Addressing bone marrow lesions that compromise osteochondral tissue repair

解决损害骨软骨组织修复的骨髓病变

• 批准号: 10822755
• 负责人: Vincent P Willard
• 金额: $ 28.23万
• 依托单位: CYTEX THERAPEUTICS INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-18 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10822755
• 关键词: 3-Dimensional; Activities of Daily Living; Address; Adult; Affect; Age; Aging; Animal Model; Apoptosis; Biological; Bone Marrow; Bone Regeneration; Bone plates; Cartilage; Characteristics; Clinical; Coagulation Process; Complex; Complication; Contusions; Cyst; Data; Defect; Degenerative polyarthritis; Detection; Deterioration; Development; Economic Burden; Edema; Ensure; Euthanasia; Failure; Femur; Gel; Goals; Health; Hip Joint; Hip Osteoarthritis; Histopathology; Hyaluronic Acid; Image; Implant; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Joints; Knee; Knee Osteoarthritis; Knee joint; Legal patent; Lesion; Life; Longevity; Magnetic Resonance Imaging; Measures; Mechanics; Medial; Methods; Minor; Modeling; Monitor; Morbidity - disease rate; Natural regeneration; Operative Surgical Procedures; Oryctolagus cuniculus; Osteogenesis; Outcome; Pain; Pain Free; Pathology; Patients; Permeability; Phase; Procedures; Quality of life; Replacement Arthroplasty; Reporting; Risk; Robot; Second Look Surgery; Severities; Small Business Technology Transfer Research; Source; Surface; Synovial Fluid; Techniques; Technology; Testing; Textiles; Therapeutic; Thick; Time; Tissues; United States; Viscosity; Work; articular cartilage; biomechanical test; bone; cartilage degradation; cartilage regeneration; cartilage repair; clinical pain; crosslink; cytokine; density; design; disability; graft failure; iatrogenic injury; implantation; in vivo; joint function; joint loading; manufacture; mechanical properties; mortality risk; osteochondral repair; osteochondral tissue; pain relief; patient population; prevent; repaired; scaffold; sheep model; standard of care; subchondral bone; success; tissue repair

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.

抽象的 诸如骨关节炎（OA）等退化性关节疾病仍然是严重疼痛和残疾的来源， 每年的经济烧伤超过4860亿美元，影响超过3000万的成年人。关节更换 是一个完善的程序，但其有限的寿命使得这种治疗对于年轻人来说是不可接受的（65岁以下） 或更多活跃的人。对于这个不断增长的患者人群，Cytex正在开发配对专利 3D编织技术具有增加的制造，以促进软骨和骨骼再生。植入物是 旨在在实施后立即支持关节加载，并允许集成和开发 骨软骨组织。其他软骨修复治疗也有望带来临床结果，但可以导致 形成纤维组织，凋亡和进一步的软骨变性。此外，在膝盖，软骨下骨 骨髓囊肿，骨髓病变（BML）和软骨修复下的水肿 在考虑到长期临床结果的考虑和复杂问题的情况下，对软骨下骨的损害 从维修过程中。 cytex instress已经证明了修复骨软骨病变的能力 并在大型髋关节动物模型中恢复长时间的无疼痛关节功能。相反，在 膝关节，我们通常会观察到导致移植失败的重要BML。滑液的入学 促炎性细胞因子进入骨骼是BML形成的拟议机制。基于此 机理，我们建立了一个BML的动物模型，并进行了成像优化，以检测BML。 当前建议的目的是开发和测试针对软骨修复的细胞植入物 BML常见的膝盖和其他关节。我们假设当时会降低植入物的渗透率 植入将防止滑动流体进入骨腔并防止BML，从而允许 植入物以恢复关节一致性。在我们的飞行员工作的基础上，我们将结合交联的透明质酸（HA） 凝胶进入我们的3D编织纺织品。这些HA凝胶显示出相对不渗透性和有限的炎症性 体内反应。我们将基于持续的相对不渗透性选择优化的凝胶，同时允许 在8周内显着的体外凝胶降解。在一项体内研究中，由此产生的Ha-gel将是 与未修饰的细胞植入物（可渗透对照）和微裂纹（“护理标准”相比 控制）具有基于BML严重程度，OA严重性和植入功能特征的成功标准 （机械性能和软骨修复）。在 我们的植入物应防止形成BML，同时还应确保Cytex植入物的能力 并再生膝盖受损的软骨。