Radiation Combined Injury Models to Study the Effects of Interventions and Wound Biomechanics

Abstract

In the event of a nuclear detonation, a considerable number of projected casualties will suffer from combined radiation exposure and burn and/or wound injury. Countermeasure assessment in the setting of radiation exposure combined with dermal injury is hampered by a lack of animal models in which the effects of interventions have been characterized. To address this need, we used two separate models to characterize wound closure. The first was an open wound model in mice to study the effect of wound size in combination with whole-body 6 Gy irradiation on the rate of wound closure, animal weight and survival (morbidity). In this model the addition of interventions, wound closure, subcutaneous vehicle injection, topical antiseptic and topical antibiotics were studied to measure their effect on healing and survival. The second was a rat closed wound model to study the biomechanical properties of a healed wound at 10 days postirradiation (irradiated with 6 or 7.5 Gy). In addition, complete blood counts were performed and wound pathology by staining with hematoxylin and eosin, trichrome, CD68 and Ki67. In the mouse open wound model, we found that wound size and morbidity were positively correlated, while wound size and survival were negatively correlated. Regardless of the wound size, the addition of radiation exposure delayed the healing of the wound by approximately 5-6 days. The addition of interventions caused, at a minimum, a 30% increase in survival and improved mean survival by ∼9 days. In the rat closed wound model we found that radiation exposure significantly decreased all wound biomechanical measurements as well as white blood cell, platelet and red blood cell counts at 10 days post wounding. Also, pathological changes showed a loss of dermal structure, thickening of dermis, loss of collagen/epithelial hyperplasia and an increased density of macrophages. In conclusion, we have characterized the effect of a changing wound size in combination with radiation exposure. We also demonstrated that the most effective interventions mitigated insensible fluid loss, which could help to define the most appropriate requirements of a successful countermeasure.

Cell-Assisted Lipotransfer Improves Volume Retention in Irradiated Recipient Sites and Rescues Radiation-Induced Skin Changes

“…Adjuvant radiation therapy is highly effective in reducing local recurrence risk following resection of various tumors . However, detrimental collateral changes frequently occur to the surrounding tissue, with macroscopic discoloration and loss of skin elasticity as well as microscopic obliteration of small vessels and dermal thickening, making reconstruction of irradiated wounds and soft‐tissue defects challenging . Rehabilitation may be addressed through autologous fat grafting, but transfer of avascular fat to hypovascular postradiation recipient beds has been associated with poor fat graft survival .…”

Evaluating the Special Needs of The Military for Radiation Biodosimetry for Tactical Warfare Against Deployed Troops

“…There is substantial evidence that, when doses as low as 1 Gy are combined with physical injury such as trauma and burns, the likelihood of experiencing poor outcomes including death is significantly increased over what would be expected from the same dose or trauma, but each experienced alone (Flynn and Goans 2012, Palmer et al 2014, Zawaski et al 2014, Mendoza et al 2012, Hare et al 2007; Kiang et al 2012). Studies of combined injury also indicate that survival is significantly increased if treatment can begin within two days of the event, largely caused by the importance of avoiding surgical complications, e.g., infections associated with early stages of acute radiation syndrome (ARS) (Flynn and Goans 2012).…”

A review of radiation countermeasures focusing on injury-specific medicinals and regulatory approval status: part I. Radiation sub-syndromes, animal models and FDA-approved countermeasures

“…Rats have also been used to study combined injury (radiation plus wound) (DiCarlo et al 2010;Zawaski et al 2014). Laminin 332 deposition was found to be diminished in the irradiated skin of WAG/RijCmcr rats when subjected to combined radiation and wound skin injury (Jourdan et al 2011).…”