ROS‐Scavenging Hydrogels Synergize with Neural Stem Cells to Enhance Spinal Cord Injury Repair via Regulating Microenvironment and Facilitating Nerve Regeneration

Abstract

Although stem cell‐based therapy is recognized as a promising therapeutic strategy for spinal cord injury (SCI), its efficacy is greatly limited by local reactive oxygen species (ROS)‐abundant and hyper‐inflammatory microenvironments. It is still a challenge to develop bioactive scaffolds with outstanding antioxidant capacity for neural stem cells (NSCs) transplantation. In this study, albumin biomimetic cerium oxide nanoparticles (CeO2@BSA nanoparticles, CeNPs) are prepared in a simple and efficient manner and dispersed in gelatin methacryloyl to obtain the ROS‐scavenging hydrogel (CeNP‐Gel). CeNP‐Gel synergistically promotes neurogenesis via alleviating oxidative stress microenvironments and improving the viability of encapsulated NSCs. More interestingly, in the presence of CeNP‐Gel, microglial polarization to anti‐inflammatory M2 subtype are obviously facilitated, which is further verified to be associated with phosphoinositide 3‐kinase/protein kinase B pathway activation. Additionally, the injectable ROS‐scavenging hydrogel is confirmed to induce the integration and neural differentiation of transplanted NSCs. Compared with the blank‐gel group, the survival rate of NSCs in CeNP‐Gel group is about 3.5 times higher, and the neural differentiation efficiency is about 2.1 times higher. Therefore, the NSCs‐laden ROS‐scavenging hydrogel represents a comprehensive strategy with great application prospect for the treatment of SCI through comprehensively modulating the adverse microenvironment.

Reactive oxygen species targeted biomaterials for spinal cord injury therapy

“…From a combination therapy perspective, [2,17,[65][66][67] enzymatic biomaterials currently demonstrate limitations in effectively synergizing with other treatment modalities, and further exploration of this challenge is needed in the context of SCI. Nonenzymatic biomaterials, including both inorganic and organic core types, are commonly paired with cell therapy, [35,45,49,65,68,69] protein therapy, [46,68,70,71] neuromodulation therapy, [2,51,72] or gene regulation therapy [41,73] for SCI treatment. Combination therapy approaches appear essential for achieving the ultimate goal of SCI repair.…”

“…Another recent development in the use of cerium oxidebased biomaterials for SCI treatment was reported by Liu et al, [35] who designed albumin biomimetic CONPs contained within a methacryloyl gelatin hydrogel, creating an injectable ROS-scavenging hydrogel. They evaluated representative ROS species, including H 2 O 2 ,•OH, and superoxide anion (O 2…”

“…Another recent development in the use of cerium oxide‐based biomaterials for SCI treatment was reported by Liu et al., [35] who designed albumin biomimetic CONPs contained within a methacryloyl gelatin hydrogel, creating an injectable ROS‐scavenging hydrogel. They evaluated representative ROS species, including H 2 O 2 ,·OH, and superoxide anion(O 2 − ) using antioxidant capacity assessments, such as the Amplex Red reagent (in vitro), hydroxyl radical absorbance capcity activity assay kit (in vitro), and DCFH‐DA and dihydroethidium (DHE) probes (cell tests for the hydrogel).…”

Hierarchically patterned protein scaffolds with nano-fibrillar and micro-lamellar structures modulate neural stem cell homing and promote neuronal differentiation

“…Nerve injury, a frequently encountered condition, seriously affects patients' quality of life and overall health. 1,2 Due to the limited regenerative capacity of nerve tissue, exogenous cellbased therapies have emerged as attractive approaches for neural regeneration. [3][4][5] Neural stem cells (NSCs) possess high potencies for self-renewal and the potential to differentiate into neurons, astrocytes, or oligodendrocytes under appropriate conditions.…”

Catalytically proficient ceria nanodots supported on redox-active mesoporous hosts for treatment of inflammatory bowel disease via efficient ROS scavenging

“…Recently, ceria-containing nanocatalysts have attracted wide attention due to their capability in valence transition between Ce 3+ (reduced) and Ce 4+ (oxidized) forms, exhibiting superoxide dismutase (SOD)-like activity to convert superoxide anions to H 2 O 2 and catalase (CAT)-like activity to convert H 2 O 2 to O 2 . 15 Ceria nanoparticles (NPs) have been widely applied to treat ROS-related diseases such as periodontitis, 16 traumatic spinal cord injury 17 and retinal diseases 18 with excellent catalase-like biomimetic bioactivity, which provides a possibility to treat IBD. Nevertheless, only CeO 2 NPs with a particle size less than 5 nm can exhibit the activity of ROS elimination in a recyclable way by reversible binding of oxygen atoms and shuttling between the Ce 3+ and Ce 4+ states on the surface.…”