Integrated scaffold structure, mechanical cues, and rbcev-based delivery for neural repair after spinal cord injury

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Spinal cord injury remains a major clinical challenge due to the limited regenerative capacity of the adult central nervous system and the complex, multi-factorial nature of the post-injury microenvironment. Following injury, disrupted tissue architecture, altered mechanical properties, inhibitory extracellular matrix deposition, and insufficient delivery of regenerative signals collectively impede axonal regeneration and functional recovery. Biomaterial scaffolds have therefore been developed to provide structural support, guide neural growth, and modulate local biological responses. However, despite substantial progress, regenerative outcomes remain highly variable, in part because scaffold architecture, mechanical cues, and biochemical delivery strategies are often optimized independently, obscuring their combined and interdependent roles in regulating tissue repair. This thesis advances an integrated regenerative strategy that systematically combines scaffold structural design, mechanical regulation, and red blood cell–derived extracellular vesicle (RBCEV)–based bioactive delivery to direct neural regeneration following spinal cord injury. Using design-driven fabrication approaches, multichannel scaffolds were engineered with precisely defined geometries to decouple architectural features from material composition. This enabled controlled modulation of effective scaffold stiffness through structural parameters, rather than through changes in polymer chemistry or concentration, thereby isolating the contribution of design-defined mechanical cues. Mechanical characterization confirmed that scaffold stiffness could be predictably tuned across a physiologically relevant range while maintaining consistent biochemical properties. The influence of scaffold structure and mechanical cues on neural tissue responses was investigated using both in vitro and in vivo spinal cord injury models. Design-defined stiffness and channel architecture were found to regulate axonal alignment and ingrowth, astrocytic distribution at the scaffold–host interface, and oligodendroglial lineage dynamics within the implant. Notably, intermediate structural stiffness promoted enhanced oligodendrocyte maturation relative to both lower- and higher-stiffness designs, highlighting a non-monotonic relationship between mechanical cues and regenerative outcomes. These findings underscore the importance of considering effective structural stiffness, rather than bulk material modulus alone, when interpreting scaffold–tissue interactions. In parallel, this thesis establishes RBCEVs as a versatile and biocompatible platform for localized delivery of regulatory nucleic acids within regenerative scaffolds. RBCEVs were isolated, characterized, and loaded with lineage-regulating microRNAs, and their incorporation into hydrogel-based scaffolds enabled sustained retention and spatially confined bioactive delivery. RBCEV-mediated delivery was shown to modulate neural progenitor and glial cell fate without compromising scaffold integrity or mechanical performance. When combined with structurally and mechanically defined scaffolds, RBCEV-based delivery enhanced lineage-specific responses, particularly in the context of oligodendroglial differentiation and myelination-associated processes. By integrating RBCEV-mediated biochemical regulation with design-defined structural and mechanical cues, this work demonstrates that neural regeneration can be more effectively directed through coordinated modulation of the scaffold microenvironment. The results reveal that physical and biochemical signals do not act independently but instead interact to shape cellular behavior and tissue integration within implanted scaffolds. Importantly, the thesis highlights how architectural design can be leveraged to control mechanical properties without confounding biochemical variables, providing a robust experimental framework for dissecting multi-parameter interactions in regenerative systems. Overall, this thesis establishes a unified design paradigm for spinal cord regenerative scaffolds that integrates structure, mechanics, and RBCEV-based bioactive delivery. The mechanistic insights and design principles derived from this work contribute to a more systematic understanding of scaffold–tissue interactions and offer a rational foundation for the development of next-generation biomaterial therapies for spinal cord injury.

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