Neuroinflammatory regulation of fracture healing after traumatic brain injury: Clinical evidence and emerging mechanistic insights

Table 2 Experimental evidence and mechanistic insights into traumatic brain injury-accelerated fracture healing

Mechanistic pathway	Study type	Key model/population	Main findings	Molecular mediators	Translational implications
Extracellular vesicle signaling[23]	Preclinical + clinical	Murine TBI model; TBI patients with concurrent fractures	Damaged neurons release osteogenic microRNA-enriched sEVs targeting osteoprogenitors; hydrogel-delivered sEVs repair bone defects	miR-328a-3p (targets FOXO4); miR-150-5p (targets CBL); fibronectin 1-mediated bone targeting	Biomaterial-assisted sEVs delivery for bone defect repair
Extracellular vesicle signaling[28]	Preclinical + clinical	TBI patients with concurrent fractures; murine fracture model	Circulating TBI-derived exosomes promote osteogenic differentiation and bone remodeling	miRNA-21-5p (targets SMAD7)	Circulating miRNA-21-enriched extracellular vesicles may serve as both a biomarker and a therapeutic target to enhance fracture healing
Sympathetic/adrenergic signaling[10]	Preclinical + retrospective cohort	Murine femoral osteotomy ± TBI; patients with long bone fractures	ADRB2 mediates TBI-enhanced fracture healing; β-blocker impairs healing; β2-agonist promotes callus vascularization	NE → ADRB2 → VEGF-A/αCGRP; type-H vessel formation	ADRB2 as therapeutic target
Sympathetic/adrenergic signaling[9]	Preclinical	Murine TBI + fracture model; β2/β3-AR knockout mice; TBI patients with concurrent fractures	TBI elevates sympathetic tone; promotes HSCs proliferation and M2 macrophage polarization	β2-AR/β3-AR agonists synergistically→ myelopoiesis → M2 macrophage infiltration	The adrenergic signals could accelerate healing
Neuroimmune modulation[2]	Preclinical	Murine combined TBI + fracture model	Reduced neutrophil and mast cell infiltration in early fracture hematoma; decreased CXCL10 expression	CXCL10 ↓ → mast cells ↓ → osteoclastogenesis ↓	Temporally regulated inflammatory response favors bone formation
Neuroimmune modulation[18]	Preclinical	Murine polytrauma model (contralateral vs ipsilateral)	Contralateral TBI + fracture shows enhanced bone formation; differential neuroinflammatory state	Systemic inflammatory markers; crossed neuroanatomy	Neuroinflammatory state modulation as therapeutic approach
Humoral factors[6]	Prospective cohort	Patients with TBI and femoral fractures	Shorter time to union; elevated osteogenic and inflammatory mediators (IL-1β)	BMP-2, PDGF, FGF-2, IL-1β	Multiple growth factors and cytokines as coordinated mediators

TBI: Traumatic brain injury; sEVs: Small extracellular vesicles; FOXO4: Forkhead box O4; CBL: Casitas b-lineage lymphoma; SMAD7: Mothers against decapentaplegic homolog 7; ADRB2: Β2-adrenergic receptor; NE: Norepinephrine; VEGF-A: Vascular endothelial growth factor A; αCGRP: Calcitonin gene-related peptide-α; HSCs: Hematopoietic stem cells; CXCL10: C-X-C motif chemokine ligand 10; BMP-2: Bone morphogenetic protein 2; PDGF: Platelet-derived growth factor; FGF-2: Fibroblast growth factor 2; IL-1β: Interleukin-1β.