Basement membranes (BMs) are exquisitely tailored protein architectures that regulate the function of epithelial cell sheets. The long term goal of the research described here is to develop biomaterial coatings capable of maximizing the formation of functional epithelial cell sheets through mimicry of BMs in order to improve the performance of devices such as dermal, corneal, or lumen- forming prostheses. Although many important signaling domains and peptide sequences have been identified that significantly influence cell behavior on synthetic biomaterial surfaces, it is highly challenging to controllably produce engineered surfaces that, like BMs, display tailored combinations of multiple motifs within a nanostructured, fibrillar network. Self-assembling approaches offer routes to multi-component materials, but self-assembled materials generally possess diminished mechanical properties that limit their applicability. To address these dual issues of designing modular, self- assembling materials as synthetic BMs while at the same time producing mechanically robust materials, the research is subdivided into the following two aims:
Aim 1) Maximize functional epithelialization using synthetic BMs;
Aim 2) Transform multifunctional synthetic BMs into robust coatings through inter-fibril coupling approaches.
These aims will be accomplished by a collaborative team of engineers and cell biologists by investigating the fibrillization, assembly, secondary structure, and gel formation of a series of designed peptide modules using TEM, HPLC, circular dichroism, and oscillating rheometry. Using factorial experimental design, complex multi-peptide formulations will then be systematically optimized to drive the rapid formation of functional epithelia in vitro. Functionality will be assessed by rapid proliferation to confluence, apical-basal polarization, and barrier function. Optimal formulations will then be stabilized by inter-fibril cross-linking methods, analyzed with oscillating rheometry, and re-evaluated in epithelial cell cultures to determine whether mechanical stabilization specifies new optimum formulations. The outcomes of this research include the development of novel biomaterials coatings that maximally drive epithelialization, which will then be evaluated as coatings on existing prosthetic materials and within tissue engineered constructs in future research. Collectively, this R21-supported project will serve as a springboard for a new research program in engineering biomaterial-tissue interfaces. This research will positively affect public health by introducing optimally tuned biomaterials coatings capable of supporting the rapid regeneration of epithelia on synthetic surfaces, which in turn will result in the enhanced performance of the interfaces between tissues and implanted devices such as corneal implants, dermal regeneration devices, and tissue engineered constructs. ? ? ?
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