Biomimetic Scaffolds for Spinal Cord Applications Exhibit Stiffness‐Dependent Immunomodulatory and Neurotrophic Characteristics

Abstract

After spinal cord injury (SCI), tissue engineering scaffolds offer a potential bridge for regeneration across the lesion and support repair through proregenerative signaling. Ideal biomaterial scaffolds that mimic the physicochemical properties of native tissue have the potential to provide innate trophic signaling while also minimizing damaging inflammation. To address this challenge, taking cues from the spinal cord's structure, the proregenerative signaling capabilities of native cord components are compared in vitro. A synergistic mix of collagen‐IV and fibronectin (Coll‐IV/Fn) is 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 is incorporated into hyaluronic acid scaffolds with aligned pore architectures but varying stiffnesses (0.8–3 kPa). Scaffolds with biomimetic mechanical properties (<1 kPa), functionalized with Coll‐IV/Fn, not only modulate primary astrocyte behavior but also stimulate the production of anti‐inflammatory cytokine IL‐10 in a stiffness‐dependent manner. Seeded SHSY‐5Y neurons generate distributed neuronal networks, while softer biomimetic scaffolds promote 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.

A decellularized spinal cord extracellular matrix-gel/GelMA hydrogel three-dimensional composite scaffold promotes recovery from spinal cord injury via synergism with human menstrual blood-derived stem cells

“…Ideal biomaterials with soft mechanical characterizations, oriented three-dimensional structures, high water content and strong deformation resistance are more favorable for the repair of spinal cord tissues. 32,33 Natural DSC had unique advantages: it had the closest biological components to spinal cord tissue and had good biocompatibility, 34 it had cell membrane receptor recognition sites on the surface that facilitated cell adhesion, growth, and survival, 35 it retained molecules such as collagen, fibronectin, laminin, etc., which can bind to integrins on the surface of the proximal growth cone when implanted in vivo, thereby acting as a short-range axon guiding signal. 17 First, we prepared a rat DSC by physical and chemical methods.…”

Protective effect of zinc oxide nanoparticles on spinal cord injury

“…Due to the nanometer size of NMs, they can not only easily carry drugs or molecules across the blood-spinal cord barrier to target tissues and cells, but also directly modulate the biological effects related to axonal regeneration, ultimately exerting therapeutic effects on SCI ( Kim et al, 2017 ; Domínguez-Bajo et al, 2019 ). However, many studies have shown that NMs play an important role in nerve regeneration after SCI, mostly in the form of scaffolds to load therapeutic drugs or provide regeneration space ( Zhao et al, 2018 ; Woods et al, 2022 ), and few people pay attention to unveil the intrinsic role of NMs in nerve regeneration. In this study, ZnO NPs function both as a natural product and as a nanoparticle.…”

The Manufacture and Characterization of Biomimetic, Biomaterial‐Based Scaffolds for Studying Physicochemical Interactions of Neural Cells in 3D Environments

“…Both cross-linkers are added in excess and are calculated as follows: EDAC = 0.8 g × total mg HyA in solution; adipic acid = 9.16 g × total mg HyA in solution (Luo, Kirker, & Prestwich, 2000;Woods et al, 2022).…”

“…A key advantage of freeze-dried scaffolds is the ability to easily tune physicochemical properties for specific applications (Woods et al, 2022). It is essential to fully characterize the produced scaffolds before embarking on a series of experiments to monitor any batch-to-batch variance and clearly understand the impact the surrounding physical environment may play on resultant cell behavior.…”

“…It is known that both stiffness and matrix composition can influence neurite extension, branching, and complexity (Leach et al, 2007;Song & Dityatev, 2018;Sundararaghavan, Monteiro, Firestein, & Shreiber, 2009;Woods et al, 2022). Immunostaining combined with light and confocal microscopy can be used to assess not only individual neurites but also the 3D networks of neuronal processes within the scaffolds.…”