Protection of sildenafil citrate hydrogel against radiation-induced skin wounds

Highlights

• Reproducible model of acute radiation induced skin injury was developed in rats using gamma irradiation.

• Sildenafil citrate hydrogel formulation was used to treat radiation wounds showed beneficial results.

• Significant reduction in percentage wound contraction and skin damage score in treated tissues as compared with non irradiated control.

• Nitric oxide recovery was found in treated tissues.

• Histopathology analysis showed high re-epithelization and repair in the treated group.

Abstract

Radiation induced skin wound/dermatitis is one of the common side effects of radiotherapy or interventional radiobiology. In order to combat impaired healing of radiation wounds, alternative therapy to use sildenafil citrate (SC) topical hydrogel as a therapeutic option was proposed that has known to enhance nitric oxide in wounds. Our aim was to develop a radiation induced skin wound model and to investigate the wound healing efficacy of 5% SC hydrogel formulation in Sprague-Dawley rats. In the present study, the radiation wound inducing dose was optimized using a multi-dose localized γ-radiation trail with 10−55 Gy range (15 Gy interval). Optimal irradiation dose for wound induction was selected based on radiation skin damage assessment criteria followed the relative change from <35 Gy or>55 Gy showed significant variation and median 45 Gy γ-dose was selected for studying acute effects of radiation on wound healing. Significant (p < 0.05) higher wound contraction (88 ± 1.02%), skin damage reduction (81 ± 0.82%), tensile strength (45 ± 1.61%), nitric oxide and protein recovery (53 ± 0.72%) at dermal level prove the wound healing efficacy of 5% SC hydrogel formulation as compared to Rad 45 Gy control. In addition, the dose modifying factor (DMF) for SC hydrogel treatment was found to be 1.83 and 1.57 with respect to total wound area contraction and skin damage reduction. Skin histopathology in treated tissues showed improved granulation tissue formation, less inflammatory infiltrates and mature collagen fibres in the dermis. Thus, the modality could help to improve delayed wound healing in irradiated skin tissues.

Introduction

Radiation induced skin wounds are gaining significance with enhanced possibility of external radiation exposures during cancer radiotherapy treatment, nuclear spoilages, radiological emergencies [1]. It carries the risk of excessive high doses to the skin which in turn, associated with radiation induced free radical generation, resulting in cascading skin reactions with deterministic effects [2,3]. The effects could be distinguished as either prompt/acute/sub acute/chronic skin reactions [4]. In present technological era, the incidence of radiation induced skin wound is no longer rare and the potential risk of radiation exposure to the skin is >3 Gy to the threshold of 10 Gy dose [1]. The prominent dose limiting effect on proliferative skin tissue ranges from a mild rash to even severe ulceration [5]. Such dose dependent exposure of radiation might cause damage to skin basal epithelial, keratinocyte (s), fibroblast (s), and dermal endothelial cells with permanent erythema, dermal atrophy and ulceration [6].

Local skin wounds induced by radiation is limit to various attributes, namely (a) radiation dose; (b) dose rate; (c) time of exposure; (d) collimation system to avoid internal scattering; (e) incident rate on skin; (f) prophylactic and curative drug application; (f) animal model system and; (g) whether the skin is intact or already broken/wounded due to extrinsic trauma [7].

The existing treatment regimens included corticosteroids, topical aloe vera lotions [8], synthetic dressings like Biobrane, Tegaderm that has shown some protection to manage radiation induced skin wounds [9]. Overall, these strategies limits the clinical severity, yet showed adverse effect profile such as variable efficacy, down regulating lipid synthesis and impaired permeability barrier function that makes them not ideal for continuous therapy [10]. One of the major challenges is standardization of suitable model in lower animals to visualise comprehensive structural and functional derangements in the skin due to such radiation induced wounds. Consequently, there is a quest to identify the potential agent that is able to mitigate the acute impact as well as long term recovery.

The present study focuses on two major aspects: first aspect was standardization of preclinical model of radiation induced skin wound (dermatitis) at increasing gamma exposure. The second focus area was to evaluate the wound healing efficacy of preselected sildenafil citrate (SC) hydrogel formulation (5% SC). In a recent study, our groups had already showed safety and significant efficacy of topical 5% SC hydrogel (˜97%) in a traumatic wound model [11]. Therefore, the present study evaluates healing efficacy of the 5% SC hydrogel formulation for radiation induced skin wounds in terms of dose modifying factor (DMF), radiation wound contraction, skin damage scoring, tensile strength, protein damage along with tissue histopathology to establish preclinical protection for gamma-irradiation induced skin wounds.