CAREER: Reverse-Engineering the Bone-Cartilage Interface for Successful Joint Repair - Coupled with a New Program to Promote Diversity in Rehabilitative Bioengineering

职业：对骨软骨界面进行逆向工程以成功修复关节 - 结合促进康复生物工程多样性的新计划

• 批准号: 1055989
• 负责人: Virginia Ferguson
• 金额: $ 44.5万
• 依托单位: University of Colorado at Boulder
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1055989&HistoricalAwards=false
• 关键词: CAREER; Reverse; Engineering; Bone; Cartilage

1055989FergusonThe osteochondral (OC) interface is a region that presents a significant engineering challenge in that it experiences rigorous shear and compressive stresses, yet it joins together two highly dissimilar tissues: stiff bone and soft cartilage. Surprisingly, the OC interface is robust and rarely fails in vivo. Cartilage replacements for joint repair have had better success when integrated into the OC interface and underlying bone. However tissue-engineering approaches have not produced a viable replacement material, in part due to a limited understanding of how the biologic tissue is formed and structured to facilitate stress transfer across the interface. The transition between bone and cartilage necessitates sophisticated measures for functional grading of mineral and extracellular matrix content, composition, and organization. Only by mimicking both the properties and the underlying function of the biologic tissue can we successfully engineer solutions for joint repair that function like and integrate into surrounding healthy tissue. To realize the PI's long-term goal of reverse-engineering the osteochondral interface for successful joint repair, two aims are proposed: Aim 1: Investigate mechanisms of load transfer across the osteochondral interface in synovial and cartilaginous joints by characterizing: (1) gradation of mechanical properties at multiple scales, (2) content, composition, organization and spatial distribution of mineral and extracellular matrix, and (3) the 3-D structure of the mineralized interface. Aim 2: Engineer functionally-graded materials that recapitulate and enable study of specific microstructural characteristics of the osteochondral interface. We seek to engineer materials to investigate the mechanical contribution of single functional grading mechanisms at relevant length scales such as step-wise decreases in mineral content, mineralized particles that are graded in density and connectivity, or aligned collagen fibers that extend from the cartilage into the adjacent mineralized region. Finite element models will enable assessment of the biologic tissue and engineered materials. Finally, we aim to engineer a complex OC interface that includes several of the most important functional grading mechanisms; where material design will be informed by characterization in Aim 1. The educational goals of this CAREER proposal are to: 1) continue inclusion of underrepresented minority and female students in the PI's research program and 2) improve recruitment and retention of 1st and 2nd year underrepresented minority and women students through graduate-student mentored research experiences that largely focus on rehabilitation or enabling technologies for those with disabilities. In pursuit of this goal, the PI is piloting a new program: "Your Own Undergraduate Research Experience at CU", YOU'RE @ CU, in 2010-11 that targets freshman and sophomores to work in research labs, improves retention in engineering, encourages vertical integration of learning, and engages undergraduates to seek graduate degrees. Graduate student mentors will gain mentoring experience and benefit from a work-life-career seminar series. The end goal is to generate a pipeline of engineers who consider research careers and especially to excite students about using engineering for applications in rehabilitation and enabling assistive technology development. Intellectual Merit: This proposed research will enable advancements in engineering solutions for common, debilitating orthopedic problems, such as osteoarthritis and spinal disc degeneration, and an improved understanding of how nature anchors soft and hard materials to facilitate load transmission. Overall, this CAREER award will enable the PI to expand her current investigation of the osteochondral interface, further extend her research program into the areas of tissue engineering, and enable her to later study a range of clinically-relevant orthopedic research questions. Broad Impact: Joint disease is one of the most frequent causes of disability in the United States, where osteoarthritis and degenerative disc disease in the spine affect 27 and 65 million Americans per year, respectively. Current efforts in osteochondral tissue-engineering are limited by the lack of understanding of how the native tissue transmits loads and resists failure. Further, engineering solutions, including surgical insertion of orthopedic devices, require improved understanding of the OC interface to ensure matching of functional behavior with the surrounding tissue. In addition, a multidisciplinary approach to study such problems will be used to develop student's critical thinking skills by using engineering concepts and tools to study biological and medical problems to develop solutions for rehabilitation and disabilities through the PI's laboratory and throughout the CU College of Engineering via a new program, YOU'RE@CU, where lowerclassmen will engage in a graduate student-mentored research experience

1055989 Ferguson骨软骨（OC）界面是一个存在重大工程挑战的区域，因为它经历严格的剪切和压缩应力，但它将两种高度不同的组织连接在一起：硬骨和软软骨。令人惊讶的是，OC界面是稳健的，很少在体内失效。用于关节修复的腕关节置换在整合到OC界面和底层骨中时具有更好的成功率。然而，组织工程方法还没有产生可行的替代材料，部分原因是对生物组织如何形成和结构化以促进跨界面的应力传递的理解有限。骨和软骨之间的过渡需要对矿物质和细胞外基质含量、组成和组织的功能分级进行复杂的测量。只有通过模仿生物组织的特性和潜在功能，我们才能成功地设计出关节修复的解决方案，使其功能与周围的健康组织相似并融入其中。为了实现PI对骨软骨界面进行逆向工程以成功修复关节的长期目标，提出了两个目标：目标1：通过表征研究滑膜和软骨关节中骨软骨界面的载荷传递机制：（1）在多个尺度下的机械性能分级，（2）矿物质和细胞外基质的含量、组成、组织和空间分布，（3）矿化界面的三维结构。目标二：设计功能分级材料，以概括并研究骨软骨界面的特定微观结构特征。我们试图设计材料，以研究相关长度尺度下单一功能分级机制的机械贡献，例如矿物质含量逐步减少，密度和连接性分级的矿化颗粒，或从软骨延伸到相邻矿化区域的对齐胶原纤维。有限元模型将能够评估生物组织和工程材料。最后，我们的目标是设计一个复杂的OC界面，其中包括几个最重要的功能分级机制;其中材料设计将根据目标1中的特征来确定。该职业建议的教育目标是：1）继续将代表性不足的少数民族和女学生纳入PI的研究计划，2）通过研究生指导的研究经验，主要集中在残疾人的康复或使能技术，改善第一和第二年代表性不足的少数民族和女学生的招聘和保留。为了实现这一目标，PI正在试行一个新的计划：“你自己的本科研究经验在CU”，你@ CU，在2010-11年，目标是新生和学生在研究实验室工作，提高工程保留，鼓励学习的垂直整合，并从事本科生寻求研究生学位。研究生导师将获得指导经验，并从工作生活职业系列研讨会中受益。最终目标是产生一个考虑研究职业的工程师管道，特别是激发学生将工程应用于康复和辅助技术开发。智力优势：这项拟议的研究将推动常见的、使人衰弱的骨科问题（如骨关节炎和椎间盘退变）的工程解决方案的进步，并更好地了解自然界如何锚定软硬材料以促进载荷传递。总的来说，这项职业奖将使PI能够扩大她目前对骨软骨界面的研究，进一步将她的研究计划扩展到组织工程领域，并使她能够在以后研究一系列临床相关的骨科研究问题。广泛影响：在美国，关节疾病是最常见的残疾原因之一，其中脊柱中的骨关节炎和退行性椎间盘疾病每年分别影响2700万和6500万美国人。目前在骨软骨组织工程方面的努力受到缺乏对天然组织如何传递载荷和抵抗失效的理解的限制。此外，工程解决方案，包括骨科器械的手术插入，需要提高对OC界面的理解，以确保功能行为与周围组织的匹配。此外，一个多学科的方法来研究这些问题将被用来发展学生的批判性思维能力，通过使用工程概念和工具来研究生物和医学问题，通过PI的实验室和整个CU工程学院通过一个新的计划，YOU 'RE @CU，低年级学生将参与研究生指导的研究经验，开发康复和残疾的解决方案