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

基本信息

批准号：
8425503
负责人：
Wendy S. Vanden Berg-Foels
金额：
$ 9万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8425503
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

项目摘要

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. PUBLIC HEALTH RELEVANCE: Temporomandibular joint articular cartilage injuries do not heal, resulting in joint degeneration that interferes with speaking and eating. Our goal is to engineer cartilage regeneration by using biomaterials and growth factors to mimic the signaling cascade that occurs during successful healing. Our approach is innovative because it will instruct the patient's own stem cells to regenerate mandibular cartilage, and it will be easy to translate to the clinic to treat patients with temporomandibular joint 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，导致关节退化会干扰说话和进食。这 TMJ关节表面是独一无二的，因为它由透明的透明软骨组成，并带有增殖性细胞和纤维球纤维层。 TMJ软骨再生很少受到关注。其他关节中的透明软骨再生已进行广泛的研究；但是，尚未产生有效的临床疗法。作为回应，软骨再生范式已开始从经验方法转变为基于发展生物学概念的理性仿生设计。成年人的成功愈合，例如骨骼愈合，概括了组织的形态发生，并通过一系列诱导趋化性，增殖和内源性间充质干细胞（MSC）的生长因子的层叠来策划。滑膜接头的本地MSC源包括滑膜（SMSC）和骨髓（BMSC）。我的目标是基于内源性MSC募集，开发原位疗法，该招募将策划耐用的TMJ软骨的再生。我的初步数据表明，从兔子TMJ中分离出的滑膜细胞在体外表现出软骨生成和骨化； 2）TGFA和PDGF-BB诱导趋化性和FGF-2在体外诱导滑膜细胞的增殖； 3）兔膝盖骨软骨缺损的生长因子递送诱导的未成熟透明软骨的再生。我的指导假设是，通过在内源性MSC进行趋化，增殖和软骨分化来策划趋化性，增殖和软骨分化，将实现强大的原位软骨再生。我们建议以以下特定目的检验这一假设：目的1：具有软骨生成潜力的细胞诱导趋化性，扩大其种群，并在体外诱导强大的软骨形成。目的2：在体外设计顺序，三阶段生长因子递送，目的3：在体内测试我们的软骨再生治疗在兔下颌cond骨骨软骨缺陷中的体内，我的TMJ软骨再生方法是创新的以及发育生物学概念以及3）胶原网络的整合和成熟将在纳米级定量表征。该疗法将很容易转化为诊所，以治疗TMJ软骨损伤的患者。公共卫生相关性：颞下颌关节关节软骨伤害无法愈合，导致关节退化会干扰说话和饮食。我们的目标是通过使用生物材料和生长因子来模仿成功愈合过程中发生的信号传导级联反应，来设计软骨再生。我们的方法具有创新性，因为它将指示患者自己的干细胞再生下颌软骨，并且很容易转化为诊所来治疗颞紧颌关节软骨损伤的患者。