Soft bioelectronics play an increasingly crucial role in high-precision therapeutics due to their softness, biocompatibility, clinical accuracy, long-term stability, and patient-friendliness. In this review, we provide a comprehensive overview of the latest representative therapeutic applications of advanced soft bioelectronics, ranging from wearable therapeutics for skin wounds, diabetes, ophthalmic diseases, muscle disorders, and other diseases to implantable therapeutics against complex diseases, such as cardiac arrhythmias, cancer, neurological diseases, and others. We also highlight key challenges and opportunities for future clinical translation and commercialization of soft therapeutic bioelectronics toward personalized medicine.

Soft Bioelectronics for Therapeutics.

Diabetic foot ulcers are chronic wounds that affect millions, and increase the risk of amputation and mortality, highlighting the critical need for their early detection. Recent demonstrations of wearable sensors enable real-time wound assessment, but they rely on bulky electronics, making them difficult to interface with wounds. Here, w e introduce a miniaturized, wireless, battery-free wound monitor that measures lactate in real-time and seamlessly integrates with bandages for conformal attachment to the wound bed. W e select lactate due to its multifaceted role in initiating healing. Studies in healthy and diabetic mice reveal distinct lactate profiles for normal and impaired healing wounds. A mathematical model based on the sensor data predicts wound closure rate within the first three days post-injury with ∼76% accuracy which increases to ∼83% when pH is included. These studies underscore the significance of monitoring biomarkers during the inflammation phase, which can offer several benefits, including short-term use of wound monitors and their easy removal, resulting in lower risks of injury and infection at the wound site. Improvements in prediction accuracy can be achieved by designing mathematical models that build on multiple wound parameters such as pro-inflammatory and metabolic markers. Achieving this goal will require designing multi-analyte wound monitors. This article is protected by copyright. All rights reserved 

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/adhm.202301280

A Miniaturized, Battery‐free, Wireless Wound Monitor that Predicts Wound Closure Rate Early

Endogenous signals, such as nitric oxide (NO) and electrons, induce multifaceted physiological functions in the regulation of cell fate as well as vascular and neuronal systems. However, clinical difficulties exist due to the short half-life of NO and the lack of tools to spatiotemporally drive gas release and electrical stimulation. Here, we propose a "magnetoelectric massager" strategy based on alternating magnetic field (AMF)-triggered on-demand NO release and electrical stimulation to restore brain function in traumatic brain injury. The NO and electron transport system was constructed as a metal-organic framework (MOF)-derived molybdenum carbide octahedron (MoCx-Cu) and an NO donor (S-nitrosoglutathione, GSNO), which was embedded in an implantable silk in a microneedle. Under AMF irradiation, eddy currents on conductive MoCx-Cu induced NO release from GSNO through electrical stimulation, thereby significantly promoting the differentiation and growth of neural stem cell (NSC) synapses. A combined strategy of in vivo traumatic brain injury allows NO and electrical stimulation-mediated inhibition of inflammation, angiogenesis, and neuronal interrogation. 

In situ magnetoelectric generation of nitric oxide and electric stimulus for nerve therapy by wireless chargeable molybdenum carbide octahedrons

Abstract Cell behavior is intricately intertwined with the in vivo microenvironment and endogenous pathways. The ability to guide cellular behavior toward specific goals can be achieved by external stimuli, notably electricity, light, ultrasound, and magnetism, simultaneously harnessed through biomaterial‐mediated responses. These external triggers become focal points within the body due to interactions with biomaterials, facilitating a range of cellular pathways: electrical signal transmission, biochemical cues, drug release, cell loading, and modulation of mechanical stress. Stimulus‐responsive biomaterials hold immense potential in biomedical research, establishing themselves as a pivotal focal point in interdisciplinary pursuits. This comprehensive review systematically elucidates prevalent physical stimuli and their corresponding biomaterial response mechanisms. Moreover, it delves deeply into the application of biomaterials within the domain of biomedicine. A balanced assessment of distinct physical stimulation techniques is provided, along with a discussion of their merits and limitations. The review aims to shed light on the future trajectory of physical stimulus‐responsive biomaterials in disease treatment and outline their application prospects and potential for future development. This review is poised to spark novel concepts for advancing intelligent, stimulus‐responsive biomaterials. 

Harnessing stimuli‐responsive biomaterials for advanced biomedical applications

In Situ Magnetoelectric Generation of Nitric Oxide and Electric Stimulus for Nerve Therapy by Wireless Chargeable Molybdenum Carbide Octahedrons

Soft, wireless electronic dressing system for wound analysis and biophysical therapy

Retinitis pigmentosa (RP) is an outer retinal degenerative disease that can lead to photoreceptor cell death and profound vision loss. Although effective regulation of intraretinal inflammation can slow down the progression of the disease, an efficient anti-inflammatory treatment strategy is still lacking. This study reports the fabrication of a hyaluronic acid-based inflammation-responsive hydrogel (IRH) and its epigenetic regulation effects on retinal degeneration. The injectable IRH was designed to respond to cathepsin overexpression in an inflammatory environment. The epigenetic drug, the enhancer of zeste homolog 2 (EZH2) inhibitors, was loaded into the hydrogel to attenuate inflammatory factors. On-demand anti-inflammatory effects of microglia cells via the drug-loaded IRH were verified in vitro and in vivo retinal degeneration 10 (rd10) mice model. Therefore, our IRH not only reduced intraretinal inflammation but also protected photoreceptors morphologically and functionally. Our results suggest the IRH reported here can be used to considerably delay vision loss caused by RP. 

Effective protection of photoreceptors using an inflammation-responsive hydrogel to attenuate outer retinal degeneration

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Soft, wireless electronic dressing system for wound analysis and biophysical therapy

Effective protection of photoreceptors using an inflammation-responsive hydrogel to attenuate outer retinal degeneration