WO2001026624A1 - Albumine lamina biocompatible et procede associe - Google Patents

Albumine lamina biocompatible et procede associe Download PDF

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Publication number
WO2001026624A1
WO2001026624A1 PCT/US2000/027535 US0027535W WO0126624A1 WO 2001026624 A1 WO2001026624 A1 WO 2001026624A1 US 0027535 W US0027535 W US 0027535W WO 0126624 A1 WO0126624 A1 WO 0126624A1
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WO
WIPO (PCT)
Prior art keywords
lamina
albumin
biocompatible
energy
serum albumin
Prior art date
Application number
PCT/US2000/027535
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English (en)
Inventor
Yasmin Wadia
Scott Alan Prahl
Original Assignee
Providence Health System - Oregon
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 Providence Health System - Oregon filed Critical Providence Health System - Oregon
Priority to AU79948/00A priority Critical patent/AU7994800A/en
Publication of WO2001026624A1 publication Critical patent/WO2001026624A1/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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/227—Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24
    • 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
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
    • A61L26/0028—Polypeptides; Proteins; Degradation products thereof
    • A61L26/0047—Specific proteins or polypeptides not covered by groups A61L26/0033 - A61L26/0042
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/12—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L31/125—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/00491—Surgical glue applicators
    • A61B2017/00504—Tissue welding
    • A61B2017/00508—Tissue welding using laser
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/00491—Surgical glue applicators
    • A61B2017/00513—Tissue soldering
    • A61B2017/00517—Tissue soldering using laser

Definitions

  • the invention relates generally to biological tissue welding, and more specifically to repairing a lesion to a solid visceral organ.
  • the invention also relates to manufacturing biocompatible albumin lamina suitable for use as a scaffold or patch in the repair of tissue of a solid visceral organ.
  • Solid visceral organs such as the liver, spleen and kidney have a soft parenchyma richly interspersed with vasculature and thinly protected by a delicate fibrous capsule with limited internal fibrous support. This structure makes such organs prone to fracture and laceration with blunt abdominal trauma. Such organs are also frequently injured following abdominal trauma. For example, the liver is the most commonly injured organ following abdominal trauma. It is the second most commonly injured following blunt injuries and the third most commonly injured in penetrating injuries.
  • the current surgical armamentarium for liver lacerations is limited to mass ligation of the lacerated liver with absorbable sutures, omental wrapping, packing with re-exploration, mesh hepatorrhaphy, fibrin sealant and ultrasonic aspiration with argon beam coagulation.
  • Suture repair of the liver frequently increases parenchymal damage and ischemic tissue loss.
  • Packing can be complicated by persistent hemorrhage and/or abdominal compartment syndrome and requires re- exploration to remove the packing. Biliary fistula and abscess formation can also complicate this technique. These difficulties also arise in repairing lesions in the kidney and spleen. They also present an obstacle to surgical treatment of solid visceral organs, for example, excision of tumors.
  • Tissue coagulation is the method of heating to denaturation the constituents of the tissue itself. Attempts at hemostasis using the CO 2 laser have failed to show significant benefit when compared to the diathermy. Other work showed that the CO 2 laser is ineffective at sealing vessels larger than 1mm and that argon and Nd: YAG lasers are ineffective at stopping flow in vessels larger than 4.5mm. These lasers achieve hemostasis by extensive (5-10mm depth) thermal coagulation of proteins, causing major collateral tissue damage.
  • the use of laser energy to join tissue by heating a protein solder, typically albumin, is referred to as tissue welding.
  • Laser soldering has been employed as an alternative to suture repair of injured tissues. Laser soldering was first utilized to anastomose rat ureters. Incorporating albumin solder into laser repairs was found to aid in controlling hemorrhage. Solders are generally viscous liquids of biocompatible compositions. A representative composition is that of U.S. Pat. No. 5,292,362 (to Bass et al.), which discloses a liquid solder of collagen or albumin. Liquidity permits the solder to be easily applied and formed to the lesion, while its concentration serves to retain the solder at the applied site until irradiated.
  • albumin solder solution has the approximate consistency of honey. Higher concentrations of albumin, i.e., above 58%, dehydrate rapidly and cannot be freely handled in air.
  • chromophore is utilized to increase and localize the absorption of energy.
  • the selection of chromophore also drives the choice of laser energy to be applied. For example, by using indocyanine green (ICG) as the exogenous chromophore, a diode laser could be operated at 800nm. These lasers have the advantage of being relatively inexpensive. Further, their near-infrared light is poorly absorbed by solid visceral organ tissue, substantially mitigating thermal damage during a laser repair.
  • ICG indocyanine green
  • the specific absorption of energy by the chromophore pinpoints the heat generation locus to the solder layer. Reducing the amount of laser light required for solder activation permits lower laser energy settings. More efficient energy abso ⁇ tion also allows the use of pulsed lasers, further reducing collateral thermal damage during laser repairs.
  • Tissue welding using only an ICG-augmented albumin solder confers no advantage in some scenarios.
  • Soldering can be employed to achieve hemostasis of severed liver venous sinusoids of larger diameters (i.e., 5mm and above).
  • the weld joints produced are brittle and of relatively low tensile strength.
  • Previous repairs focus on nerve, ureter and vesicular and usually further include stay sutures.
  • Solid visceral organs require a support contribution from the repair material. Solders exhibit low tensile strength and are not well-suited to provide this support.
  • laser soldering applications have not shown a clear benefit over conventional suture repair, and have not gained clinical acceptance
  • Solid biocompatible materials have been employed to repair injuries to tissues needing greater structural support than is offered by solder alone.
  • Compositions include gelatin (U.S. Pat. No. 5,931,165 to Reich et al.); elastin (U.S. Pat. No. 6,1 10,212 to Gregory, et al.); and collagen (U.S. Pat. No. 5,749,895 to Sawyer et al).
  • Sawyer et al. teach making and using a sheet preferably made of collagen.
  • the reference also mentions albumin as one of a number of alternative candidate materials.
  • Sawyer et al. provide no description of the manufacture, method of use or physical characteristics of an albumin film.
  • none of the prior art references describe using an albumin film in the repair of injuries to solid visceral organs, such as liver, kidney and spleen.
  • the albumin lamina of the present invention addresses this need by focusing on the preparation of thin albumin films, providing for the application of albumin of uniform and consistent thickness to a weld site.
  • Applications of energy to living tissue have the additional drawback of thermal damage to the lesion site under repair. The degree of damage varies according to the energy type and the amount applied, but can in some cases be substantial.
  • tissue coagulation for example, the tissue is literally melted and then fused.
  • An argon ion beam coagulator used in this procedure, produces damage penetrating 3-4 mm into the tissue. While this repair technique seals the surface over an incision, superficial injury is sustained by the organ parenchyma well beyond the precise area of the incisive trauma. Such thermal damage also increases the risk of improper healing, spawning fistulae and other unwanted post-procedural complications. While thermal damage is more limited in soldering, a need exists to further minimize and control damage to healthy tissue surrounding or adjacent to a lesion in a locus of repair.
  • the present invention relates to the use of laser welding techniques on liver, kidney and spleen - solid tissues that are notoriously difficult to repair with sutures.
  • Applicant's experimental efforts achieved rapid hemostasis of in vivo liver lacerations (10 cm long and 1 cm deep) and lobar resections (5 by 2 cm) in swine.
  • an integral part of the success of the swine experiments was the use of the pig's omentum as a welding patch.
  • a piece of the omentum was harvested during the procedure and placed over albumin-ICG solder.
  • the omentum was then welded to the liver. Due to its transparent nature, the omentum let nearly 100% of the laser energy pass through and a strong weld occurred. The omentum thus served successfully as a hemostatic patch, reinforcing the albumin solder.
  • an albumin patch according to the present invention which transmits 90% of incident laser energy. Being composed of albumin, the patch forms a strong bond with liquid albumin solder. Though not as strong a weld as those using omentum, the patch provided significant reinforcement to the weld site. Using the albumin lamina material provides substantially greater weld strength than solder alone.
  • the present invention provides a denatured albumin lamina, useful for repairing lesions on solid visceral organs.
  • the lamina comprises human serum albumin, formed into a thin, pliant sheet and denatured.
  • the denatured lamina can be sterilized and stored until used. As well, it can be impregnated with a variety of bioagents. Its mechanical properties make it especially suitable for use in tissue welding on solid visceral organs.
  • a method is provided for manufacturing the denatured albumin lamina. The method comprises placing a quantity of viscous albumin solution between two nonporous sheets, then spreading the albumin solution between the sheets to a selected and substantially uniform thickness.
  • the albumin solution sandwich thus formed is placed into a container, which is then evacuated.
  • the sandwich is then heated, by autoclaving or immersion in a water bath of at least 86°C. Denaturation of the entrapped albumin solution changes its state from a viscous liquid to a flexible solid.
  • Another aspect of the present invention is a method for using the albumin lamina according to the present invention to repair a lesion on a solid visceral organ.
  • the method comprises welding the albumin lamina over a lesion on a solid visceral organ.
  • a laser solder is deployed beneath the lamina to weld it to the organ surface.
  • the albumin lamina is produced with additives in the form of bio-active agents.
  • FIG. 1 is a physical representation of an albumin lamina according to the present invention.
  • FIG. 2 is a scatter-plot of ultimate strength data for one embodiment of the lamina of FIG. 1.
  • FIG. 3 is a scatter-plot of elasticity data for one embodiment of the lamina of FIG. 1.
  • FIG. 4. is a scatter-plot of ultimate strength data as a function of curing temperature, curing time and curing method in the manufacture of lamina according to one aspect of the present invention.
  • FIG. 5 shows a method of making a denatured albumin lamina according to one embodiment of the invention.
  • FIG. 6 shows a method of repairing a lesion to a solid visceral organ surface using a denatured albumin lamina according to one embodiment of the invention.
  • the albumin lamina of the present invention is made from FDA-approved human serum albumin. It is therefore completely biocompatible and biodegradable. Typically, other biomate ⁇ als (gelatin, collagen or elastm) are culled from animal sources These materials engender attendant concerns about antigenicity, immune rejection and foreign body reactions Furthermore, transmission of animal viruses and diseases is a concern Use of human serum albumin substantially mitigates these concerns, as the protein sequence and structure vary little between individuals As well, human serum albumin is amenable to sterilization and obviates the risk of animal diseases crossing species barriers into humans
  • a typical lamina 10, shown in FIG. 1, is a film having a predetermined thickness
  • the preferable thickness is 200 ⁇ m, although the lamina can be manufactured to greater or lesser thicknesses in a range of 75 ⁇ m to greater than 300 ⁇ m
  • a denatured albumin lamma is clear, thm, flexible and preferably of uniform thickness It can be manipulated by hand easily and without special care, due to its sufficiently high tensile strength and pliability Although possessive of slight tackiness, it does not bond or stick to itself
  • the denaturation leaves the lamina stable in a variety of environments
  • the denatured albumin lamina will not solubihze in water or saline solution or after contact with tissue
  • the denatured albumin lamina of the present invention is also stable in air
  • the denatured lamma requires vacuum storage but maintains its pliancy for as long as approximately 15 minutes on the benchtop
  • the lamma can be impregnated with one or more bioactive agents, comprising pharmaceuticals, hormones, hemostatic agents, or other therapeutic agents Spot-weldmg the lamina to the lesion site avoids irradiation of the entirety of the lamina, preserving such compounds during the welding process Compounds can be selected which are not damaged by the particular energy type used in the welding method.
  • bioactive agents comprising pharmaceuticals, hormones, hemostatic agents, or other therapeutic agents Spot-weldmg the lamina to the lesion site avoids irradiation of the entirety of the lamina, preserving such compounds during the welding process
  • Compounds can be selected which are not damaged by the particular energy type used in the welding method.
  • the denatured albumin lamina can be sterilized by autoclaving or gamma irradiation. Because denaturation is desired, autoclaving can accomplish both the sterilization and denaturation steps in the manufacture of the lamina.
  • Ultimate strength results are shown in FIG. 2. The ultimate strengths were recorded along with the exact width and thickness of each sample. The ultimate strength was calculated by dividing the force required to break the sample by the cross-sectional area (width x thickness).
  • Ultimate strength is seen in FIG. 2 to increase almost linearly up until 200 seconds, after which strengths vary only trivially.
  • the data indicate that there may be a strength increase in the sheet, if it is cured at temperatures exceeding 95°C.
  • FIG. 3 shows the elasticity of albumin strips denatured at 100°C. Young's modulus of elasticity was calculated for each sample by a linear fit of stress/strain data for strains ranging from 0 to 0.1. For denatured albumin strips cured at 100°C, the stiffness (Young's modulus) increases with increasing curing time, with the most increase occurring in the first 200 seconds.
  • FIG. 4 shows the ultimate strengths in kilopascals for albumin strips denatured by heat bath immersion at 85°C, 90°C and 95°C. As well, the effects were assessed of heating by autoclaving at 110°C, with and without a brief (15-30 second) heat bath immersion prior to autoclaving.
  • temperatures of at least 90°C are needed to achieve strips with an acceptable ultimate strength Only a marginal increase in both ultimate strength and elasticity was imparted by boiling in excess of 200 seconds
  • the denatured albumin lamma of the present invention has varied applications It can be employed as a substrate for temporary external integument replacement in burn treatment or other areas of extensive tissue loss In this use, the capacity of the lamina to be impregnated with antibiotics or other bioagents is particularly beneficial Alternatively, the lamina may be manufactured with substantial structure in all three dimensions A lamma so cast is useful as a scaffolding, for example, in the tissue-engineering of organs
  • a liquid albumin solution of approximately 53% to 57% is utilized in a preferred embodiment, the albumin solution is concentrated to 53-55%
  • FIG. 5 shows a method of making denatured albumin lamina
  • a first step 500 the concentrated albumin 52 is placed between two nonporous sheets 51, e g , the main panels of a Kapak bag plastic Typically, approximately lcc of albumin solution is placed between the edges of the two aligned plastic sheets These sheets are then placed in another Kapak bag 55 (not shown in steps 510 and 520 for clarity) and the entire unit rolled 510 through a rolling mill 53, forward and backward, to spread the albumin evenly 520 and to a uniform thickness 52
  • the roller 54 height can be calibrated using known thickness of materials placed between the rollers
  • the outer bag is evacuated 530, l e , with a vacuum pump/trap 56, and the open edge heat-sealed (not shown)
  • the entire package is placed 540 in a hot water bath 57 of controlled temperature to denature the albumin During the heating step, the albumin protein is denatured It is believed that the molecules interact and form a polymer upon cooling Alternatively, sheets are cured at 90°C for 15 seconds and then autoclaved at
  • albumin lamina is denatured by autoclaving only.
  • the factors most greatly impacting the properties of the resultant denatured albumin lamina are serum albumin solution concentration (50-57%), curing temperature (86-120°C), curing time (15 seconds to 10 minutes) and curing pressure (1-3 atm).
  • the denatured albumin lamina are typically double-packaged and stored to prevent dehydration and maintain pliancy. While so stored, the lamina can be gamma-irradiated (25-35 Gy) to sterilize the biomaterial and container.
  • a method of using the denatured albumin lamina of the present invention in the repair of lesions on solid visceral organs is herein disclosed. Efficacy has been assessed directly in benchtop experiments.
  • a lesion 60 on a solid visceral organ can be repaired using the denatured albumin lamina of the present invention.
  • the repair begins with the application to the lesion site of a quantity of an energy-absorbing material 62.
  • an energy-absorbing material is liquid albumin solution (solder) doped with a chromophore.
  • solder of 53% to 55% albumin is used, further containing
  • ICG at a concentration of approximately 0.1 mg/ml.
  • the lesion site is then irradiated 620 with energy 64 from an energy source
  • solder Because the solder is energy-absorbing, it denatures. Surface tissue in contact with the solder also heats and denatures. With sufficient energy irradiation, fusion of sinusoids results in substantial hemostasis at the lesion site. In in vivo applications, this step serves to achieve substantial hemostasis at the lesion site.
  • hemostasis is not necessary for the subsequent laminar welding with high strength, hemostasis is a desired consequence of the lesion repair. Blood loss is thereby further minimized and the lesion more efficaciously treated.
  • a denatured albumin lamina 68 according to the present invention is then placed 630 over the welded energy-absorbing material 62 on the lesion site 60.
  • the lamina is first trimmed to roughly conform to the particular dimensions of the lesion.
  • the lesion site is then again irradiated 640 with energy 64 from an energy source 66.
  • the lamina being transparent to the laser light at the chosen wavelength, absorbs little light energy and hence heats minimally as compared to the solder.
  • the energy-absorbing material beneath the lamina absorbs energy and heats, conducting heat to the lamina.
  • the albumin solder and the denatured albumin lamina are denatured at the protein level. It is believed that the albumin molecules intertwine with one another and with tissue.
  • the lesion site Upon cooling, the lesion site is weld-sealed, wherein the denatured albumin lamina and the lesion site are welded together.
  • the lesion site is irradiated 620 with energy 64 after the deposition 610 of solder 62 and before the placement thereon 630 of the denatured albumin lamina 68.
  • Hepatic lesion repair performed according to a less preferred embodiment of the current method, achieved complete hemostasis at a rate of about 9.4 sec/cm 2 . This modality effectively seals the liver surface and joins lacerations with minimal thermal injury. Further, the present method works independently of the patient's coagulation status.
  • tissue welding One drawback to tissue welding is that a dry operating field is needed, necessitating Pringle's maneuver perform the procedure. Therefore, for grade IV and V liver trauma repair, total hepatic isolation may be required. The ten minutes required to complete a laser repair of the liver is well within ischemic time tolerated by the liver. The time required for tissue welding is comparable to suture repair. This time can be shortened by using larger laser spot sizes with correspondingly higher laser pulse energies. Another advantage of laser soldering is that the 800nm laser energy is selectively absorbed by ICG dye; accidental misdirection of the laser beam at the energy levels used had no effect on the surrounding viscera. More rapid repairs may be dictated by those patients presenting with other critical injuries; i.e., extensive trauma or injuries to numerous body sites.
  • a benefit of the present invention is its mitigation of collateral damage inflicted upon the tissue during repair.
  • the damage sustained by the liver in the above examples was significantly less for tissue weld repairs (typically 0.5-1.0mm) than the 1cm ischemic region seen in the conventional suture repair.
  • tissue weld repairs typically 0.5-1.0mm
  • thermal damage is confined primarily to the albumin on the surface, with some heating of the surface of the liver caused by heat conduction. This depth of damage is about an order of magnitude smaller than that of other techniques that rely on thermal coagulation of parenchyma to achieve hemostasis (e.g., electrocoagulation, argon ion beam coagulation, and focused ultrasound).
  • Even suture repair is accompanied by a significant layer of ischemic parenchyma that may eventually become necrotic with attendant complications.
  • the denatured albumin lamina are stable and retain their transparent quality even when heated to the high temperatures of 80°C to 120°C that are required for laser welding.
  • the lamina needs to be energy-transparent at these temperatures so that the laser light reaches the albumin-ICG solder interface unrestricted.
  • Collagen and other protein scaffold materials denature at 60°C. They also cloud over and restrict laser light penetration.
  • the method of organ repair according to the present invention holds promise for repair of solid visceral organ trauma even in the presence of coagulation failure or heparin.
  • Experimental animals were given a single dose of heparin to imitate the coagulopathy that is usually seen in liver trauma.
  • Tissue welding is safe, quick and reliable in the presence of heparin. Repairs of porcine liver injuries using a method according to the present invention were straight-forward and resulted in small volumes of parenchymal damage. This teclinique can potentially reduce the morbidity and mortality associated with liver trauma and injury.
  • the lesion repair method of the present invention can be performed in conventional open surgical procedures, i.e. where access to internal body tissues and/or organs is achieved through a relatively large percutaneous surgical incision permitting laminar placement and exposure of the tissue/lamina to energy.
  • the albumin lamina of the present invention can thus be introduced by the surgeon while directly viewing the target region and manipulating the lamina through the incision.
  • the method of the present invention for welding tissue can be performed via less invasive surgical events, e.g., by laparoscopy, thoracoscopy, arthroscopy, or the like.
  • Such procedures typically rely on creating small percutaneous penetrations and accessing the target region through cannulas placed within such penetrations.
  • the target region is viewed through an associated viewing scope.

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Abstract

L'invention concerne une lamina albumine dénaturée, un procédé de fabrication et un procédé d'utilisation de cette lamina pour réparer les lésions sur des organes viscéraux solides. La lamina peut être imprégnée de divers agents biologiques.
PCT/US2000/027535 1999-10-08 2000-10-06 Albumine lamina biocompatible et procede associe WO2001026624A1 (fr)

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AU79948/00A AU7994800A (en) 1999-10-08 2000-10-06 Biocompatible albumin lamina and method

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US15866699P 1999-10-08 1999-10-08
US60/158,666 1999-10-08

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5292362A (en) * 1990-07-27 1994-03-08 The Trustees Of Columbia University In The City Of New York Tissue bonding and sealing composition and method of using the same
US5749895A (en) * 1991-02-13 1998-05-12 Fusion Medical Technologies, Inc. Method for bonding or fusion of biological tissue and material

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5292362A (en) * 1990-07-27 1994-03-08 The Trustees Of Columbia University In The City Of New York Tissue bonding and sealing composition and method of using the same
US5749895A (en) * 1991-02-13 1998-05-12 Fusion Medical Technologies, Inc. Method for bonding or fusion of biological tissue and material

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