Unicondylar Resurfacing in an Ovine Osteoarthritis Disease Model

摘要 骨关节炎（OA）是发达国家残疾的主要原因，影响了世界上3000多万成年人。 美国每年的经济负担超过4860亿美元。晚期OA最常采用全 关节置换术，但这是次优的年轻患者，特别是那些55岁以下谁领导的积极 生活方式，因为多次翻修手术的发生率很高。对于这一不断增长的患者群体， Cytex正在开发植入物，将专利的3D编织技术与增材制造相结合， 关节软骨和骨再生。该植入物设计用于在关节面处立即支持关节负荷。 植入时间，并允许骨软骨组织的整合和发育。既有非细胞的 植入物和将脱细胞支架与自体细胞组合的组织工程化植入物具有 在OA的大型动物模型中证实了修复骨软骨损伤和恢复骨软骨的能力。 无痛关节功能延长时间。所述组织工程化植入物特别适合于 患者没有有效的内源性细胞来源来重新填充无细胞植入物并合成成熟的 细胞外基质。Cytex选择髋关节股骨髋臼撞击（FAI）作为电极导线 无细胞植入物的初步临床研究的适应症。FAI出现在活跃的年轻患者中， 是修复骨软骨损伤的良好选择，骨软骨损伤进展为更严重的OA。组织 工程植入物将跟随脱细胞产品进入临床研究。自动细胞，就像我们的前- 临床研究需要耗时的细胞分离和扩增步骤。相反，Cytex将使用同种异体 来源于骨髓的间充质干细胞（MSC）表达非常低水平的主要 组织相容性复合体（MHC）I类和II类抗原。制备同种异体组织工程 对于临床研究的植入物，Cytex必须进一步开发组织工程植入物，以克服特定的 商业化障碍。该提案的目标是解决这些障碍：1）Cytex必须识别和 开发测定接种细胞生物活性的效价试验，并设定以下验收标准： 这些化验。2)Cytex将确定植入物的冷冻保存和储存条件， 因为外科医生和病人不太可能等上几个星期才能按订单制作植入物。 3)组织工程植入物的制造将转移到合同制造商， 监管批准所需的现行药品生产质量管理规范（cGMP）。4)Cytex，带有 经验丰富的监管咨询公司，将与美国FDA讨论临床研究的要求 批准这个项目的高潮将是一个现成的组织工程植入软骨修复 这将使Cytex能够扩大其植入产品组合，并为目前没有 良好的临床选择，无论是因为他们的高龄或疾病状态。

Abstract Osteoarthritis (OA) is a leading cause of disability in the developed world, affecting over 30 million adults in the US with an economic burden of over $486 billion per year. Advanced OA is most commonly treated with total joint replacement, but this is suboptimal for younger patients, especially those under 55 who lead an active lifestyle, because of the high occurrence of multiple revision surgeries. For this growing patient population, Cytex is developing implants pairing a patented 3D weaving technology with additive manufacturing to facilitate cartilage and bone regeneration in the joint. The implant is designed to support joint loading immediately at the time of implantation and to allow integration and development of osteochondral tissue. Both an acellular implant and a tissue engineered implant that combines the acellular scaffold with autologous cells have demonstrated in large animal models of OA the capability of repairing osteochondral lesions and restoring pain-free joint function for extended durations. The tissue engineered implant is particularly desirable for patients without a potent endogenous cell source to repopulate the acellular implant and synthesize a mature extracellular matrix in vivo. Cytex has chosen femoroacetabular impingement (FAI) in the hip as a lead indication for a pilot clinical study with the acellular implant. FAI presents in active, young patients, with no good option to repair the resulting osteochondral lesions, which progress into more severe OA. The tissue engineered implant will follow the acellular product into clinical study. Autologous cells, as used in our pre- clinical studies, require time-consuming cell isolation and expansion steps. Instead, Cytex will use allogeneic mesenchymal stem cells (MSCs) derived from bone marrow, which express very low levels of major histocompatibility complex (MHC) class I and class II antigens. To prepare the allogeneic tissue engineered implants for clinical study, Cytex must further develop the tissue engineered implant to overcome specific commercialization hurdles. The goal of this proposal is to address these hurdles: 1) Cytex must identify and develop potency assays that measure the biological activity of the seeded cells and set acceptance criteria for those assays. 2) Cytex will identify cryopreservation and storage conditions for the implants to be available off- the-shelf because surgeons and patients are unlikely to wait several weeks for an implant to be made-to-order. 3) manufacturing of the tissue engineered implants will be transferred to a contract manufacturer that follows the current good manufacturing practices (cGMPs) required for regulatory approval. 4) Cytex, with an experienced regulatory consulting firm, will engage with the US FDA to discuss requirements for clinical study approval. The culmination of this project will be an off-the-shelf tissue engineered implant for cartilage repair that will enable Cytex to broaden its implant portfolio and enable treatment for patients that currently have no good clinical options either because of their advanced age or disease state.