Wearable Bioelectronics for Chronic Wound Management

Abstract

Chronic wounds are a major healthcare issue and can adversely affect the lives of millions of patients around the world. The current wound management strategies have limited clinical efficacy due to labor-intensive lab analysis requirements, need for clinicians' experiences, long-term and frequent interventions, limiting therapeutic efficiency and applicability. The growing field of flexible bioelectronics enables a great potential for personalized wound care owing to its advantages such as wearability, low-cost, and rapid and simple application. Herein, recent advances in the development of wearable bioelectronics for monitoring and management of chronic wounds are comprehensively reviewed. First, the design principles and the key features of bioelectronics that can adapt to the unique wound milieu features are introduced. Next, the current state of wound biosensors and on-demand therapeutic systems are summarized and highlighted. Furthermore, we discuss the design criteria of the integrated closed loop devices. Finally, the future perspectives and challenges in wearable bioelectronics for wound care are discussed.

Keywords: bioelectronics; biosensors; drug delivery; wearable devices; wound healing.

Figure 1.

Schematic illustration of wearable bioelectronics for wound biosensing and on-demand therapy administration. Wound-specific conditions should be considered to enable stable and reliable device operation. A variety of biomarkers, including physical signals, small molecules, macromolecules and microorganisms, are available in the wound milieu for wound condition assessments. Controlled by advanced algorithms, smart wearable bioelectronics could deliver therapeutic strategies such as drugs, electrical stimulation, and photodynamic therapy to the wounds responsively and timely.

Figure 2.

Mechanical and adhesive properties for smart bandages. A. Schematic of an adhesive based on physical entanglement. B. Adhesion energy measurement of hydrogel with different formulations applied to glass slides. Reproduced with permission.^[57] Copyright 2020, Wiley-VCH. C. Schematic of a covalent adhesive interface between wounds and dissipate hydrogel matrix. D. Measured adhesion energy on porcine skin. Reproduced with under the terms of the CC-BY license.^[59] Copyright 2019, AAAS. E. Schematic of an e-bioadhesive interface enable interfacial fluid removement and rapid adhesion. F. Characterization of mechanical compliance and interfacial toughness on various tissues. Reproduced with permission.^[61] Copyright 2020, Springer Nature.

Figure 3.

Wearable physical biomarker sensing. A. Schematic of a thermosensitive material integrated wound temperature sensor. B. Photograph of applying the sensor on a human skin. C. Calibration curve of resistance as a function of temperature. Reproduced with permission.^[70] Copyright 2020, Elsevier. D. A fully integrated temperature sensor and its application scenario. E. Photograph of applying the temperature sensor on a pig full-thickness wound. F. Real-time wound and rectal temperature monitoring curve of a late phase infection model. Reproduced with permission.^[72] Copyright 2020, Elsevier. G. Photograph of a flexible wound impedance sensor array. H. Impedance plots of skin tissue with or without damages. I. Schematic of operating the sensor array to map skin tissue impedance. Reproduced under the terms of the CC-BY license.^[73] Copyright 2015, Springer Nature. J. Working mechanism of bioelectronic suture for wireless operation. K. Photograph of applying the suture to close muscle incision. L. Changes of signals in response to simulated gastric leakage and breakage on muscles. Reproduced with permission.^[74] Copyright 2021, Springer Nature. M. Schematic and photograph of plantar pressure mapping sensor. N. Heat maps of plantar pressure with different postures. Reproduced under the terms of the CC-BY license.^[75] Copyright 2020, Springer Nature.

Figure 4.

Wearable small molecule sensing. A. Photograph of a wearable pH sensor with a potentiostat. B. SEM characterization of the PANI-based pH sensor. C. Calibrated impedance as a function of the pH value. Reproduced with permission.^[93] Copyright 2018, Elsevier. D. Schematic of a UA sensor design. E. Uricase-based sensor response to variation of UA concentration. Reproduced with permission.^[70] Copyright 2020, Elsevier. F. Photograph of a wound dressing integrated with oxygen sensors and generators. G. Oxygen measurement in response to H₂O₂ perfusion. Reproduced under the terms of the CC-BY license.^[97] Copyright 2020, Springer Nature. H. Working mechanism of a colorimetric pH and glucose dual sensor. I. Images of hydrogel color changes in response to different glucose concentration or pH values. J. Measured wound glucose in comparison with blood glucose level. Reproduced with permission.^[96] Copyright 2019, Wiley-VCH.

Figure 5.

Wearable macromolecule sensing. A. Schematic of an aptamer-based wound sensor integrated with wound extrude collection and wireless data transmission modules. B. Patient’s fluctuations of various biomarker levels were measured and correlations among these signals were observed. Reproduced under the terms of the CC-BY license.^[118] Copyright 2021, AAAS. C. Schematic of a colorimetric sensor for nucleic acid detection. D. Selective detection of target DNA against other viruses was observed. Reproduced with permission.^[126] Copyright 2018, Elsevier. E. Schematic of a DNase sensing hydrogel for pathogen detection. F. Schematic of DNA gel integrated device with wireless communication module for data transfer. G. Signal changes of DNA hydrogel on control and S. aureus infected mice wound models. Reproduced under the terms of the CC-BY-NC license.^[127] Copyright 2021, AAAS. H. Mechanism of sensing toxins released by bacteria for wound infection detection. I. Fluorescence intensity variation of bacterial-sensitive dressing in response to the growth of different bacterial species. Reproduced with permission.^[128] Copyright 2011, Elsevier.

Figure 6.

Endogenously responsive drug delivery. A. Schematic of a pH and glucose dual-responsive hydrogel design for glucose and L929 fibroblast cell delivery. Reproduced with permission.^[145] Copyright 2017, American Chemical Society. B. Schematic of a pH and ROS responsive hydrogel for antibiotics and anti-inflammatory drug delivery. Reproduced with permission.^[146] Copyright 2020, Elsevier. C. Design of a plasmin-responsive hydrogel for growth factor sequential delivery. D. Sequential growth factor release in diabetic mouse wound models. Reproduced with permission.^[147] Copyright 2015, Wiley-VCH.

Figure 7.

Exogenously responsive drug delivery. A. Schematic of a wireless heat-responsive woven dressing for controllable drug release. Reproduced with permission.^[148] Copyright 2017, Wiley-VCH. B. A electrical simulation-controlled wound patch for pH-responsive drug delivery. Reproduced with permission.^[150] Copyright 2018, Wiley-VCH. C. Schematic of an electrically controlled drug release system coupling with electrical stimulation wound therapy. D. Electrical potential related drug release rates were observed. Reproduced with permission.^[161] Copyright 2021, Elsevier. E. Design of NIR irradiation-mediated CO₂ delivery for wound treatment. Reproduced with permission.^[153] Copyright 2017, American Chemical Society. F. Schematic of a light responsive microalga hydrogel dressing for oxygen delivery. G. Photograph of a microalga hydrogel patch adhered to a subject’s arm. H. Comparison of wound healing process by applying with alga-gel patch and other treatments for oxygen delivery on mouse. Reproduced under the terms of the CC-BY-NC license.^[154] Copyright 2020, AAAS.

Figure 8.

Electrical stimulation and photodynamic therapy. A. Schematic and photograph of a high-voltage monophase pulsed wound dressing. Reproduced under the terms of the CC-BY license.^[156] Copyright 2021, Elsevier. B. Photograph of patterning DoS electronics on a subject’s skin. C. Photograph of applying low-voltage electrical stimulation on a mice wound model. Reproduced under the terms of the CC-BY license.^[157] Copyright 2020, Springer Nature. D. A nanogenerator-powered bandage for electric simulation. E. Voltages generated from various rat body motions. F. Representative images of the healing process after treating with or without EF after 3 days. Reproduced with permission.^[158] Copyright 2018, American Chemical Society. G. Schematic of a TiO₂-based nanoarray generating ROS to kill bacteria. Reproduced with permission.^[159] Copyright 2018, Elsevier. H. Schematic of a hydrogel matrix containing ZnO and Ag for photodynamic therapy. I. Light-responsive S. aureus damage were observed with different hydrogel formulations. Reproduced with permission.^[160] Copyright 2017, American Chemical Society.

Figure 9.

Self-powered bandages. A. Photograph of the piezoelectric patch applied on wound for active wound therapy. B. Schematic illustration and calculation of the piezoelectric potential generated from the wound patch. C. Piezoelectric voltage generated by animal motions. Reproduced with permission. Reproduced with permission.^[182] Copyright 2016, Wiley-VCH. D. Operation concept of a wound patch integrated with a biofuel powered electrochromic timer for drug dosing. E. Quantification of the color depth and CV current of BFC. Reproduced with permission.^[183] Copyright 2019, Elsevier. F. Schematic of an NFC-based wound sensor. G. Photograph of applying the NFC sensor on a human’s arm and realize wireless data transmission. Reproduced with permission. Reproduced with permission.^[184] Copyright 2018, Wiley-VCH.

Figure 10.

Algorithm-assisted closed-loop wound management systems. A. Schematic and photograph (inset) of a closed-loop drug delivery system for infection sensing and responsive antibiotics release. Reproduced with permission.^[149] Copyright 2018, Wiley-VCH. B. Schematic diagram of a smart electronic patch that controls UV-triggered drug release based on pH sensors. C. Photograph of the UV controllable closed loop wound patch. D. Real-time temperature monitoring and responsive drug release after bacterial inoculation at the wound site using anal temperature as a reference. Reproduced under the terms of the CC-BY license.^[155] Copyright 2020, Wiley-VCH. E. Schematic of a wireless closed-loop wound patch that is powered by a smartphone for pH, temperature, and uric acid as well as controlled drug delivery. F. Photograph of a flexible and wireless wound patch. G. Image of the wound patch adhered on a rat wound with an NFC-enabled data transmission. Reproduced with permission.^[151] Copyright 2021, Wiley-VCH.

Figure 11.

Perspective of AI-implemented wearable bioelectronics for future wound management. Patient-specific database would be established and incorporate multiplexed information of patients and wound conditions. Advanced training methodologies would be involved to process diverse samples to generate clustered individual network metrics and identify patterns from previous occurrences. With AI-enabled rapid and accurate interpretations, personalized therapeutic decisions could be made to improve therapeutic efficiency and accelerate the advancement of new wound care modalities development.