US20040170610A1 - Compositions comprising bone marrow cells together with demineralized and/or mineralized bone matrix and uses thereof in the induction of bone and cartilage formation - Google Patents

Compositions comprising bone marrow cells together with demineralized and/or mineralized bone matrix and uses thereof in the induction of bone and cartilage formation Download PDF

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US20040170610A1
US20040170610A1 US10/471,031 US47103104A US2004170610A1 US 20040170610 A1 US20040170610 A1 US 20040170610A1 US 47103104 A US47103104 A US 47103104A US 2004170610 A1 US2004170610 A1 US 2004170610A1
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bone
dbm
bmc
cartilage
mbm
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Shimon Slavin
Olga Gurevitch
Basan Kurkalli
Tatyana Prigeshina
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Hadasit Medical Research Services and Development Co
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Hadasit Medical Research Services and Development Co
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Publication of US20040170610A1 publication Critical patent/US20040170610A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/32—Bones; Osteocytes; Osteoblasts; Tendons; Tenocytes; Teeth; Odontoblasts; Cartilage; Chondrocytes; Synovial membrane
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1875—Bone morphogenic factor; Osteogenins; Osteogenic factor; Bone-inducing factor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics

Definitions

  • the present invention relates to compositions comprising bone marrow cells (BMC) and demineralized and/or mineralized bone matrix (DBM and MBM, respectively) and to their novel uses in induction of new bone and cartilage formation in mammals.
  • BMC bone marrow cells
  • DBM demineralized and/or mineralized bone matrix
  • New bone formation such as in the case of damage repair or substitution of a removed part of the bone in postnatal mammals, can only occur in the presence of the following three essential components, (i) mesenchymal progenitor cells; (ii) a conductive scaffold for these cells to infiltrate and populate; and (iii) Bone Morphogenetic Proteins.
  • mesenchymal progenitor cells a conductive scaffold for these cells to infiltrate and populate
  • bone Morphogenetic Proteins Unfortunately, local conditions usually do not satisfy the requirements of osteogenesis, and thus substitution of removed, damaged or destroyed bones does not occur spontaneously.
  • DBM (and/or MBM) has been shown to play the role of supportive material or structure that is essential for promoting engraftment of mesenchymal progenitor cells and their proliferation and differentiation in the course of bone and cartilage development, whenever mesenchymal cells are introduced as a cell suspension (Inventor's unpublished results). It serves as a conductive scaffold for cartilage and bone regeneration, while providing a natural source for inducing both chondro- and osteogenesis, thus combining all the essential inductive and conductive features.
  • DBM also has additional advantageous, that can be summarized as follows: (i) it is mechanically flexible and slowly biodegradable, with the degradation time compatible with the period of de novo chondro- and osteogenesis; (ii) it is strong enough to provide at least partially biomechanical properties of the flat bone and joint surface during the period of new bone and cartilage formation; (iii) it can be provided as an amorphous powder that can be inserted locally, without major surgical intervention, while avoiding iatrogenic damage; (iv) it is a low immunogenic material even when used as a xenograft, and when used in an allogeneic combination, it is practically non-immunogenic [Block, J. E. and Poser, J.
  • BMPs are growth factors that play an important role in the formation of bone and cartilage [Ducy, P. and Karsenty, G. (2000) Kidney Int 57(6):2207-14; Schmitt, J. M. et al. (1999) J Orthop Res 17(2):269-78].
  • DBM is a natural source of BMPs.
  • induction of cartilage and bone may be enhanced by additional exogenous supply of BMPs that are not even species-specific [Sampath, T. K. and Reddi, A. H. (1983) Proc Natl Acad Sci USA 80(21): 6591-5; Bessho, K. et al. (1992) J Oral Maxillofac Surg 50(5):496-501], together with DBM [Niederwanger, M. and Urist, M. R. (1996) J Oral Implantol 22(3-4):210-5].
  • Arthropathies are a group of chronic progressive joint diseases that can result from degenerative changes in the cartilage and hypertrophy of bone at the articular margins. Arthropathies can be secondary to trauma, inflammatory (autoimmune or infectious), metabolic or neurogenic diseases. Hereditary and mechanical factors may be an additional factor involved in the pathogenesis of arthropathies.
  • autologous grafts are the most commonly used bone and cartilage graft material.
  • the use of autografts has limitations, such as donor site discomfort, infection and morbidity and limited sizes and shapes of available grafts. Even if enough tissue is transplanted there is an acute limitation in the number of mesenchymal stem cells with high proliferative potential present in the differentiated bone tissue implanted.
  • the most promising approach should involve the combined transplantation of cells capable of hyaline cartilage formation and a matrix, providing means for induction/conduction and support of cartilage development and maintenance.
  • Conductive scaffold should be non-immunogenic, non-toxic and susceptible to biodegradation simultaneously with the development of new cartilage.
  • composition of the invention comprising BMC and DBM and/or MBM overcomes the above shortcomings and provides, upon administration into a damaged joint, replacement and/or restoration of hyaline cartilage together with subchondral bone, in a one-step transplantation procedure, without any preliminary cultivation of mesenchymal progenitor cells.
  • the present invention relates to compositions comprising a mixture of bone marrow cells (BMC) and demineralized and/or mineralized bone matrix (DBM and MBM, respectively) and to their novel uses in the transplantation of mesenchymal progenitor cells into joints and cranio-facial-maxillary bones.
  • BMC bone marrow cells
  • DBM demineralized and/or mineralized bone matrix
  • the present invention relates to a composition
  • a composition comprising bone marrow cells (BMC) and demineralized bone matrix (DBM) and/or mineralized bone matrix (MBM).
  • BMC bone marrow cells
  • DBM demineralized bone matrix
  • MBM mineralized bone matrix
  • said composition comprising BMC and DBM and/or MBM is for use in transplantation of mesenchymal progenitor cells present in the bone marrow into a joint and/or a cranio-facial-maxillary bone of a subject in need, wherein said subject is a mammal, preferably a human.
  • the DBM and MBM comprised within the composition of the invention are of vertebrate origin, and they may be of human origin.
  • the DBM or MBM comprised within the composition of the invention are in powder or slice form.
  • the particle size of the DBM may be about 50 to 2500 ⁇ . Preferably, said particle size is about 250 to 500 ⁇ . The most preferable particle size will depend on the specific needs of each case.
  • the composition of the invention is for restoring and/or enhancing the formation of a new hyaline cartilage and subchondral bone structure.
  • the composition of the invention is intended for the treatment of a patient suffering from any one of a hereditary or acquired bone disorder, a hereditary or acquired cartilage disorder, a malignant bone or cartilage disorder, conditions involving bone or cartilage deformities and Paget's disease. Additionally, the invention is also intended for the treatment of a patient in need of any one of correction of complex fractures, bone replacement and formation of new bone in plastic or sexual surgery.
  • composition of the invention may further optionally comprise a pharmaceutically acceptable carrier or diluent, as well as additional active agents.
  • the present invention relates to a method for transplantation of a mixture comprising BMC with DBM and/or MBM and optionally further comprising pharmaceutically acceptable carrier or diluent, into a joint and/or a cranio-facial-maxillary bone of a subject in need, wherein said method comprises introducing into said joint or bone the composition of the invention.
  • the mixture is administered by any one of the following procedures injection, minimally invasive arthroscopic procedure, or by surgical arthroplasty into the site of implantation, wherein said method is for support or correction of congenital or acquired abnormalities of the joints, cranio-facial-maxillary bones, orthodontic procedures, bone or articular bone replacement following surgery, trauma or other congenital or acquired abnormalities, and for supporting other musculoskeletal implants, particularly artificial and synthetic implants.
  • the invention relates to a method of treating a damaged or degenerative arthropathy associated with malformation and/or dysfunction of cartilage and/or subchondral bone in a mammal in need of such treatment, comprising administering into an affected joint or bone of said mammal a mixture comprising BMC with DBM and/or MBM, said mixture optionally further comprising a pharmaceutically acceptable carrier or diluent and/or additional active agents.
  • the BMC which are present in the administered mixture are either allogeneic or said mammal's own.
  • the DBM or MBM which is present in the administered mixture is in a slice, powder, gel, semi-solid or solid form embedded in or encapsulated in polymeric or biodegradable materials.
  • the present invention relates to a non-invasive (through injection), minimally invasive (through arthroscopy) or surgical transplantation method for support of implants of joints or other musculoskeletal implants, comprising introducing a graft into a joint or a cranio-facial-maxillary bone of a subject in need, wherein said graft comprises a mixture of BMC and DBM or MBM.
  • the present invention relates to the use of a composition comprising BMC and DBM and/or MBM as a graft of mesenchymal and/or mesenchymal progenitor cells for transplantation/implantation into a mammal, wherein said mammal is preferably a human.
  • the transplantation is to be performed into a joint or into a cranio-facial-maxillary bone, for the development of new bone and/or cartilage.
  • the composition used in said transplantation is intended for the treatment of a patient suffering from any one of a hereditary or acquired bone disorder, a hereditary or acquired cartilage disorder, a malignant bone or cartilage disorder, conditions involving bone or cartilage deformities and Paget's disease.
  • said composition is intended for the treatment of a patient in need of any one of correction of complex fractures, bone replacement and formation of new bone in plastic or sexual surgery.
  • composition used in the invention further comprises an active agent.
  • the DBM and MBM comprised within the composition used in the invention are of vertebrate origin, and they may be of human origin. Moreover, said DBM and MBM may be in powder, strips, thin layers, or slice form.
  • the present invention concerns the use of a mixture of BMC with DBM and/or MBM in the preparation of a graft for the treatment of a bone or cartilage disorder.
  • the present invention provides a kit for performing transplantation into a joint or a cranio-facial-maxillary bone of a mammal of BMC in admixture with DBM and/or MBM, wherein said kit comprises:
  • the kit of the invention may optionally further comprise a carrier and/or a diluent for the BMC and DBM and/or MDM mixture.
  • FIGS. 1 A-L Photomacrographs and micrographs of sagital knee joint sections 2 to 24 weeks after the experimentally created microfracture drilling defect (Picroindigocarmin, PIC, staining).
  • FIG. 1A Photomacrograph of a normal rat knee joint section.
  • FIG. 1B Photomicrograph of the entire normal osteo-chondral complex in the interchondylar region of the femur.
  • FIG. 1C Photomicrograph of the articular cartilage in the normal osteo-chondral complex shown in FIG. 1B.
  • FIG. 1D Microfracture drilling (full thickness defect), immediately after damage.
  • FIG. 1E Micro-fracture left without the implant, two weeks after damage. The drilled hole, filled with connective tissue, can be seen.
  • FIG. 1F Micro-fracture left without the implant, 24 weeks after damage. Regenerated subchondral bone and damaged joint surface constituted of fibro-cartilaginous tissue can be seen.
  • FIG. 1G DBM particles alone were transplanted into defect area, two weeks after transplantation. DBM particles are clearly seen in the site of transplantation surrounded mostly with connective tissue.
  • FIG. 1H DBM particles alone were transplanted into defect area, 24 weeks after transplantation. Regenerated sub-chondral bone and damaged joint surface covered with connective tissue together with fibro-cartilage could be observed.
  • FIG. 1I DBM particles together with BMC were transplanted into defect area, 2 weeks after transplantation. Extensively developing hyaline cartilage surrounding the implanted DBM particles could be seen.
  • FIG. 1J DBM particles together with BMC were transplanted into defect area, 4 weeks after transplantation. Extensively developing hyaline cartilage, as well as considerably degraded DBM particles can be seen.
  • FIG. 1K DBM particles together with BMC were transplanted into defect area, 8 weeks after transplantation. Almost complete regeneration of subchondral bone; surface of the damaged area is built of a continues layer of extensively developing young hyaline cartilage.
  • FIG. 1L DBM particles together with BMC were transplanted into defect area, 24 weeks after transplantation.
  • the histological structure of the regenerated osteo-chondral complex is indistinguishable from normal.
  • FIGS. 2 A-G Laser Capture Microdissection and PCR analysis of cells captured from the newly reconstituted osteochondral complex of the knee joint (6 months after transplantation of DBM with donor male BMC into female recipient).
  • FIG. 2A Laser shot general area, new cartilage formation.
  • FIG. 2B Laser shot cap, new cartilage formation.
  • FIG. 2C Magnification ( ⁇ 20) of laser shot cap, new cartilage formation.
  • FIG. 2D Laser shot general area, new subchondral bone formation.
  • FIG. 2E Laser shot cap, new subchondral bone formation.
  • FIG. 2F Magnification ( ⁇ 20) of laser shot cap, new subchondral bone formation.
  • FIG. 2G Detection of donor-derived cells by PCR analysis. Lanes: 1, DNA size markers ( ⁇ X714 cut with HaeIII), arrows point to the 194 bp-long and 118 bp-long bands, respectively; 2, Amplification of male rat DNA derived from cartilage area of female rat knee joint; 3, Amplification of male rat DNA derived from subchondral bone area of female rat knee joint; 4, Male rat DNA derived from hematopoietic marrow area of female rat knee joint; 5, Internal positive control DNA from male blood.
  • the PCR results confirm the expression of donor derived cells in all the three tissues composing the newly reconstituted osteochondral complex. Abbreviations: Targ. Ar. LCM Kn.
  • FIGS. 3 A-F Correction of the calvarial defect by transplantation of demineralized bone matrix (DBM) and bone marrow cells (BMC) in rats, shown by sagital sections stained with Picroindigocarmin (PIC).
  • DBM demineralized bone matrix
  • BMC bone marrow cells
  • PIC Picroindigocarmin
  • FIG. 3A Photomacrographs of a normal rat cranium. Region marked by a square (D) is shown in FIG. 3B in higher magnification.
  • FIG. 3B Site of the artificial defect (D) in the parietal region of the cranium.
  • FIG. 3C Photomacrograph of the defect area (DA) between the two cut edges.
  • FIG. 3D Photomicrograph of cranial section 8 days after the experimentally created calvarial defect (PIC staining). Defect left untreated. Cut edge (CE) and the fibrous connective tissue can be seen.
  • FIG. 3E Photomicrograph of cranial section 8 days after the experimentally created calvarial defect (PIC staining). DBM particles alone were transplanted into defect area. Actively proliferating fibroblastic cells surrounding the cut edge and DBM particles could be seen.
  • FIG. 3F Photomicrograph of cranial section 8 days after the experimentally created calvarial defect (PIC staining). DBM particles together with BMC were transplanted into defect area. Active remodeling of the transplanted DBM particles, areas of new bone formation are clearly visible. Abbreviations: Norm. Ra. Cran., normal rat cranium; Def., defect; Def. Ar., defect area; Def. Al., defect alone; D., day(s); Po. Transpl., post-transplantation.
  • FIGS. 4 A-L Photomacro- and micrographs of cranial sections 15 and 30 days after the experimentally created calvarial defect (Sagital sections, Picroindigocarmin, PIC, staining).
  • FIG. 4A 15 days post-operation, control (no transplant).
  • FIG. 4B 15 days post-transplantation, transplantation of DBM alone.
  • FIG. 4C 15 days post-transplantation, transplantation of DBM and BMC.
  • FIG. 4D 15 days post-operation, control (no transplant), 10 ⁇ magnification. There is no new bone formation in the area of defect.
  • FIG. 4E 15 days post-transplantation of DBM alone, 10 ⁇ magnification. Remodeling of DBM particles results in bridging the area of defect with the newly formed bone tissue.
  • FIG. 4F 15 days post-transplantation of DBM and BMC, 10 ⁇ magnification.
  • the cut edge of the parietal bone could hardly be distinguished in the continuous uniform layer of actively remodeling bony tissue.
  • FIG. 4G 30 days post-operation, control (no transplant).
  • FIG. 4H 30 days post-transplantation of DBM alone.
  • FIG. 4I 30 days post-transplantation of DBM and BMC.
  • FIG. 4J 30 days post-operation, control (no transplant), 10 ⁇ magnification. There is no new bone formation in the area of defect.
  • FIG. 4K 30 days post-transplantation of DBM alone, 10 ⁇ magnification. Remodeling of DBM particles results in bridging the area of defect with the newly formed bone tissue.
  • FIG. 4L 30 days post-transplantation of DBM and BMC, 10 ⁇ magnification.
  • the cut edge of the parietal bone could hardly be distinguished in the continuous uniform layer of actively remodeling bony tissue.
  • FIGS. 5 A-F Laser Capture Microdissection (LCM) and PCR analysis of cells captured from the newly developing bony tissue in the area of the experimentally created calvarial defect after transplantation of DBM together with donor male BMC to female recipient.
  • LCD Laser Capture Microdissection
  • FIG. 5A General view of the normal rat cranium with the place where the defect was inflicted highlighted (D).
  • FIG. 5B Regenerating bony tissue, area target for LCM.
  • FIG. 5C Higher magnification, area target for LCM.
  • FIG. 5D Laser shot caps; cells captured from this area were used for PCR analysis.
  • FIG. 5E Laser shot caps, 10 ⁇ magnification, cells captured for PCR analysis.
  • FIG. 5F Detection of donor-derived cells by PCR analysis. Lanes: 1, DNA size markers ( ⁇ X714 cut with HaeIII), arrows point to the 194 bp-long and 118 bp-long bands, respectively; 2, male rat DNA derived from bone area of female knee cranium; 3, internal positive control, DNA from male blood.
  • the results of the PCR analysis confirm the expression of donor derived cells in the newly forming bony tissue.
  • BM bone marrow
  • BMC bone marrow cell(s)
  • BMP bone morphogenetic protein
  • DBM demineralized bone matrix
  • MBM mineralized bone matrix
  • PIC Picroindigocarmin, a dye used in histological staining.
  • the present invention relates to compositions comprising a mixture of bone marrow cells (BMC) and demineralized and/or mineralized bone matrix (DBM and MBM, respectively) and to their novel uses in the transplantation of mesenchymal progenitor cells into joints and cranio-facial-maxillary bones.
  • BMC bone marrow cells
  • DBM and MBM demineralized and/or mineralized bone matrix
  • the present invention relates to a composition
  • a composition comprising bone marrow cells (BMC) and demineralized bone matrix (DBM) and/or mineralized bone matrix (MBM).
  • BMC bone marrow cells
  • DBM demineralized bone matrix
  • MBM mineralized bone matrix
  • DBM is a preferable essential ingredient in the composition of the invention in view of its advantageous ability to combine all the features needed for making it an excellent carrier for mesenchymal progenitor cells.
  • the properties of DBM can be summarized as follows:
  • DBM can be a conductive scaffold essential for the engraftment, proliferation and differentiation of mesenchymal progenitor cells, in the course of bone and cartilage formation.
  • DBM is the natural source of BMPs, which are active in stimulating osteo- and chondrogenesis, thus also fulfilling the inductive function.
  • DBM is slowly biodegradable, the degradation time being compatible with the period of de novo chondro- and osteogenesis.
  • DBM has very low immunogenicity when used as a xenograft, and it is practically non-immunogenic when used in allogeneic combinations.
  • DBM is sufficiently flexible and strong to provide biomechanical properties to the joint surface during the period of new cartilage formation.
  • DBM can be provided as an amorphous powder that can be injected locally, without major surgical intervention, thus avoiding iatrogenic damage to complex joints.
  • said composition comprising BMC and DBM and/or MBM is for use in transplantation of mesenchymal cells and/or mesenchymal progenitor cells into a joint and/or a cranio-facial-maxillary area of a subject in need, wherein said subject is a mammal, preferably a human.
  • the DBM and MBM comprised within the composition of the invention are of vertebrate origin, and they may be of human origin.
  • the DBM and MBM comprised within the composition of the invention are in powder or slice form.
  • the particle size of the DBM may be about 50 to 2500 ⁇ . Preferably, said particle size is about 250 to 500 ⁇ . The most preferable particle size will depend on the specific needs of each case.
  • the composition of the invention is for restoring and/or enhancing the formation of a new hyaline cartilage and subchondral bone structure.
  • bone marrow cells may provide a source for mesenchymal stem cells, which are capable of inducing osteo- and chondrogenesis.
  • BMC bone marrow cells
  • the composition of the invention is intended for the treatment of a patient suffering from any one of a hereditary or acquired bone disorder, a hereditary or acquired cartilage disorder, a malignant bone or cartilage disorder, metabolic bone diseases, bone infections, conditions involving bone or cartilage deformities and Paget's disease. Said disorders are listed in detail in Table 1. Additionally, the invention is also intended for the treatment of a patient in need of any one of correction of complex fractures, bone replacement, treatment of damaged or degenerative arthropathy and formation of new bone in plastic or sexual surgery.
  • composition of the invention may further optionally comprise a pharmaceutically acceptable carrier or diluent, as well as additional active agents.
  • a pharmaceutically acceptable (or physiologically acceptable) additive, carrier and/or diluent mean any additive, carrier or diluent that is non-therapeutic and non-toxic to recipients at the dosages and concentrations employed, and that does not affect the pharmacological or physiological activity of the active agent.
  • compositions are well known in the art and has been described in many articles and textbooks, see e.g., Remington's Pharmaceutical Sciences, Gennaro A. R. ed., Mack Publishing Company, Easton, Pa., 1990, and especially pages 1521-1712 therein.
  • Active agents of particular interest are those agents that promote tissue growth or infiltration, such as growth factors.
  • BMPs which may enhance the activity of the composition of the invention.
  • Other exemplary growth factors for this purpose include epidermal growth factor (EGF), osteogenic growth peptide (OGP), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), transforming growth factors (TGFs), parathyroid hormone (PTH), leukemia inhibitory factor (LIF), insulin-like growth factors (IGFs), and growth hormone.
  • Other agents that can promote bone growth such as the above-mentioned BMPs, osteogenin [Sampath et al. (1987) Proc. Natl. Acad. Sci. USA 84:7109-13] and NaF [Tencer et al. (1989) J. Biomed. Mat. Res. 23: 571-89] are also preferred.
  • Other active agents may be anti-rejection or tolerance inducing agents, as for example immunosupressive or immunomodulatory drugs, which can be important for the success of bone marrow allografts or xenografts transplantion.
  • said active agents may be for example antibiotics, provided to treat and/or prevent infections at the site of the graft.
  • anti-inflammatory drugs can also be added to the composition of the invention, to treat and/or prevent inflammations at the site of the graft. Said inflammations could be the result of for example rheumatoid arthritis, or other conditions.
  • Biodegradable materials are pharmaceutically acceptable carriers and diluents.
  • Biodegradable films or matrices, semi-solid gels or scaffolds include calcium sulfate, tricalcium phosphate, hydroxyapatite, polylactic acid, polyanhydrides, bone or dermal collagen, fibrin clots and other biologic glues, pure proteins, extracellular matrix components and combinations thereof.
  • Such biodegradable materials may be used in combination with non-biodegradable materials, to provide desired mechanical, cosmetic or tissue or matrix interface properties.
  • the composition of the invention contains BMC suspensions at cell concentrations ranging from 1 ⁇ 10 6 /ml to 1 ⁇ 10 8 /ml and DBM at a ratio of from 1:1 to 20:1, preferably between 2:1 to 9:1, most preferably the composition of the invention is at a ratio of 4 parts BMC concentrate to 1 part of DBM in powder form (volume:volume).
  • the absolute number of BMC and DBM is dependent on the size of the joint that needs to be corrected or the size (surface, shape and thickness) of the bone that needs to be replaced
  • the present invention relates to a method for transplantation of a mixture comprising BMC with DBM and/or MBM and optionally further comprising pharmaceutically acceptable carrier or diluent, into a joint and/or a cranio-facial-maxillary bone of a subject in need, wherein said method comprises introducing into said joint or bone the composition of the invention.
  • composition of the invention which possesses all the essential features for accomplishing local bone formation wherever it is implanted, could be efficiently applied for all kinds of bone repair or substitution, especially in places lacking or deprived of mesenchymal stem cells.
  • the most problematic places in this sense are joints, cranio-facial-maxillary areas and different kinds of segmental bony defects.
  • the present invention may be explained as a complex graft, comprising all necessary components, and which its implantation into a damaged joint or bone is sufficient for regeneration or substitution of removed, damaged or destroyed cartilage and/or bone.
  • the mixture is administered by any one of the following procedures, injection, minimally invasive arthroscopic procedure, or by surgical arthroplasty into the site of implantation, wherein said method is for support or correction of congenital or acquired abnormalities of the joints, cranio-facial-maxillary bones, orthodontic procedures, bone or articular bone replacement following surgery, trauma or other congenital or acquired abnormalities, and for supporting other musculoskeletal implants, particularly artificial and synthetic implants.
  • the invention relates to a method of treating a damaged or degenerative arthropathy associated with malformation and/or dysfunction of cartilage and/or subchondral bone in a mammal in need of such treatment, comprising administering into an affected joint or bone of said mammal a mixture comprising BMC with DBM and/or MBM, said mixture optionally further comprising a pharmaceutically acceptable carrier or diluent and/or additional active agents.
  • the process of induced development (i.e. proliferation and differentiation) of mesenchymal progenitor cells present within the BMC/DBM mixture can accomplish bone and cartilage formation wherever the mixture is transferred to.
  • the findings presented by the inventors indicate that administration of the composition of the invention into a damaged area of the joint, results in generation of new osteochondral complex consisting of articular cartilage and subchondral bone.
  • the composition of the invention results in generation of full intramembranous bone development at the site of transplantation.
  • New tissue formation follows a differentiation pathway, producing different types of bone and cartilage, depending on the local conditions. Thus, the newly formed tissue meets precisely the local demands.
  • the BMC which is present in the administered mixture are either allogeneic or said mammal's own.
  • the DBM or MBM which is present in the administered mixture is in a slice, powder, gel, semi-solid or solid form embedded in or encapsulated in polymeric or biodegradable materials.
  • the procedure of applying the composition of the invention into a damaged joint or cranial area comprises the following steps:
  • the donor may be allogeneic or the BMC may be obtained from the same treated subject (autologous transplantation).
  • DBM may be supplied commercially and since it is not immunogenic, there are no limitations for a specific donor.
  • DMB and/or MBM may be in powder, granules or in slice form.
  • the particle size of the DBM may be about 50 to 2500 ⁇ . Preferably, said particle size is about 250 to 500 ⁇ . The most preferable particle size will depend on the specific needs of each case.
  • composition comprising a suspension of BMC, at a cell concentration ranging from 1 ⁇ 10 6 /ml to 1 ⁇ 10 8 /ml and mixing it with DBM at a ratio of from 1:1 to 20:1, preferably between 2:1 to 9:1, most preferably the composition of the invention is at a ratio of 4 parts BMC concentrate to 1 part of DBM in powder form (volume:volume).
  • MDM may be used instead of DBM.
  • BMP may optionally be included in the composition.
  • compositions may be administered so that it is encapsulated within normal tissue membranes.
  • the composition may be contained within a membranous device, made of a selective biocompatible membrane that allows cells, nutrients, cytokines and the like to penetrate the device, and at the same time retains the DBM and/or MBM particles within the device.
  • a membranous device, bone strips or additional scaffolds are preferably surgically introduced.
  • the composition may be administered within a biocompatible and biodegradable polymeric device retaining the DBM and/or MBM particles within the device and suitable to create the needed shape of the transplanted complex.
  • the present invention relates to a non-invasive transplantation method comprising introducing a graft into a joint or a cranio-facial-maxillary bone of a subject in need, wherein said graft comprises a mixture of BMC and DBM or MBM.
  • the inventors show that administration of the composition of the present invention (e.g. BMC in admixture with DBM, as in Example 1) into a damaged area of the joint is essential and sufficient for the generation of new osteochondral complex, consisting of articular cartilage and subchondral bone, at the site of transplantation.
  • the newly formed donor-derived osteochondral complex was capable of long-term maintenance, remodeling and self-renewal, as well as carrying out specific functions of joint surface, such as motion and weight bearing.
  • the present invention relates to the use of a composition comprising BMC and DBM and/or MBM as a graft of mesenchymal and/or mesenchymal progenitor cells for transplantation into a mammal, wherein said mammal is preferably a human.
  • the transplantation is to be performed into a joint or into a cranio-facial-maxillary bone, for the development of new bone and/or cartilage.
  • the graft of said transplantation may also be for supporting orthodontical procedures for bone augmentation caused by aging, or by congenital, acquired or degenerative processes.
  • the composition used in said transplantation is intended for the treatment of a patient suffering from any one of a hereditary or acquired bone disorder, a hereditary or acquired cartilage disorder, a malignant bone or cartilage disorder, conditions involving bone or cartilage deformities and Paget's disease.
  • said composition is intended for the treatment of a patient in need of any one of correction of complex fractures, bone replacement, treatment of damaged or degenerative arthropathy and formation of new bone in plastic or sexual surgery.
  • the method of the invention may also be used to induce or improve the efficiency of bone regeneration in damaged cranio-facial-maxillary areas, for therapeutic and cosmetic purposes.
  • composition used in the invention further comprises an additional active agent.
  • the DBM and MBM comprised within the composition used in the invention are of vertebrate origin, and they may be of human origin. Moreover, said DBM and MBM is in powder or slice form.
  • the present invention concerns the use of a mixture of BMC with DBM and/or MBM in the preparation of a graft for the treatment of a bone or cartilage disorder, and/or for support of musculoskeletal implants, as a ‘glue’ to enforce metal implants, joints, etc. that may become lose with time, or to provide a constantly adapting “biological glue” to support such non-biological implants.
  • the invention could be for the support of limb transplants, especially in the articular/bone junction.
  • the present invention provides a kit for performing transplantation into a joint or a cranio-facial-maxillary bone of a mammal of BMC in admixture with DBM and/or MBM, wherein said kit comprises:
  • the kit of the invention may optionally further comprise a carrier and/or a diluent for the BMC and DBM and/or MDM mixture.
  • transplantation of multipotent mesenchymal stem cells, and not of differentiated bone or chondrocytes, for remodeling and restoration of a healthy joint or cranio-facial-maxillary structure in arthropathy, is especially important for the following reasons:
  • Chondrocytes, as well as the cells transferred within a bone transplant are already fully differentiated cells, with relatively low metabolic activity and limited self-renewal capacity that may be sufficient to maintain healthy cartilage or bone, but is certainly insufficient for the development of large areas of bone or of hyaline cartilage de novo.
  • a graft composed of DBM and/or MBM and bone marrow cells transplanted into a damaged joint or cranial bone led to successful replacement of damaged cartilage and subchondral bone.
  • the same kind of a graft composed of DBM and/or MBM and bone marrow cells transplanted into experimentally created partial bone defect in the parietal bone of the cranium led to successful replacement of the removed part of the bone.
  • the new tissue formation follows a differentiation pathway, producing different types of bone and cartilage depending on the local conditions, such that the newly formed tissue meets precisely the local demands.
  • DBM Demineralized bone matrix
  • MBM Mineralized bone matrix
  • the exogenous BMP that is optionally added to the composition of the invention is not a mandatory ingredient.
  • DBM exhibits conductive properties essential for the engraftment, proliferation and differentiation of mesenchymal progenitor cells transplanted within BMC suspension, in the course of bone and cartilage formation.
  • DBM is the natural source of BMPs (bone morphogenetic proteins) active in stimulating osteo- and chondrogenesis, thus fulfilling also the inductive function. Addition of exogenous BMPs may enhance the efficiency of the induction.
  • a standard artificial damage in the articular cartilage and subchondral bone in the rat knee joint was induced as described. Following anesthesia, the knee joint was accessed by a medial parapatellar incision, and the patella was temporarily displaced towards the side. A microfracture drilling (for a full thickness defect) of 1.5 mm in diameter and 2.0 mm in depth was made in the interchondylar region of the femur.
  • the defect was filled with DBM (or MBM) in the form of powder (with particle size of 300-450 micron, or in the form pf slice), alone (control) or together with the BMC suspension, prepared as described above.
  • Another control consisted of transferring only BMC into the damaged area.
  • the transplanted material was fixed in place with fibrinogen-thrombin tissue adhesive glue, the patella was returned into its place and the incision was sutured with bioresorbable thread.
  • the skin was closed with stainless clips.
  • the damaged area was closed with fibrinogen-thrombin tissue adhesive glue only, without the addition of any of DBM, MBM or BMC.
  • PCR analysis of the harvested cells was performed using a set of primers specific to the Sry gene—the sex determination region of the Y chromosome [An, J. et al. (1997) J Androl. 18(3):289-93].
  • the autopsied material was fixed in 4% neutral buffered formaldehyde, decalcified, passed through a series of ethanol grades and xylene, and then embedded in paraffin. Serial sections (5-7 microns thick) were obtained. One set of representative serial sections of each sample was stained with Hematoxylin & Eosin (H&E), and another one with Picroindigocarmin (PIC).
  • H&E Hematoxylin & Eosin
  • PIC Picroindigocarmin
  • FIG. 1 presents the results of experiments carried out to test whether the mesenchymal stem cells present within the bone marrow cells of the composition of the invention could be induced to develop hyaline (articular) cartilage and subchondral bone, when transplanted into the damaged areas of the knee joints.
  • FIGS. 1A, 1B and 1 C show healthy undamaged knee joint of the rat with osteo-chondral complex in the interchondylar region of the femur.
  • FIG. 1D the microfracture drilling (full thickness defect) can be seen immediately after damage.
  • DBM powder mixed with BMC was transplanted into the drilled hole, areas of extensively developing hyaline cartilage surrounding implanted DBM particles were observed already two weeks after transplantation, when slight degradation of DBM particles could be observed (FIG. 1I).
  • FIG. 1J One month after transplantation the DBM particles were already considerably degraded, and areas of extensively developing hyaline cartilage surrounding implanted DBM particles were still present.
  • PCR analysis of isolated cells from different tissues composing newly developed osteo-chondral complex, captured by LCM techniques after implantation of DBM together with BMC into the micro-fracture drilling was performed (FIGS. 2 A-F).
  • the results of the PCR showed the presence of donor derived cells within newly formed articular cartilage and subchondral bone (FIG. 2G). This is strong evidence that active mesenchymal progenitor cells, transplanted within the donor BMC suspension, took an active part in the development of a new osteo-chondral complex.
  • the specificity of the artificial defect model used in the present experiments resided in the penetration of the microfracture drill into the subchondral bone, thus supplying the damaged area with locally existing bone marrow containing mesenchymal progenitor cells potentially capable of restoring both subchondral bone and articular cartilage, when local conditions stimulating osteo- and chondrogenesis were supplied.
  • non-healing cranial defects allow for the observation of both osteo-conductive and osteo-inductive components of the healing process.
  • the non-healing cranial defect represents an appropriate model for evaluating the ability of the composition of the present invention (in this Example, BMC together with DBM) to accomplish intramembranous bone formation when transplanted into a damaged area of the crania.
  • FIG. 3A shows the normal (undamaged) cranium of a rat.
  • FIGS. 3B and 3C show the experimental defect in the parietal bone area.
  • composition of the present invention in this case, DBM together with BMC
  • administration of the composition of the present invention into an experimentally created calvarial defect was sufficient for active and complete intramembranous bone formation at the site of transplantation. This procedure could be extended to treat facial-maxillary defects.

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US7815926B2 (en) 2005-07-11 2010-10-19 Musculoskeletal Transplant Foundation Implant for articular cartilage repair
US7837740B2 (en) 2007-01-24 2010-11-23 Musculoskeletal Transplant Foundation Two piece cancellous construct for cartilage repair
US7901457B2 (en) 2003-05-16 2011-03-08 Musculoskeletal Transplant Foundation Cartilage allograft plug
USRE42208E1 (en) 2003-04-29 2011-03-08 Musculoskeletal Transplant Foundation Glue for cartilage repair
US8292968B2 (en) 2004-10-12 2012-10-23 Musculoskeletal Transplant Foundation Cancellous constructs, cartilage particles and combinations of cancellous constructs and cartilage particles
US8435551B2 (en) 2007-03-06 2013-05-07 Musculoskeletal Transplant Foundation Cancellous construct with support ring for repair of osteochondral defects
US9701940B2 (en) 2005-09-19 2017-07-11 Histogenics Corporation Cell-support matrix having narrowly defined uniformly vertically and non-randomly organized porosity and pore density and a method for preparation thereof
US10077420B2 (en) 2014-12-02 2018-09-18 Histogenics Corporation Cell and tissue culture container
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USRE42208E1 (en) 2003-04-29 2011-03-08 Musculoskeletal Transplant Foundation Glue for cartilage repair
USRE43258E1 (en) 2003-04-29 2012-03-20 Musculoskeletal Transplant Foundation Glue for cartilage repair
US8221500B2 (en) 2003-05-16 2012-07-17 Musculoskeletal Transplant Foundation Cartilage allograft plug
US7901457B2 (en) 2003-05-16 2011-03-08 Musculoskeletal Transplant Foundation Cartilage allograft plug
US8292968B2 (en) 2004-10-12 2012-10-23 Musculoskeletal Transplant Foundation Cancellous constructs, cartilage particles and combinations of cancellous constructs and cartilage particles
US7815926B2 (en) 2005-07-11 2010-10-19 Musculoskeletal Transplant Foundation Implant for articular cartilage repair
US9701940B2 (en) 2005-09-19 2017-07-11 Histogenics Corporation Cell-support matrix having narrowly defined uniformly vertically and non-randomly organized porosity and pore density and a method for preparation thereof
US7837740B2 (en) 2007-01-24 2010-11-23 Musculoskeletal Transplant Foundation Two piece cancellous construct for cartilage repair
US8906110B2 (en) 2007-01-24 2014-12-09 Musculoskeletal Transplant Foundation Two piece cancellous construct for cartilage repair
US8435551B2 (en) 2007-03-06 2013-05-07 Musculoskeletal Transplant Foundation Cancellous construct with support ring for repair of osteochondral defects
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US11583402B2 (en) 2019-07-16 2023-02-21 William Baumgartl Method for treating joint pain

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