
  • Type I collagen is ubiquitous and readily extracted from animal tissues such as dermis and tendon. Common sources are calf hide, tendon and steer hide.
  • U.S. Pat. No. 4,969,912 "Human Collagen Processing and Autoimplant Use", describes unique methods to disperse and solubilize human tissue. The preferred source is derivatized as shown in the Examples.
  • telopeptide telopeptide
  • a variety of collagen solubilization procedures can be used to prepare soluble collagen solutions useful for the instant invention.
  • Native collagen is liberated from non-collagen connective tissue constituents (lipids, sugars, proteins, etc.) and isolated after subjecting it to proteolytic enzymatic treatment by an enzyme other than collagenase. Suitable proteolytic enzymes include pronase and pepsin.
  • the enzymatic treatment removes portions of the immunogenic non-helical portions of native collagen (telopeptide) and provides a monomeric collagen material which is soluble in dilute acidic aqueous media.
  • a solution containing crude solubilized collagen is then subjected to a series of treatments to purify the soluble atelopeptide collagen from insoluble collagen, protease and non-collagen products resulting from the proteolytic enzymatic procedure.
  • Conventional method for preparing pure, acid soluble, monomeric collagen solutions by dispersing and solubilizing native collagen are described, for example, in U.S. Pat. Nos. 3,934,852; 3,121,049; 3,131,130; 3,314,861 ; 3,530,037; 3,949,073; 4,233,360 and 4,488,91 1.
  • a method for preparing a collagen solution is provided in the examples that follow.
  • Suitable acylating agents for use in the instant invention include aliphatic, alicyclic and aromatic anhydrides or acid halides.
  • Non-limiting examples of acylating agents include glutaric anhydride, succinic anhydride, lauric anhydride, diglycolic anhydride, methylsuccinic anhydride, methyl glutaric anhydride, dimethyl glutaric anhydride, succinyl chloride, glutaryl chloride, and lauryl chloride. These chemicals are available from Aldrich Chemical Company (Milwaukee, Wis.).
  • Preferred acylating agent for use in the present invention is glutaric anhydride.
  • An effective amount of an acylating agent is broadly from about 2.5 to 20% wt total collagen (an excess based upon moles required to react all free amines).
  • acylating agents having secondary reactive functionalities within their chemical structure are also useful for modifying protein monomers.
  • secondary functionalities include by way of non-limiting examples: epoxy, cyano, halo, alkenyl, and alkynyl.
  • Non-limiting examples of acylating agents bearing secondary functionalities include exo-3,6-epoxy-l,2,3,4-tetrahydrophthalic anhydride, methacrylic anhydride, 3,6-endoxo-3- methylhexahydrophthalic anhydride, and endo-3,6-endoxohexa hydrophthalic anhydride.
  • acylating agents are exo-3,6-epoxy-l,2,3,4-tetrahydrophathalic anhydride and methacrylic anhydride.
  • the secondary functionalities present in acylating agents can react covalently with amino acid residues under acylation conditions or during polymerization to enhance polymerization. . .
  • Useful sulfonating agents for the preparation of modified protein monomers of the present invention include aliphatic, alicyclic and aromatic sulfonic acids or sulfonyl halides.
  • Non-limiting examples of sulfonating agents for use in the present invention include anthraquinone-l ,5-disulfonic acid, 2-(chlorosulfonyl)-anthraquinone, 8-hydroxyquinoline sulfonic acid, 2-naphthalene-sulfonyl chloride, beta-styrene sulfonyl chloride and 2-acrylamido- 2-methyl-l -propane sulfonic acid.
  • the preferred sulfonating agent for preparing adhesive collagen materials is 3.5 dicarboxybenzenesulfonyl chloride. Such compounds, in non-toxic effective amounts, can be safely employed in collagen-based compounds for medical use as sealants.
  • An effective amount of sulfonating agent is broadly from about 2.5 to 20% wt total collagen.
  • the amount of acylating agent and sulfonating agent in total is preferably from about 2.0 to 20% wt total collagen.
  • Acylation of collagen is carried out at alkaline pH, for example, in the range from about 7.5 to 10.0, preferably from about 8.5 to 9.5, and more preferably at about pH 9.0.
  • the acylation reaction can be monitored by the decrease in pH.
  • the reaction is complete when pH remains stable.
  • the reaction can also be monitored by removing aliquots and measuring the free amine concentration of precipitated, washed collagen product.
  • the acylation reaction should be complete in about 5 to 90 minutes, preferably from about 20 to 40 minutes.
  • the reactions should be carried out at temperatures from about 4°C. to 37°C, preferably from about 4°C. to 25°C.
  • the reaction can be stopped by adjusting the pH to 12.0 for 2 minutes. This destroys residual, unreacted acylating agent.
  • the modified collagen is then precipitated by reducing the pH using hydrochloric acid, acetic acid, nitric acid, sulfuric acid, or other acid. The amount of acid must be sufficient to precipitate out the chemically derivatized collagen. Generally, precipitation occurs at a pH of between about 3.5 and 6.0, preferably between about 4.0 and 5.0.
  • the precipitate of reacted collagen which now contains substituent groups reacted with amine groups is recovered from the mixture using conventional techniques such as centrifugation or filtration. Centrifugation at about 3,000 to about 15,000 rpm for about 20 to 60 minutes, preferably from about 4,000 to 12,000 for about 20 to 30 minutes provides efficient recovery of the precipitate. After recovery, the precipitate is washed with deionized water and subsequently dissolved in a physiological solution, e.g., phosphate buffer (0.1M) at pH 7.2. It is often necessary to adjust the pH to the preferable range of 8.2 to 8.5 by addition of sodium hydroxide solution.
  • a physiological solution e.g., phosphate buffer (0.1M) at pH 7.2. It is often necessary to adjust the pH to the preferable range of 8.2 to 8.5 by addition of sodium hydroxide solution.
  • the solution is generally filtered by conventional filtering means, i.e., a 5 micron filter, and then centrifuged to remove air bubbles.
  • filtering means i.e., a 5 micron filter
  • the resulting solution containing chemically modified collagen monomers exhibits a viscous consistency and varying degrees of transparency and clarity depending on the extent of acylation and on the state of solubility of the starting collagen material.
  • the extent of acylation determines the biological stability of the resultant sealant. Complete acylation, reaction with all available free amines, produces a collagen composition with desirable solubility. In some cases the acylation reaction produces desirable amounts of moieties that are helpful in adhering the material to tissue.
  • the biological stability of resultant sealants is affected by controlling the extent of acylation. The greater the acylation, the less stable is the polymerizable material, generally.
  • the extent of acylation may be modulated by varying the amount of acylation agent, the pH, the temperature and the time of the reaction. In addition, the method of addition of the acylating agents will affect the reaction. Reactions are generally slower if the acylating agent is added as a solid or powder rather than as a solution.
  • the chemically modified collagen solution thus obtained is subsequently subjected to polymerization or crosslinking conditions to produce the polymerized collagen composition of the present invention.
  • Polymerization may be carried out using irradiation, e.g., UV, gamma, or fluorescent light.
  • UV irradiation may be accomplished in the short wave length range using a standard 254nm source of UV. It also preferably is accomplished using a broader range light source such as 250-550 nm light source (EFOS, Model Novacure, 100 ss+ Missisauga, Ontario, CA).
  • Excess UV exposure will begin to depolymerize the collagen polymers. Polymerization using gamma irradiation can be done using from 0.5 to 2.5 Mrads. Excess gamma exposure will also depolymerize collagen polymers. Polymerization in the presence of oxygen requires the addition of an initiator to the fluid prior to exposure.
  • initiators include sodium persulfate, sodium thiosulfate, ferrous chloride tetrahydrate, sodium bisulfite and oxidative enzymes such as peroxidase or catechol oxidase. When initiators are employed, polymerization occurs in 10 seconds to 3 or more minutes, preferred ranges depending upon the polymer selected and tissue being treated.
  • Preferred as a polymerizing agent is UV irradiation.
  • Collagen products containing methacrylic acid polymerize spontaneously in air. This polymerization can be accelerated under UV irradiation in the absence of oxygen.
  • the foregoing discussion is meant to be a general teaching relating to the preparation of polymerizable collagen. The most preferred embodiments are detailed in the examples below. In general, the exact composition will depend upon the particular tissue being treated and the particular polymer selected. In connection with lung tissue, a concentration of derivatized collagen of between 15 and 50 mg/ml is preferred, most preferably the concentration being between 20 and 25 mg/ml.
  • the concentration of collagen is preferably between 20 mg/ml to 90 mg/ml, most preferably between 40 mg/ml to 80 mg/ml. In general, collagen concentrations will beneficially range between 5 mg/ml (5%) to 100 mg/ml (10%).
  • a conventional plasticizer to the viscous fluid, such as glycerol, sorbitol, manitol, erythritol, xylitol, polyethylene glycol etc.
  • Compositions can include the addition of collagen fibers, preferably Avitene obtained from MedChem, Inc., a subsidiary of CR. Bard, Woburn, MA. These fibers are important for their tensile strength in such applications. They may be short (less than 850 microns), long (greater than 850 microns and less than 2 millimeters) or mixed short and long fibers. Their concentration is between 10 and 30 mg/ml and preferably 15-25 mg/ml.
  • the persulfate is present at between 0.01 M final concentration and 0.2M final concentration.
  • Useful levels include 0.3M stock - at 1.6 to 8.0 ml collagen (0.05M final), 0.5M stock - at 1.6 to 8.0 ml collagen (0.08M final) and 0.7M stock - at 1.6 to 8.0 ml collagen (0.116M final).
  • the final preparation preferably has a pH of 6.0-9.0, preferably 8.2-8.5.
  • the collagen and persulfate may be mixed together immediately prior to application (with pH adjustment occurring if persulfate is added in water and not in a buffered solution).
  • the collagen material may be applied to the tissue and then overcoated with persulfate, preferably in buffered solution.
  • the material is in the form of a viscous fluid and is applied in a 1-2 mm even overcoat, after which the material is irradiated.
  • the material is applied in a thinner coating and is massaged into the tissue surfaces before light polymerization.
  • the preferred light source is a broad band from 250 to 550 nm (Novacure, 100 ss+).
  • the intensity x time ranges from 2500 mW x 15 seconds to 4500 mW x 45 seconds and preferably 3000 mW x 15 seconds to 4500 mW x 30 seconds.
  • the intensity x time preferably is 2500 mW x 75 seconds to 4500 mW x 180 seconds, more preferably 2500 mW x 15 seconds to 4500 mW x 45 seconds.
  • the polymerizable proteins described above form a strong seal over damaged tissue when subjected to polymerization or crosslinking conditions.
  • the strength of the seal can be enhanced further by applying a primer solution to the tissue prior to applying the polymerizable protein.
  • a primer solution to the tissue prior to applying the polymerizable protein.
  • the surface of a damaged tissue to which the polymerizable protein is to be applied may be coated with various naturally-occurring proteins and/or blood, the presence of which may influence the intimate contact between the sealant and the tissue surface. Simple flushing of the tissue surface with saline solution may not remove or displace these substances. It was found according to one aspect of the invention that a tissue surface coated with various naturally- occurring proteins and/or blood can be pre-treated with a primer solution in order to enhance the contact between the tissue and the polymerizable proteins.
  • a primer is a biologically compatible adhesive protein solution. Proteins useful as primers include collagen, albumin, gelatin, elastin, and fibrinogen.
  • a preferred primer is a dilute solution of collagen in 0.1 M phosphate buffer. The collagen concentration is 1 to lOmg/ml, more preferably 4 to 8 mg/ml. The pH of the solution is 6.0 to 9.0, more preferably 8.2 to 8.5. Optionally the solution may be supplied in a plastic syringe.
  • the primer may be used in various combinations with polymerizable proteins of the invention. For instance, a collagen primer may be used with polymerizable proteins that are collagen, elastin, fibrinogen, etc.
  • the primer may also be a combination of adhesive proteins.
  • the primer may be, for example, a combination of collagen and elastin.
  • the primer is applied to the tissue prior to the polymerizable protein.
  • First the tissue surface is blotted with a sponge to remove excess proteins and/or blood and then the primer is applied, preferably, using a syringe.
  • the primer may be gently rubbed in to the surface and the excess primer removed.
  • the polymerizable protein is added to the primer coated surface while the primer is still moist.
  • a preferred embodiment for sealing a tissue using a primer is set forth in more detail in the examples below.
  • the primer may be used with any protein based adhesive.
  • the primer is used with the polymerizable proteins of the invention.
  • the primer may be used with any protein based adhesive known in the art, such as those disclosed in the background of the invention.
  • protein based adhesives such as those disclosed in the background of the invention.
  • modified collagen-based adhesives, and fibrin glues are well known protein based adhesives.
  • Collagen was prepared from powdered bovine corium. This powder is subsequently heat sterilized to produce Avitene (MedChem Products, Inc., Woburn, MA). The powder is primarily composed of type I collagen.
  • Powdered bovine corium was suspended in 0.5M acetic acid at 3 grams per liter.
  • Pepsin Sigma Chemical Co., 1 :60,000
  • the digested collagen mixture was filtered through a coarse filter or centrifuged at
  • Type I collagen was purified by the addition of NaCl (sodium chloride) to a final concentration of 0.85M. The suspension was mixed for at least two hours and the collagen precipitate recovered by centrifugation for 30 minutes at 9,000 rpm.
  • the pellet was redissolved in 0.1 M acetic acid to a concentration of approximately 3 mg/ml (0.3%) and filtered through a series of filters, i.e., approximately l ⁇ prefilter, 0.45 ⁇ filter and finally sterile filtration through a 0.22 ⁇ filter.
  • This purified Type I collagen suspension was then used for chemical derivatization.
  • the sterile filtered collagen suspension was pH adjusted to 9.0 using ION and IN NaOH.
  • Glutaric anhydride was added at 10% (weight of collagen) and mixed for 30 minutes while maintaining the pH at about 9.0. Glutaric anhydride reacts with deprotonated ⁇ - and terminal free amines resulting in the addition of a carboxyl group to the amine.
  • Derivatized collagen was recovered by reducing the suspension to its new pKa of approximately 4.3. This was accomplished using 6N and IN Hcl. The precipitate was collected by centrifugation for 20 minutes at 9,000 rpm.
  • the recovered derivatized-collagen pellet was dissolved in 0.1 M phosphate buffer (pH 8.2-8.5) to which was added IN NaOH, if necessary, to adjust the final pH to about 8.2-8.5.
  • concentration ranges for various formulations were from 18 mg/ml to 90 mg/ml and dynamic viscosities ranged from about 50,000 cps to more than 200,000 cps.
  • the final concentration depends on application. However, the preferred concentration appears to be about 50 mg/ml and exhibits a dynamic viscosity of about 80,000 cps.
  • the strength of the polymerized collagen sealant was enhanced by adding Avitene fibers at a concentration of 5-20 mg/ml.
  • the preferred concentration depends on application but is generally about 10 mg/ml.
  • the polymerizable protein sealant was prepared for application by mixing 0.8ml of collagen gel with 0.16ml of a 0.7M solution of sodium persulfate in 0.1 M phosphate buffer to produce a final solution having a pH 8.2-8.5.
  • the solutions were mixed in two 1ml syringes connected by a syringe adapter. A first 1ml syringe was filled with 0.8ml collagen gel and a second 1ml syringe was filled with 0.16ml of sodium persulfate solution.
  • the two syringes were connected by a syringe adapter and the solutions were mixed by transferring the two solutions back and forth between the two syringes 40 to 50 times over a 25 to 30 second time interval. Care was taken to avoid introducing air bubbles into the mixture.
  • the solutions may be mixed by any traditional technique for combining solutions, such as in a test tube with a spatula. The syringe method, however, is preferred because of its ease of handling and ability to avoid air bubbles as well as its sterility.
  • the final pH of the sealant was between 8.2 and 8.5. The sealant was incubated in a capped 1ml syringe for 5 to 10 minutes at room temperature before application to the tissue. Incubation temperatures up to 35 D C may be used.
  • the surface tissue of a deflated lung was thoroughly dried with gauze. Approximately 0.2ml of sealant was applied to the tissue surface and gently rubbed into the exposed lung tissue, as well as 5mm of surrounding pleura for 30 seconds, with a dry gloved fingertip and/or a spatula. A larger volume of sealant may be applied to the tissue for the treatment of larger surface areas. More sealant was then applied over the exposed lung tissue and pleura already having an initial coat of sealant, to produce a 1-2 mm layer of sealant over the tissue and pleura. Care was taken to avoid generating bubbles at the site.
  • the sealant was polymerized, or "cured" by exposure to ultraviolet-A light delivered through a liquid-filled light guide by an EFOS Novacure unit.
  • the ultraviolet light intensity used was in the range of 3000m W/cm 2 .
  • the exposure time was 135 seconds but the exposure time may range from 1 to 300 seconds.
  • the light guide distance was 3 inches but the light guide distance may be anywhere between 1 and 3 inches, depending on the surface area to be exposed as well as the exposure time. Light exposure was repeated over all areas to which sealant was applied in order to ensure that the sealant was evenly polymerized.
  • Example 3 In vivo and ex vivo analysis of the polymerizable protein sealant as a hemostat and a lung sealant.
  • the vessel was then pressurized up to 300 mm of mercury by opening the saline reservoir. Although the vessel distended approximately 30 percent, the sealant held in place at least up to 300 mm of mercury. Other in vitro tests have shown that the sealant is capable of sealing tissues under normal blood pressure for extended periods of time.
  • the tip of an inflated porcine lung lobe was removed to expose a bronchus of approximately 1 mm in diameter.
  • the surface was blotted and the polymerizable protein sealant was applied over the exposed tissue as well as at least 5 mm of surrounding pleura.
  • the sealant was gently rubbed into the exposed lung tissue and pleura for thirty seconds, with a dry gloved fingertip and/or a spatula. Additional sealant was applied to produce a 1-2 mm layer of sealant over the entire exposed area.
  • the sealant was cured for fifteen seconds with an ultraviolet light. Absence of an air leak was verified by pressurizing the lung up to 60 mm of mercury, which corresponds to 80 cm of water.
  • a lobe of porcine lung tissue was severed to reveal a tissue surface area.
  • the sealant was applied as described above and was cured with ultraviolet light for fifteen seconds. The absence of an air leak was verified by dripping saline solution over the sealant.
  • Example 4 Preparation and analysis of a primer/polymerizable protein sealant as a hemostat.
  • Collagen was prepared as described in Example 1 above. The collagen was then diluted with 0.1M phosphate buffer pH 8.2 to produce a concentration of 4 to 8 mg/ml. The pH of the solution was adjusted to a value of 8.35 using 0.1N NaOH. The dilute collagen solution was loaded into a plastic syringe for administration.
  • a 15 mm longitudinal arteriotomy was created, then repaired with a continuous suture of 6-0 polypropylene, leaving gaps approximately 3.5 mm long between stitches.
  • the distal clamp was released momentarily to confirm that the suture line was not hemostatic.
  • Excess blood was rinsed away with saline, and the artery surface blotted with a gauze sponge.
  • Primer was applied using a syringe to all surfaces to which sealant application was anticipated. The primer was gently rubbed into the surface using the blunt tip of the syringe. Excess primer was blotted so that the tissue surface is left slightly moist, or glistening, but not dry.
  • the polymerizable protein solution was then applied to the prepared site to form a 1-2 mm layer and cured by ultraviolet light.
  • the artery clamps were released, distally then proximally, and hemostasis was achieved.
  • the use of primer resulted in superior hemostasis results. Immediate hemostasis was achieved in 3 of 6 arteriotomies without the primer, and in 6 of 7 arteriotomies with the use of primer.

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Abstract

Procédés et produits permettant de bloquer rapidement et de manière étanche une fuite de fluide dans un tissu. Une protéine polymérisable est appliquée sur un tissu présentant une ouverture, ce qui provoque une fuite de fluide du tissu, afin de fermer de manière étanche ladite ouverture. La zone tissulaire et l'ouverture recouvertes de la protéine polymérisable sont exposées à un initiateur destiné à polymériser le bouchon protéique in situ et à créer une fermeture étanche de l'ouverture pour empêcher la fuite de fluide. Les procédés et produits de la présente invention peuvent être utilisés, par exemple, pour fermer de manière étanche des perforations laissant passer l'air dans des blessures pulmonaires, ainsi que des anastomoses et des sutures de vaisseaux sanguins.
PCT/US1997/008124 1996-05-14 1997-05-14 Procedes et produits permettant de bloquer de maniere etanche une fuite de fluide d'un tissu WO1997042986A1 (fr)

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US5874537A (en) * 1991-01-29 1999-02-23 C. R. Bard, Inc. Method for sealing tissues with collagen-based sealants
WO2000062832A1 (fr) * 1999-04-16 2000-10-26 Endospine Ltd. Systeme pour la reparation de disques intervertebraux
US6183498B1 (en) 1999-09-20 2001-02-06 Devore Dale P. Methods and products for sealing a fluid leak in a tissue
WO2001045761A1 (fr) * 1999-12-22 2001-06-28 Surgical Sealants, Inc. Methodes et compositions permettant de bloquer les fuites dans des tissus
US6610043B1 (en) 1999-08-23 2003-08-26 Bistech, Inc. Tissue volume reduction
US6921532B1 (en) 2000-06-22 2005-07-26 Spinal Restoration, Inc. Biological Bioadhesive composition and methods of preparation and use
WO2007092998A1 (fr) * 2006-02-14 2007-08-23 Commonwealth Scientific And Industrial Research Organisation Jonction et/ou collage de tissus par réticulation photo-activée de protéines matricielles
US7597687B2 (en) 2004-10-29 2009-10-06 Spinal Restoration, Inc. Injection of fibrin sealant including an anesthetic in spinal applications
US8124075B2 (en) 2004-07-16 2012-02-28 Spinal Restoration, Inc. Enhanced biological autologous tissue adhesive composition and methods of preparation and use
US8206448B2 (en) 2004-10-29 2012-06-26 Spinal Restoration, Inc. Injection of fibrin sealant using reconstituted components in spinal applications
US8403923B2 (en) 2004-10-29 2013-03-26 Spinal Restoration, Inc. Injection of fibrin sealant in the absence of corticosteroids in spinal applications
US8419722B2 (en) 2004-10-29 2013-04-16 Spinal Restoration, Inc. Apparatus and method for injection of fibrin sealant in spinal applications
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US9044569B2 (en) 2004-04-28 2015-06-02 Smith & Nephew Plc Wound dressing apparatus and method of use
US9198801B2 (en) 2004-04-05 2015-12-01 Bluesky Medical Group, Inc. Flexible reduced pressure treatment appliance
US9956121B2 (en) 2007-11-21 2018-05-01 Smith & Nephew Plc Wound dressing
US10058642B2 (en) 2004-04-05 2018-08-28 Bluesky Medical Group Incorporated Reduced pressure treatment system
US10071190B2 (en) 2008-02-27 2018-09-11 Smith & Nephew Plc Fluid collection
US10143784B2 (en) 2007-11-21 2018-12-04 T.J. Smith & Nephew Limited Suction device and dressing
US10159604B2 (en) 2010-04-27 2018-12-25 Smith & Nephew Plc Wound dressing and method of use
US10207035B2 (en) 2004-05-21 2019-02-19 Smith & Nephew, Inc. Flexible reduced pressure treatment appliance
US10265445B2 (en) 2002-09-03 2019-04-23 Smith & Nephew, Inc. Reduced pressure treatment system
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WO2000062832A1 (fr) * 1999-04-16 2000-10-26 Endospine Ltd. Systeme pour la reparation de disques intervertebraux
US6428576B1 (en) 1999-04-16 2002-08-06 Endospine, Ltd. System for repairing inter-vertebral discs
US7300428B2 (en) 1999-08-23 2007-11-27 Aeris Therapeutics, Inc. Tissue volume reduction
US6610043B1 (en) 1999-08-23 2003-08-26 Bistech, Inc. Tissue volume reduction
US7654999B2 (en) 1999-08-23 2010-02-02 Aeris Therapeutics, Inc. Tissue volume reduction
US6183498B1 (en) 1999-09-20 2001-02-06 Devore Dale P. Methods and products for sealing a fluid leak in a tissue
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