Addressing bone marrow lesions that compromise osteochondral tissue repair

摘要 退行性关节疾病如骨关节炎（OA）仍然是严重疼痛和残疾的来源， 影响了超过3000万成年人，美国每年的经济负担超过4860亿美元。关节置换 是一个完善的程序，但其有限的寿命使这种治疗不能接受年轻人（65岁以下） 或更活跃的个体。对于这一不断增长的患者群体，Cytex正在开发植入物， 3D编织技术与增材制造，以促进软骨和骨再生。植入物 设计用于在植入后立即支持关节负荷，并允许整合和发展 骨软骨组织其他软骨修复治疗具有有希望的临床结果，但可能导致 纤维组织的形成、细胞凋亡和进一步的软骨退化。此外，在膝盖，软骨下骨 骨髓囊肿、骨髓病变（BML）和水肿通常会破坏软骨修复， 对软骨下骨的损伤导致长期临床结局的相当大和复杂的问题 从修复过程中。Cytex植入物已证明具有修复骨软骨损伤的能力 以及在髋关节OA的大型动物模型中长时间恢复无痛关节功能。相反，在 在膝关节，我们经常观察到导致移植物失败的显著BML。滑液进入 与促炎细胞因子一起进入骨中是BML形成的一种建议机制。基于此 机制，我们建立了一个动物模型的BML的同时成像优化检测BML。 目前建议的目的是开发和测试一种特定于软骨修复的脱细胞植入物， BML常见的膝关节和其他关节。我们假设降低植入物的渗透性 将防止滑液进入骨腔并防止BML， 植入物以恢复关节一致性。在我们的试点工作的基础上，我们将把交联透明质酸（HA） 凝胶到我们的3D纺织品中。这些HA凝胶已经显示出相对的不渗透性和有限的炎症性。 体内反应。我们将根据持续的相对不渗透性选择优化的凝胶，同时考虑到 在8周内显著的体外凝胶降解。在体内研究中，将对所得HA-凝胶植入物进行 与未修饰的无细胞植入物（可渗透对照）和微骨折（“护理标准”）相比， 对照组），成功标准基于BML严重度、OA严重度和植入物功能特征 （机械性能和软骨修复）。在纺织品组件中形成临时生物屏障， 我们的植入物应该防止BML的形成，同时也确保Cytex植入物的修复能力， 并再生膝盖受损的软骨

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.