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

关节软骨损伤和病变是导致残疾的主要原因，33%的成年人患有这种疾病。 人口最先进的关节软骨破坏治疗方法受到严重限制。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， 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 可注射软骨细胞载体，成功再生高质量软骨。为了规避这两个 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 通过注射新型NF-HMS再生软骨并抑制肥大和退化 微载体，其递送关键生物分子以激活内源性骨髓基质细胞 （BMSCs）用于透明软骨再生和抑制。首先，我们将机械地确定是否 HIF-1、HIF-2或两者促进软骨形成并防止肥大/变性。二是 开发TGF-β和HIF稳定剂释放NF-HMS，以促进软骨形成分化， 人和兔BMSCs的体外和皮下移植模型。第三，我们将利用小说 可注射NF-HMS载体以协同内源性BMSC的TGF-β和HIF活性， 在兔骨软骨修复模型中再生并保持高质量的软骨。通过完成 这些具体目标，我们将大大加深我们对影响的关键因素的理解， 软骨形成，软骨再生，防止肥大和软骨退化， 涉及一种不使用外源或外源操纵的细胞的新的软骨修复疗法。的 在这个项目中开发的理解和策略也可以用于工程化其他组织。 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