de novo Fabrication of Dense Collagen Matrices with Patterned Hierarchical Structures for Corneal Stromal Tissue Repair

Abstract Collagen is a versatile biological building block that is guided by extracellular cues to self‐assemble into diverse hierarchical structures that perform various tissue functions. Here, the use of top‐down inputs and controlled contextual cues is reported for the de novo fabrication of patterned dense collagen matrices with spatially varying tailored mesoscale structures. Initially, imposed electrical inputs are used to guide collagen triple helix molecules to partially assemble into a dense metastable molten fibril state that can be induced by permissive contextual cues (especially humidity) to undergo further assembly. Spatially‐controlled optical inputs that induce riboflavin‐based photo‐crosslinking can locally‐trap partially assembled states (e.g., molten fibrils). To illustrate the potential of collagen patterning, a functional corneal stromal substitute is specifically fabricated that mimics the microstructures of collagen in cornea‐sclera and demonstrates that it can restore histological structure and function in a corneal defect rabbit model. This generic approach for the de novo fabrication of mesoscale‐structured collagen is envisioned to have broad applications in regenerative medicine.