Modular Self-Assembled Coatings for Biomaterials

描述（由申请人提供）：许多植入生物材料，包括血管移植物、角膜假体、泌尿假体和培养皮肤替代品，在通常衬有上皮或内皮的组织界面上发挥作用。然而，在大多数情况下，这些装置不能充分支持其表面上皮或内皮的形成，使它们容易出现一系列并发症，包括血栓形成、免疫反应性、周围细胞生长失调或屏障功能差。这项研究的长期目标是开发用于植入生物材料的涂层，能够通过模仿其天然基质基底膜（BM）的结构来支持功能性上皮细胞和内皮细胞的形成。 BM 是精心定制的蛋白质结构，其中已鉴定出许多信号传导域、肽序列、机械因子和配体的空间模式，这些信号域、肽序列、机械因子和配体的空间模式会影响它们所支持的上皮细胞和内皮细胞的行为。然而，在合成生物材料涂层中可靠地整合和调整多种因素的复杂性目前具有挑战性。本研究的目的是设计基于模块化肽共组装的生物材料涂层，允许合并、调整和优化许多这些因素，从而引发快速且功能性的上皮化或内皮化。此外，将采取措施避免任何潜在的免疫原性肽组合。这项工作分为四个目标： 目标 1）设计一个自组装肽和蛋白质结构域的模块化系统，其中配体身份、配体聚类和粘弹性可以独立且精确地调整；目标 2) 鉴定能够显着提高合成 BM 免疫原性的任何肽或肽组合；目标 3) 使用析因实验，确定导致功能性上皮化和内皮化的配体组合、粘弹性模量和配体空间排列；目标 4) 将合成的 BM 应用到现有的生物材料上，并在体外重新评估上皮化和内皮化。这项工作将由工程师、免疫学家、细胞生物学家、生物物理学家和外科医生组成的协作团队完成，通过设计和研究一系列能够共同组装成精确定义的水凝胶的肽和蛋白质结构域，并独立控制配体身份、纳米级和微米级配体聚类以及基质粘弹性。经过实验优化的涂层将应用于常用的 ePTFE 和胶原蛋白植入材料。这项研究的成果将包括可在未来研究中在大型动物模型中进行评估的涂层假体，以及一组自组装肽，这些肽可能另外可用于各种其他生物医学应用，包括 3D 细胞培养或受控治疗释放。公共健康相关性：这项研究将通过引入能够支持合成表面上皮和内皮快速再生的优化调整的生物材料涂层，对公共健康产生积极影响，这反过来又会提高植入设备的性能，例如血管假体、角膜植入物、培养皮肤替代品和其他组织工程结构。

DESCRIPTION (provided by applicant): Many implanted biomaterials, including vascular grafts, corneal prostheses, urological prostheses, and cultured skin substitutes, function at tissue interfaces that would normally be lined with epithelia or endothelia. However, in most cases these devices do not adequately support the formation of epithelia or endothelia on their surfaces, making them prone to a host of complications including thrombogenesis, immunoreactivity, disregulation of cell growth around them, or poor barrier function. The long-term goal of this research is to develop coatings for implanted biomaterials capable of supporting the formation of functional epithelia and endothelia by mimicking the construction of their native substrates, basement membranes (BMs). BMs are exquisitely tailored protein architectures, and many signaling domains, peptide sequences, mechanical factors, and spatial patterns of ligands have been identified in them that influence the behavior of the epithelia and endothelia they support. However, integrating and tuning this complexity of multiple factors reliably in synthetic biomaterials coatings is currently challenging. The objective of this research is to design biomaterials coatings based on modular peptide co-assembly allowing the incorporation, adjustment, and optimization of many of these factors so as to elicit rapid and functional epithelialization or endothelialization. In addition, steps will be taken to avoid any potentially immunogenic combinations of peptides. The work is divided into four aims: Aim 1) Design a modular system of self-assembling peptides and protein domains where ligand identity, ligand clustering, and viscoelasticity can be independently and precisely adjusted; Aim 2) Identify any peptides or combinations of peptides that significantly raise the immunogenicity of the synthetic BMs; Aim 3) Using factorial experimentation, identify combinations of ligands, viscoelastic moduli, and spatial arrangements of ligands that lead to functional epithelialization and endothelialization; Aim 4) Apply synthetic BMs to existing biomaterials and re-evaluate epithelialization and endothelialization in vitro. This work will be accomplished by a collaborative team of engineers, immunologists, cell biologists, biophysicists, and surgeons by designing and investigating a series of peptides and protein domains capable of co-assembling into precisely defined hydrogels with independent control over ligand identity, ligand clustering on the nanoscale and micron-scale, and matrix viscoelasticity. Experimentally optimized coatings will be applied to commonly used ePTFE and collagen implant materials. The outcomes of this research will include coated prostheses that can be evaluated in large animal models in future investigations, as well as a self-assembling set of peptides that may additionally be useful for a variety of other biomedical applications, including 3-D cell culture or controlled therapeutic release. PUBLIC HEALTH RELEVANCE: This research will positively affect public health by introducing optimally tuned biomaterials coatings capable of supporting the rapid regeneration of epithelia and endothelia on synthetic surfaces, which in turn will result in the enhanced performance of implanted devices such as vascular prostheses, corneal implants, cultured skin substitutes, and other tissue engineered constructs.