Classifications

• • 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
  • A61F2/022—Artificial gland structures using bioreactors
• • 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
• • 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
  • 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
  • A61L27/24—Collagen
• • 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
  • A61F2310/00—Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
  • A61F2310/00005—The prosthesis being constructed from a particular material
  • A61F2310/00365—Proteins; Polypeptides; Degradation products thereof
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
  • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10S623/00—Prosthesis, i.e. artificial body members, parts thereof, or aids and accessories therefor
  • Y10S623/901—Method of manufacturing prosthetic device
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
  • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10S623/00—Prosthesis, i.e. artificial body members, parts thereof, or aids and accessories therefor
  • Y10S623/92—Method or apparatus for preparing or treating prosthetic
  • Y10S623/921—Blood vessel

Definitions

• This skin ⁇ like tissue is formed in a round or rectangular vessel with, or without, a frame of stainless steel mesh lying on the floor of the vessel.
• the lattice contracts in all dimensions; in its presence as the lattice sets it becomes anchored to th mesh and contracts in the thickness dimension only.
• the mesh resembling a picture frame, holds the lattice of living tissue within it.
• the contracted lattice, with or without the stainless steel mesh frame can be seeded with epidermal cells from the potential graft recipient. When a sheet of epidermal cells forms, the two layered skin equivalent is grafted.
• the resultant graft is unique as compared to any other graft obtained from artificial skin since its basic organization is like that of skin and its living constit ⁇ uent cells are . donated by potential ' graft recipients.
• This invention relates to the casting of living collagen lattices .contracted by living cells, such as fibroblasts, smooth muscle cells, or elements of cells such as blood platelets.
• the lattices are cast into shapes which provide internal surface areas and tubular shaped terminals, or end'structures, particularly effective for making connections, in vivo, with existing tubular structures, such as capillaries, blood vessels and glandular tissues.
• the internal surface of the cast structure is lined with specialized cells, depending on the function of the structure. For example, en othelial cells are used for the internal surface of an artery, vein, or other structures with internal surfaces. * Alternatively, in some applications it may be desir- able to line the internal surface with specialized cells having a predetermined therapeutic value.
• pancreatic ⁇ cells may be lined with pancreatic ⁇ cells to boost the insulin supply in the blood.
• Pancreatic islets islets of Lange ' rhansJ , hepa- tocytes or other types of glandular cells may also be used for lining the inner surface of the vessel-equiva ⁇ lent structures.
• the structure is in the form of 0a tube, or cylinder.
• the central core for forming the tube consists of polyethelene or glass tubing. This core is axially centered within a cylindrical mold. Suitable tissue forming constituents are poured into the cylindrical mold. After a suitable period of time, the tissue forming constituents contract the lattice and close in around the central core. This procedure can be repeated as many times as desired with the same or dif ⁇ ferent cell types in the same or different proportions to yield a multilayer tube. After each layer contracts the fluid expressed from the contracting lattice is poured off to acco odate the tissue forming constituents of the next layer. The central core may then be removed and suitable cells, predicated on the function of the cast structure, may then be cultured on the inner surface of the hollow tissue cylinders, to form, for example, a vessel-equivalent structure.
• the fortuitous fact that the lattice contracts radially about the central core structure to form tubes enables one to form various shaped structures defined by the inner core surface. If, instead, the lattice con ⁇ tracted in all directions, the resultant structure would end up as .a shapeless mass at the bottom of the mold. It is also important to note that in the formation of vessel-equivalent structure, in accordance with the invention, the sequential addition of cells in an ordered pattern of layers is essential. 5
• the vessel-equivalent structure thus far described is devoid of elastin, the fibrous mucoprotein which is the major connective tissue protein of elastic structures (e.g. large blood vessels). Without this elastic property it is possible that the vessel could burst under pressure.
• a plastic mesh may be optionally provided between two layers or within a layer of the tissue forming con- 15 stituents during the molding process, as will be des ⁇ cribed in detail.
• This mesh serves to reinforce the resultant vessel and at the same time provide a degree of elasticity to the structure so that it may expand and contract in the manner 20of a natural blood vessel, having elastin.
• Fig. 1 is a perspective view of a first embodiment of the invention showing the structure of the casting chamber.
• Fig. 1A is a cross-sectional view of Fig. 1 showing 25 a vessel as cast.
• Fig. IB is a perspective view showing a plastic mesh on a support tube which is used to position the mesh during casting.
• Fig. 2 is a schematicized view showing the culturing 30.apparatus of the invention.
• ffRE Fig. 3 is a top view of an embodiment suitable for producing a plurality of connecting elements, such as capillaries, within a lattice structure.
• Fig. 4 is a side-section showing the mold used in connection with Fig. 3.
• Fig. 5 is a top view of a further embodiment of the invention.
• the following description generally relates to the 0 casting of cylindrical structures intended as prosthesis for vessels or capillaries since such structures are commonly found in the human body.
• other shapes may be conveniently cast in accordance with the teachings herei-n and the invention is not intended to be limited to 5 any particular shape or body structure.
• Fig. 1 shows a preferred form of casting chamber for fabricating a blood vessel-equivalent of living matter
• the casting chamber 10 comprises a central rod or mandrel 12 disposed in " a cylinder 16.
• the central rod and cylin- er are mounted on a base or stand 14.
• the rod 12 is provided with three arms or spokes 18 at t e top of the rod for centering the rod within the cylinder 16.
• the base is provided with an appropriate collar 20 to accept the central rod 12.
• the outer cylinder has an internal diameter such that when the arms 18 are disposed as shown and the central rod is located in the collar 20, the rod 12 will be centered within cylin ⁇ der 16.
• the outer diameter of the rod 12 determines the inner diameter of the cast vessel and for many applications would be in the range of from 2-10 mm.
• the inner diameter of cylinder 16 will determine the final thickness of the cast layer, and typically may ran ⁇ e from 1-4 cm to produce a final thickness of about 0.5-2 mm, the final thickness being proportional to the diameter.
• the height of the chamber determines the length of the vessel and would typically be between 10-30 cm in height.
• the casting chamber parts should be made from material which may be readily cleaned and is autoclavable.
• the cylinder 16 should be made from material which is clear and which will permit diffusion of carbon 0 dioxide and other gases.
• the rod 12 may be made of glass or metal and the cylinder 16 should preferably be made of autoclavable plastic, such as polycarbonate.
• the stand 14 may be made of glass, plastic or metal, such as stainless steel.
• the size and structure of blood vessels varies in accordance with the function of the particular blood vessel. Blood vessels may be generally characterized by their cellu ⁇ lar composition and the composition of the matrix or col ⁇ lagen lattice with which other extracellular elements, such as elastin fibers and proteoglycans are associated.
• the collagen, elastin, and proteoglycans are the biosynthetic products of the cells in each of the layers..
• the cell types are endothelial, smooth muscle, and fibroblasts (called pericytes) and are found respectively in successive layers from the lumen outward.
• pericytes fibroblasts
• the respec ⁇ tive layers may be laid down in order. Alternatively, several can be laid down concurrently. All vessels contain an inner endothelial lining.
• smooth muscle surrounds the endothelium and the final out ⁇ side layer is made up of fibroblasts.
• the smooth muscle layer is fabricated.
• a mixture of nutrient medium e.g. McCoy's medium containing fetal bovine serum
• the ingredients are mixed in the following ratio: 9.2 ml of 1.76 x concentrate of McCoy's medium and 1-8 ml of fetal bovine serum.
• the pH is raised by addition of 1.0 ml of 0.1N NaOH.
• the foregoing mixture of medium and serum is poured onto a dish in which 1.5 ml of native collagen in a 1-1000 acidic acid solution has been prepared.
• a collagen lattice or gel forms immediately on casting the mixture-,
• the collagen fibrils are gradually compacted by the cells so that fluid is squeezed out of the lat ⁇ tice.
• the result is contraction of the collagen lattice around the central core or rod 12.
• the smooth muscle layer will have set in a cylindrical structure having sufficient structural integ ⁇ rity to simulate, or replicate, the smooth muscle layer of a typical blood vessel.
• the fluid expressed during contraction of the first lattice is poured off and. second complete mixture of all ingredients is added to replace the fluid.
• the process may be repeated as many times as desired to give a multilayered structure.
• the layers may be poured si ul- taneously with a removable separation or sleeve (not shown) between them. As soon as gelation begins the sleeve is removed.
• a plastic mesh sleeve 11 about the outer surface of the smooth muscle layer cylinder or the mesh may be embedded in the smooth muscle layer.
• This mesh will serve to reinforce the resulting structure and provide some degree of elasticity so that the resulting structure will be better able to withstand the pressures it will be subjected to in use.
• Meadox Medicals, Inc., 103 Bauer Drive, Oakland, New Jersey 07436, supplies a Dacron® mesh sleeve. Part No. 01H183, which has proved particularly suitable for this purpose.
• Other suitable meshes are readily available in various inert plastics, such as Teflon , nylon, etc.
• the invention is not to be limited to a particular plastic materi-al.
• the mesh should be treated to render it more electronegative by, for example, subject ⁇ ing it to plasma. This results in better cell attach ⁇ ment to the plastic sleeve and hence an increase in the strength of the resultant structure.
• the sleeve 11 should be placed on the smooth muscle cell cylinder by first disposing the sleeve 11 on metal tube 15 (as shown in Fig. IB) which has an inner diameter larger than the outer diameter of the smooth muscle cell cylinder.
• a fibroblast layer may be cast around the inner smooth muscle layer(s) and sleeve 11 so as to completely enclose the sleeve 11, as shown in Fig. 1A.
• the ingredients described above in connection with the fabrication of a smooth muscle layer are used to con ⁇ stitute a fibroblast layer, except that cultured aorta fibroblasts are substituted for the smooth muscle cells.
• the incubation period for the fibroblast layer may be 2 days to a week.
• the resultant multi-layered structure consisting of inner smooth muscle layer(s) and an outer fibroblast layer with a mesh sleeve sandwiched between the two layers 0 is now ready to be cultured with an inner endothelial lin ⁇ ing of living endothelial cells.
• the cylindrical tissue tube of several layers is slipped off the casting rod 12 to receive the endothelial cells as a suspension. It is supported in the culturing appara- 5tus shown in Fig. 2.
• the apparatus of Fig. 2 comprises a transparent chamber 24, within which a rotatable rod 26 is inserted at one end and a rotatable tube 36 is inserted at the opposite end.
• the tube 36 and rod 26 are tied together by wire frame member 30 such that when the rod 26 is rotated, the tube 36 will rotate in unison in the same direction.
• Rod 26 is coupled to motor 28 such that when motor 28 is energized the rod 26 will rotate in the direction shown by the arrow.
• the rod is attached to the motor in such a way that the length of the rod inserted into the chamber 24 may be adjusted in accordance with the length of the vessel-equivalent 44 being supported within the culture chamber 24.
• Rod 26 is provided at one end with a nipple 32 to which a vessel 44 (such as the structure previously des ⁇ cribed in connection with Figs. 1, 1A and IB comprising an inner cylinder smooth muscle cell layer, and an outer cylinder of fibroblast cells with a mesh sleeve sand ⁇ wiched between) may be attached.
• a vessel 44 such as the structure previously des ⁇ cribed in connection with Figs. 1, 1A and IB comprising an inner cylinder smooth muscle cell layer, and an outer cylinder of fibroblast cells with a mesh sleeve sand ⁇ wiched between
• tube 36 is provided with a complementary nipple 34 to which the opposite end of the vessel 44 may be attached.
• the vessel 44 is suspended between the rod 26 and tube 36 and a culture medium may be introduced from reser ⁇ voir 42 through tubing 40 and fixed connecting tube 38, through tube 36 and into the interior lining of blood vessel-equivalent 44 .
• a culture medium may be introduced from reser ⁇ voir 42 through tubing 40 and fixed connecting tube 38, through tube 36 and into the interior lining of blood vessel-equivalent 44 .
• water- tight seal bearings are provided at both ends of chamber 24 to permit the rod and tube to be inserted . into the chamber.
• Reservoir 42 is supplied with a suspension of about 200,000 cultured aorta or other endothelial cells in McCoy's medium * supplemented with a 20% fetal bovine serum. This mixture is fed by hydrostatic pressure from the reservoir into the vessel 44 as previously mentioned.
• the vessel 44 is slowly rotated by means of motor 28 which preferably runs at a speed of between .1 and 1 r.p.m. Rotation of the vessel 44 enables distribution of the endothelial cells evenly on the inner lining of the vessel and the hydrostatic pressure head from the reservoix enables the lumen, or inner opening, of the vessel-equivalent to remain open. It should be emphasized that the above procedures are intended to be carried out asceptically.
• Figs. 3 and 4 takes the form of a plurality of fine tubing or threads of nylon or stainless steel 54 suspended between a pair of plastic tubes or rings of dehydrated collagen 50 and 52.
• the threads 54 are inserted through the rings 50 and 52 and held in spaced-apart relationship by the rings.
• a collagen lat ⁇ tice with appropriate cells is cast in a pan 56 in a two- step procedure.
• a first layer 66 is laid down and allowed to con ⁇ tract.
• This layer is of sufficient height to receive the threads 54 and prevent the threads from touching the bottom of the pan 56.
• a second layer 58 is then poured covering the threads 54.
• the threads may be pulled out one at a time from either end.
• the plastic tube or ring 50 or 52 of dehydrated collagen, which is now free of the threads 54, is now ready to receive a pipette within which a suspension of appropriate cells..is disposed. These cells are introduced into the capillaries formed in the lattice by removal of the threads and allowed to attach to the inner surfaces and culture. Fluid under slight pressure is allowed to flow through the capillaries at a slow rate to keep the chan- nels open.
• the sheet of living lattice material compris ⁇ ing lower layer 56 and upper layer 58, may be transferred to recipient and connection made at the points of con- fluency of the small capillary channels left when the thread has been removed.
• FIG. 5 A further apparatus for casting capillaries in a slab lattice is shown in Fig. 5.
• nylon or other threads are threaded through a threading cylinder 60, a threading tube 64 and an exit tube 66.
• Threading tube 64 may be formed of suitably dimensioned autoclavable plastic or glass.
• Cylinder 60 and exit tube 66 may be formed of dried collagen.
• the assembly shown in Fig. 5 is disposed in a pan just above the bottom, so that lattice material will flow below and around it when poured. Alternatively, it may be laid into or on a freshly poured lattice. If the latter procedure is used, a second layer of lattice material may be poured over the assembly.
• each thread 62 is pulled out through cyl ⁇ inder 66 leaving capillary channels in the lattice.
• a set of channels con ⁇ necting., or anastomosing, at cylinder 60 will constitute a bed of capillary vessels.
• threading tube 64 may be withdrawn from the lattice and a suspension of endothelial cells may be injected via the cylindrical opening at 60 into the channel.
• flow under pressure is allowed to flow through the capillaries at a slow rate to keep them open.
• the bed is ready for implementa ⁇ tion, since by that time, the endothelial cells will have lined the inner channel surfaces.
• Connecting tubes of dried collagen may- be sewn to the severed ends of the blood vessel of the host organ- ism from which the cells used to populate the fabricated capillary bed were taken.
• the connecting tubes are then inserted into the recesses of tube 66 and tube 60 and are secured by sutures. This capillary- equivalent is then allowed to form "in vivo".
• connecting tubes may be formed of vessel-equivalent structures produced by using the cyl ⁇ indrical ends of the capillary bed as the core for mold ⁇ ing a vessel-equivalent structure on each end to serve as a connecting tube between the capillary bed-equivalent and the severed ends of the blood vessel of the host organism.
• Such a vessel-equivalent structure would be formed substantially as previously described in connec- tion with Figs. 1-2.
• glandular cells such as pancreatic ⁇ cells (to boost insulin supply in the blood) or hepatocytes (liver) cells.
• the vessels of the capillary beds provide a large surface area through which the blood may flow.
• Glandular cells lining the interior surface of these ves ⁇ sels can provide a source of secretory products of thera ⁇ Commissionic value.
• bovine cells have been used in the process since such cells were readily available for experimentation. It is contemplated, however, that for most applications, the cells will be donated by the poten- tial recipient of the prosthesis.
• lattice or matrix constituents as proteo- glycans, glycosaminoglycans or elastin may be added to the mixture with the collagen.

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• Health & Medical Sciences (AREA)
• Transplantation (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Oral & Maxillofacial Surgery (AREA)
• General Health & Medical Sciences (AREA)
• Engineering & Computer Science (AREA)
• Biomedical Technology (AREA)
• Vascular Medicine (AREA)
• Cardiology (AREA)
• Heart & Thoracic Surgery (AREA)
• Chemical & Material Sciences (AREA)
• Dermatology (AREA)
• Medicinal Chemistry (AREA)
• Epidemiology (AREA)
• Pulmonology (AREA)
• Gastroenterology & Hepatology (AREA)
• Biophysics (AREA)
• Prostheses (AREA)
• Materials For Medical Uses (AREA)

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Cited By (28)

Families Citing this family (92)

Citations (6)

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• 1982
  • 1982-02-26 US US06/352,585 patent/US4546500A/en not_active Expired - Lifetime
  • 1982-05-05 WO PCT/US1982/000594 patent/WO1982003764A1/en not_active Ceased
  • 1982-05-05 DE DE8282901886T patent/DE3275057D1/de not_active Expired
  • 1982-05-05 EP EP82901886A patent/EP0078314B1/en not_active Expired
  • 1982-05-05 JP JP57501868A patent/JPS58500695A/ja active Granted

Patent Citations (6)

Non-Patent Citations (2)

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