The 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
