Formation of stable cartilage
Inventors
Robey, Pamela Gehron • Kuznetsov, Sergei • Gorodetsky, Raphael • Hailu-Lazmi, Astar • Shirvan, Mitchell • Featherall, Joseph
Assignees
Hadasit Medical Research Services and Development Co • US Department of Health and Human Services
Publication Number
US-10940241-B2
Publication Date
2021-03-09
Expiration Date
2038-05-31
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Abstract
Methods are provided for promoting cartilage growth and/or repair. The methods include, administering locally to a site in a subject in need thereof, bone marrow stromal cells attached to fibrin microbeads comprising crosslinked hyaluronic acid and thereby producing stable cartilage locally at the site in the subject.
Core Innovation
The invention provides methods for promoting cartilage growth and repair by locally administering bone marrow stromal cells attached to fibrin microbeads comprising crosslinked hyaluronic acid, resulting in the production of stable cartilage at the site in the subject. The bone marrow stromal cells used are naïve, meaning they are undifferentiated and not pre-treated to induce cartilage formation prior to administration.
The problem being addressed is the inability of existing medicinal and surgical approaches to effectively heal cartilage defects such as those caused by osteoarthritis and other degenerative cartilage diseases that affect a large proportion of the elderly population. Previous attempts using pre-differentiated bone marrow stromal cells failed to produce stable, hyaline-like cartilage resistant to hypertrophic mineralization in vivo. There remains a need for methods that utilize naïve bone marrow stromal cells to form stable cartilage in vivo to repair and regrow cartilage effectively.
Claims Coverage
The patent includes one independent claim which covers a method for promoting cartilage growth and/or repair using a combination of bone marrow stromal cells and fibrin microbeads crosslinked with hyaluronic acid. Key inventive features relate to the composition of the microbeads, the nature of the bone marrow stromal cells, and the method of administration.
Method of promoting cartilage growth and/or repair
Administering locally to a site in need in the subject bone marrow stromal cells attached to fibrin microbeads comprising crosslinked hyaluronic acid to produce stable cartilage at the site.
Stable cartilage persistence
The cartilage produced is stable for more than 5 to 8 weeks after administration of the bone marrow stromal cells attached to the fibrin microbeads.
Hyaline-like cartilage formation
The cartilage formed is hyaline-like, expressing type II collagen, aggrecan, or both, and lacks expression of type X collagen beyond 28 weeks, indicating resistance to hypertrophic mineralization.
Bone marrow stromal cell markers
The bone marrow stromal cells used express one or more of CD29, CD73, CD90, CD140b, and CD146, identifying them as naïve bone marrow stromal cells.
Routes and sites of administration
Administration can be via injection, including intra-articular or trans-osseous injection, or via minimally invasive surgical procedures, targeting joints such as the knee, shoulder, wrist, or hip.
Fibrin microbead production and properties
Fibrin microbeads are produced by mixing dense fibrin gel in heated oil at 60 to 80° C., followed by mixing for 4 to 10 hours. The microbeads contain 70% or more fibrin, have a density greater than 1.15 g/mL (preferably 1.25 to 1.35 g/mL), and a mean diameter of 80 to 250 μm. They do not comprise methacrylic anhydride.
Crosslinking of hyaluronic acid to fibrin microbeads
Hyaluronic acid is crosslinked to fibrin microbeads by chemical agents such as 1-ethyl-3-(3-(dimethylamino) propyl) carbodiimide (EDC), divinyl sulfone (DVS), glutaraldehyde (GTA), and/or poly(ethylene glycol) diglycidyl ether (EX 810). The hyaluronic acid has an estimated molecular weight range of about 50,000 to 200,000 Da.
Subject and cell type specifications
The subject treated can be human, and the bone marrow stromal cells can be autologous or human bone marrow stromal cells. The method can also include administering an anti-inflammatory agent, such as a non-steroidal anti-inflammatory drug.
The claims cover a method of producing stable cartilage in vivo by locally administering naïve bone marrow stromal cells attached to fibrin microbeads crosslinked with hyaluronic acid, detailing the scaffold composition, cellular characteristics, administration routes, and cartilage properties to achieve durable, hyaline-like cartilage growth and repair.
Stated Advantages
The method produces stable, hyaline-like cartilage that is resistant to hypertrophic mineralization and persists for prolonged periods in vivo.
Use of naïve (undifferentiated) bone marrow stromal cells enables effective cartilage formation without requiring pre-differentiation.
The fibrin microbeads crosslinked with hyaluronic acid provide a stable scaffold that supports long-lasting cartilage formation and resists vascularization and degradation.
The method enables local administration via minimally invasive techniques, including intra-articular injection, allowing targeted repair in joints.
The approach can potentially restore damaged articular cartilage in vivo, addressing conditions for which current medicinal and surgical treatments are inadequate.
Documented Applications
Treatment and repair of cartilage injury and damage in subjects at risk of or having osteoarthritis, osteochondritis dissecans, osteochondrodysplasias, or other cartilage injuries.
Use in repairing subchondral bone injuries including microtrauma, microfractures, and subchondral fractures associated with cartilage injury.
Local administration to joints such as the knee, shoulder, wrist, and hip for cartilage growth and repair.
Regeneration of cartilage in veterinary subjects, including injection of autologous bone marrow stromal cells with fibrin microbeads into cartilage lesions in animals such as wounded horses.
Use in intra-articular osteochondral defect repair models in murine and rat preclinical models to study cartilage regeneration and repair.
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