Electrical stimulation modulates inflammation, angiogenesis and innervation..

NuroKor’s Chief Clinical & Scientific Advisor (BSC Hons) MB BS PhD, Dr Ardeshir Bayat collates his laboratory and clinical research on Electrical Stimulation (ES) to showcase its ability to promote tissue repair and enhance tissue healing. He also discusses how electrical stimulation modulates inflammation, angiogenesis and innervation during this process. Electrical stimulation is the foundation of bioelectronic medicine, and a core element to the makeup of NuroKor’s technology.

Electrical stimulation modulates inflammation, angiogenesis and innervation as it accelerates skin repair

by Professor Ardeshir Bayat

LinkedIn | Research Gate

The ability to heal is one of the most fundamental defence mechanisms the human body has against traumatic injury. Cutaneous wound healing necessitates a coordinated series of complex cellular and molecular processes to help restore the skin’s structural integrity as well as its normal function. However, total regeneration (restoring normal skin to its uninjured state) only occurs in phylogenetically primitive species and in the early gestational foetal stages of mammals. Therefore, it is apparent that from an evolutionary perspective, there is no tangible interest in retaining the regenerative capacity in complex organisms, especially in their adult form.

The future of healthcare is in our hands

It is therefore incumbent upon us as humans, to identify ways and means of accelerating and optimising the process of tissue repair with modern technology. Over the years, many different therapeutic modalities have been tried and tested from various pharmaceutically-based drug approaches to non-pharmaceutical energy-based modalities including biophotonics and electromagnetic therapy amongst others.

Of interest to me, electrical stimulation (ES) has long been thought to be able to promote tissue repair. Indeed, ES as a physical therapy to enhance tissue healing has been shown in many studies to be clinically successful. The rationale for using ES in wound healing is supported by the experimental observation of the effect of ES on cellular biological processes, in addition to positive therapeutic outcomes.

The exogenous application of an appropriate electrical waveform in the right setting has been the ultimate goal in order to promote wound healing both experimentally in the laboratory in vitro, and ex vivo as well as clinically in humans, in vivo.

**Figure 1 - Randomised Clinical Trial: 3D Imaging of Biopsy Sites in Upper Arm**

We previously demonstrated that ES has a significant positive effect in human wound healing in vitro (1-4), ex vivo (5 and Figure 2); and in vivo in randomised clinical trials of human volunteers (6-10) and in patients (11-12).

**Figure 2 - Ex Vivo Human Skin Wound Model**

Electrical Stimulation Accelerates Wound Healing

We demonstrated that ES results in accelerated wound healing by enhancing epidermal proliferation, stimulating angiogenesis, and reducing inflammation; as well as, upregulating neurogenesis.

Even though the exact molecular mechanisms through which ES impacts on wound healing and the key target cell populations remains essentially unknown, we are beginning to learn more about this profoundly phenomenal effect.

Laboratory and Clinical Application of Electrical Stimulation

In order to dissect and understand these mechanisms further, we have performed several studies in the laboratory as well as clinical studies involving transcriptional profiling of sequential biopsies taken from spontaneously healing human skin wounds with and without application of ES (randomised clinical trial- Figure 3).

Interestingly, gene expression profiling of tissue biopsies at different time points post-wounding, suggested that the neural differentiation related genes were significantly up-regulated post-ES.

**Figure 3 - Full field Laser Perfusion Imaging of punch biopsies in upper arm**

The analyses showed that innervation was significantly and progressively up-regulated (Figure 4) and in particular sensory nerve fibres and Merkel cells (mechanosensory and neurosecretory epithelial cells that can be connected to sensory nerve fibres) were significantly increased in wounded human skin in ES-treated samples compared to untreated control samples (Figure 5).

**Figure 5** - Co-staining of Merkel cells and TUBB3

Conclusion

In summary, our studies to date have shown that application of ES profoundly accelerates cutaneous healing, in vitro, ex vivo and importantly in vivo. Evidence gathered to date as a result of our previous work demonstrates that ES not only modulates but enhances cutaneous innervation post injury, and raises the question whether this phenomenon contributes to the recognised acceleration of cutaneous wound healing by ES.

I believe the future looks extremely promising in this emerging field and there's undoubtedly an untapped potential, albeit an electric one!

Figure 6 - Electrical Stimulation and Wound Healing

References:

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About NuroKor

Founded in 2018, NuroKor is a company committed to the development of bioelectronic technologies. NuroKor develops and formulates programmable bioelectronic software for clinical and therapeutic applications, in a range of easy to use, wearable devices. It provides the highest-quality products, delivering personalised pain relief and recovery support and rehabilitation to patients.

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