Addressing bone marrow lesions that compromise osteochondral tissue repair

Cytex Therapeutics Inc., Durham NC

Investigators

Abstract

ABSTRACT Degenerative joint diseases such as osteoarthritis (OA) remain the source of significant pain and disability, affecting over 30 million adults with an annual US economic burden of more than $486 billion. Joint replacement is a well-established procedure, but its finite life span makes this treatment unacceptable for younger (under 65) or more active individuals. For this growing patient population, Cytex is developing implants pairing a patented 3D weaving technology with additive manufacturing to facilitate cartilage and bone regeneration. The implant is designed to support joint loading immediately upon implantation and to allow integration and development of osteochondral tissue. Other cartilage repair treatments have promising clinical results, but can lead to the formation of fibrous tissue, apoptosis, and further cartilage degeneration. Further, in the knee, subchondral bone marrow cysts, bone marrow lesions (BML), and edema commonly undermine cartilage repair, with iatrogenic damage to the subchondral bone resulting in considerable and complex issues for long-term clinical outcomes from the repair procedure. Cytex implants have demonstrated the capability of repairing osteochondral lesions and restoring pain-free joint function for extended durations in large animal models of hip OA. Conversely, in the knee joint, we have routinely observed significant BMLs that result in graft failure. The ingress of synovial fluid with pro-inflammatory cytokines into the bone is a proposed mechanism for BML formation. Based on this mechanism, we established an animal model of BMLs alongside imaging optimization for detection of BMLs. The objective of the current proposal is to develop and test an acellular implant specific to cartilage repair in the knee and other joints where BMLs are common. We hypothesize that reducing implant permeability at the time of implantation will prevent the ingress of synovial fluid into the bone cavity and prevent BMLs, allowing the implant to restore joint congruity. Building on our pilot work, we will incorporate crosslinked hyaluronic acid (HA) gels into our 3D woven textile. These HA gels have shown relative impermeability and limited inflammatory response in vivo. We will select an optimized gel based on sustained relative impermeability while allowing for significant in vitro gel degradation over 8 weeks. In an in vivo study, the resulting HA-gel implants will be compared against an unmodified acellular implant (permeable control) and microfracture (“standard of care” control) with success criteria based on BML severity, OA severity, and implant functional characteristics (mechanical properties and cartilage repair). Forming a temporary biological barrier in the textile component of our implant should prevent the formation of a BML while also ensuring the ability of the Cytex implant to repair and regenerate the damaged cartilage in the knee.