CAREER: Understanding Collagen Microcracks in Soft Tissues Under Normal Body Loads

研究人员已经广泛地描述了骨关节炎中亚毫米级裂缝的特征，但PI的实验室最近发现，通常被认为是无害的撞击实际上会导致人类软骨胶原蛋白中的微米级裂缝。这些微裂纹可能导致临床前骨关节炎，但在正常日常活动中，它们在重复负荷下生长的程度尚不清楚。这个教师早期职业发展（CAREER）计划奖支持基础研究，通过验证新的计算机模拟与新的实验数据来了解软组织中胶原微裂纹的生长。了解和建模软骨微裂纹可能会导致新的治疗和/或生活方式的改变策略骨关节炎患者。骨关节炎困扰着近20%的美国人口;每年花费超过1855亿美元（2007年）;并导致疼痛，功能限制，收入损失和抑郁症，但我们既不了解其原因也不了解其进展。该研究不仅将表征可能与骨关节炎相关的最早可观察到的恶化迹象之一，而且还将促进其他组织和工程材料的研究。此外，这项研究将整合教育和推广，以促进不同的代表性不足的学生对科学的兴趣。利用软骨作为模型系统，利用健康和受损的人体组织以及NIH资助的骨关节炎倡议的纵向磁共振图像，该奖项将测试正常生理负荷导致临界阈值大小的现有裂缝在软骨胶原蛋白网络中传播的假设。为了量化和预测软组织损伤传播的起源，研究小组将量化软骨成分的微观力学;建立基于图像的多尺度模拟;预测体外微裂纹传播;并测试预测灵敏度。验证研究定量微裂纹扩展离体将确认离体和体内模拟的预测能力。接下来，该团队将使用全膝关节的多尺度模拟来预测生理负荷下体内软骨微裂纹的传播，例如跑步，并测试软骨微裂纹密度增加的区域是否与早期骨关节炎中观察到的软骨变薄相匹配。该团队将利用每一步积极吸引学生。该奖项将提供：（1）微裂纹扩展的基线数据;（2）根据宏观变形预测多孔纤维材料局部微观损伤力学的有效工具;（3）更广泛研究纤维承重组织力学功能的平台技术（例如韧带）和工程材料;（4）对骨关节炎可能途径的机制理解;（5）评估针对早期软骨退变的治疗效果的新标志物;（6）吸引不同学生的教育平台。

Researchers have extensively characterized sub-millimeter-scale fissures in osteoarthritis, but the PI's lab recently discovered that an impact usually considered non-injurious in fact causes micrometer-scale cracks in collagen of human cartilage. These microcracks may lead to pre-clinical osteoarthritis, but the extent to which they grow under repetitive loads during normal daily activities is unknown. This Faculty Early Career Development (CAREER) Program award supports fundamental research to understand growth of collagen microcracks in soft tissues by validating novel computer simulations with new experimental data. Understanding and modeling cartilage microcracks will likely lead to new therapies and/or lifestyle modification strategies for osteoarthritis patients. Osteoarthritis afflicts nearly 20 percent of the US population; costs over $185.5BN a year (2007); and causes pain, functional limitations, lost earnings and depression, yet we understand neither its cause nor progression. The research will not only characterize one of the earliest observable signs of deterioration likely related to osteoarthritis, but also facilitate studies of other tissues and engineering materials. Moreover, this research will integrate education and outreach to promote interest in science among diverse underrepresented students. Leveraging cartilage as a model system, with availability of healthy and damaged human tissues and longitudinal magnetic reasonance images from the NIH-funded Osteoarthritis Initiative, this award will test the hypothesis that normal physiological loading causes existing cracks of a critical threshold size to propagate in the collagen network of cartilage. To quantify and predict origins of soft tissue damage propagation, the research team will quantify the micro-mechanics of cartilage's constituents; establish image-based, multi-scale simulations; predict microcrack propagation ex vivo; and test prediction sensitivity. Validation studies quantifying microcrack propagation ex vivo will confirm the predictive power of ex vivo and in vivo simulations. Next, the team will predict propagation of cartilage microcracks in vivo under physiological loads, e.g. running, using multi-scale simulations of full knee joints, and test whether areas with increased cartilage microcrack density collocate with cartilage thinning observed in early-stage osteoarthritis. The team will leverage every step to actively engage students. This award will provide: (1) baseline data on microcrack propagation; (2) validated tools to predict local micro-mechanics of damage in porous, fibrous materials from macroscopic deformations; (3) platform technologies to more broadly study mechanical function of fibrous load-bearing tissues (e.g. ligaments) and engineering materials; (4) mechanistic understanding of a likely path to osteoarthritis; (5) new markers to evaluate efficacy of therapies targeting early cartilage degeneration; (6) an educational platform to engage diverse students.