Dynamic tuning of barrier properties of biogels using weakly adhesive third-party crosslinkers

水凝胶由悬浮在水环境中的纤维网络组成，在生命系统中无处不在。水凝胶不仅具有独特的结构和机械性能，对许多生理功能至关重要，而且还可以作为外来物种的屏障。目前调整生物水凝胶（生物凝胶）作为物理屏障的能力的方法通常依赖于改变纤维之间的间距，或者通过调整纤维的分子组成。然而，这两种方法都有重要的局限性。在这里，我们将探索第三方分子的使用，这些分子可以通过与外来物种紧密结合而与基质纤维轻微结合来将外来物种与基质交联。我们将研究各种生物凝胶，以确定交联剂可以在纤维上结合的特定分子。我们还将探索通过调整其与纤维的相互作用和/或其与外来物种交联的能力来提高交联剂的效力。最后，我们将发展数学理论和计算模型，可以解释实验观察。总之，这些研究应该有助于我们实质性地推进一种新的方法来改变生物凝胶作为屏障的有效性。技术摘要：目前调节生物水凝胶（生物凝胶）屏障特性的方法通常涉及刺激诱导的基质网格间距的体积变化和/或基质元素的共价修饰。这些方法极大地限制了动态调整生物凝胶对不同物种的屏障特性的能力。在本文中，我们将阐明第三种策略，基于利用自适应第三方交联剂，这种交联剂可以与基质元件弱相互作用，并特异性地结合外源表位，以调节生物凝胶对纳米颗粒和具有分子特异性的活性体的屏障特性。特别是，我们将重点利用抗体（Ab），我们最近发现它可以通过其Fc结构域的n -聚糖与粘蛋白和层粘连蛋白短暂相互作用，作为模型第三方交联剂。在Aim 1中，我们将探索Ab与各种生物凝胶的相互作用；系统筛选将使我们能够获得生物凝胶基质上介导与Ab相互作用的特定元素的分子见解。在Aim 2中，我们将探索是否调整Ab对基质成分的亲和力，或提高Ab的凝集能力，将导致生物凝胶中活性物质的更有效固定。最后，在目标3中，我们将开发一个全面的理论框架和实验观测的计算模型。这项研究的成功完成将大大提高我们对这种调整生物凝胶屏障特性的新策略的理解。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。

Non-Technical AbstractHydrogels, composed of a network of fibers suspended in an aqueous environment, are ubiquitous in living systems. Hydrogels not only offer unique structural and mechanical properties essential for numerous physiological functions, but also serve as a barrier against foreign species. Current methods to tune the ability of biological hydrogels (biogels) to function as a physical barrier typically rely on either changing the spacing between the fibers, or by tuning the molecular composition of the fibers. However, both methods have important limitations. Here, we would explore the use of third-party molecules that can crosslink foreign species to the matrix by binding tightly to the foreign species while binding lightly to the matrix fibers. We will study a variety of biogels to identify the specific molecules that the crosslinkers can bind to on the fibers. We will also explore improving the potency of the crosslinkers by tuning its interactions with the fibers and/or its ability to crosslink foreign species. Finally, we will develop mathematical theory and computational model that can account for the experimental observations. Altogether, these studies should help us substantially advance a novel approach to changing the effectiveness of biogels to serve as a barrier.Technical AbstractCurrent methods to tune the barrier properties of biological hydrogels (biogels) typically involve either stimuli-induced bulk changes to the mesh spacings of the matrix, and/or covalent modification of the matrix elements. These methods greatly limit the ability to dynamically tune the barrier properties of biogels against diverse species. In this proposal, we will elucidate a third strategy, based on harnessing adaptive third-party crosslinkers that can interact weakly with matrix elements and bind specifically to foreign epitopes to tune the barrier properties of biogels against nano-sized particles and active bodies with molecular specificity. In particular, we will focus on utilizing antibodies (Ab), which we have recently discovered can interact transiently with mucins and laminin via N-glycans on its Fc domain, as model third party crosslinkers. In Aim 1, we will explore the interactions of Ab with a variety of biogels; the systemic screening will allow us to gain molecular insights into the specific elements on biogel matrix that mediate the interactions with Ab. In Aim 2, we will explore whether tuning Ab affinity to matrix constituents, or improving the ability of Ab to agglutinate, will result in more effective immobilizing of active species in biogels. Finally, in Aim 3, we will develop a comprehensive theoretical framework and computational model of the experimental observations. Successful completion of the proposed studies will substantially improve our understanding of this novel strategy to tune the barrier properties of biogels.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.