Engineering Bimodal Degrading Hydrogels

描述(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，这种水凝胶能够支持体内的正常力量，同时允许基质沉积和新组织生长。目前这种水凝胶的发展局限可概括如下：(A)高交联度水凝胶可以抵抗载荷，但限制了基质扩散，从而阻止了新组织的生长(B)相反，低交联度允许基质扩散，但导致不可接受的微弱体积性能，不能承受正常的力。因此，这项工作的目的是引入一种可以控制其空间和时间降解的水凝胶系统，以更好地匹配组织发育。我们的全球假设是，双峰降解水凝胶结合了局部和细胞介导(酶)和整体(水解性)降解，在保持机械完整性的同时允许基质形成，并且存在实现结果的优化设计空间。为了验证我们的假设，将结合实验开发数学模型，以便准确地描述凝胶降解和基质沉积的综合影响。具体来说，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个部分。首先，我们现有的基质降解模型将与基于酶负载微粒的实验测量结果进行验证。其次，将开发一个与水解性降解相结合的ECM产生和沉积模型，并根据初步数据进行验证。2.表征了单模和双模降解水凝胶的降解行为和基质演化。这一目标将把数学模型扩展到双峰降解和ECM沉积相结合的一般情况，以评估水凝胶参数对凝胶降解和ECM沉积之间竞争的影响。然后提出了两种实验策略，同时测试酶降解凝胶和双峰可降解凝胶，以验证和校准该模型。在这项探索性研究完成后，我们预计将开发出一种基于交联型聚乙二醇基的新型双峰降解水凝胶，其中交联物可以通过细胞介导的酶降解(即被包裹的软骨细胞分泌的侵入物)或通过水解性降解(即聚乳酸链段)来降解。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在允许宏观组织进化的同时保持机械完整性。在未来的工作中，该模型系统将使我们能够开发出更好的可降解性水凝胶，这将为寻找具有竞争力的NIH R01并追求其(前)临床应用奠定基础。

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.