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

使用纳米纤维空心微球并协同 TGF-β 和 HIF 再生透明软骨

基本信息

批准号：
10268987
负责人：
PETER X MA
金额：
$ 26.43万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-23 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10268987
关键词：
Adopted Adult Affect Autologous Biochemical Biological Biomimetics Bone Marrow Cartilage Cell Differentiation process Cell Therapy Cells Chondrocytes Chondrogenesis Clinic Defect Dose Engineering Environment Extracellular Matrix Family Formulation Genetic Transcription Glycolates Histologic Human Hyaline Cartilage Hyperostosis Hypertrophy Hypoxia Hypoxia Inducible Factor Immobilization In Situ In Vitro Injectable Joints Microspheres Modeling Molecular Mus Nanosphere Natural regeneration Nude Mice Oryctolagus cuniculus Oxygen Population Prevention Procedures Regulation Role Shapes Signal Transduction Specificity Stains Standardization Stromal Cells Supporting Cell Symptoms System Techniques Technology Testing Time Tissue Engineering Tissues Transforming Growth Factor beta arthropathies bHLH-PAS factor HLF base biomechanical test cartilage degradation cartilage regeneration cartilage repair controlled release disability gain of function hypoxia inducible factor 1 implantation in vivo loss of function member mimetics minimally invasive nano nanofiber novel novel strategies osteochondral repair osteochondral tissue patient population poly-L-lactic acid prevent repair model repaired self assembly stem cells subcutaneous time use transcription factor wound

项目摘要

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

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维持高质量的软骨。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