J Neurotrauma. 2018 Mar 15;35(6):815-824. doi: 10.1089/neu.2017.5405.

Impact of Complete Spinal Cord Injury on Healing of Skin Ulcers in Mouse Models.

Kumar S1, Yarmush ML1,2, Dash BC3, Hsia HC3, Berthiaume F1.
1Department of Biomedical Engineering, Rutgers, The State University of New Jersey , Piscataway, New Jersey.
2Center for Engineering in Medicine, Massachusetts General Hospital and Shriners Burns Hospital , Boston, Massachusetts.
3Department of Surgery, Yale School of Medicine, Yale University , New Haven, Connecticut.

Abstract

Pressure ulcers (PUs) are common debilitating complications of traumatic spinal cord injury (SCI) and tend to occur in soft tissues around bony prominences. There is, however, little known about the impact of SCI on skin wound healing because of the lack of suitable animal models for studies in controlled experimental settings. Herein, we describe a reproducible and clinically relevant mouse model of PUs in the context of complete SCI. Adult male mice (BALB/c) were subjected to thoracic (T9-T10) complete SCI. Immediately after, a skin fold on the back of mice was lifted and sandwiched between two magnetic discs held in place for 12ā€‰h, thus creating an ischemic area that developed into a PU over the following days. The wounded areas demonstrated tissue edema and epidermis disappearance by day 3 post-magnet removal. PUs spontaneously healed, although slower in SCI mice compared to control non-SCI mice (5 vs. 3 weeks; pā€‰<ā€‰0.001). A similar delay in healing was observed for full-thickness excisional wounds. Histology data showed that there was a slower migration of epidermal cells over the granulation tissue in the SCI group compared to the control group. The SCI group also showed the smaller thickness of epidermis and dermis, lower blood vessel density, decreased numbers of proliferating cells, and decreased expression of alpha-smooth muscle actin compared to the control group at the time of wound closure. Taken together, these data suggest that SCI significantly slows down the dynamics of skin wound healing in experimental pressure and excisional wounds in mice.

KEYWORDS:

alpha-smooth muscle actin; excisional wound; pressure ulcer; skin; spinal cord injury

PMID: 29160147

 

Supplement:

There are approximately 291,000 persons with spinal cord injury (SCI) living in the United States and about 17,000 new cases each year (Jain et al. 2015; Lasfargues et al. 1995). Pressure ulcers (PUs) or sores are a major common debilitating secondary complication from SCI besides sensorimotor dysfunction (Rappl LM, 2008). Patients with SCI tend to develop PUs because of prolonged immobility and lack of sensation. PUs usually form in soft tissues around bony prominences where pressure is concentrated during sitting or lying in a supine position (e.g. sacral areas, heels) (Rappl LM, 2008). Because PUs often heal slowly (and sometimes not at all) with conventional measures, and as patients get older, they often develop co-morbidities, such as diabetes, anemia, or malnutrition, that severely increase the risk for chronic wound development (Krause JS, 1998). Overall, 41% of patients with SCI in their first-year present PUs with a reoccurrence chance of 60ā€“85%. Moreover, PUs have a significant negative impact on the daily life of SCI patients (Krause JS, 1998; Marin et al. 2013).

There is currently little known about the impact of SCI on the skin wound healing process due to a lack of controlled animal studies to investigate this question. In this study (Kumar et al. 2018), we developed a novel, simple, reproducible, and a clinically relevant mouse model of PUs in the context of complete SCI to evaluate the impact of SCI on skin wound healing. PUs were induced by a 12-hour application of two 12-mm-diameter disc magnets on a dorsal skinfold (Kumar et al. 2019). Such wounds healed with dynamics that were very similar to that observed in commonly used 1 x 1 cm full-thickness excisional wounds. Post-SCI, skin wounds below the level of SCI healed much slower, taking 35 days instead of 21 days (Figure 1B-C). Skin wounds exhibited decreased wound contraction, which resulted in a larger scar with thinner epidermis and dermis. Markers that are associated with the wound healing process, such as Ki67, CD31, and a-SMA, were expressed at lower levels in wounds of SCI animals. Taken together, these results show that SCI slows down skin wound healing in mice. Importantly, these observations were specifically observed in skin wounds below the innervation level of the SCI, because wounds made above the SCI level were largely unaffected in their wound healing pattern as compared to the control non-SCI group.

 

 

Figure 1: [A] Schematic presentation of mouse with SCI injury (T9-10, complete transection) and skin wound (1×1 cm) above (A-W) and below (B-W) SCI. [B] In normal non-SCI mouse, pressure ulcers/excision skin wounds induced either above or below sham injury healed at the same time, whereas in the SCI mouse [C], the below SCI site wound healed in longer time (>14 days versus above wound, indicated by arrow).

 

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