Development of an H2S-Associated Matrix Based on Rhizostoma pulmo Jellyfish Collagen: A Pilot Evaluation of Neuroprotective Effects and Cx43/p53 Regulation in Penetrating Traumatic Brain Injury.

Severe traumatic brain injury (TBI) is one of the leading causes of mortality and disability worldwide. To date, there are no clinically effective neuroprotective agents. Biomaterials that combine structural support for damaged tissue with a depot for therapeutic agents may represent a key solution to this problem. To evaluate the neuroprotective potential of a collagen matrix derived from the jellyfish Rhizostoma pulmo (R. pulmo) and modified with sodium thiosulfate (Na2S2O3) as an hydrogen sulfide (H2S) donor in a bioengineered platform for the treatment of severe TBI. Comprehensive characterization of the collagen matrix (electrophoresis, fluorescence microscopy), its implantation in a mouse model of severe TBI, and subsequent morphological, histological, ultrastructural, and immunohistochemical analyses of connexin 43 (Cx43) and p53 protein (p53) were performed. In addition, molecular dynamics simulations of the interactions between sulfur-containing compounds and target proteins were conducted. The effects were compared with inhibition of endogenous H2S synthesis using aminooxyacetic acid (AOAA). The collagen matrix retains the properties of type I collagen and forms a three-dimensional porous structure with high hydrophilicity and biocompatibility. Implantation ensures effective defect filling, reduces cystic degeneration, and preserves cortical structure. Modification with Na2S2O3 results in a significant reduction in both nuclear and cytoplasmic accumulation of p53, prevention of Cx43 dysregulation, a decrease in the proportion of damaged neurons and inflammatory infiltration, and preservation of tissue ultrastructure. In contrast, inhibition of CBS with AOAA exacerbates pathological changes. Molecular modeling demonstrated that S2O32- is capable of forming stable electrostatic interactions with domains of p53 and Cx43 under conditions of acidosis and elevated Ca2+. A collagen matrix derived from R. pulmo and modified with Na2S2O3 represents a promising biodegradable platform that combines structural support with local H2S-dependent regulation of key mechanisms of secondary brain injury. This approach provides a multilevel neuroprotective effect and opens new opportunities for the development of therapeutic implants for severe TBI.