Biomimetic Scaffolds for Spinal Cord Applications Exhibit Stiffness-dependent Immunomodulatory and Neurotrophic Characteristics.

After spinal cord injury (SCI), tissue engineering scaffolds offer a potential bridge for regeneration across the lesion and support repair through pro-regenerative signalling. Ideal biomaterial scaffolds, which mimic the physicochemical properties of native tissue have the potential to provide innate trophic signalling while also minimizing damaging inflammation. To address this challenge, taking cues from the spinal cord's structure, the pro-regenerative signalling capabilities of native cord components were compared in vitro. A synergistic mix of collagen-IV and fibronectin (Coll-IV/Fn) was found to optimally enhance axonal extension from neuronal cell lines (SHSY-5Y and NSC-34) and induce morphological features typical of quiescent astrocytes. This optimal composition was incorporated into hyaluronic acid scaffolds with aligned pore architectures but varying stiffnesses (0.8-3KPa). Scaffolds with biomimetic mechanical properties (<1 kPa), functionalized with Coll-IV/Fn, not only modulated primary astrocyte behavior but also stimulated the production of anti-inflammatory cytokine IL-10 in a stiffness-dependent manner. Seeded SHSY-5Y neurons generated distributed neuronal networks, while softer biomimetic scaffolds promoted axonal outgrowth in an ex vivo model of axonal regrowth. These results indicate that the interaction of stiffness and biomaterial composition plays an essential role in vitro in generating repair-critical cellular responses and demonstrates the potential of biomimetic scaffold design. This article is protected by copyright. All rights reserved.