WO1994009722A1 - Procede et dispositif de reconstruction du cartilage articulaire - Google Patents

Procede et dispositif de reconstruction du cartilage articulaire Download PDF

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Publication number
WO1994009722A1
WO1994009722A1 PCT/US1993/010050 US9310050W WO9409722A1 WO 1994009722 A1 WO1994009722 A1 WO 1994009722A1 US 9310050 W US9310050 W US 9310050W WO 9409722 A1 WO9409722 A1 WO 9409722A1
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WIPO (PCT)
Prior art keywords
biodegradable
precursor cells
providing
bone
cells
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/US1993/010050
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English (en)
Inventor
John H. Brekke
Richard D. Coutts
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
THM Biomedical Inc
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THM Biomedical Inc
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Filing date
Publication date
Application filed by THM Biomedical Inc filed Critical THM Biomedical Inc
Priority to CA 2147359 priority Critical patent/CA2147359A1/fr
Priority to AU54457/94A priority patent/AU5445794A/en
Priority to BR9307280A priority patent/BR9307280A/pt
Publication of WO1994009722A1 publication Critical patent/WO1994009722A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/38—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells
    • A61L27/3804—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells characterised by specific cells or progenitors thereof, e.g. fibroblasts, connective tissue cells, kidney cells
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Definitions

  • the present invention relates generally to techniques and devices for repair of cartilage defects, and specifically to techniques and devices for repair of articular cartilage defects, and particularly to techniques and devices for repair of articular cartilage defects utilizing cell grafts secured in the articular cartilage deficiency utilizing a carrier formed from biodegradable material such as polylactic acid.
  • Polylactic acid a high-molecular-weight polymer of the cyclic diester of lactic acid, has been utilized as suture material, as surgical dressing following dental extraction, and as surgical rods, plates, and screws.
  • Polylactic acid has several advantages as a biodegradable prosthetic material. It is a nontoxic workable materials which can be manufactured into a spectrum of forms with different physical characteristics; it elicits minimal immunological or inflammatory response and has good tissue compatibility; it allows the gradual ingrowth of fibrous connective tissue; and it undergoes hydrolytic deesterification to lactic acid, a normal metabolite of carbohydrate metabolism.
  • periosteal grafts have been sutured to the end of a polylactic plug such as reported in The Use of Polylactic Acid Matrix and Periosteal Grafts for the Reconstruction of Rabbit Knee Articular Defects, H. P. von Schroeder et al., Journal of Bio edical Materials Research, Volume 25, 329-339 (1991).
  • the source of cells is carried by and locked into place in the lesion by the polylactic plug which serves as a template for bone formation if it is in contact with bone tissue.
  • the biodegradable device utilized in the investigations reported above was formed of polylactic acid and was of the type shown and described in U.S. Patent No. 4,186,443 (which is hereby incorporated herein by reference) .
  • the cells carried by the biodegradable device are the mediators of repair tissue and must become attached at the site of repair in order to effect that repair.
  • the gross structure of the body member of the device is composed of a biologically acceptable, biodegradable polymer arranged as a one piece porous body with "enclosed randomly sized, randomly positioned and randomly shaped interconnecting voids, each void communicating with all the others, and communicating with substantially the entire exterior of the body" (quoted portion from U.S. Patent No. 4,106,448).
  • Polylactic acid (PLA) is the polymer currently used to form the gross structure.
  • Other members of the hydroxy acid group of compounds can also be used.
  • the gross, or macro, structure of the invention fulfills three major functions for osteogenesis: 1) restoration of mechanical architectural and structural competence, 2) provides biologically acceptable and mechanically stable surface structure suitable for genesis, growth and development of new non-calcified and calcified tissue, 3) functions as a carrier for other constituents of the invention which do not have mechanical and structural competence.
  • the microstructure of the body member is composed of a chemotactic ground substance which in a preferred form is hyaluronic acid (HA) .
  • HA hyaluronic acid
  • Interstices of the gross (polylactic acid) structure of the body member are invested with the chemotactic ground substance in the form of a velour having the same architecture of interconnecting voids as described for the gross structure, but on a microscopic scale.
  • chemotactic ground substance microstructure Functions of the chemotactic ground substance microstructure are listed as; 1) attraction of fluid blood throughout the device, 2) chemotaxis for mesenchymal cell migration and aggregation, 3) carrier for osteoinductive and chondroinductive agent(s), 4) generation and maintenance of an electronegative wound environment, 5) agglutination of other connective tissue substances with each other and with
  • SUBSTITUTE SHEET itself.
  • Other examples of chemotactic ground substance are fibronectin and, especially for the reconstruction of articular cartilage, an RGD attachment moiety of fibronectin.
  • the osteoinductive agent bone morphogenetic protein, has the capacity to induce primitive mesenchymal cells to differentiate into bone forming cells.
  • Another osteogenic agent bone derived growth factor, stimulates activity of more mature mesenchymal cells to form new bone tissue.
  • Other biologically active agents which can be utilized, especially for the reconstruction of articular cartilage include transforming growth factor B and basic fibroblastic growth factor.
  • the biodegradable graft substitute device acts as a carrier for precursor cells harvested for the production of connective tissue and secured to the device, with the device and precursor cells secured thereto being press fit into the site of repair.
  • the chemotactic ground substance in the form of an RGD attachment moiety of fibronectin facilitates the attachment of free, precursor cells carried to the repair site.
  • Objects of the present invention include:
  • a biodegradable structure to carry and support a chemotactic ground substance which is in the form of a filamentous velour (having incomplete, interconnecting intersticies) ;
  • Granular form each granule loaded with chemotactic ground substance (hyaluronic acid, fibronectin, an RGD attachment moiety of fibronectin) and biologically active agent (bone morphogenetic protein, bone derived growth factor, transforming growth factor B and/or basic fibroblastic growth factor) ;
  • chemotactic ground substance hyaluronic acid, fibronectin, an RGD attachment moiety of fibronectin
  • biologically active agent bone morphogenetic protein, bone derived growth factor, transforming growth factor B and/or basic fibroblastic growth factor
  • SUBSTITUTESHEET a biodegradable polymer of either solid, open cell eshwork form, or in either form or both forms; Provides a biodegradable structure to carry and support precursor repair cells for repair sites; and Creates conditions and environment for facilitating the attachment of free, precursor cells for carriage to the repair site.
  • FIG. 1 illustrates a sectional view of the gross structure and architecture of the present invention including randomly shaped, randomly positioned, and randomly sized interconnecting voids;
  • FIG. 2 is an enlarged view of FIG. 1;
  • FIG. 3 is a sectional view of the gross polymeric structure after the voids of the gross structure have been invested with velour of chemotactic ground substance;
  • FIG. 4 is an enlarged view of FIG. 3;
  • FIG. 5 is a sectional view of the FIGS. 3 and 4;
  • FIG. 6 is an enlarged view of FIG. 5;
  • FIG. 7 is a diagramatic view of a method for reconstruction of articular cartilage according to the preferred teaching of the present invention.
  • a device and method are provided for treating mammalian bone deficiencies, defects, voids and conformational discontinuities produced by congenital deformities, osseous and/or soft tissue pathology, traumatic injuries (accidental and/or surgical) and functional atrophy.
  • the present invention provides a one piece molded body member composed of four substances, each of which contributes to the invention a specific requirement or requirements for osteoneogenesis. Taken as a whole, the functions of these device constituents are integrated into a single body member which, when implanted into a bone defect, has the capacity to restore architectural and structural integrity, initiate osteoinduction, stimulate osteogenesis, and maintain the biological process of bone formation and remodeling while the host organism is simultaneously biodegrading the body member.
  • the ultimate result of the functioning of this invention is formation of healthy, viable bone tissue where there was not bone before, while, simultaneously, the entire device is hydrolyzed and completely metabolized by the host organism.
  • the body member is composed of four disparate elements. Each of these entities contributes to the invention essential biologic function or functions prerequisite to the processes of osteoneogenesis.
  • Structural Competence gross structure of the invention restores mechanical, architectural and structural competence to the bone defect while it simultaneously provides mechanical support and structural surface areas for the dynamic biological processes of wound healing and osteogenesis;
  • SUBSTITUTESHEET varying degrees of maturation into the wound void from adjacent healthy tissues and from the collateral circulation servicing the wound void;
  • Electronegative Fiel production and maintenance of an electronegative environment within the healing bone wound by electrokinetic and electrochemical means
  • Osteoinduction production by chemical agents of fundamental genetic changes in primitive mesenchymal cells (perivascular pericytes) such that their future course of maturation is predetermined to result in their transformation into mature bone forming cells (osteoblasts) .
  • Osteogenesis stimulation of biosynthetic processes of cells already induced to mature as osteoblasts.
  • Biodegradable Polymeric Macrostructure The gross structure of the body member is composed of a biologically acceptable, biodegradable polymer arranged as a one piece porous body with "enclosed randomly sized, randomly positioned and randomly shaped interconnecting voids, each void communicating with all the others, and communicating with substantially the entire exterior of the body" (quoted portion from U.S. Patent No. 4,186,448).
  • the material currently used to form the gross structure is the polymer of lactic acid (polylactic acid) .
  • polylactic acid polylactic acid
  • This is a specific example of a biodegradable polymer.
  • Lactic acid is a member of the hydroxy acid group of organic compounds.
  • Other members of this group, such as glycolic acid, malic acid and alpha hydroxybutyric acid, can also be polymerized into biodegradable polymer suitable for use in the gross
  • SUBSTITUTESHEET structure of this invention SUBSTITUTESHEET structure of this invention.
  • compounds of other metabolic pathways such as fumaric acid, can be polymerized and used in similar manner.
  • the gross structure is composed of a poly (hydroxy) acid and in the form of an interconnecting, open-cell meshwork, duplicates the architecture of human cancellous bone from the iliac crest and possesses physical property (strength) values at least equal to those of human, iliac crest, cancellous bone for a minimum of 90 days following implantation.
  • Biodegradable Macrostructure is composed of a poly (hydroxy) acid and in the form of an interconnecting, open-cell meshwork, duplicates the architecture of human cancellous bone from the iliac crest and possesses physical property (strength) values at least equal to those of human, iliac crest, cancellous bone for a minimum of 90 days following implantation.
  • the gross, or macro, structure of the invention fulfills three major functions required for osteogenesis. These functions are:
  • Biodegradation of the hydroxy acids is initiated by the process of hydrolysis.
  • the polymer at body temperature, takes on water and is first hydrolyzed to the dimer of lactic acid, lactide. Lactide units are further hydrolyzed to free lactic acid which is then incorporated into adjacent cells and metabolized, via the Kreb's Cycle, to energy (in the form of adenosine triphosphate) , water and carbon dioxide.
  • the microstructure of the body member is composed of a chemotactic ground substance.
  • Glycoproteins such as collagen and fibronectin would be suitable chemotactic ground substances for this invention.
  • the glycosa inoglycan , hyalcronic acid, is another suitable chemotactic ground
  • Hyaluronic acid is the chemotactic ground substance of choice because it is commercially available in quantity and because it possesses several favorable properties in addition to its chemotactic 5 qualities .
  • Hyaluronic acid is a prime constituent of all naturally occurring, mammalian connective tissues (calcified as well as non-calcified connective tissues) .
  • the hyaluronic acid used can be synthesized by bacteria such as that used in known 0 processes. Following purification of the material, the hyaluronic acid can be processed into a velour composed of hyaluronate fibrils with intercalated voids of microscopic dimensions. Each void communicates with all others within the hyaluronic velour. 5 Interstices of the gross (polylactic acid) structure of the body member are invested with chemotactic ground substance, such as the velour of hyaluronic acid. In final form, the velour of chemotactic ground substance completely occludes all of the interstices of the polylactic acid o macrostructure of the body member.
  • the velour of chemotactic ground substance accomplishes several biochemical and biomechanical functions essential for bone wound healing and osteogenesis. These functions, five in number, are listed as follows: 1. Attraction of Fluid Blood - Hyaluronic acid is extremely hydrophilic. It is capable of taking on between 500X and 1,000X its own weight in water. It does, therefore, attract any water based fluid, such as whole blood, blood plasma and serum. This quality of hyaluronate is valuable for drawing fluid blood to all regions of the bone void being treated and establishing a viable blood clot in all areas of the bone void in question. 2. Chemotactic for Mesenchymal Cell Migration and Aggregation - By virtue of its hydrophilia and by
  • hyaluronic acid is an important matrix (or substrate) for embryonic and wound healing mesenchymal cell migrations, proliferations and aggregations. Its presence facilitates movement of undifferentiated mesenchymal cells from their points of origin in surrounding healthy tissues and collateral circulation to all regions of the bone void under treatment. 3.
  • Carrier for Osteoinductive/Osteogenic Aqent(s) By chemical binding, as well as by mechanical entrapment, hyaluronic acid is capable of being joined to osteoinductive/osteogenic agents such as the bone morphogenetic protein (BMP) and the bone-derived growth factor (BDGF) .
  • BMP bone morphogenetic protein
  • BDGF bone-derived growth factor
  • Hyaluronic acid is hydrolyzed by the enzyme, hyaluronidase. This enzyme is produced in the lysoso es of the cells which develop with the hyaluronate polymer matrix.
  • Osteoinduetive/Ostengenic Substance(s) Locates within the organic phase of bone tissue are substances which have the capacity to induce primitive mesenchymal cells to differentiate into bone forming cells (osteoblasts) or stimulate activity of more mature mesenchymal cells. These substances are present in all normal, viable bone tissues as well as in autologous, allogeneic and zenogeneic bone graft specimen. At least two such substances have been identified, isolated, purified, and partially characterized. One of these is the bone-derived growth factor (BDGF); the other is the bone morphogenetic protein (BMP) . Predifferentiated cartilage or osteoprogenetor cells are the target cells for BDGF.
  • BDGF bone-derived growth factor
  • BMP bone morphogenetic protein
  • BDGF is a paracrine-autocrine substance that increases activity of already active desoxyribonucleic acid (DNA) sequences to accelerated activities and rates of replication, presumably by releasing controls or constraints that would normally hold these genes in check.
  • Bone morphogenetic protein (BMP) has, as its target cell, mesenchymal cells which are very primitive, having little or no degree of differentiation. These are know as perivascular parasites. BMP initiates activity of entirely new DNA sequences within these cells which lead to genesis of an entire embryonic type
  • Either or both of these substances is incorporated into the hyaluronic acid microstructure immediately prior to implantation of the device into bone void being treated.
  • these agents are evenly distributed throughout the volume of the body member and are, therefore, evenly distributed throughout the bone void being treated.
  • osteogenesis will be accelerated wherever a more differentiated cartilage or osteoprogenetor cell contacts bone-derived growth factor in the hyaluronic acid microstructure.
  • FIG. 1 is a sectional view of the gross structure and architecture of the present invention consisting of randomly shaped, randomly positioned, randomly sized interconnecting voids.
  • the incomplete partitions of these voids are composed of biodegradable structural polymer.
  • that structural polymer is polylactic acid.
  • the randomly sized, shaped and positioned voids are empty.
  • FIG. 2 is an enlarged view of FIG. 1 to demonstrate more clearly the interconnecting void architecture of the structural polymer.
  • FIG. 3 is a sectional view of the gross polymeric structure shown in FIG. 1 after the voids of the gross structure have been invested with a velour of chemotactic ground substance, such as a glycosaminoglycan or glycoprotein - specifically hyaluronic acid or fibronectin.
  • the dark heavy lines represent the structural biodegradable polymer, polylactic acid, while the fine line network represented the velour of chemotactic ground substance, i.e. hyaluronic acid.
  • FIG. 4 is an enlarged view of FIG. 3 to demonstrate more clearly the relationship between the gross polymeric structure of the device composed of polylactic acid and the micro-structure of the device composed of a filamentous network of chemotactic ground substance.
  • the velour of chemotactic ground substance coats all surfaces of the gross structural polymer with a dense network of glycosaminoglycan or glycoprotein fibrils. This same velour of chemotactic ground substance fills or occludes all void areas between structural polymer partitions with a network of
  • the fibrillar network of chemotactic ground substance velour coating the surfaces of structural polymer is identical with and continuous with the fibrillar network of chemotactic ground substance velour which occludes the voids partioned by the structural polymer.
  • FIG. 5 is a sectional view of the device as shown in FIGS. 3 and 4.
  • the device is being infused with a solution of biologically active agent or agents i.e. the osteoinductive agent known as bone morphogenetic protein.
  • This solution is dispersed throughout the volume of the device, enveloping all of the fibrils of the chemotactic ground substance velour and coating all surfaces of the structural polymer.
  • FIG. 6 is an enlarged view of FIG. 5 to demonstrate more clearly the infusion of biologically active agent solution into the device and the dispersion of this solution throughout the entire volume of the body member.
  • the device facilitates the healing of structural voids in bone and includes a gross structure made form a biodegradable element, providing architecture and structural/mechanical integrity to the bone void being treated; a micro-structure formed from a chemotactic ground substance and integrated throughout spaces in the gross structural component; and a biologically active agent (or agents) and/or therapeutic agent (or agents) carried by either the gross or micro-structural elements or at the interface between the gross and micro-structural components.
  • the device also facilitates the healing of structural voids in bone and includes a gross structure formed from a biodegradable polymer which is either a homogenous poly(hydroxy) acid or a co-polymer of two or more
  • SUBSTITUTESHEET poly(hydroxy) acids a micro-structure formed from a chemotactic ground substance, specifically, a glycosaminoglycan(s) and/or a glycoprotein(s) or a combination of these substances; and biologically and/or therapeutically active agent(s), specifically, an osteoinductive substance known as the bone morphogenetic protein and an osteogenic substance known as the bone-derived growth factor.
  • the device facilitates the healing of structural bone defects whose gross structure, composed of a biodegradable polymer such as polylactic acid, is in the form of partially “enclosed, interconnected, randomly positioned and randomly sized and shaped voids; each void connecting with the others and communicating with the exterior of the body" (quoted portion from U.S. Patent No. 4,186,448).
  • a biodegradable polymer such as polylactic acid
  • the device also facilitates the healing of structural bone defects whose micro-structure, composed of a biodegradable chemotactic ground substance such as the glycosaminoglycan known as hyaluronic acid or the glycoprotein known as fibronectin, is likewise in the form of partially complete, interconnecting, randomly positioned and randomly sized and shaped intersticies; each interstice connecting with all the others and communicating with any exterior location of the chemotactic ground substance.
  • the device also facilitates the healing of structural bone defects in which the filamentous velour of chemotactic ground substance is invested into the interconnecting voids (intersticies) of the polymeric gross structure.
  • Juxtaposition of different forms of the constituent elements occurs as solid form of structural polymer with open-cell meshwork (velour) form of the chemotactic ground substance; solid form of chemotactic ground substance with open-cell meshwork (velour) form of structural polymer; and solid form of chemotactic ground substance with solid form of structural polymer.
  • Therapeutic and/or biologically active agent(s) can be carried by the structural polymer. Therapeutic and/or biologically active agent(s) can be carried by the chemotactic ground substance. Therapeutic and/or biologically active agent(s) can be carried by entrapment between the chemotactic ground substance and the structural polymer at their interface.
  • the polylactate macrostructure and the hyaluronate microstructure are hydrolyzed and metabolized by the variety of mesenchymal cells which compose the genealogy of the osteoblasts, by various scavenger cells such as macrophages and by occasional foreign body giant cells.
  • the bone void volume formerly occupied by constituents of the body member becomes progressively occupied by new bone generated from the multiple foci of osteoneogenesis initiated int he hyaluronic acid microstructure by osteoinductive/osteogenic agents.
  • the device is applied in the same manner as any autologous or allogeneic bone graft material.
  • the macro and micro-structure complex is injected with a solution of sterile water, plasma or serum containing the osteoinductive
  • SUBSTITUTESHEET and/or osteogenic agent bone morphogenetic protein and/or bone derived growth factor
  • osteogenic agent bone morphogenetic protein and/or bone derived growth factor
  • Various flanges, rods, bars and other appendages are used to affix the macrostructure of the device to surrounding healthy bone using wires, screws (also of polylactic acid) and PLA staples and sutures.
  • the macro-structure is formed by a vacuum foaming process using an adaptation of standard lyophilization techniques.
  • the micro-structure is formed by lyophilization of the alcohol gel solution of hyaluronic acid after the interstices of the macrostructure have been invested with the HA gel.
  • the osteoinductive/osteogenic agent is injected into the P A/HA complex structure immediately before the device is inserted into the bone void being treated. This is done by the operating surgeon or a surgical assistant.
  • the open-cell meshwork architecture of hyaluronic acid polymer is composed of hyaluronate in the form of a filamentous velour.
  • This velour is characterized by randomly positioned, randomly shaped and randomly sized voids all of which are incompletely partitioned. These incomplete voids are, in fact, intercommunicating interstices each of which communicates with all of its neighboring voids and possesses and unimpeded avenue of communication with any point on the surface of the hyaluronic acid portion of the device.
  • hyaluronic acid Utilizing the hydrophilic properties of hyaluronic acid, a sterile solution of biologically active agent (in this case the bone morphogenetic protein and/or bone derived growth factor) is evenly distributed throughout the volume of the device and the agent itself is attached to the hyaluronic acid velour such that cells invading the device are attracted to the substance and held in contact with it by virtue of hyaluronate's chemotactic properties.
  • biologically active agent in this case the bone morphogenetic protein and/or bone derived growth factor
  • Electronegative wound environments have been demonstrated to be favorable for osteogenesis.
  • hyaluronate in the form of an open-cell velour, creates an electronegative wound field until it is biodegraded past a critical minimum concentration.
  • chemotactic ground substances are; hyaluronic acid and fibronectin.
  • biodegradable structural polymers are: the poly(hydroxy_ acids (i.e. polylactic acid, polyglycolic acid) and polysulfone.
  • the chemotactic ground substance which in the preferred form is an RGD attachment moiety of fibronectin, the biologically active portion of protecins that function to attach cells, can be carried by the porous macrostructure and specifically can be located in the voids and carried by and separate from the biodegradable polymer preformed into the gross structure, with the voids interconnecting and communicating with all the others and substantially the entire exterior of the gross structure, with the biodegradable polymer being preformed into the gross structure prior to the introduction of the chemotactic ground substance.
  • biological modifiers can be incorporated into the biodegradable device, with the biological modifiers being in the form of growth factors in the most preferred form.
  • Growth factors are the mediators of cellular activity and either up-regulate or down-regulate certain cellular functions, with growth factors being utilized to stimulate cell division or to stimulate the cell to produce the extracellular matrix.
  • biological modifiers such as transforming growth factor B or basic fibroblastic growth factor can be used to enhance cell replication and matrix production in the repair of articular cartilage lesions.
  • SUBSTITUTESHEET utilized to stimulate the appropriate cellular response that in turn would produce the repair.
  • the biodegradable graft substitute device acts as a carrier for cells which have demonstrated the ability to differentiate into cartilage cells, i.e. bone marrow, periosteal, or perichondrial cells, with the latter being preferred. Further, such cells should be blastic, i.e. prepared to divide and produce repair tissue, as opposed to cells which are already differentiated such as cells from articular cartilage.
  • Such autologous precursor cells for the production of connective tissue can be harvested from a variety of sources. Perichondrium, a thin tissue which is attached to the surface of cartilage, can be harvested from a portion of the ribs which is made of cartilage as diagramatically shown in Figure 7.
  • Chondrocytes can be harvested from cartilage, preferably articular cartilage, but also from cartilage of the ribs. They can also be harvested from growth plates from fetal tissue. Bone marrow is present in almost all of the bones of the body and can be harvested by inserting a needle into the space between the bone cortex where the marrow resides and by aspirating from that space. Periosteum is similar to perichondrium except that it invests all of the bones of the body and can be harvested by stripping off of the bone with instruments called periosteal elevator. The selection of the particular source of precursor cells centers around the availability of cells, i.e.
  • Perichondrium and periosteum have precursor cells which have to be freed from the surrounding tissue and their numbers are relatively small.
  • Chondrocytes are cells that have already developed a phenotypic expression and have to be harvested from cartilage. Again, their numbers ar relatively small compared
  • SUBSTITUTE SHEET to the amount of tissue that has to be harvested. Bone marrow is easily harvested but contains a mixture of various cells, and separation of the precursor cells has to be performed. The precursor cells are then secured to the biodegradable device in a manner to maintain their viability and allow the cells to continue to grow, proliferage, and produce the repair matrix. As tissue, perichondrium and periosteum are cut to the desired size of the biodegradable device and can be attached to the biodegradable device by a suturing technique as diagramatically shown in Figure 7, although other techniques such as gluing may be possible.
  • the biodegradable device, attached tissue, and the chemotactic ground substance and preferably the biological modifiers are then transplanted to an articular cartilage defect which has been drilled to create a bone defect of equal surface dimension into which the biodegradable device is press fit to thereby secure the biodegradable device and the tissue sutured thereto in the bone defect which is diagramatically shown in Figure 7.
  • the precursor cells then proliferage and produce a matrix which is identical to normal articular cartilage while bone forms in the biodegradable device in contact with bone tissue, thereby repairing the bone and cartilage defect.
  • chondrocytes and bone marrow require in vitro technical capability and particularly are grown in culture, within or upon the biodegradable device, and need to attach to the biodegradable device by virtue of biological processes. Specifically, receptors in the cells' surface need to attach to the biodegradable device.
  • the chemotactic ground substance which is an RGD attachment moiety of fibronectin in the most preferred form of the present invention facilitates the attachment of
  • the precursor cells can be harvested from either perichondrium, periosteum or bone marrow.
  • the precursor cells are cultured using standard cartilage culturing methods using either the techniques of 1) placing the precursor tissue in culture and allowing the cells to proliferate out of the tissue, or 2) digesting the tissue with collagenase, thereby freeing the cells, which in turn are placed in the culture medium and grown.
  • the precursor cells When the precursor cells have grown to confluence (cells covering the surface of a culture plate) , they are trypsinized to free them from their attachment to the culture plate and are suspended in culture medium at a high concentration in the range of 500 thousand-to-1.5 million per 1-5 mililiter solution .
  • the dry biodegradable device is then placed in the culture medium, allowing the suspended cells to infiltrate the porous structure of the biodegradable device of the preferred form and become attached.
  • the biodegradable device in the preferred form formed of polylactic acid attracts the solution into it, thereby effecting transfer of the cells into the voids of the gross structure.
  • This process of attachment may be assisted by the use of chemotactic and chemoattractant ground substances such as fibronectin and preferably an RGD attachment moiety of fibronectin.
  • the biodegradable device may also be pretreated with growth factors, such as a transforming growth factor B or basic fibroblastic growth factor to assist the process of cell proliferation once the cells are attached to the biodegradable device.
  • growth factors such as a transforming growth factor B or basic fibroblastic growth factor to assist the process of cell proliferation once the cells are attached to the biodegradable device.
  • This composite of the biodegradable device and attached precursor cells is then implanted into the articular cartilage defect which has been drilled to create a bone defect of equal surface dimension into which the biodegradable device is press fit to thereby secure the biodegradable device and the cells cultured thereto in the bone defect as diagrammatically shown in Figure 7.
  • the use of the biodegradable device to secure the periosteum graft or other source of precursor cells in the articular cartilage deficiency is particularly advantageous.
  • the press fit of 5 the biodegradable device into the bone cavity locks the biodegradable device and the attached precursor cells into place without the use of a cover such as a periosteal cover which is very restrictive for use especially in humans.
  • the biodegradable device including the periosteum graft or ° other source of precursor cells attached thereto has peripheral contact with the bone and/or cartilage inside of the lesion.
  • the biodegradable device acts as an osteoconductive and chondroconductive agent serving as a template for bone and cartilage formation if it is in contact with bone and/or cartilage tissue.
  • the biodegradable device and attached precursor cells can be fabricated in a form to totally cover the surface of a joint, replicating the convexities or concavities as well as the dimensions of the joint—corresponding to the particular joint to be treated. In essence, the biodegradable device and attached precursor cells would cap the entire bone surface that contributes to the joint, achieving stability by virtue of an interference fit.

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Abstract

Dispositif biodégradable destiné à faciliter le rétablissement des vides de structure dans les os, les cartilages et les tissus mous. Selon le mode préféré de réalisation, le dispositif comprend une macrostructure poreuse constituée d'un polymère biodégradable et d'une substance fondamentale chimiotactique sous forme d'une fraction de fixation de RGD de fibronectine ayant la forme d'une structure microporeuse. Afin de reconstruire le cartilage articulaire, on fixe des cellules précurseurs prélevées au véhicule biodégradable dont la forme permet sa mise en place sous pression dans la lésion du cartilage articulaire. Selon le mode de réalisation le plus préféré, la substance fondamentale chimiotactique améliore l'intérêt du dispositif biodégradable sur le plan de la fixation de cellules au niveau du site de reconstruction, et facilite la fixation au dispositif biodégradable de cellules précurseurs libres telles que les chondrocytes et la moelle osseuse. Selon le mode de réalisation le plus préféré, on incorpore au dispositif biodégradable des modificateurs biologiques tels que le facteur de croissance transformant B et le facteur de croissance fibroblaste basique, afin d'assurer la médiation de l'activité cellulaire et de réguler les fonctions cellulaires.
PCT/US1993/010050 1988-03-14 1993-10-20 Procede et dispositif de reconstruction du cartilage articulaire Ceased WO1994009722A1 (fr)

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CA 2147359 CA2147359A1 (fr) 1992-10-20 1993-10-20 Methode et dispositif de reconstitution du cartilage articulaire
AU54457/94A AU5445794A (en) 1988-03-14 1993-10-20 Method and device for reconstruction of articular cartilage
BR9307280A BR9307280A (pt) 1992-10-20 1993-10-20 Processo e dispositivo para reconstrução de cartilagem articular

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US16737088A 1988-03-14 1988-03-14
US96380992A 1992-10-20 1992-10-20
US07/963,809 1992-10-20

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WO1995031157A1 (fr) * 1994-05-13 1995-11-23 Thm Biomedical, Inc. Dispositif et procedes pour la mise en culture in vivo de diverses cellules tissulaires
EP0692227A1 (fr) * 1994-07-11 1996-01-17 SULZER Medizinaltechnik AG Implant en nappe
EP0814731A4 (fr) * 1995-02-07 1998-04-15 Matrix Biotechnologies Inc Unite de reparation de cartilage
WO1998008469A3 (fr) * 1996-08-30 1998-04-23 Vts Holdings Ltd Methode, instruments et kit de greffe autologue
WO1998052498A1 (fr) * 1997-05-23 1998-11-26 Volkmar Jansson Structures pour le remplacement de l'os ou du cartilage
US5904717A (en) * 1986-01-28 1999-05-18 Thm Biomedical, Inc. Method and device for reconstruction of articular cartilage
US5935594A (en) * 1993-10-28 1999-08-10 Thm Biomedical, Inc. Process and device for treating and healing a tissue deficiency
US5981825A (en) * 1994-05-13 1999-11-09 Thm Biomedical, Inc. Device and methods for in vivo culturing of diverse tissue cells
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WO2008107482A1 (fr) 2007-03-07 2008-09-12 Coloplast A/S Echafaudage pour la régénération des cartilages
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US5935594A (en) * 1993-10-28 1999-08-10 Thm Biomedical, Inc. Process and device for treating and healing a tissue deficiency
US8795242B2 (en) 1994-05-13 2014-08-05 Kensey Nash Corporation Resorbable polymeric device for localized drug delivery
US5981825A (en) * 1994-05-13 1999-11-09 Thm Biomedical, Inc. Device and methods for in vivo culturing of diverse tissue cells
WO1995031157A1 (fr) * 1994-05-13 1995-11-23 Thm Biomedical, Inc. Dispositif et procedes pour la mise en culture in vivo de diverses cellules tissulaires
US8697108B2 (en) 1994-05-13 2014-04-15 Kensey Nash Corporation Method for making a porous polymeric material
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EP0814731A4 (fr) * 1995-02-07 1998-04-15 Matrix Biotechnologies Inc Unite de reparation de cartilage
US6200606B1 (en) 1996-01-16 2001-03-13 Depuy Orthopaedics, Inc. Isolation of precursor cells from hematopoietic and nonhematopoietic tissues and their use in vivo bone and cartilage regeneration
US7902172B2 (en) * 1996-03-05 2011-03-08 Depuy Spine, Inc. Method of promoting bone growth with hyaluronic acid and growth factors
EP1384452A1 (fr) * 1996-08-30 2004-01-28 Verigen Transplantation Service International (VTSI) AG Méthode, instruments et kit pour greffe autologue
US7137989B2 (en) 1996-08-30 2006-11-21 Verigen Ag Method, instruments, and kit for autologous transplantation
US6592599B2 (en) 1996-08-30 2003-07-15 Verigen Transplantation Service International (Vtsi) Method, instruments, and kit for autologous transplantation
US6599301B2 (en) 1996-08-30 2003-07-29 Verrgen Transplantation Service International (Vtsi) Method, instruments, and kit for autologous transplantation
US6599300B2 (en) 1996-08-30 2003-07-29 Verigen Transplantation Service International (Vtsi) Method, instruments, and kit for autologous transplantation
US6569172B2 (en) 1996-08-30 2003-05-27 Verigen Transplantation Service International (Vtsi) Method, instruments, and kit for autologous transplantation
WO1998008469A3 (fr) * 1996-08-30 1998-04-23 Vts Holdings Ltd Methode, instruments et kit de greffe autologue
EP1459709A1 (fr) * 1996-08-30 2004-09-22 Verigen AG Méthode, instruments et kit pour greffe autologue
EP1181908A1 (fr) * 1996-08-30 2002-02-27 VTS Holdings, Ltd. Méthode, instruments et kit pour greffe autologue
US6379367B1 (en) 1996-08-30 2002-04-30 Verigen Transplantation Service International (Vtsi) Ag Method instruments and kit for autologous transplantation
US6592598B2 (en) 1996-08-30 2003-07-15 Verigen Transplantation Service International (Vtsi) Method, instruments, and kit for autologous transplantation
US7048750B2 (en) 1996-08-30 2006-05-23 Verigen Ag Method, instruments, and kits for autologous transplantation
WO1998052498A1 (fr) * 1997-05-23 1998-11-26 Volkmar Jansson Structures pour le remplacement de l'os ou du cartilage
USRE41286E1 (en) 1997-08-14 2010-04-27 Zimmer Orthobiologics, Inc. Compositions for regeneration and repair of cartilage lesions
US6866668B2 (en) 1998-08-14 2005-03-15 Verigen Transplantation Service International (“VTSL”) AG Methods, instruments and materials for chondrocyte cell transplantation
WO2001032107A3 (fr) * 1999-11-02 2002-04-04 Tutogen Medical Gmbh Implant osseux
US6988015B1 (en) 1999-11-02 2006-01-17 Tutogen Medical Gmbh Bone implant
US7867232B2 (en) 1999-12-03 2011-01-11 University Of Leeds Fixation technology
EP1719463A1 (fr) * 1999-12-03 2006-11-08 University Of Leeds Réparation de tissu altéré
US7427284B2 (en) 1999-12-03 2008-09-23 University Of Leeds Fixation technology
WO2001039694A3 (fr) * 1999-12-03 2001-12-20 Univ Leeds Technique de fixation
US7963997B2 (en) 2002-07-19 2011-06-21 Kensey Nash Corporation Device for regeneration of articular cartilage and other tissue
WO2004071354A1 (fr) * 2003-02-12 2004-08-26 Australian Surgical Design And Manufacture Pty Limited Procede et dispositif d'implantation de chondrocytes arthroscopique
WO2008107482A1 (fr) 2007-03-07 2008-09-12 Coloplast A/S Echafaudage pour la régénération des cartilages
US9295762B2 (en) 2007-03-07 2016-03-29 Coloplast A/S Scaffolds for the regeneration of cartilage
US9744123B2 (en) 2009-06-30 2017-08-29 Kensey Nash Corporation Biphasic implant device providing gradient
US10016278B2 (en) 2009-06-30 2018-07-10 Dsm Ip Assets B.V. Biphasic implant device providing joint fluid therapy

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