Regenerating Hyaline Cartilage Using Nanofibrous Hollow Microspheres and Synergizing TGF-beta and HIF

关节软骨损伤和病变是致残的主要原因，33%的成年人患有此病 人口。最先进的治疗方法严重限制了关节软骨的破坏。组织工程 迄今未能再生高质量的软骨并防止随后的软骨肥大和 退化。我们开发了可生物降解的纳米纤维空心微球(NF-HMS)作为一种新型的 可注射的软骨细胞载体，并成功再生高质量的软骨。为了绕过这两个 自体软骨细胞的短缺和基于细胞的治疗的监管障碍，我们建议 注射新型核因子-HMS促进软骨再生及抑制肥大和退变 运送关键生物分子激活内源性骨髓基质细胞的微载体 (BMSCs)用于透明软骨的再生和抑制。首先，我们将机械地确定是否 HIF-1和/或HIF-2促进软骨形成，防止肥大/退变。第二，我们将 开发转化生长因子-和释放核因子-巨噬细胞集落刺激因子的稳定剂促进兔成软骨细胞分化 人和兔骨髓间充质干细胞的体外和皮下移植模型。第三，我们将用小说 可注射NF-HMS载体协同内源性骨髓间充质干细胞转化生长因子-和缺氧诱导因子活性 在兔骨软骨修复模型中再生和维持高质量的软骨。通过完成 这些具体目标，我们将大幅加深对影响关键因素的认识 软骨生成，软骨再生，防止肥大和软骨退化，领导 涉及一种新的软骨修复疗法，而不使用外源或外源操纵的细胞。这个 在这个项目中开发的理解和策略也可以用于设计其他组织。 1

Traumatized and diseased joint cartilage is the leading cause of disability, afflicting 33% of the adult population. State-of-the-art treatments for destroyed joint cartilage are seriously limited. Tissue engineering has this far failed to regenerate high-quality cartilage and prevent subsequent cartilage hypertrophy and degeneration. We have developed biodegradable nanofibrous hollow microspheres (NF-HMS) as a novel injectable carrier for chondrocytes and successfully regenerated high-quality cartilage. To circumvent both the shortage of autologous chondrocytes and the regulatory barriers to cell-based therapies, we propose to regenerate cartilage and suppress hypertrophy and degeneration by injecting the novel NF-HMS microcarrier that delivers key biological molecules to activate endogenous bone marrow stromal cells (BMSCs) for hyaline cartilage regeneration and suppress. First, we will mechanistically determine whether HIF-1, HIF-2, or both promote chondrogenesis and prevent hypertrophy/degeneration. Second, we will develop TGF- and the HIF stabilizer releasing NF-HMS to facilitate the chondrogenic differentiation of human and rabbit BMSCs using in vitro and a subcutaneous implantation model. Third, we will use the novel injectable NF-HMS carrier to synergize TGF- and HIF activities of endogenous BMSCs in order to regenerate and maintain high-quality cartilage in a rabbit osteochondral repair model. By accomplishing these specific aims, we will substantially deepen our understanding of the key factors that affect chondrogenesis, cartilage regeneration, and prevention of hypertrophy and cartilage degeneration, leading to a novel cartilage repair therapy without using exogenous or exogenously manipulated cells. The understandings and strategies developed in this project can also be utilized to engineer other tissues. 1