NEUROINFLAMMATION ACROSS BOUNDARIES: INSIGHTS FROM HUMAN ISCHEMIC STROKE AND BIOMATERIAL CRANIOPLASTY

Neuroinflammation is a complex process, involving cellular and molecular events, which is activated in the central nervous system by acute and chronic insults such as ischemic stroke and traumatic brain injury (TBI). While this response can initially protect against tissue damage and promote repair, its chronic or dysregulated activation often exacerbates neural injury and impairs functional recovery. Glial cells—microglia, astrocytes, and oligodendrocytes—are key players in these mechanisms, influencing both tissue repair and degeneration. In clinical practice, interventions such as cranioplasty (CP) add further complexity, as the introduction of biomaterials and the risk of post-surgical infection can directly and indirectly modulate the inflammatory environment and patient outcomes. On these bases, the overarching aim of this thesis is to elucidate the role of neuroinflammation in two major clinical contexts: (1) human ischemic stroke, with a focus on glial cell responses and fluid biomarker analysis, and (2) CP with biomaterials, particularly in relation to infection risk and strategies for clinical management. To this end, the work is organized in two sections. The first part combines advanced histopathological and molecular analyses to dissect the spatial and temporal dynamics of glial activation and tissue repair in human post-mortem stroke specimens. A particular focus is given to microglial and astrocytic responses in the peri-infarct region, the accumulation and fate of oligodendrocyte precursor cells, and sex-specific differences in glial reactivity. Bulk transcriptomics analysis provides molecular context, revealing robust upregulation of TREM2-driven phagocytic pathways, providing mechanistic context to histological findings. In parallel, fluid biomarker analysis demonstrates that glia-associated markers (sTNFR2 and sTREM2) are increased in the cerebrospinal fluid (CSF) of female stroke patients, while these changes are less pronounced in plasma, indicating a compartment-specific immune response. Ongoing spatial transcriptomics analyses will further refine the understanding of region-specific gene expression and glial dynamics in stroke lesions. Post-mortem human stroke brain specimens, plasma and CSF were made available through a collaboration with prof. Kate Lykke Lambertsen from the University of Southern Denmark (Odense, DK). The second part addresses the management of patients undergoing CP with porous hydroxyapatite implants (CustomBone Service, FinCeramica Faenza Spa, Faenza, Italy), using data from a multicenter cohort and experimental in vitro assays. This work identifies key clinical and surgical predictors of post-CP infection and demonstrates that tailored infection control strategies—including antibiotic regimens and surgical debridement—can increase implant retention and facilitate patient recovery. In vitro, hydroxyapatite exhibits antibacterial properties, supporting its role as a bioactive material that may contribute to a tissue environment more permissive to brain repair, likely indirectly modulating neuroinflammation by reducing infectious complications. In summary, this thesis advances understanding of neuroinflammatory mechanisms and their clinical implications in both spontaneous (ischemic) and post-surgical brain injury. The findings highlight the value of integrating post-mortem human tissue and fluid biomarkers with clinical data to refine patient monitoring and personalized management and support the pursuit of targeted therapies aimed at optimizing neural recovery and outcomes after stroke and neurosurgical intervention.