Mandibular Cartilage Regeneration In Situ by Endogenous Stem Cell Recruitment

通过内源干细胞募集进行下颌软骨原位再生

• 批准号: 8536785
• 负责人: Wendy S. Vanden Berg-Foels
• 金额: $ 8.8万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8536785
• 关键词: ALCAM gene; Adult; Attention; BMP7 gene; Biocompatible Materials; Biodegradable microsphere; Biological Assay; Biomimetics; Bone Marrow; Cartilage; Cartilage injury; Cell Density; Cells; Chemotaxis; Chemotaxis Induction; Chitosan; Chondrogenesis; Clinic; Clinical; Collagen; Collagen Type I; Data; Defect; Developmental Biology; ENG gene; Eating; Encapsulated; Engineering; Exhibits; Fibroblast Growth Factor 2; Fibrocartilages; Gene Expression; Glycosaminoglycans; Goals; Growth Factor; Healed; Helium; Histocytochemistry; Hyaline Cartilage; Hyaluronic Acid; Hydrogels; In Situ; In Vitro; Ions; Joints; Kinetics; Knee; Mandible; Mandibular Condyle; Mesenchymal Stem Cells; Methods; Microscopy; Microspheres; Morphogenesis; Natural regeneration; Oryctolagus cuniculus; Patients; Phase; Platelet-Derived Growth Factor; Population; Population Heterogeneity; Production; Research; Resolution; SOX9 protein; Signal Transduction; Source; Staging; Stem cells; Structure; Surface; Synovial Cell; Synovial Membrane; Temporomandibular Joint; Testing; Tissues; Translating; articular cartilage; base; bone healing; cartilage regeneration; cell motility; controlled release; crosslink; design; healing; in vitro Assay; in vitro testing; in vivo; innovation; nano; nanoscale; osteochondral tissue; response; success; therapy development

DESCRIPTION (provided by applicant): Temporomandibular joint (TMJ) articular cartilage injuries do not heal, resulting in joint degeneration that interferes with speaking and eating. The TMJ articular surface is unique because it consists of hyaline cartilage overlaid with a proliferative cell and a fibrocartilage layer. TMJ cartilage regeneration has received little attention. Hyaline cartilage regeneration in other joints has been subject to extensive research; however, no effective clinical therapy has been produced. In response, the cartilage regeneration paradigm has begun to shift from empirical approaches to rational biomimetic designs based on developmental biology concepts. Successful healing in adults, such as bone healing, recapitulates tissue morphogenesis and is orchestrated by a cascade of growth factors that induce chemotaxis, proliferation, and differentiation of endogenous mesenchymal stem cells (MSC). Local MSC sources for synovial joints include the synovial membrane (sMSC) and the bone marrow (bMSC). My goal is to develop an in situ therapy, based on endogenous MSC recruitment that will orchestrate regeneration of durable TMJ cartilage. My preliminary data show that 1) synovial cells isolated from the rabbit TMJ exhibit chondrogenesis and ostogenesis in vitro; 2) TGFa and PDGF-bb induce chemotaxis and FGF-2 induces proliferation by synovial cells in vitro; and 3) growth factor delivery in rabbit knee osteochondral defects induced regeneration of immature hyaline cartilage. My guiding hypothesis is that robust in situ cartilage regeneration will be achieved by delivering an optimized growth factor cascade to orchestrate chemotaxis, proliferation, and chondrogenic differentiation by endogenous MSC. We propose to test this hypothesis with the following specific aims: Aim 1: To induce chemotaxis by cells with chondrogenic potential, to expand their population, and to induce robust chondrogenesis in vitro. Aim 2: To design sequential, 3-stage growth factor delivery in vitro, Aim 3: To test our cartilage regeneration therapy in vivo in a rabbit mandibular condyle osteochondral defect, My TMJ cartilage regeneration approach is innovative because 1) engineered growth factor delivery will orchestrate chemotaxis, proliferation, and differentiation by endogenous sMSC and bMSC, 2) the therapy is based on rational design principles and developmental biology concepts, and 3) collagen network integration and maturation will be quantitatively characterized at the nano-scales. This therapy will be easily translated to the clinic to treat patients with TMJ cartilage injuries.

描述（由申请人提供）：颞下颌关节（TMJ）关节软骨损伤无法愈合，导致关节退化，影响说话和进食。的 颞下颌关节面是独特的，因为它是由透明软骨与增殖细胞和纤维软骨层覆盖。颞下颌关节软骨再生很少受到关注。其他关节中的透明软骨再生已经进行了广泛的研究;然而，尚未产生有效的临床治疗。作为回应，软骨再生范式已经开始从经验方法转向基于发育生物学概念的合理仿生设计。成人的成功愈合，如骨愈合，重演了组织形态发生，并通过诱导内源性间充质干细胞（MSC）的趋化性，增殖和分化的生长因子级联精心策划。滑膜关节的局部MSC来源包括滑膜（sMSC）和骨髓（bMSC）。我的目标是开发一种原位疗法，基于内源性MSC募集，将协调持久的TMJ软骨再生。我的初步数据显示：1）从兔TMJ分离的滑膜细胞在体外表现出软骨形成和骨形成; 2）TGF α和PDGF-bb诱导滑膜细胞在体外的趋化性，FGF-2诱导增殖;和3）在兔膝骨软骨缺损中的生长因子递送诱导未成熟透明软骨的再生。我的指导性假设是，通过提供优化的生长因子级联来协调内源性MSC的趋化性、增殖和软骨形成分化，将实现稳健的原位软骨再生。我们建议测试这一假设，具有以下具体目标：目的1：诱导趋化性的细胞与软骨形成的潜力，扩大其人口，并在体外诱导强大的软骨形成。目标二：为了设计体外连续3阶段生长因子递送，目的3：为了在兔下颌骨髁突骨软骨缺损中测试我们的体内软骨再生疗法，我的TMJ软骨再生方法是创新的，因为1）工程化生长因子递送将协调内源性sMSC和bMSC的趋化性、增殖和分化，2）该疗法基于合理的设计原则和发育生物学概念，以及3）胶原网络整合和成熟将在纳米尺度上定量表征。这种疗法将很容易转化为临床治疗颞下颌关节软骨损伤的患者。