Gradient-based strategy for osteochondral regeneration

基于梯度的骨软骨再生策略

• 批准号: 8451200
• 负责人: Michael S. Detamore
• 金额: $ 24.17万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8451200
• 关键词: Adult; Affect; American; Anabolism; Animal Model; Arthritis; Biocompatible Materials; Biological Process; Biology; Blood Cells; Bone Marrow; Bone Tissue; Canis familiaris; Cartilage; Cells; Complement; Data; Data Set; Defect; Degenerative polyarthritis; Embryonic Development; Encapsulated; Endothelial Cells; Engineering; Equus caballus; FDA approved; Family suidae; Future; Glycolates; Goals; Gold; Growth Factor; Harvest; Healed; Hematopoietic; Human; Image Analysis; Immune; Immune Tolerance; Implant; In Vitro; Investigation; Joints; Knee; Lead; Length; Life; Ligaments; Mechanics; Mesenchymal; Mesenchymal Stem Cells; Microspheres; Modeling; Muscle; Musculoskeletal; Nanotechnology; Natural regeneration; Nature; Nerve Regeneration; Neurons; Orthopedic Surgery procedures; Orthopedics; Oryctolagus cuniculus; Patients; Preparation; Production; Property; Publishing; Qualifying; Quality of life; Rattus; Relative (related person); Research; Research Personnel; Risk; Signal Transduction; Skin; Source; Stem cells; Structure; Techniques; Technology; Tendon structure; Testing; Tissue Engineering; Tooth structure; Transforming Growth Factors; Translational Research; Trauma; Umbilical Cord Blood; Umbilical cord structure; United States; Veins; Wound Healing; base; bone; bone morphogenetic protein 2; clinical application; controlled release; cost; design; disability; experience; healing; immunogenicity; immunoregulation; improved; in vivo; innovation; interfacial; joint injury; nanoparticle; new technology; novel; osteochondral tissue; osteogenic; repaired; scaffold; spatiotemporal; statistics; stem cell biology; treatment strategy

The long-term objective of this application is to develop a stem-cell based osteochondral biomaterial that can be used for reconstructing joints damaged by osteoarthritis (OA) and trauma. Toward this objective, we have developed a novel gradient scaffold technology that affords precise spatiotemporal control of the scaffold design, creating both signal (growth factor) and mechanical stiffness gradients of any desired profile. Although signal gradients are vital to embryogenesis, wound healing, and countless other biological processes, they have yet to be systematically investigated in musculoskeletal tissue engineering. Moreover, stiffness gradients remain virtually unexplored in biomaterials, and our unique approach introduces an entirely new technology to accommodate the contrasting mechanical demands of bone and cartilage. Also new to musculoskeletal tissue engineering are umbilical cord matrix stem cells (UCMSCs), which possess tremendous potential with numerous key advantages over other stem cell sources. The overall goal of this proposal is thus to employ a combination of these innovative approaches to engineer seamless osteochondral constructs for the treatment of rabbit knee defects. The significance of the seamless design lies in the ability to create a single, integrated osteochondral tissue instead of discrete bone and cartilage regions. The chief hypothesis is that UCMSCs in a novel gradient-driven scaffold design will lead to a mechanically viable osteochondral construct that will mimic the seamless transition of native tissue from bone to zonally organized cartilage. To test this hypothesis, we propose the following specific aims: 1) to develop and characterize novel scaffolds containing stiffness- and growth factor-gradients, 2) to engineer seamless osteochondral constructs in vitro, and 3) to determine the efficacy of osteochondral constructs in a rabbit knee defect model. Our overall strategy is to develop a heterogeneous scaffold that will contain a mechanical stiffness gradient, increasing from the cartilage region to the bone region, and also release precisely-controlled and opposing gradients of chondrogenic and osteogenic factors to differentiate stem cells. These gradients are accomplished by varying the relative numbers of "osteogenic" and "chondrogenic" microspheres along the scaffold length, which differ in material composition and encapsulated signal. The material composition and growth factor loading for these microspheres will be determined in the design-driven first aim. The gradient-based scaffolds will be seeded with stem cells in the next two aims, where UCMSCs will be compared to the long standing gold standard, bone-marrow derived mesenchymal stem cells (BMSCs), to test the hypothesis that UCMSCs will outperform BMSCs both in vitro and in vivo. Successful completion of this project will deliver gradient-based scaffolds comprised of FDA-approved materials in combination with a readily available, non-controversial, and immune-compatible human cell source. Moreover, this technology will have a high impact on other fields in the future where a gradient or integrated interface is desired, such as nerve regeneration, the ligament/bone interface, and beyond.

这项应用的长期目标是开发一种基于干细胞的骨软骨生物材料，可用于重建骨关节炎和创伤损伤的关节。为了实现这一目标，我们开发了一种新的梯度支架技术，可以对支架设计进行精确的时空控制，创建任何所需轮廓的信号（生长因子）和机械刚度梯度。尽管信号梯度对胚胎发生、伤口愈合和无数其他生物过程至关重要，但它们在肌肉骨骼组织工程中尚未得到系统的研究。此外，刚度梯度在生物材料中几乎没有被探索过，我们独特的方法引入了一种全新的技术来适应骨和软骨的不同机械需求。脐带基质干细胞（UCMSCs）也是肌肉骨骼组织工程的新成员，与其他干细胞来源相比，它具有许多关键优势，具有巨大的潜力。因此，本建议的总体目标是采用