Facile Fabrication of Uniform Collagen Micro‐Fibrils for Engineering Stem Cell Spheroids and Spinal Cord Injury Repair

ABSTRACT Stem cell spheroids represent a promising strategy for neural tissue construction and spinal cord injury repair (SCI). However, the stem cell‐assembled spheroids lack the extracellular matrix (ECM) as well as the ECM‐cell interactions naturally present in tissues, making it difficult to actively tune the stem cell fate and tissue development. Here, we develop a simple and efficient method for the fabrication of collagen micro‐fibrils with intact periodic banding and triple‐helical structure to serve as the ECM of stem cell spheroids. These uniform‐sized and well‐dispersed collagen micro‐fibrils can be self‐assembled with neural stem cells (NSCs) to form engineered spheroids. Similar to the native tissue, the collagen micro‐fibrils form a fibrillar network and are distributed uniformly in the engineered spheroids, which led to the alleviation of hypoxia, enhancement of ECM‐cell interactions, and improvement in the viability of NSCs. More importantly, these fibrils can serve as reservoirs for differentiation‐modulators to precisely guide the neuronal differentiation of NSCs, yielding functional neural microtissues. The collagen micro‐fibril‐engineered spheroids exhibit superior survival and neuronal differentiation after implantation, accelerating motor and tissue recovery of SCI mice. These collagen micro‐fibrils with intact micro‐nano structure and collagen micro‐fibrils‐engineered spheroids hold great potential for the construction of microtissues and SCI repair.