Engineering Multi-Tissue Interfaces

工程多组织界面

• 批准号: 7906918
• 负责人: Paul Hugo Krebsbach
• 金额: $ 35.26万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7906918
• 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）：阐明关节是一个复杂的系统，经常受到创伤，炎症和代谢过程。在美国，超过2000万人患有症状性骨关节炎，并患有某些关节的衰弱，因此发展干预和再生医学治疗方法是国家的优先事项。我们的项目旨在更了解重建关节关节（例如颞下颌关节（TMJ））的骨/软骨界面的发展。该提案的长期目标是制定策略以重新生成多组织界面，重点是骨骼界面。我们提出了一个基于生物工程脚手架的快速制造的假设和设计驱动的组织工程项目，并具有定制的表面化学，该项目控制着生物活性因子的空间和时间释放，以再生骨骼和软骨界面。该界面的受控产生将通过体内再生基因治疗方法指向。中心假设是，生物活性信号传导因子（BMP-2和SOX9）传递到设计支架的不同区域可以控制响应细胞的谱系承诺以开发骨/软骨界面。 1。定制零件具有精确设计的生物信号传导特性的生物材料的表面化学。聚5-辅助酮（PCL）表面将通过化学蒸气沉积（CVD）进行修饰，以建立具有多种聚合物特性和共轭化学的表面涂层。在这一特定目的中，将开发三种不同的固定模型，以通过生物素/avidin和生物材料相互作用的动态平衡来获得对病毒释放的最大控制。 2。将两个不同的病毒固定在单个支架上以控制特定的生物信号传导因子的传递，并了解这些信号如何控制生物界面的发展。将修改材料表面以控制多个腺病毒的递送。双向CVD还将用于生成信号梯度，以模仿界面处的自然发育信号传导模式。 3。通过使用体内再生基因转移策略在设计的生物材料支架上引导反应性细胞向骨骼和软骨的谱系发展来开发骨骼界面。组织界面将在体内生物材料支架上产生。将通过在脚手架的一个区域和拮抗剂（例如Noggin或相邻表面上的显性负BMP受体）上传递BMP-2来研究界面发育的精度。通过受控的BMP-2（骨）和SOX-9（软骨）的控制递送，将研究骨/软骨界面的发展。 公共卫生相关性：当先天性异常，创伤性伤害或炎症性和退化性疾病涉及诸如颞下颌关节（TMJ）之类的关节时，这种影响通常在物理，财务和情感上衰弱。不幸的是，尽管有数十年的有针对性的临床和基础科学研究，但修复或再生此类关节的建立良好的方法仍然难以捉摸，从而产生了巨大的未满足的临床需求。该提案的长期目标是制定策略来再生骨骼界面，以再生像TMJ这样的加入。