Modular Self-Assembled Coatings for Biomaterials

描述（由申请人提供）：许多植入的生物材料，包括血管移植物、角膜假体、泌尿外科假体和培养的皮肤替代物，在通常内衬上皮细胞或内皮细胞的组织界面处发挥作用。然而，在大多数情况下，这些装置不能充分支持上皮细胞或内皮细胞在其表面上的形成，使得它们易于发生许多并发症，包括血栓形成、免疫反应性、它们周围的细胞生长失调或屏障功能差。本研究的长期目标是开发用于植入生物材料的涂层，该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，并且已经在其中鉴定了许多信号传导结构域、肽序列、机械因子和配体的空间模式，这些结构域、肽序列、机械因子和配体的空间模式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这种复杂的多个因素目前具有挑战性。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，允许并入、调整和优化这些因素中的许多，以引起快速和功能性上皮化或内皮化。此外，将采取步骤以避免肽的任何潜在免疫原性组合。本论文的工作分为四个目标：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、配体聚集和粘弹性可以独立和精确地调节;目标2）鉴定任何显著提高合成BM的免疫原性的肽或肽的组合;目的3）通过析因实验，确定导致功能性上皮化和内皮化的配体组合、粘弹性模量和配体的空间排列;目的4）将合成的骨基质应用于现有的生物材料，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，生物药理学家和外科医生组成的合作团队完成，通过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，并独立控制配体身份，纳米级和微米级的配体聚集以及基质粘弹性。实验优化的涂层将应用于常用的ePTFE和胶原植入材料。这项研究的成果将包括涂层假体，可以在未来的研究中在大型动物模型中进行评估，以及一组自组装的肽，这些肽可能还可用于各种其他生物医学应用，包括3D细胞培养或控制治疗释放。公共卫生相关性：这项研究将通过引入能够支持合成表面上上皮细胞和内皮细胞快速再生的最佳调谐生物材料涂层来积极影响公众健康，这反过来将导致植入设备的性能增强，如血管假体，角膜植入物，培养的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.