Epidermal growth factor (EGF) is an excellent drug for promoting wound healing; however, its conventional administration strategies face pharmacodynamic challenges. First, with regard to topical administration in the form of creams commonly used in clinics, the high molecular weight of EGF (Mw≈6 kDa) limits its penetration into the stratum corneum. Although EGF can be delivered transdermally by injection, this poses a risk of bacterial infection to the patient, and the pain caused by the injection also reduces patient compliance, both of which are detrimental to wound treatment. Secondly, EGF has low stability in vivo; this is because glutathione (GSH) disrupts the disulfide bonds that stabilize the EGF structure, resulting in the reduction and inactivation of EGF, which greatly reduces its efficacy. Finally, EGF promotes cell proliferation and migration by specifically binding to EGFR and thereby activating the downstream factor PI3K; however, an EGF-rich microenvironment can lead to rapid endocytosis of EGFR into endosomes and eventual degradation in lysosomes. Thus, long-term EGF treatment leads to desensitization and attenuation of EGFR, terminating the signaling pathway. Therefore, improving the pharmacodynamics of EGF in wound healing can be approached from the following aspects: (i) increase the permeability in a minimally invasive manner; (ii) maintain chemical stability of EGF and prevent its reduction by GSH; (iii) upregulate EGFR expression to compensate for receptor desensitization.

In biological systems, the expression of certain growth factor receptors has been shown to correlate with bioelectric fields. This phenomenon inspires us to develop a device with transcutaneous electrical stimulation (ES) and transdermal drug delivery capabilities to improve drug permeability while compensating for receptor desensitization. A Microneedle system with transdermal, drug-loaded, and conductive capabilities is an ideal therapeutic medium. As minimally invasive devices, microneedles (MNs; length < 1 mm) can penetrate the stratum corneum without bleeding or pain; drug molecules can be encapsulated in dissolvable MNs and diffused directly into the skin as MNs degrade. Meanwhile, conductive MNs could be used as electrodes to reach the low-resistance dermis (~10 kΩ) and bypass the high-resistance stratum corneum (~10 MΩ), thus enabling transcutaneous ES.

In light of this consideration, we designed a microneedle-based self-powered transcutaneous electrical stimulation system (mn-STESS) to improve the pharmacodynamics of EGF in wound treatment. The integrated mn-STESS consisted of a sliding free-standing triboelectric nanogenerator (sf-TENG) and two-stage gold-coated polylactic acid/cross-linked gelatin–cross-linked hyaluronic acid (PLA-Au/cGel-cHA) composite microneedle patches (CMNPs). The mn-STESS was wireless, passive, and easily attached to the skin. The built-in sf-TENG converted the biomechanical energy generated by finger sliding into biosafe microcurrent without causing skin damage or drug inactivation. CMNP penetrated the stratum corneum and continuously released EGF into the skin for 24 hours. Meanwhile, CMNP utilized the current generated by the sf-TENG for transcutaneous ES. As an electrical adjuvant, self-powered ES improved the pharmacodynamics of EGF in various aspects. (1) mn-STESS enhanced penetration rate and utilization rate of EGF. mn-STESS could pierce the stratum corneum and continuously release EGF into the skin, enabling long-term transdermal drug delivery. (2) mn-STESS suppressed the reduction reaction against EGF by modulating the molecular motion behavior of GSH. ES produced by mn-STESS did not change the protein activity, but altered the molecular movement behavior of GSH. Molecular dynamics calculations showed that the electric field generated by mn-STESS significantly increased the intermolecular distance between GSH and EGF, thereby inhibiting the reduction of EGF by GSH. (3) ES generated by mn-STESS upregulated EGFR expression, thereby compensating for receptor desensitization. From cell to animal experiments, it has been confirmed that mn-STESS possessed a strong receptor sensitization effect, which completely overwhelmed the drug-induced downregulation of EGFR. The comprehensive improvement of EGF pharmacodynamics by mn-STESS further activated the EGF/EGFR pathway and downstream PI3K, thereby promoting cell proliferation and migration. Translational medicine studies showed that mn-STESS promoted wound re-epithelialization, vascularization, and hair follicle formation, ultimately accelerating the wound healing process.

To the best of our knowledge, this work is the first paradigm to propose a self-powered electrical adjuvant to improve drug pharmacodynamics. This proof-of-concept and implementation provides a potential solution for humans to overcome resistance to classical drugs. mn-STESS is expected to improve the quality of treatment for patients by enhancing the efficacy of classic drugs, while reducing additional medical insurance expenditures associated with the use of expensive new drugs.

Fig.1. mn-STESS improved EGF pharmacodynamics to promote wound healing.