Modular Self-Assembled Coatings for Biomaterials

描述(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、泌尿系统假体和培养的皮肤替代物，在通常情况下与上皮或内皮细胞连接的组织界面上发挥作用。然而，在大多数情况下，这些设备不能充分支持其表面上皮或内皮细胞的形成，使它们容易发生一系列并发症，包括血栓形成、免疫反应、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植入生物材料的涂层，通过模仿其天然基质基底膜(BMS)的结构来支持功能上皮和内皮的形成。BMS是一种精心定制的蛋白质结构，已在其中发现了许多影响其支持的上皮细胞和内皮细胞行为的信号域、肽序列、机械因素和配体的空间模式。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是具有挑战性的。本研究的目的是设计基于模块化多肽共组装的生物材料涂层，允许许多这些因素的掺入、调整和优化，从而诱导快速且有功能的上皮化或内皮化。此外，将采取措施避免任何潜在的免疫原性多肽组合。这项工作分为四个目标：目的1)设计一个自组装的多肽和蛋白质结构域的模块化系统，其中配体的识别、配体的聚集和粘弹性可以独立和精确地调节；目的2)确定任何能够显著提高合成的BMS的免疫原性的多肽或多肽的组合；目的3)利用析因实验，确定导致功能性上皮化和内皮化的配体、粘弹性模数和配体的空间排列的组合；目的4)将合成的BMS应用于现有的生物材料，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合作团队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多肽和蛋白质结构域来完成，这些水凝胶能够独立控制配基的识别、纳米和微米尺度上的配基聚集以及基质粘弹性。经过实验优化的涂层将应用于常用的ePTFE和胶原植入材料。这项研究的结果将包括在未来的研究中可以在大型动物模型中评估的涂层假体，以及一组自组装的多肽，这些多肽可能另外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。与公共健康相关：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经过优化的生物材料涂层来积极影响公共健康，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构建。

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.