Engineering Multi-Tissue Interfaces

工程多组织界面

• 批准号: 7859604
• 负责人: Paul Hugo Krebsbach
• 金额: $ 0.71万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-02 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7859604
• 关键词: Address; Adenoviruses; Avidin; Basic Science; Binding; Biocompatible Materials; Biological; Biomedical Engineering; Biotin; Bone Development; Cartilage; Cells; Chemicals; Chemistry; Clinical; Complex; Custom; Degenerative Disorder; Degenerative polyarthritis; Deposition; Development; Dominant-Negative Mutation; Engineering; Equilibrium; Experimental Models; Future; Gene Transfer; Generations; Immobilization; Individual; Inflammatory; Injury; Joints; Life; Masks; Medical; Metabolism; Methods; Modeling; Natural regeneration; Organism; Pattern; Poly-5; Polymers; Principal Investigator; Property; Protocols documentation; Research; SOX9 protein; Signal Transduction; Surface; System; Temporomandibular Joint; Tissue Engineering; Tissues; Trauma; United States; Viral; Viral Vector; Virus; base; bone; bone morphogenetic protein 2; bone morphogenetic protein receptors; caprolactone; cellular transduction; design; frontier; gene therapy; in vivo; multidisciplinary; programs; public health relevance; reconstruction; regenerative; repaired; scaffold; surface coating; vapor

DESCRIPTION (provided by applicant): The articulating joint is a complex system that is regularly subjected to trauma, inflammatory and metabolic processes. More than 20 million individuals in the United States have symptomatic osteoarthritis and suffer from some debilitation of the joints and therefore developing interventive and regenerative medical cures is a national priority. Our projects are aimed at gaining a greater understanding of the development of bone/cartilage interfaces for the reconstruction of articular joints such as the temporomandibular joint (TMJ). The long-term objective of this proposal is to develop strategies to regenerate multi-tissue interfaces with a focus on the bone-cartilage interface. We propose a hypothesis and design-driven tissue engineering project based on rapid fabrication of bioengineered scaffolds, with custom-tailored surface chemistry, that control the spatial and temporal release of bioactive factors to regenerate the bone and cartilage interface. The controlled generation of this interface will be directed via an in vivo regenerative gene therapy approach. The central hypothesis is that delivery of bioactive signaling factors (BMP-2 and Sox9) to distinct regions of designed scaffolds can control the lineage commitment of responsive cells to develop a bone/cartilage interface. 1. To custom-tailor the surface chemistry of biomaterials with precisely designed biological signaling properties. Poly 5-caprolactone (PCL) surfaces will be modified by chemical vapor deposition (CVD) to establish surface coatings with a variety of polymer properties and conjugation chemistries. Three different immobilization models will be developed in this specific aim to gain maximal control of viral release through a dynamic equilibrium of biotin/avidin and biomaterial interactions. 2. To immobilize two different viruses on a single scaffold to control delivery of specific biological signaling factors and to understand how these signals control the development of a biological interface. Material surfaces will be modified to control the delivery of multiple adenoviruses. Two-way CVD will also be used to generate signaling gradients to mimic natural developmental signaling patterns at an interface. 3. To develop a bone-cartilage interface by directing the lineage progression of responsive cells to bone and cartilage using in vivo regenerative gene transfer strategies on designed biomaterial scaffolds. Tissue interfaces will be generated on biomaterial scaffolds in vivo. The precision of interface development will be studied by delivering BMP-2 on one region of a scaffold and antagonists such as noggin or dominant negative BMP receptors on the adjacent surfaces. The development of bone/cartilage interfaces will be studied in vivo by the controlled delivery of BMP-2 (bone) and Sox-9 (cartilage). PUBLIC HEALTH RELEVANCE: When congenital anomalies, traumatic injuries or inflammatory and degenerative diseases involve an articulating joint such as the temporomandibular joint (TMJ), the effects are often physically, financially and emotionally debilitating. Unfortunately, despite decades of targeted clinical and basic science research, well established methods to repair or regenerate such joints remain elusive, resulting in a significant unmet clinical need. The long-term objective of this proposal is to develop strategies to regenerate the bone-cartilage interface to regenerate joins like the TMJ.

描述（由申请人提供）：关节是一个复杂的系统，经常受到创伤、炎症和代谢过程的影响。在美国，有超过2000万人患有骨关节炎症状，并遭受关节衰弱的折磨，因此发展干预和再生医学治疗是国家的优先事项。我们的项目旨在更好地了解骨/软骨界面的发展，以重建关节关节，如颞下颌关节（TMJ）。本建议的长期目标是开发以骨-软骨界面为重点的多组织界面再生策略。我们提出了一个假设和设计驱动的组织工程项目，基于快速制造生物工程支架，具有定制的表面化学，控制生物活性因子的空间和时间释放，以再生骨和软骨界面。这种界面的受控生成将通过体内再生基因治疗方法进行指导。核心假设是，将生物活性信号因子（BMP-2和Sox9）递送到设计的支架的不同区域可以控制应答细胞的谱系承诺，以形成骨/软骨界面。1. 定制具有精确设计的生物信号特性的生物材料的表面化学。聚5-己内酯（PCL）表面将通过化学气相沉积（CVD）来修饰，以建立具有各种聚合物性能和共轭化学性质的表面涂层。三种不同的固定化模型将通过生物素/亲和素和生物材料相互作用的动态平衡来最大限度地控制病毒释放。2. 将两种不同的病毒固定在一个支架上，以控制特定生物信号因子的传递，并了解这些信号如何控制生物界面的形成。材料表面将被修改以控制多种腺病毒的传递。双向CVD还将用于产生信号梯度，以模拟界面上的自然发育信号模式。3. 在设计的生物材料支架上使用体内再生基因转移策略，通过引导应答细胞向骨和软骨的谱系进展，开发骨-软骨界面。生物材料支架在体内会产生组织界面。通过将BMP-2传递到支架的一个区域，并将拮抗剂（如noggin或显性阴性BMP受体）传递到邻近表面，可以研究界面发育的精度。骨/软骨界面的发展将通过BMP-2（骨）和Sox-9（软骨）的控制递送在体内进行研究。