In Search for Biomarkers Reflecting Neural Implant-Induced Tissue Response Dynamics

Extracellular matrix (ECM) remodeling is a fundamental determinant of neural tissue repair and implant integration, yet its conserved regulatory architecture remains undefined. While transcriptomic alterations following neural injury and implantation have been described, the ECM-centered programs that unify traumatic injury and neural implant responses remain unclear. Here, integrative systems-level transcriptomic analysis identifies a dominant and conserved ECM regulatory axis linking traumatic brain injury (BI), spinal cord injury (SCI), and neural implant–induced injury. By integrating transcriptomic datasets from brain and spinal cord injury models using weighted gene co-expression network analysis (WGCNA), six conserved ECM-associated gene modules are identified, with hyaluronan (HA)-centered networks emerging as the dominant and conserved regulatory axis across both injury types. Modules enriched for low-molecular-weight HA (LMW-HA) are linked to Toll-like receptor signaling and pro-inflammatory cytokine expression, whereas high-molecular-weight HA (HMW-HA)–associated modules correlate with Cd44 signaling, tissue stabilization and repair. Furthermore, independent validation in thin-film intracortical microelectrode datasets confirms robust activation of HA damage-associated molecular pattern (HA-DAMP) signaling following implantation, with 9/10 injury-derived modules preserved and 88% of transcripts exhibiting resolving temporal dynamics. These findings indicate that neural implants engage conserved trauma-associated ECM programs rather than a conventional foreign-body response, highlighting HA-related metabolisms. Given that HA fragments and HA-modifying enzymes are detectable in cerebrospinal fluid and peripheral circulation, HA-associated signatures may serve as minimally invasive biomarkers of neural injury and implant biocompatibility, enabling longitudinal monitoring and informing next-generation neural interface design.