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

1055989弗格森骨软骨(OC)界面是一个具有重大工程挑战性的区域，因为它承受着严格的剪切和压缩应力，但它将两个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接口非常坚固，在活体中很少失败。关节软骨置换术在与OC界面和底层骨结合时取得了较好的修复效果。然而，组织工程方法还没有产生一种可行的替代材料，部分原因是对生物组织如何形成和结构以促进界面上的应力传递的了解有限。骨和软骨之间的过渡需要复杂的措施，对矿物和细胞外基质的含量、组成和组织进行功能分级。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功能类似于周围健康组织并整合到周围健康组织中的关节修复解决方案。为了实现PI对成功修复关节的骨软骨界面进行逆向工程的长期目标，提出了两个目标：目的1：通过表征(1)多尺度力学性能的分级，(2)矿物和细胞外基质的含量、组成、组织和空间分布，以及(3)矿化界面的三维结构，来研究滑膜和软骨关节中通过骨软骨界面的载荷转移机制。目的2：设计功能梯度材料，概括和研究骨软骨界面的特殊微结构特征。我们试图设计材料来研究相关长度尺度上单一功能分级机制的力学贡献，例如矿物质含量的逐步减少，密度和连通性分级的矿化颗粒，或从软骨延伸到邻近矿化区域的排列的胶原纤维。有限元模型将使评估生物组织和工程材料成为可能。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评分机制；其中材料设计将通过目标1中的特征来提供信息。此职业提案的教育目标是：1)继续将未被充分代表的少数族裔和女性学生纳入PI的研究计划，2)通过研究生导师的研究经验，主要侧重于残疾人的康复或使能技术，来改善对未被充分代表的少数族裔和女性学生的招募和留住。为了追求这一目标，PI正在试行一个新项目：“你自己在CU的本科生研究体验”，You‘re@CU，在2010-11年度，目标是一年级和二年级的学生在研究实验室工作，提高工程学方面的留存，鼓励垂直整合学习，并吸引本科生攻读研究生学位。研究生导师将获得指导经验，并从工作-生活-职业研讨会系列中受益。最终目标是培养一批考虑从事研究职业的工程师，特别是激发学生将工程学应用于康复和实现辅助技术开发的兴趣。智力价值：这项拟议的研究将使常见的、使人衰弱的骨科问题(如骨关节炎和脊柱退变)的工程解决方案取得进展，并提高对大自然如何锚定软和硬材料以促进载荷传递的理解。总体而言，这一职业奖项将使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与临床相关的整形外科研究问题。广泛的影响：在美国，关节疾病是导致残疾的最常见原因之一，每年分别有2700万美国人和6500万美国人受到骨性关节炎和脊柱退行性椎间盘疾病的影响。由于缺乏对天然组织如何传递载荷和抵抗失败的了解，目前在骨软骨组织工程方面的努力受到限制。此外，工程解决方案，包括整形外科设备的手术插入，需要更好地了解OC界面，以确保功能行为与周围组织的匹配。此外，还将使用多学科方法来研究此类问题，通过使用工程概念和工具来研究生物和医学问题，以开发康复和残疾的解决方案，通过PI的实验室和整个CU工程学院的一个新计划，You‘s@CU，在那里低年级学生将参与研究生指导的研究体验

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