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Progressive Neurovascular and Fibrotic Remodeling Drive Functional Decline Following Extremity Radiation
Alex G. Lambi
*1, Brendan Hilliard
2, Frank L. Chen
2, Lewis Bright-Rowe
2, Ryan E. Tomlinson
3, Mary F. Barbe
21University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; 2Lewis Katz School of Medicine at Temple University, Philadelphia, PA; 3Thomas Jefferson University, Philadelphia, PA
BACKGROUND: Radiation-induced fibrosis leads to progressive functional impairment, yet the temporal relationship between fibrosis, neurovascular injury, and functional decline remains poorly defined. We developed a rat model of extremity irradiation to characterize chronic structural and functional changes following radiation exposure.
METHODS: Studies were conducted on 20 young adult female, Sprague-Dawley rats (IACUC-approved). We constructed a beam restriction and shielding device to limit irradiation to the elbow-digits, connected through a manifold for isoflurane anesthesia. Rats underwent forelimb irradiation (5, 10, or 20 Gy), with contralateral limbs serving as controls. Animals were evaluated longitudinally at timepoints up to 5 months. Functional outcomes included grip strength and mechanical sensitivity testing. Muscle fibrosis was assessed using picrosirius red staining, nerve fibrosis with trichrome staining, and microvascular changes using microCT-based vascular analysis.
RESULTS: Radiation resulted in progressive, dose-dependent functional declines. Grip strength was significantly reduced and mechanical sensitivity impaired at 2 and 5 months in 10 and 20 Gy groups. Structural analysis demonstrated increased muscle collagen deposition at 5 months, consistent with established fibrosis. Nerve fibrosis was also increased at 5 months in 10 and 20 Gy irradiated limbs. Microvascular density was reduced beginning at 2 months in 10 Gy limbs and further decreased by 5 months, with similar reductions observed at higher radiation doses (Fig. 1). Notably, vascular loss preceded peak fibrotic changes.
CONCLUSION: Chronic radiation injury is characterized by progressive microvascular loss that precedes and parallels fibrosis and neuromuscular functional decline, identifying vascular compromise as a potential driver of irreversible extremity dysfunction. These findings identify neurovascular injury as a potential therapeutic target and support a staged model of radiation-induced dysfunction relevant to reconstructive planning
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