Unicondylar Resurfacing in an Ovine Osteoarthritis Disease Model

摘要 骨关节炎(OA)是发达国家导致残疾的主要原因之一，在世界上有3000多万成年人受到影响。 美国每年的经济负担超过4860亿美元。晚期骨性关节炎最常用的治疗方法是 关节置换术，但对于较年轻的患者，特别是那些55岁以下的活跃患者来说，这是次优的 生活方式，因为多次翻修手术的发生率很高。对于不断增长的患者群体来说， Cytex正在开发植入物，将专利3D编织技术与添加剂制造相结合，以促进 关节内的软骨和骨再生。植入物的设计是为了支持关节立即承受载荷。 植入时间，并允许骨软骨组织的整合和发展。两人都是无细胞的 植入物和将脱细胞支架与自体细胞相结合的组织工程化植入物 在骨性关节炎的大型动物模型中证明了修复骨软骨损伤和修复的能力 无痛关节功能，延长持续时间。组织工程化植入物尤其适用于 没有强大的内源性细胞来源的患者重新植入无细胞植入物并合成成熟的 体内的细胞外基质。Cytex选择了髋部的髋臼撞击(FAI)作为先导 用于无细胞植入物的试点临床研究的适应症。FAI出现在活跃的年轻患者中，没有 修复导致的骨软骨损伤是一个很好的选择，它会进展为更严重的骨关节炎。组织 工程植入物将跟随脱细胞产品进入临床研究。自体细胞，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 来自骨髓的间充质干细胞(MSCs)，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。同种异体组织工程化材料的制备 对于植入物的临床研究，Cytex必须进一步开发组织工程植入物，以克服特定的 商业化的障碍。该提案的目标是解决这些障碍：1)Cytex必须识别和 开发效力分析，以测量种子细胞的生物活性，并为 那些化验结果。2)Cytex将确定植入物的冷冻保存和储存条件- -货架，因为外科医生和患者不太可能等待几个星期才能定制植入物。 3)组织工程植入物的制造将移交给下列合同制造商 目前的良好制造规范(CGMP)需要获得监管部门的批准。4)Cytex，带有 经验丰富的监管咨询公司，将与美国FDA接洽，讨论临床研究的要求 批准。该项目的高潮将是一种用于软骨修复的现成组织工程植入物。 这将使Cytex能够扩大其植入物组合，并使目前没有 很好的临床选择，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.