A soft bioaffinity sensor array for chronic wound monitoring

Smart wound care systems that are capable of analyzing biomarkers in the wound microenvironment and reporting data to healthcare professionals and patients can overcome many of the limitations and challenges associated with chronic wound healing. Lim and colleagues reported a novel multiplexed bioaffinity sensor array that could detect multiple inflammatory and physiological biomarkers in the wound bed. The outcome of this work can improve wound management and patient health and potentially reduce healthcare costs. Smart wound care systems that are capable of analyzing biomarkers in the wound microenvironment and reporting data to healthcare professionals and patients can overcome many of the limitations and challenges associated with chronic wound healing. Lim and colleagues reported a novel multiplexed bioaffinity sensor array that could detect multiple inflammatory and physiological biomarkers in the wound bed. The outcome of this work can improve wound management and patient health and potentially reduce healthcare costs. Chronic wounds arising from impaired wound healing are affecting over 4.5 million Americans, which results in substantial economic and psychosocial costs.1Jones R.E. Foster D.S. Longaker M.T. Management of Chronic Wounds-2018.JAMA. 2018; 320: 1481-1482Crossref PubMed Scopus (79) Google Scholar Chronic wounds develop due to different pathologic states, including diabetes, unrelieved pressure, arterial or venous insufficiency, and infection.1Jones R.E. Foster D.S. Longaker M.T. Management of Chronic Wounds-2018.JAMA. 2018; 320: 1481-1482Crossref PubMed Scopus (79) Google Scholar Given the increase of the elderly population and the prevalence of diabetes in the world, the clinical and economic burden of chronic non-healing ulcers will undoubtedly increase.2Boyle J.P. Thompson T.J. Gregg E.W. Barker L.E. Williamson D.F. Projection of the year 2050 burden of diabetes in the US adult population: dynamic modeling of incidence, mortality, and prediabetes prevalence.Popul. Health Metr. 2010; 8: 29Crossref PubMed Scopus (933) Google Scholar Currently, quantitative assessment of wound biomarkers is limited to time-consuming laboratory testing, such as enzyme-linked immunosorbent assays (ELISAs). In addition, current smart wound monitoring technologies can only detect a limited number of biomarkers (e.g., pH, temperature). Thus, a smart and noninvasive wound care platform that is capable of in situ monitoring of multiple wound biomarkers can play a critical role in patient health.3Yang Y. Gao W. Wearable and flexible electronics for continuous molecular monitoring.Chem. Soc. Rev. 2019; 48: 1465-1491Crossref PubMed Google Scholar In addition, monitoring the wound healing process (wound management) can reduce hospitalization time, lower the health risks, and assist in the development of new therapeutics. The chemical composition of wound exudates changes significantly during the progression of wound healing. Different parameters such as temperature, pH, cytokines, and growth factors could indicate the stage of healing and the presence of infection. Quantitative assessment of wound parameters was investigated over the years and wearable wound management devices were constructed to monitor wound parameters.3Yang Y. Gao W. Wearable and flexible electronics for continuous molecular monitoring.Chem. Soc. Rev. 2019; 48: 1465-1491Crossref PubMed Google Scholar,4Derakhshandeh H. Kashaf S.S. Aghabaglou F. Ghanavati I.O. Tamayol A. Smart bandages: the future of wound care.Trends Biotechnol. 2018; 36: 1259-1274Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar From the design point of view, an ideal smart wound monitoring technology should (i) create a sterile, humid, and warm environment; (ii) be breathable; (iii) protect the wound bed from bacterial infiltrations; (iv) be flexible and possess sufficient mechanical integrity; (v) modulate wound exudate level; (vi) be biocompatible and non-allergenic; (vii) measure crucial biomarkers in the wound bed and exudate; and (viii) contain a wireless communication module to send real-time clinical feedback to healthcare professionals/patients. A research group led by Prof. Chwee Teck Lim engineered a flexible and smart microfluidic biosensing bandage for point-of-care measurement of different wound biomarkers.5Gao Y. Nguyen D.T. Yeo T. Lim S.B. Tan W.X. Madden L.E. Jin L. Long J.Y.K. Aloweni F.A.B. Liew Y.J.A. et al.A flexible multiplexed immunosensor for point-of-care in situ wound monitoring.Sci. Adv. 2021; 7: eabg9614Crossref PubMed Scopus (16) Google Scholar The presented new platform (VeCare) allows quantitative in situ profiling of the inflammation and physiochemical biomarkers in the wound microenvironment as well as the pathogenic bacteria (infection) in the wound (Figure 1). In addition, the biosensors are integrated into a platform design that includes a microfluidic wound fluid collector and wireless flexible electronics to facilitate real-time clinical feedback. Therefore, the above design criteria have been considered in engineering the VeCare platform. The essential element of the designs (i–iv) in the dressing are met by an engineered, multilayer platform composed of a perforated wound contact layer, a wound exudate collector, a biosensor layer, and a breathable barrier. The perforated wound contact layer creates a gap to protect the sensor layer from direct contact with the wound bed, to avoid disruption of the newly formed granulation tissue. The breathable barrier supports sufficient oxygenation and allows the transportation of moisture vapor. In addition, the smart bandage is transparent, which allows visual evaluation of the wound bed. Using a flexible printed circuit board (FPCB) for the wireless analyzer device provides flexibility to the final patch, which prevents discomfort to the patient. Design criterium (v) is met by a bioinspired microfluidic platform that can collect wound fluid and facilitate its transfer to the biosensor layer. More specifically, inspired by the skin of Texas horned lizard (Phrynosoma cornutum), the authors designed a special sawtooth-shaped capillary-based system that enables smooth directional fluid flow toward the sensing layer while inhibiting reverse flow direction. The next critical design element is biocompatibility and lack of allergenic reactions after dressing application (vi). Gao et al. assessed this criterion by histopathological analysis of the wound tissue upon placement of the smart bandage. Their finding showed no visual signs of allergic reactions (e.g., redness, swelling, and degeneration) on the skin surface that was in contact with the biosensor up to 5 days post application. In addition, the bandage did not alter the rate of wound closure, reepithelialization distance, nascent epidermal thickness, and immune cell infiltration when compared to the control wounds without the bandage. Another important element of the VeCare platform is the multiplexed aptamer sensor array that can detect inflammatory biomarkers tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-8 (IL-8). The elevated level of cytokines and chemokines in wound fluids can be a sign of inflammation and can indicate the progression of healing. Moreover, to evaluate the dermal healing process in the wound, the VeCare also includes aptamer-based sensors for transforming growth factor-β1 (TGF-β1), which plays a crucial role in regulating dermal fibroblast phenotype, and its excess level may result in fibrotic scarring response and keloid.6Pakyari M. Farrokhi A. Maharlooei M.K. Ghahary A. Critical role of transforming growth factor beta in different phases of wound healing.Adv. Wound Care (New Rochelle). 2013; 2: 215-224Crossref PubMed Google Scholar The VeCare platform can also detect physicochemical markers including pH, temperature, and Staphylococcus aureus (S. aureus) infection. The pH of the wound bed is another important biochemical indicator of the status of the wound during the healing process. The pH of native skin is acidic (pH 4.0–6.0), while over 80% of chronic wounds with alkaline pH (pH > 8) are most likely infected. In addition, the acidic environment can support the proliferation of fibroblasts.4Derakhshandeh H. Kashaf S.S. Aghabaglou F. Ghanavati I.O. Tamayol A. Smart bandages: the future of wound care.Trends Biotechnol. 2018; 36: 1259-1274Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar Wound temperature provides information on local blood flow, inflammation, and infection where an increase in temperature can delay the healing process, and the temperature decreases as the wound progresses toward healing.4Derakhshandeh H. Kashaf S.S. Aghabaglou F. Ghanavati I.O. Tamayol A. Smart bandages: the future of wound care.Trends Biotechnol. 2018; 36: 1259-1274Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar The authors extensively evaluated the performance of the multiplexed bioaffinity sensor system in vitro, in vivo, and against clinical samples. For instance, for the in vivo work, Lim and colleagues used a wound healing model in mice, where the VeCare was applied to the wounds, followed by daily in situ wound monitoring (1 h per day). Based on their observation, the longitudinal pH was decreased (6%) as the healing progressed. The decrease in pH could be due to hypoxia and lactic acid production during the reepithelialization of the wound.7Shields R.L. Lai J. Keck R. O’Connell L.Y. Hong K. Meng Y.G. Weikert S.H. Presta L.G. Lack of fucose on human IgG1 N-linked oligosaccharide improves binding to human Fcgamma RIII and antibody-dependent cellular toxicity.J. Biol. Chem. 2002; 277: 26733-26740Abstract Full Text Full Text PDF PubMed Scopus (1324) Google Scholar The aptamer sensor measurement also indicated a significant elevation in TNF-α from days 0 to 1 (44%), which could be due to the inflammatory response after wounding.8Abraham D.J. Shiwen X. Black C.M. Sa S. Xu Y. Leask A. Tumor necrosis factor α suppresses the induction of connective tissue growth factor by transforming growth factor-β in normal and scleroderma fibroblasts.J. Biol. Chem. 2000; 275: 15220-15225Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar The authors did not observe any alteration in the temperature and level of S. aureus during the healing process, indicating the absence of infection. To enable real-time clinical feedback, the VeCare platform is equipped with a portable wireless analyzer that can control signal transduction and perform electrochemical measurements. The measured data could be directly transmitted to a remote mobile device using Bluetooth Low Energy (BLE). After data transfer, a graphical user interface (GUI) facilitates the analysis, visualization, and management of a patient’s wound status. Overall, the novel wireless and flexible multiplexed biosensor system in this study could be potentially used for precise and point-of-care in situ monitoring, evaluation, and analysis of wound microenvironment in patients with chronic ulcers. Future studies in diabetic and large animals are required to validate the reliability of the biosensors prior to clinical testing. Considering that the therapeutic element is also a crucial parameter in designing smart wound care technologies, further technological development can rely on the integration of drug/therapeutic agents with the sensing platform to work as a multifunctional closed-loop system for monitoring and treatment of chronic wounds.