The Role of Percolation in the Hydrogel-to-Tissue Transition for Cartilage Growth

活细胞在三维水凝胶中的封装为组织工程提供了巨大的潜力，它为细胞提供了指导性线索，并为新组织的形成提供了结构支持。成功的一个关键障碍是需要将水凝胶的降解/分解与新组织的合成结合起来，以便在从水凝胶到组织的过渡过程中保持机械完整性。该项目结合了计算模型和实验研究，以确定控制水凝胶中组织生长的潜在基本原理。该项目的成果将使水凝胶设计适用于广泛的细胞群，包括那些组织合成能力较差的细胞群（例如老年人），从而使组织工程的方法更加个性化。计划的活动包括K-12和本科生的主动学习模块，这些学生参与研究，以及研究生在材料，组织工程和数学建模界面方面的独特培训机会。该项目的研究目标是深入了解水凝胶中组织生长的基本机制。组织生长过程中的一个功能要求是从水凝胶到组织的无缝过渡，保持三维（3D）结构的机械完整性。在过渡期间保持连通性的一种方法是通过由水凝胶和组织组成的互穿网络共存，这是机械渗透理论所描述的概念。为此，该项目将机械渗透引入物理驱动的多尺度数学模型中，以捕获负责水凝胶降解和新组织生长的机制。采用综合实验和计算方法，该项目的总体研究目标是(a)在细胞水平上证明对凝胶到组织过渡的合理控制，(b)建立中尺度异质性以控制从凝胶到组织的机械过渡，以及(c)应用模型辅助方法设计水凝胶，实现凝胶到组织的无缝过渡，跨越不同类型的供体，其组织合成能力各不相同。从这项研究中获得的知识将填补我们目前对水凝胶中组织生长的理解的关键空白，并将有助于水凝胶在组织工程中应用的成功翻译。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

The encapsulation of living cells in a three-dimensional hydrogel offers tremendous potential for tissue engineering by providing instructive cues to cells and a structural support for new tissue formation. A critical barrier to success is the need to couple the degrading/breaking down of the hydrogel to the synthesis of new tissue in order to maintain mechanical integrity during the transition from hydrogel to tissue. This project combines computational modeling and experimental studies to identify the underlying fundamental principles that govern tissue growth in a hydrogel. The outcomes from the project will enable hydrogel designs for a wide range of cell populations including those that have poor tissue synthesis capabilities (e.g., older adults), thus enabling a more personalized approach to tissue engineering. Planned activities include active learning modules for K-12 and undergraduate students, the involvement of these students in research, and unique training opportunities to graduate students at the interface of materials, tissue engineering, and mathematical modeling. The research goal of this project is to gain fundamental insight into the mechanisms that govern tissue growth in hydrogels. A functional requirement in the process of tissue growth is a seamless transition from hydrogel to tissue that retains mechanical integrity of the three-dimensional (3D) construct. One way to maintain connectivity during the transition is through the co-existence of an interpenetrating network made of hydrogel and tissue, a concept described by the theory of mechanical percolation. To this end, this project introduces mechanical percolation into a physically-driven multiscale mathematical model to capture the mechanisms responsible for hydrogel degradation and neotissue growth. Applying an integrated experimental and computational approach, the overall research objectives for this project are to (a) demonstrate rational control over the gel-to-tissue transition at the cellular level, (b) build mesoscale heterogeneities to control the mechanical transition from gel-to-tissue, and (c) apply a model-assisted approach to designing hydrogels that achieve a seamless gel-to-tissue transition across different types of donors whose tissue synthesis capabilities vary. The knowledge gained from this research will fill a critical gap in our current understanding of tissue growth in hydrogels and will aid in the successful translation of hydrogels for use in tissue engineering.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.