Classifications

• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
  • C12M23/00—Constructional details, e.g. recesses, hinges
  • C12M23/02—Form or structure of the vessel
  • C12M23/06—Tubular
• • 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
  • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
  • A61L27/507—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials for artificial blood vessels
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
  • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
  • A61F2/02—Prostheses implantable into the body
  • A61F2/04—Hollow or tubular parts of organs, e.g. bladders, tracheae, bronchi or bile ducts
  • A61F2/06—Blood vessels
  • A61F2/062—Apparatus for the production of blood vessels made from natural tissue or with layers of living cells
• • 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
  • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
  • A61L2/24—Apparatus using programmed or automatic operation
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
  • C12M21/00—Bioreactors or fermenters specially adapted for specific uses
  • C12M21/08—Bioreactors or fermenters specially adapted for specific uses for producing artificial tissue or for ex-vivo cultivation of tissue
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
  • C12M25/00—Means for supporting, enclosing or fixing the microorganisms, e.g. immunocoatings
  • C12M25/14—Scaffolds; Matrices
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
  • C12M35/00—Means for application of stress for stimulating the growth of microorganisms or the generation of fermentation or metabolic products; Means for electroporation or cell fusion
  • C12M35/04—Mechanical means, e.g. sonic waves, stretching forces, pressure or shear stimuli

Definitions

• the present invention relates to the sterilization, seeding, culturing, storing, shipping, and testing of
• the present invention relates to an apparatus and method for sterilizing vascular grafts and then seeding and culturing the grafts with human cells, resulting in grafts populated with viable human cells.
• Vascular grafts are used by vascular and thoracic surgeons to repair or replace segments of arterial and venous blood vessels that are weakened, damaged, or obstructed due to trauma or disease such as aneurysm, atherosclerosis, and diabetes mellitus.
• vascular grafts have been either homografts, such as the patient's own saphenous vein or internal mammary artery, prosthetic grafts made of
• polyester e.g., Dacron
• ePTFE expanded polytetraflouroethylene
• homografts requires extensive surgery which is time- consuming, costly, and traumatic to the patient.
• Fixed tissue grafts do not allow for infiltration and colonization by the host cells, which is essential to remodeling and tissue maintenance. Consequently, fixed tissue grafts degrade with time and will eventually malfunction.
• tissue engineered grafts Due to the inadequacies of these currently available synthetic and biological grafts, as well as the cost and limited supply of homografts, tissue engineered grafts are being developed which have been sterilized and then seeded and cultured, in vitro, with cells. These tissue engineered grafts may be superior to other grafts for use in replacement therapy in that they more closely display the long term dimensional stability and patency of native arteries and vessels with normal physiologic functionality.
• an apparatus and method for sterilizing, seeding, culturing, storing, shipping, and testing vascular grafts is provided.
• the present invention is an apparatus and method for seeding and culturing vascular grafts with human cells, resulting in a tissue-engineered vascular graft populated with viable human cells.
• the apparatus comprises a fluid reservoir, a pump, at least one graft treatment
• the invention advantageously utilizes a vascular graft with cells and their fibers oriented so as to more likely tolerate the physiological conditions found in the human body.
• the invention advantageously utilizes a
• FIG. 1 ii a schematic diagram illustrating an apparatus according to the present invention for sterilizing, seeding, culturing, storing, shipping, and testing a prosthesis
• FIG. 2 is a block diagram illustrating a preferred embodiment of an alternating pressure source
• FIG. 3 is a schematic diagram illustrating an
• FIG. 4 is a schematic diagram illustrating yet another alternative exemplary embodiment of an apparatus according to the present invention for sterilizing, seeding, culturing, storing, shipping, and testing a prosthesis.
• FIG. 1 discloses a system for sterilizing, seeding, culturing, storing, shipping, and testing vascular grafts.
• this system primarily comprises a fluid reservoir 10, a pump 12, a treatment chamber 14, and an alternating pressure source 16.
• Fluid reservoir 10 is used to store fluid for the system.
• Two illustrative suitable reservoirs are the Gibco- BRL 1L media bag and any rigid container capable of
• Reservoir 10 may include a one way filter so as to provide a direct source of gas to the fluid within the system.
• fluid which may be used in the system include, but are not limited to, sterilizing fluid, tanning fluid, fluid containing cells, or fluid containing a culture medium. It is to be understood that during testing, seeding, and culturing in a preferred embodiment, the fluid may be advantageously kept at human body temperature, and may be composed of a fluid which approximates the viscosity of human blood.
• Fluid line 18 The fluid contained in reservoir 10 is retrieved through fluid line 18 by pump 12.
• Fluid line 18, as well as all other fluid lines in the system, may be made of any type of medical grade, durable tubing suitable for transporting the fluid in use.
• Pump 12 may be preferably any fluid pump which can achieve variable flow rates .
• One such pump is the
• Pump 12 propels the fluid from reservoir 10 to treatment chamber 14 through fluid line 20.
• Treatment chamber 14 preferably may be composed of any biocompatible, rigid material capable of being sterilized such as Teflon, polycarbonate, PVC, or stainless steel.
• Treatment chamber 14 may be comprised of two sections which are secured and made leak proof through any standard means such as inner and outer threads or the use of bonding agents .
• a viewing port may be placed at any point on the chamber, or alternatively, the chamber may be made of an optically clear material such as polycarbonate or PVC.
• Inlet port 28 and outlet port 30 of treatment chamber 14 allow for the
• Inlet port 28 and outlet port 30 are also used to attach treatment chamber 14 to fluid lines 20 and 22
• Fluid line 22 connects chamber 14 back to fluid reservoir 10 so as to create a closed system.
• Treatment chamber 14 houses an expandable tube 32 upon which may be placed a vascular graft scaffolding 26.
• scaffolding 26 may illustratively consist of any knitted, braided, woven, felted, or synthesized materials that are bioresorbable and/or biocompatible, as well as any native graft scaffolding material.
• Tube 32 may be comprised of any suitable elastomeric material, such as PET or silicone angioplasty balloons, which is capable of expanding and contracting.
• Treatment Chamber 14 and tube 32 may be made any length or diameter so as to hold a vascular graft
• scaffolding 26 of any length or diameter. This is
• the system may be used to sterilize, seed, culture, store, ship, and test vascular grafts of any size, such as coronary, carotid, iliac, and peripheral leg grafts.
• a porous clip or grommet 33 may be placed on tube 32 at both ends of scaffolding 26 to hold the scaffolding firmly in place on the tube during treatment.
• any structure which allows for retention of the scaffolding 26 on tube 32 may be used.
• Grommets 33 are beneficial, as the tubing can be made smaller than the grafts so as to allow for the perfusion and/or circulation of fluids in between the graft and the tube, without the possibility of slippage of the graft on the tube.
• Tube 32 may be expanded and contracted by alternating pressure source 16, a preferred embodiment of which is shown in detail in FIG. 2.
• a pump 34 which may be any standard pump capable of providing both positive pressure and negative (or vacuum) pressure, such as a piston or diaphragm pump.
• Valve 36 accepts the positive pressure and negative pressure from pump 34 through lines 40 and 42 respectively. Due to signals- from timer 38, valve 36 causes alternating pressure to be applied to tube 32 from line 24.
• Valve 36 may be any type of inline valve capable of directing and regulating multiple pressure lines.
• One such valve is the MAC 45S, model 45A-AA1-DAAA-1BA.
• tube 32 By expanding and contracting tube 32 with alternating pressure source 16, tube 32 places a varying radial stress on vascular graft scaffolding 26. This radial stress is
• vascular grafts are formed with cells and their fibers configured so as to more likely tolerate the physiological conditions found in the human body.
• the system according to the present invention may contain a plurality of chambers 14 for treating a plurality of vascular grafts.
• FIG. 3 discloses a system according to the present invention which contains two treatment chambers 14. Although FIG. 3 illustrates the connection of only two treatment chambers to the system, it will be apparent to one skilled in the art that any number of chambers may be
• line 20 may be split to connect to each inlet 28
• line 24 may be split to connect to each tube 32
• line 22 may be split to connect to each outlet 30 of each chamber 14 in the system. In this manner, a plurality of vascular grafts may be simultaneously seeded, cultured, or tested.
• each treatment chamber 14 may be
• a pump 12 with multiple pump lines may also be used so that each treatment chamber 14 in the system would use the same alternating pressure source and same pump 12 (each using a different pump line), but would be connected to a different media reservoir 10.
• FIG. 4 discloses an alternative embodiment of the invention for sterilizing, seeding, culturing, storing, shipping, and testing vascular grafts.
• the system primarily comprises a fluid reservoir 10, a bladder pump 50, a treatment chamber 46, and an alternating pressure source 54.
• Fluid reservoir 10 and the fluids which it may contain are described in detail in conjunction with FIG. 1.
• the fluid contained in reservoir 10 is retrieved through fluid line 60 by bladder pump 50.
• Fluid line 60, as well as all other fluid lines in the system, may be made of any type of medical grade, durable tubing suitable for transporting the fluid in use.
• Bladder pump 50 is comprised of a pneumatic pressure chamber 51 and a bladder 53, which may be comprised of an suitable elastomeric material.
• suitable bladder is the Cutter/Miles double valved hand activated blood pump.
• Bladder pump 50 forces fluid from reservoir 10 to treatment chamber 46 through fluid line 58 by being alternately compressed and expanded by alternating pressure source 54 in conjunction with valve 52 and timer 55.
• Alternating pressure source 54 preferably may be any standard pump capable of providing both positive pressure and negative (or vacuum) pressure, such as a piston or diaphragm pump.
• Valve 52 accepts the positive pressure and negative pressure from pump 54 through lines 64 and 66, respectively. Due to signals from timer 55, valve 52 causes alternating positive and negative pressure to be applied to bladder 53 from line 62.
• Valve 52 may be any type of inline valve capable of directing and regulating multiple lines. One such valve is the MAC 45S, model 45A-AA1-DAAA-1BA.
• Treatment chamber 46 preferably may be composed of any biocompatible, rigid material capable of being sterilized such as Teflon, polycarbonate, PVC, or stainless steel.
• Treatment chamber 46 may be comprised of two sections which are secured and made leak proof through any standard means such as inner and outer threads or the use of bonding agents.
• a viewing port may be placed at any point on the chamber, or alternatively, the chamber may be made of an optically clear material such as polycarbonate or PVC.
• Inlet port 68 and outlet port 70 of treatment chamber 46 allow for the
• Inlet port 68 and outlet port 70 are also used to attach treatment chamber 46 to fluid lines 58 and 56
• Fluid line 56 connects chamber 46 back to fluid reservoir 10 so as to create a closed system. It is to be understood that although only one treatment chamber 46 is shown in FIG. 4, fluid lines 56, 58, and 60 may be branched so as to connect more than one treatment chamber in parallel to the system.
• Treatment chamber 46 houses a porous tube 48 upon which may be placed a vascular graft scaffolding 26. Scaffolding 26 is discussed in detail in conjunction with FIG. 1 above.
• Porous tube 48 may be comprised of any suitable rigid
• porous tubing such as Teflon, PVC, polycarbonate, or stainless steel, which may be made fluid permeable.
• porous tube 48 may be comprised of any suitable elastomeric material, such as PET or silicone angioplasty balloons, which is capable of expanding and contracting, and which may be made fluid permeable.
• Treatment Chamber 46 and tube 48 may both be made any length or diameter so as to hold a vascular graft scaffolding 26 of any length or diameter. This is advantageous, as the system may be used to sterilize, seed, culture, store, ship, and test vascular grafts of any size.
• Porous clips or grommets 33 may be placed on tube 48 at both ends of scaffolding 26 to hold the scaffolding in place on the tube during treatment.
• tube 48 is comprised of a rigid porous material, then the varying fluid pressure caused by the action of bladder pump 50 will force fluid through the porous material. The fluid force through the porous material will place a varying radial stress on the vascular graft scaffolding.
• tube 48 is comprised of a porous
• tube 48 may be expanded and contracted by the varying fluid pressure provided by bladder pump 50.
• bladder pump 50 By expanding and contracting porous tube 48 with bladder pump 50, tube 48 places a varying radial stress on vascular graft scaffolding 26.
• the fluid flow through the elastomeric porous material will also place a varying radial stress on scaffolding 26. In this manner, a cyclical radial loading of the scaffolding and cells supported thereon is created, resulting in vascular grafts which are formed with cells and their fibers configured so as to more likely tolerate the physiological conditions found in the human body.
• the inlet port and outlet port of treatment chamber 14 may be sealed in a known manner (e.g., luer locks or threaded plugs) so as to create a sealed treatment chamber free from contamination.
• the sealed chambers may be used to sterilize, store, and ship vascular grafts or other protheses.
• a vascular graft scaffolding 26 which is secured within the sealed chambers 14 or 46 may be sterilized by some chemical means such as ethylene oxide or peracetic acid, radiation means such as an electron beam or gamma rays, or by steam sterilization. Sealed treatment chambers 14 or 46,
• vascular graft scaffolding containing the sterilized vascular graft scaffolding, may then be placed back into the systems of FIGS. 1, 3 and 4 for seeding and culturing and unsealed without contaminating the system or the vascular graft .
• Seeding and culturing of the vascular graft in treatment chambers 14 and 46 is generally accomplished by known
• maintaining the culture may also be readily adapted by a person of ordinary skill in the art for use with the present invention.
• vascular graft Once the vascular graft has reached the desired level of cell density, a preservative may then be pumped into
• the preservative is a cryo-preservative so that the graft may be frozen in chambers 14 or 46. In this manner, sealed
• treatment chambers 14 or 46 may be used to sterilize

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Engineering & Computer Science (AREA)
• Chemical & Material Sciences (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Organic Chemistry (AREA)
• Wood Science & Technology (AREA)
• Zoology (AREA)
• General Health & Medical Sciences (AREA)
• Biomedical Technology (AREA)
• Genetics & Genomics (AREA)
• Biotechnology (AREA)
• Biochemistry (AREA)
• General Engineering & Computer Science (AREA)
• Sustainable Development (AREA)
• Microbiology (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Animal Behavior & Ethology (AREA)
• Oral & Maxillofacial Surgery (AREA)
• Clinical Laboratory Science (AREA)
• Vascular Medicine (AREA)
• Epidemiology (AREA)
• Transplantation (AREA)
• Cell Biology (AREA)
• Pulmonology (AREA)
• Dermatology (AREA)
• Mechanical Engineering (AREA)
• Molecular Biology (AREA)
• Immunology (AREA)
• Gastroenterology & Hepatology (AREA)
• Medicinal Chemistry (AREA)
• Cardiology (AREA)
• Heart & Thoracic Surgery (AREA)
• Apparatus Associated With Microorganisms And Enzymes (AREA)
• Prostheses (AREA)
• Materials For Medical Uses (AREA)
• Micro-Organisms Or Cultivation Processes Thereof (AREA)
• Pretreatment Of Seeds And Plants (AREA)
• Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)

Applications Claiming Priority (3)

Publications (2)

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Family Applications (1)

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• 1996
  • 1996-04-09 WO PCT/US1996/005151 patent/WO1996034090A1/en not_active Application Discontinuation
  • 1996-04-09 KR KR1019970707594A patent/KR19990008070A/ko not_active Application Discontinuation
  • 1996-04-09 NZ NZ306304A patent/NZ306304A/xx unknown
  • 1996-04-09 CA CA002219202A patent/CA2219202A1/en not_active Abandoned
  • 1996-04-09 AU AU54843/96A patent/AU703117B2/en not_active Ceased
  • 1996-04-09 EP EP96911759A patent/EP0822978A4/de not_active Withdrawn
  • 1996-04-09 JP JP53256996A patent/JP4059301B2/ja not_active Expired - Fee Related

Patent Citations (4)

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