Nature's Electric Potential: A Systematic Review of the Role of Bioelectricity in Wound Healing and Regenerative Processes in Animals, Humans, and Plants

Abstract

Natural endogenous voltage gradients not only predict and correlate with growth and development but also drive wound healing and regeneration processes. This review summarizes the existing literature for the nature, sources, and transmission of information-bearing bioelectric signals involved in controlling wound healing and regeneration in animals, humans, and plants. It emerges that some bioelectric characteristics occur ubiquitously in a range of animal and plant species. However, the limits of similarities are probed to give a realistic assessment of future areas to be explored. Major gaps remain in our knowledge of the mechanistic basis for these processes, on which regenerative therapies ultimately depend. In relation to this, it is concluded that the mapping of voltage patterns and the processes generating them is a promising future research focus, to probe three aspects: the role of wound/regeneration currents in relation to morphology; the role of endogenous flux changes in driving wound healing and regeneration; and the mapping of patterns in organisms of extreme longevity, in contrast with the aberrant voltage patterns underlying impaired healing, to inform interventions aimed at restoring them.

Keywords: Vmem; electric field; regeneration; voltage mapping; wound current.

Figure 1

Mechanisms in animals that transduce electrical signals into second-messenger cascades through a series of sequential phases. 1. Signals arrive via gap junction connections, or are initiated from variations in ion channels/pumps, or leaks across wounded cells/cell layers. 2. These signals are carried by membrane potential changes, pH gradients, fluxes (flow of ions), or electric fields. 3. Next, various mechanisms act as biophysical receptors for these signals. 4. The signals activate a number of genetic signaling pathways such as integrin and Slug/Sox10. 5. The resulting transcriptional cascades orchestrate changes in cell behavior (such as proliferation and differentiation), and remote tissues, enabling wounds to discern what already exists and what must be recreated (from Sundelacruz et al., , reprinted with permission).

Figure 2

Wound current in the mammalian corneal epithelium model. (A) Tight junctions (purple dots) seal neighboring cells to each other and restrict lateral mobility of membrane proteins. The apical domain of each polarized cell is therefore enriched in Na⁺ channels (black) and Cl⁻ transporters (blue), whereas the basolateral domain contains Na⁺-K⁺ ATPases (green); this polarized distribution results in net movement of Na⁺ and K⁺ inward into the stromal layer and net movement of Cl⁻ outward into the tear fluid (arrows). The separation of charge across the tightly sealed epithelium results in a transepithelial potential (TEP) difference of ~40 mV, with the stroma positive relative to the tear fluid. (B) Upon injury, the TEP collapses to zero at the wound center, but it remains ~40 mV distally. This voltage gradient establishes an EF (red arrows) in the tissues parallel to the epithelial surface (from McCaig et al., , reprinted with permission).

Figure 3

Effect of V_mem disruption on brain development in Xenopus embryos, and subsequent rescue by forced hyperpolarization. GFP-labeled to show subsequent developing brain structures at Stage 45. (i) Control, showing normal development of nostrils, olfactory bulb/forebrain, midbrain, and hindbrain (arrows). (ii) Tadpoles injected with constitutively active notch ICD at 4-cell stage showed severely malformed neural patterning with absent forebrain and a mispatterned midbrain at Stage 45 (blue arrowheads). (iii) Tadpole injected with both Notch ICD and hyperpolarizing Bir10 ion channel (leading to forced hyperpolarization) showed restoration of neural patterning with intact nostrils and distinct forebrain, midbrain, and hindbrain [arrowhead colors as in panel (i)]. (From Pai et al., , reprinted with permission).

Figure 4

Proposed model of electric field during wound healing in normal skin compared with diabetic skin and wounds recalcitrant to healing. Hypothetical schematic diagram (adapted from McCaig et al., 2005). Electric field (blue lines) in tissues and wound bed, with arrows indicating direction of field lines. The “wound current” flows in the same direction of arrows, to drive migration of cells into wound bed, promoting wound healing. (A) Electric field of normal skin wound. (B) Wound of diabetic skin, aged normal skin, and other recalcitrant wounds may have a diminished electric field and associated wound current, which could explain the impaired wound healing in these various patients.