Modular Self-Assembled Coatings for Biomaterials

描述（由申请人提供）：许多植入式生物材料，包括血管移植物、角膜假体、泌尿外科假体和培养皮肤替代品，在正常情况下内衬上皮或内皮的组织界面上起作用。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细胞的形成，使它们容易产生一系列并发症，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。本研究的长期目标是通过模拟其天然基质基底膜（BMs）的构建，为植入生物材料开发能够支持功能性上皮和内皮形成的涂层。脑转移瘤是精心定制的蛋白质结构，许多信号域、肽序列、机械因素和配体的空间模式已经在其中被确定，这些因素影响着它们所支持的上皮和内皮的行为。然而，在合成生物材料涂层中可靠地整合和调整这种多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，允许整合、调整和优化许多这些因素，从而引发快速和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。该工作分为四个目标：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和精确地调节；目标2)鉴定任何能显著提高合成脑转移瘤免疫原性的肽或肽的组合；目的3)使用析因实验，鉴定导致功能性上皮化和内皮化的配体组合、粘弹性模量和配体的空间排列；目的4)将合成脑转移瘤应用于现有生物材料，并重新评估体外上皮化和内皮化。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合作团队完成，他们将设计和研究一系列肽和蛋白质结构域，这些肽和蛋白质结构域能够共同组装成精确定义的水凝胶，并独立控制配体的身份、配体在纳米尺度和微米尺度上的聚类以及基质的粘弹性。实验优化后的涂层将应用于常用的ePTFE和胶原植入材料。这项研究的结果将包括涂层假体，可以在未来的研究中在大型动物模型中进行评估，以及一组自组装肽，这些肽可能对各种其他生物医学应用有用，包括3-D细胞培养或控制治疗释放。公共卫生相关性：本研究将通过引入优化的生物材料涂层，能够支持合成表面上皮和内皮的快速再生，从而对公共卫生产生积极影响，这反过来将导致植入设备（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）的性能增强。

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.