Engineering Bimodal Degrading Hydrogels

描述（由申请人提供）：我们的长期目标是开发用于再生关节软骨的可生物降解的合成水凝胶，其能够支持体内的正常力，同时允许基质沉积和新组织生长。这种水凝胶的开发中的当前限制可以总结如下：（a）高度交联的水凝胶可以抵抗负荷，但限制基质扩散，这防止新组织的生长（B）然而，低交联密度允许基质扩散，但导致不可接受的弱体积性质，其不能维持正常力。因此，这项工作的目的是引入一种水凝胶系统，可以控制其空间和时间降解，以更好地匹配组织发育。我们的总体假设是，双峰降解水凝胶，结合局部和细胞介导的（酶）和散装（水解）降解，保持机械完整性，同时允许基质的发展，并存在一个优化的设计空间，以实现的结果。为了验证我们的假设，将开发数学模型与实验相结合，以准确描述凝胶降解和基质沉积的综合影响。具体而言，该项目的具体目标是：1.开发、验证和校准双峰降解水凝胶的数学模型。这一目标将分解为两部分。首先，我们现有的基质降解模型将被验证对实验测量的基础上加载酶的微粒。第二，ECM的生产和沉积，结合水解降解的模型将开发和验证初步数据。 2.表征单模式和双模式降解水凝胶中的降解行为和基质演变。 该目的将数学模型扩展到双峰降解和ECM沉积的组合的一般情况，以评估水凝胶参数对凝胶降解和ECM沉积之间的竞争的影响。两个实验策略，测试酶和双峰可降解凝胶，然后提出验证和校准模型。在完成这项探索性研究时，我们预计已经开发出一类新的基于交联聚（乙二醇）的双峰降解水凝胶，其中交联可以通过细胞介导的酶促降解（即，由截留的软骨细胞分泌的聚集蛋白聚糖）或水解（即，聚（乳酸）链段）。通过将实验与建模相结合，我们希望清楚地了解双峰可降解凝胶如何用于保持机械完整性，同时允许宏观组织演变。在未来的工作中，该模型系统将使我们能够开发上级可降解水凝胶，这将为竞争性地寻求NIH R01和追求其（前）临床实用性奠定基础。

DESCRIPTION (provided by applicant): Our long-term goal is to develop biodegradable synthetic hydrogels for regenerating articular cartilage, which are capable of supporting the normal forces in vivo while simultaneously permitting matrix deposition and new tissue growth. Current limitations in the development of such hydrogels can be summarized as follows: (a) highly cross-linked hydrogel can resist loads but restrict matrix diffusion, which prevents growth of new tissue (b) reversely, low cross-link density permits matrix diffusion but results in unacceptably weak bulk properties that cannot sustain normal forces. The objective of this work is thus to introduce a hydrogel system for which spatial and temporal degradation can be controlled to better match tissue development. Our global hypothesis is that a bimodal degrading hydrogels, incorporating localized and cell-mediated (enzymatic) and bulk (hydrolytic) degradation, maintains mechanical integrity while simultaneously allowing matrix development and that there exists an optimized design space to achieve the outcomes. To test our hypothesis, mathematical models will be developed in tandem with experiments in order to accurately describe the combined effects of gel degradation and matrix deposition. In particular, the specific aims of the project are to: 1. Develop, validate, and calibrate a mathematical model for bimodal degrading hydrogels. This aim will be decomposed in two parts. First, our existing model for matrix degradation will be validated against experimental measurement based on enzyme-loaded microparticles. Second, a model for ECM production and deposition, combined with hydrolytic degradation will be developed and validated against preliminary data. 2. Characterize degradation behavior and matrix evolution in single and dual mode degrading hydrogel. This aim will extend the mathematical model to the general case of a combination of bimodal degradation and ECM deposition in order to assess the effect of hydrogel parameters on the competition between gel degradation and ECM deposition. Two experimental strategies, testing both enzymatic and bimodal degradable gels, are then proposed to validate and calibrate the model. At the completion of this exploratory research, we expect to have developed a new class of bimodal degrading hydrogels based on crosslinked poly(ethyelene glycol) where the crosslinks can be degraded either through cell-mediated enzymatic degradation (i.e., aggrecanses secreted by entrapped chondrocytes) or hydrolytically (i.e., poly(lactic acid) segments). By merging experiments with modeling, we expect to clearly understand how a bimodal degradable gel can be used to maintain mechanical integrity while permitting macroscopic tissue evolution. In future work, this model system will enable us to develop superior degradable hydrogels, which will lay the foundation for seeking competitively a NIH R01 and to pursue their (pre)clinical utility.