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

Table 1 Summary of clinical studies investigating fracture healing in patients with traumatic brain injury

Ref.	Population/cohort characteristics	Key findings	Mechanistic/biomarker clues	Major caveats
Prospective cohort[6]	Patients with TBI and femoral fractures	Shorter time to union; increased osteogenic and inflammatory mediators	BMP-2, PDGF, FGF-2, IL-1β significantly elevated in TBI + fracture group	Moderate sample size; correlation not causation confirmed
Retrospective study[4]	TBI patients with tibial fractures	Patients with TBI showed earlier callus formation and increased callus ratio, in parallel with enhanced hematoma formation	Points to amplified early inflammatory/hematoma phase as a driver of repair	Site-specific evidence; radiographic metrics may vary with fixation strategy
Prospective cohort[20]	Long-bone fractures with vs without TBI	Shorter union time; elevated osteogenic/inflammatory mediators; larger callus volume	Coordinated endocrine-inflammatory activation rather than single mediator effect	Small sample size limits subgroup/interaction analysis; X-ray-based callus assessment is less precise than CT
Retrospective case-control study[5]	Patients with TBI and long-bone fracture vs fracture alone	Shorter time to union; increased callus formation in TBI group	TBI serum induced higher osteoblast proliferation in vitro	Small sample size; specific humoral factors not identified; heterogeneous fracture types
Preclinical (murine) + retrospective cohort[10]	Mice with femoral osteotomy ± cortical impact TBI; patients with long bone fractures	TBI enhanced fracture healing via ADRB2; β2-agonist promoted healing; β-blocker impaired healing	Norepinephrine stimulated VEGF-A and αCGRP via ADRB2; promoted type-H vessel formation	Animal model; retrospective human data; confounding factors

TBI: Traumatic brain injury; BMP-2: Bone morphogenetic protein-2; PDGF: Platelet-derived growth factor; FGF-2: Fibroblast growth factor 2; IL-1β: Interleukin-1β; CT: Computed tomography; ADRB2: Β2-adrenergic receptor; VEGF-A: Vascular endothelial growth factor A; αCGRP: Calcitonin gene-related peptide-α.