Systemic Evaluation of Electrical Stimulation for Ischemic Wound Therapy in a Preclinical In Vivo Model

Abstract

Objective: In a systematic preclinical investigation of ischemic wound healing, we investigated the hypothesis that electrical stimulation (ES) promotes the healing of ischemic wounds. Approach: The effects of varying clinically relevant ES variables were evaluated using our modified version of the Gould F344 rat ischemic wound model. Stimulation was delivered using the novel lightweight integrated, single-channel, current-controlled modular surface stimulation (MSS) device. Stepwise variation allowed the effects of five different stimulation paradigms within an appropriate current density range to be studied. Within each group, 8-10 animals were treated for 28 days or until the ischemic wounds were healed and 5 animals were treated for 12 days. Eight rats received sham devices. A quantitative multivariable outcomes assessment procedure was used to evaluate the effects of ES. Results: Ischemic wounds treated with a decreased interpulse interval (IPI) had the highest rate of complete wound closure at 3 weeks. Wounds treated with decreased pulse amplitude (PA) had a lower proportion of closed wounds than sham ischemic wounds and showed sustained inflammation with a lack of wound contraction. Innovation: Our systematic study of varying ES paradigms using the novel MSS device provides preliminary insight into potential mechanisms of ES in ischemic wound healing. Conclusion: Clinically appropriate ES can more than double the proportion of ischemic wounds closed by 3 weeks in this model. Ninety percent of wounds treated with a decreased IPI healed by 21 days compared with only 29% of ischemic wounds treated with decreased PA, which appears to inhibit healing.

Kath M. Bogie, DPhil

Figure 1.

Wound images and sections (all sections 10×). (A) Control wound at POD12. (B) Electrical stimulation-treated ischemic wound at POD28. (C) Sham ischemic wound at POD28.| |, wound margins. Note that wound margin could not be delineated on sham ischemic wounds. H&E, hematoxylin and eosin; POD, postoperative day; VEGF, vascular endothelial growth factor. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound

Figure 2.

Percentage of wounds closed at POD21. ⇑, increased; ⇓, decreased. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound

Figure 3.

Relative wound size over time. Error bars show standard deviations. **p<0.01. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound

Figure 4.

Composite wound histology (CWH) score. Error bars show standard deviations. **p<0.0.1. Key: See Fig. 2. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound

Figure 5.

Relative immunofluorescence marker activity in wound area. Error bars show standard deviations. **p<0.01 versus POD28. DHE, dihydroethidium; EpCAM, epithelial cell adhesion molecule. Key: See Fig. 2. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound