Highlights
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The design and application of conductive biomaterials for wound healing are comprehensively reviewed, including versatile conductive agents, the various forms of conductive wound dressings, and different in vivo applications.
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Three main strategies of which conductive biomaterials realizing their applications in wound healing and skin tissue engineering are discussed.
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The challenges and perspectives in designing multifunctional conductive biomaterials and further clinical translation are proposed.
Abstract
Conductive biomaterials based on conductive polymers, carbon nanomaterials, or conductive inorganic nanomaterials demonstrate great potential in wound healing and skin tissue engineering, owing to the similar conductivity to human skin, good antioxidant and antibacterial activities, electrically controlled drug delivery, and photothermal effect. However, a review highlights the design and application of conductive biomaterials for wound healing and skin tissue engineering is lacking. In this review, the design and fabrication methods of conductive biomaterials with various structural forms including film, nanofiber, membrane, hydrogel, sponge, foam, and acellular dermal matrix for applications in wound healing and skin tissue engineering and the corresponding mechanism in promoting the healing process were summarized. The approaches that conductive biomaterials realize their great value in healing wounds via three main strategies (electrotherapy, wound dressing, and wound assessment) were reviewed. The application of conductive biomaterials as wound dressing when facing different wounds including acute wound and chronic wound (infected wound and diabetic wound) and for wound monitoring is discussed in detail. The challenges and perspectives in designing and develo** multifunctional conductive biomaterials are proposed as well.
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1 Introduction
As the largest organ of the human body, skin displays significant influence on diverse human activities and functions, including protection from pathogens, sensing of external environment, and thermoregulation [1]. However, laying on the outmost of the human body and facing incessant conflicts, skin owing to its elastic and soft nature is susceptible to generate defects that are referred to as wounds [2, 3]. Even though human skin could self-repair spontaneously to restore its structural and functional integrity, wound care is still of great necessity to prevent infection and desiccation, alleviate pain, protect the open site, accelerate the healing process, and avoid scar formation, especially for large and open wounds or burns [4,5,6]. In 2014, 17.2 million hospital visits by acute wounds were recorded in the USA [7]. Currently, about 1–2% of the population in developed countries suffers from chronic wounds [8]. Meanwhile, ascribing to diseases, aging or inappropriate treatment, chronic wounds as diabetic ulcers, vascular ulcers, and pressure ulcers possessing a long and cruel healing period do not only affect patients’ daily life but also associate with high morbidity and mortality [9, 10]. The global advanced wound care products market is growing rapidly, about $12 billion in 2020 and estimated to be $18.7 billion by 2027 [7]. At present, wound healing remains a hot and challenging issue both in clinic and scientific research.
To date, the physiology of wound healing has been well established [11]. The healing process comprises four overlap** phases: hemostasis, inflammation, proliferation, and remodeling, along with diverse growth factors, enzymes, and cytokines exerting significant effects in synergistically modulating relevant cell activities [5, 12,13,14]. There are many types of wounds: acute incision and excision wound can go through normal healing process, while chronic wounds have aberrant healing conditions [10]. In clinic, wound healing management varies according to the tissue feature, the intrinsic regenerative capacity, wound classification, and other environmental variables [6, 10, 15,16,17]. The therapeutic strategies for wounds are versatile, including hyperbaric oxygen therapy [18,19,20], negative-pressure therapy [21], vacuum-assisted closure [22], ultrasound [23], electrotherapy [24, 25], auto/allograft and xenograft [4, 26, 27], cell-based therapy and engineered skin graft [4, 28, 29], and topical drug and growth factor delivery [30,31,32]. No matter which class the wounds belong to, and which wound care strategy would be chosen, wound dressing is requisite [33]. Traditional passive wound dressings like gauze, bandage, and cotton wool could hardly fit the open wounds and exert no active effect in wound healing [9]. Even worse, they would adhere to the skin tissue, causing dehydration and second injury upon replacement. In contrast, modern biomaterial-based wound dressings integrating multifunction as maintaining a moist environment, managing exudate and protection from pathogens, antibacterial capacity, antioxidant property, injectability, self-healing capacity, adhesiveness, and suitable mechanical properties have recently surged and demonstrated extraordinary advantages in more complicated situations [4, 34, 35].
Except for the above-mentioned features, our human skin possesses another key characteristic, the conductive nature of the intact skin, which plays a vital role in human activities [36,37,38]. Once the skin is disrupted, endogenous wound-induced electric fields ranging from 40–200 mV/mm generate and immediately initiate wound healing [39,40,41,42]. Accordingly, electrical stimulation-based electrotherapy has been developed and applied in practice since the end of the twentieth century, especially for chronic wounds. The electrical stimulation (ES) accelerates the wound healing process in all stages through diverse pathways [39,40,41, 43,44,45]. It can alleviate edema around the electrode, guide keratinocyte migration, enhance re-epithelialization, direct dermal angiogenesis, modulate a variety of genes relevant with wound healing, and generate antibacterial effects [43, 46, 47]. But the application of electrotherapy must be carried out with a large extracorporeal ES device and requires careful and precise evaluation of the relevant parameters, including voltage, current, mode, and working time, depending on the nature and condition of the wound [48, 49]. Moreover, the efficacy of electrotherapy is limited by the uneven distribution of ES ascribing to a large amount of body fluid, irregular wound shape, the exudates induced metal electrodes corrosion, and wound status [24, 25, 50].
In the past decade, wound treatment strategy relating to the conductive nature of human skin has emerged and attracted much attention for its high efficacy, processing flexibility, and ease in handling and management. The sophisticated conductive biomaterial-based wound dressings with similar conductivity to that of human skin have demonstrated significant enhancement in wound healing and exhibited great potential in different types of wounds, as full-thickness acute wound, infected wound, and diabetic wound [37, 51, 52]. The basic principle of fabricating conductive wound dressing is to incorporate the electroactive substances mainly including carbon nanomaterial [5, 53, 52]. The stability, degradability, and cytotoxicity of CPs under physiological conditions also matter a lot [87]. Carbon nanomaterials and metal nanomaterials could not even degrade in vivo [88]. Besides, the incorporation of conductive substances would make a great difference on the mechanical properties of the pristine biomaterial [89]. The balance and compromise between the conductivity, biocompatibility and mechanical properties should be fully investigated before in vivo application.
Excitingly, novel 2D inorganic conductive nanomaterials as black phosphorus (BP) and transition metal carbides and nitrides (MXene) have recently attracted great attention for their electroactivity and demonstrated great potential in biomedical applications for the biodegradability, photothermal effect, and antibacterial activities [90,134]. Simmons and his colleagues reported an antiseptic film based on CNT and polyvinylpyrrolidone-iodine, in which CNT was solubilized by polyvinylpyrrolidone-iodine and encased in a polymer monolayer with a helical coil conformation [124, 125]. Polyvinylpyrrolidone–iodine with slow release of iodine also provided this film with antiseptic and antibacterial properties. Combining the flexibility, oxygen permeability, high bacterial killing efficacy, biocompatibility, and conductivity (10 kΩ sq−1), the author suggested this film with promise as bandage for wound healing application. However, according to cell viability assay on human keratinocytes, the application of this film meets limitation. Iodine-containing films were suitable for severely infected wound but should be limited in the wounds that require rapid proliferation of keratinocytes and other mammalian cells.
Graphene possessing excellent conductivity at room temperature than any other carbon materials, a high optical absorptivity, high thermal conductivity, and high mechanical strength has great value in many fields [135]. However, graphene tends to aggregate, and the poor dispersion extremely restricts its application, especially as biomaterials. Graphene oxide (GO) and reduced graphene oxide (rGO) are covalently functionalized graphene which have been mostly studied [5, 53]. A large number of oxygen-containing groups as hydroxyl, epoxy, and carboxyl group supports GO with good dispersion. However, the covalent functionalization of carbon atom converting the planar sp2 hybridization to a tetrahedral sp3 hybridization would largely reduce the conductivity compared with graphene. For example, Shahmoradi et al. reported a graphene/silver incorporated wound dressing, only taking the advantages of reinforced mechanical properties of GO and its synergistic antibacterial effect with Ag NPs, without considering the electroactivity [136]. rGO containing few unreduced, covalently bonded oxy groups has a relative higher conductivity than GO [53]. Aycan et al. designed a conductive polymeric film consisting of sodium alginate, gelatin, hyaluronic acid and rGO [97]. The homogeneous rGO suspension was formed after ultrasonic treatment. rGO was incorporated into the polymeric network through strong Van der Waals interaction and hydrogen bonding. The conductive film demonstrated enhanced mechanical properties, good biocompatibility, adequate water vapor transmission rate, and improved oxygen permeability. Moreover, this conductive film was loaded with an anti-inflammatory drug ibuprofen and demonstrated a controlled release profile. Therefore, the author suggested this conductive film has great potential in wound dressing. Khamrai et al. synthesized a cellulose/rGO/Ag NPs composite film as multifunctional dressing with conductivity, and antimicrobial activity [117]. Notably, as the cellulose was modified with dopamine, this film exhibited an adhesive nature which could facilitate the adhesion and proliferation of NIH 3T3 fibroblast cell. A multifunctional composite film based on similar components was developed by Zhang et al. [121]. The difference is that polydopamine was utilized as a ligand to prevent Ag NPs agglomeration and silver loss.
3.1.5 Metals and Metal Oxides
Ag and Zn dots printed on polyester sheets or cotton nonwovens could work as bioelectronic wound dressings and have already proven significant effect on the improvement of human keratinocyte, cellular behavior activation, and wound healing by generating sustained microelectric potentials and restoring disrupted physiologic bioelectric signals on wound sites, while the voltage was depended on the size of the dots and the distances between metal dots [45, 111, 120].
As mentioned above, the application of electrotherapy generally requires extracorporeal power supplies, which is not convenient for patients. Recently, the innovation of triboelectric nanogenerators that could harvest biomechanical energy and further generate periodic ES has expanded the development of facile electrotherapy [50]. Zhang et al. created a conductive hydrogel using Zn2+ and PPy as the conductive components and chitosan as the main polymer backbone. This hydrogel was capable of sensing temperature and strain variations and accelerating the infected chronic wounds with ES [190]. More impressively, Jeong et al. developed an ionic hydrogel dressing based on LiCl and combined the dressing with a prototypical wearable triboelectric nanogenerator [194]. The nanogenerator can harvest biophysical energy from friction between skin and deliver ES to hydrogel, while the hydrogel dressing directly distributes ES to the whole wound.
Another attractive feature of hydrogel biomaterial is the great potential in tissue engineering by acting as scaffold to support cells and biomolecules. Mesenchymal stem cell combined with an ECM-mimicking biomaterial has attracted much attention in chronic wound healing [205,206,207]. Conductive hydrogel has been employed as scaffold for the treatment of diabetic wounds. ** et al. recently reported a conductive hydrogel scaffold based on AT, hyaluronic acid and gelatin [227].
Wound dressings and skin tissue scaffolds are of great importance in wound care and skin tissue regeneration [27, 160]. There have been developed plenty commercial products to fulfill the requirements for different wounds. Biomaterials with specific functions have also been symmetrically studied in promoting wound healing, such as antibacterial, hemostatic, adhesive, injectable, and antioxidant property. Conductive biomaterials demonstrate promising potential in wound healing as well, because they could regulate and promote cell attachment and relevant activities with or without ES that have been convinced by in vitro and in vivo assays [44, 61, 230]. So far, researchers have successfully validated the effectiveness of conductive biomaterials in different types of wounds, both for acute and chronic wounds. Moreover, due to the intrinsic electroconductivity, conductive wound dressings can be applied in real-time diagnosis. It is worth mentioning that conductive biomaterials are usually combined with other bioactive substances to meet the requirements in practice.
5.1 Acute Wound
An acute wound is an unintentional injury to skin that can be caused by surgical incisions, bites, deep lacerations, abrasions, and burns [2, 3, 11, 33]. Acute wounds can spontaneously heal in an orderly routine even without any external intervention. In scientific research, clean incisional and excisional wounds with controlled area and facile surgery are frequently utilized to evaluate the effectiveness of wound dressings. Generally, a full-thickness wound with clear edge is created by surgical incision on the back of rat or pig. Full-thickness wound means a loss of all layers of the skin and great potential of the exposure of underlying tissues. Deep infection and fluid exudate affect the healing process, as well [15]. To address such issues, conductive biomaterials-based wound dressings integrating multiple functions are of high needs.
5.1.1 2D Conductive Biomaterials for Acute Wound
As incisional and excisional wounds on rat or pig skin have light exudate, 2D biomaterial-based wound dressings can meet the requirements of wound care. Conductive film, membrane, and nanofibers have all realized their applications in acute full-thickness wounds. CPs and oligomers incorporated biomaterials have obtained great attention for their facile synthesis. In 2015, Gharibi et al. developed a series of polyurethane/siloxane-based conductive wound dressing containing aniline tetramer moieties [148]. These wound membranes displayed electroactivity, antimicrobial activity, and antioxidant ability which could promote fibroblast growth and proliferation. Besides, these CSA-doped membranes revealed comparable equilibrium water absorption value and water vapor transmission rate to some commercially available dressings, and suitable surface hydrophilicity to support cellular activity. Thus, the authors suggested these membranes could work as wound dressings for acute and chronic wounds, because the above three parameters are important to evaluate whether a product could maintain a moist environment for wounds. In an in vivo animal assay last for 20 days, the designed membranes exhibited accelerated wound healing than commercial cotton gauze. Our group synthesized a conductive polyurethane film, in which PCL provided mechanical properties, PEG contributed to surface wettability and AT supported electroactivity [118]. Through in vitro and in vivo assays, the conductive film with 12% AT content revealed improved cell adhesion and proliferation, and enhanced wound healing performance than nonelectroactive commercial dressing. Recently, our group also proved the viability of conductive nanofibers as wound dressing in practice. The electroactive nanofibers were electrospun from PCL and QCSP, thus demonstrating suitable mechanical properties, electroactivity and antibacterial properties [165]. The microporous structure can not only support cellular activities, but also guarantee the nanofibers to absorb exudate from wounds. The balance between antibacterial activity and cell proliferation should be taken into consideration as well, for bilateral properties of QCSP. Eventually, the conductive nanofibers with 15 wt% of QCSP were selected as the optimum dressings. Indeed, compared with TegadermTM film, the electroactive nanofibers exhibited improved wound healing efficiency with rapid wound contraction, higher collagen deposition, lower production of TGF-α, and higher expression of VEGF within 14 days.
Except for the antibacterial activities, metals and metal oxides can generate ES under specific conditions. Liu et al. utilized template-assisted magnetron sputtering method to modify commercial spunlace cotton nonwovens with metal dots (Ag, Zn), as shown in Fig. 11 [120]. The low content of metals enabled the dressing with good cytocompatibility. Interestingly, this conductive Ag/Zn@Cotton dressing demonstrated enhanced cell migration and accelerated wound healing, which was attributed to the generation of ES and inherent antibacterial activities of Ag+/Zn2+ with continuous release under moist conditions. Bhang et al. developed a piezoelectric dermal patch based on zinc oxide nanorod and applied this patch in treating full-thickness wounds [115]. Under small mechanical deformations, this patch generated electrical fields. In animal assay, the patch was found to promote wound healing process via a series of cellular activities, including inflammation regulation, cell proliferation, re-epithelization, angiogenic factor secretion, and tissue remodeling.
Copyright 2020, American Chemical Society
Schematic illustration (a), photograph (b) and metal coating area percentage (c) of Ag/Zn@Cotton dressing. (d) SEM images and corresponding EDS map** of metal dots on the Ag/Zn@Cotton dressing. Reprinted from Ref. [120].
In common, to address complications in acute wounds, 2D conductive biomaterials always need to be endowed with multiple bioactive functions while fulfilling basic requirements. However, the application of 2D conductive biomaterials in acute wound healing is still restricted by some parameters, such as the limited capacity for managing exudate, loading bioactive agents and maintaining their biological activities, further functionalization, and low adhesion to skin.
5.1.2 3D Conductive Biomaterials for Acute Wound
3D biomaterials including hydrogels, foams, and sponges possess great potential in assembling ECM-like structure, so they have attracted much more attention in wound dressing and skin tissue scaffolds. Since there are diverse fabrication methods that can circumvent the limitations of these conductive substances, all types of conductive substances have been incorporated into various forms of 3D biomaterials and proved their merits in acute full-thickness wound treatment.
Compared with 2D biomaterials, 3D biomaterials owning highly interconnected porous structure demonstrate several advantages. Bioactive agents including drugs and growth factors can be easily loaded into 3D biomaterials and exhibit sustained release profiles, which can benefit would healing [183, 185]. The higher water absorption capacity makes 3D biomaterials fit for wounds with large exudate and avoid frequent removal. The injectability and self-healing capacity at ambient environment make the hydrogel-based wound dressing suitable for irregular and deep wounds [171, 174, 181, 189]. Moreover, the mechanical properties of hydrogels could be easily adjusted to have suitable modulus and highly stretchable to comply with wounds at any part of the body, especially for wounds under large and incessant movement [171, 174, 179, 195]. Recently, Li et al. presented a conductive hydrogel based on PEDOT:PSS and guar slime, and verified its application on wounds in stretchable parts of the body [186]. The hydrogel exhibited rapid gelation within 1 min, injectability and self-healing ability. Compared with the dorsum of rats mostly being in static, nape is in frequent movement including compression, tension and twist. As shown in Fig. 12a, b, the designed dressings were applied on wounds constructed on the nape and dorsum of rats. Obviously, large movement would lead to delayed healing process. But when treated with a compliant conductive hydrogel-based wound dressing, wounds on the nape demonstrated an improved healing process according to the statistical data summarized in Fig. 12c–e. For this reason, 3D conductive biomaterials with compliance and high adhesiveness have paved way for the treating of wounds under incessant movement, for they could not adhere tightly to the wound without extra assistant, but also maintain structural integrity supporting full coverage for wound bed.
Copyright 2020, Wiley–VCH
Wound healing in the stretchable parts of rats. Photographs (a) and correspondingly enlarged images (b) of wounds treated with different dressings. (c–e) statistics of wound healing rate on nape or dorsum by determined time. Reprinted from Ref. [186].
Due to the low adhesiveness, traditional wound dressings and novel 2D biomaterial-based wound dressings always require additional medical tape to be retained in wound sites. Large wounds often need commercial adhesives to promote wound closure and healing. Some novel adhesive conductive hydrogel-based wound dressings solve these two issues and improve the hemostatic effect at the same time. Conductive hydrogels containing Schiff base [174, 181] or polydopamine [179, 180] have been proven with high tissue adhesiveness, comparable or even better to that of commercial dressings. To combine the advantages of conductive biomaterials and adhesiveness, our group developed an injectable, self-healing hydrogel (QCS/rGO-PDA/PNIPAm), containing PDA and QCS for antibacterial properties and strong adhesiveness, PNIPAm for biomechanical activities, and rGO for electroconductivity [185]. Eventually, this hydrogel significantly promoted the full-thickness wound healing process demonstrating higher granulation tissue thickness, collagen disposition, and enhanced vascularization. The enhanced wound healing effect of this conductive hydrogel could be ascribed to accelerated wound closure through biomechanical adhesiveness and multiple biochemical functions simultaneously.
Conductive hydrogels can also work as electrode to promote the efficiency of electrotherapy in curing full-thickness wounds. Mao et al. employed a regenerated bacterial cellulose/MXene composite hydrogel as the wound dressing and electrode for ES [141]. The composite hydrogel with 2% MXene content demonstrated the highest electrical conductivity, the best biocompatibility, and suitable mechanical properties. By in vitro electrostimulated cell culture assay and in vivo animal assay, this conductive hydrogel containing MXene was found to remarkably promote wound healing by applying 100 mV mm−1 DC electric field strength for 1 h every two days via wound contraction analysis and histopathologic evaluations, as illustrated in Fig. 13.
Copyright 2020, Wiley–VCH
Schematic representation of in vivo wound healing experiment assisted by ES (a). Photographs of wounds treated with different wound dressings (b). Photographs of wounds on determined times and granulation tissue on day 14 in different groups (c). Reprinted from Ref. [141].
Overall, due to the versatile structures with high tolerance to accommodate multiple functions and properties, 3D conductive biomaterials have made great achievement in wound healing, especially for acute wounds.
5.2 Chronic Wound
Chronic wound, including arterial, diabetic, pressure, and venous ulcers, is a serious threat to human health, and it takes decades to heal and accompanies by severe complication, amputations and even death [10, 33]. Traditional passive wound dressings are not effective enough for wound care of chronic wounds, because they could only provide protection against from exposure and moist balance [35, 67, 145]. The tissue debridement and infection control need further surgery and drug delivery. Overall, novel 3D conductive biomaterials integrating wound care and treatment have been paid much attention and need further development. Infected wound is one classic type of chronic wounds. Ideally, asepsis wounds will pass through the inflammatory phase after 2–5 days and gradually proceed into the proliferation and remodeling phases. Excessive and prolonged inflammation is obnoxious inevitably results in delayed healing and even death [231]. Actually, chronic wounds including diabetic wounds and ulcers could hardly proceed beyond the inflammatory phase [232]. Disinfection of infected wounds and prevention of wounds from bacteria invasion during the entire healing procedure are both essential for wound management [233]. Conductive biomaterials certainly exert positive effects during the inflammatory phase ascribing to their inherent antibacterial activities and photothermal antibacterial properties if necessary, thus prompting the transition to the proliferation phase. Besides, conductive biomaterials have been proved to exhibit antioxidant activity and enhance cell attachment, migration, and proliferation, which benefits both the inflammatory, proliferation, and remodeling phases [234]. In addition, when applied as electrodes in electrical therapy, conductive wound dressing can improve cell migration, alignment, proliferation and differentiation with specific programmed electrical stimulation [235]. In overall, conductive biomaterials could enhance wound healing through multiple pathways. Nevertheless, considering the complex in different wounds especially for chronic wounds, conductive biomaterials need to be tailored with multifunction or combined with other specific bioactive agents.
5.2.1 Infected Wound
Bacterial infection has long been a severe threat to human health. On one hand, they could induce many diseases and increase more complication during the treatment. On the other hand, bacterial resistance caused by abuse of antibiotics continues presenting significant burden on public health [50]. Zhang et al. created a conductive self-healing hydrogel based on Zn2+and PPy [190]. The group of diabetic wounds covered with the conductive hydrogel and stimulated by a direct current voltage of 3 V for 1 h per day demonstrated the optimum wound healing performance than the group only covered with hydrogel and the control group. Overall, conductive biomaterials have demonstrated excellent performance in managing diabetic wounds though different pathways. Still, considering the variety and complexity of chronic wounds, the usage of conductive biomaterials, their combination with other reagents and specific implementation approaches need to be further explored [246].
5.3 Wound Monitoring
Wound healing is a dynamic process comprising four overlapped stages, in which many parameters including humidity, temperature, pH, and glucose levels will change [247]. Compared with healthy skin, wounds demonstrate typical differences according to their types. On one hand, these differences could be utilized to design smart wound dressings that can specifically react to wounds but are inert to healthy skin [232, 239]. So far, numerous wound dressings with stimuli-responsiveness have been developed which can actively sense the variations and then self-adapt to the wounds. However, stimuli-responsive conductive wound dressings have not been widely explored [248]. At present, stimuli-responsive conductive wound dressings can be classified into two categories according to the sources of the two features. The first method is employing two distinct functional groups that endow wound dressings with stimuli-responsiveness and conductivity, correspondingly. Thus, the evaluation of stimuli-responsiveness and conductivity and their effects on wound healing could be studied separately. Zhao et al. reported a multifunctional hydrogel dressing consisting of boronate-based dynamic network and conductive component Ag NWs [192].The boronate-based dynamic network would collapse when treated with glucose, which benefits diabetic foot wound healing by facile on-demand removal. Eventually, wounds treated with this hydrogel dressing demonstrated rapid wound contraction rate and lower glucose level. Our group developed a hydrogel wound dressing exhibiting pH-responsiveness derived from Schiff base based network and conductivity from CNT [183]. The pH-responsiveness is conducive for controlled drug release when treating infected wounds which exhibiting acidic pH. In the second method, both stimuli-responsiveness and conductivity are derived from the same substance. Sung et al. synthesized a conductive chitosan derivate grafted with mercaptopropylsulfonic acid-doped polyaniline (NMPA-CS) and applied this derivate in treating infected wounds [201]. The CS derivative would self-assemble into micelles in acidic aqueous and form colloidal gel when increasing pH to 7.0. Thus, when injected into an infected wound, the NMPA-CS solution will completely cover the acidic area until gelation occurs when encountering healthy tissue. In their subsequent work, PANI-GCS NPs demonstrating positive charge under acidic environment can form aggregation with negatively charged bacteria, further facilitating photothermal ablation of focal infection [240]. Since the conductivity of CPs would be significantly affected by pH, the conductivity of the dressings would also change when the wound dressings undergo a specific change after sensing this stimulus [249].
On the other hand, wound monitoring has been developed. Diagnosis and monitoring of wounds are very imperative, especially for chronic wounds [6, 228]. Physical examination and the parameters including wound location, size, depth, and drainage should be well recorded and further treatment needs to be adjusted depending on the healing degree. However, long-term monitoring relies on patients’ hospitalization and frequent screening. Moreover, visual evaluation is far from accuracy and promptness. Some electrochemical sensors have been designed for wound diagnosis, but the wound dressing and wound treatment could not complete simultaneously [232, 250, 251]. Conductive wound dressings which can sense the wound variations and then convert them into electrical signals enabling synchronous wound care and wound monitoring are of great value in modern wound care. Recently, Zhao et al. fabricated an antibacterial conductive hydrogel as wound dressing based on polydopamine, Ag NPs, PANI, and PVA [182]. This hydrogel could directly adhere to human skin and respond to human mechanical deformation. Excitingly, they found that this hydrogel could distinguish diabetic rats from normal rats by movement, because diabetic rats have a relative slower respond to thermal stimuli. Jia et al. fabricated a PEDOT coated conductive silk microfiber integrated patch, and then employed this patch as ECG and EMG electrode for diagnosis in diabetes while promoting wound healing [168].
Another characteristic of chronic wound is the pH value. Compared with healthy skin with acidic pH ranging 5.5–6.5, chronic wounds exhibit alkaline pH between 7 and 9 or extremely acidic pH by severe infection [252, 253]. The level of pH can be continuously measured to monitor the chronic wound healing process. Recently, several works reported conductive biomaterials that can be used both as wound dressing and sensor. PANI is a proton-selective polymer and the conductivity of PANI is depended on protonation and deprotonation under different conditions [77, 82, 132]. Thus, PANI can be used to fabricate pH sensors monitoring wound status [254]. Mostafalu et al. developed a wound dressing integrating PANI-based pH sensors and flexible microheater with alginate hydrogel loaded with thermo-responsive drug carriers for antibacterial drug [255]. The dressing was also assembled with a wireless Bluetooth module for real-time monitoring, as illustrated in Fig. 16.
Copyright 2018, Wiley–VCH
Schematic and conceptual view of the automated smart bandage for diabetic wounds integrating flexible pH sensors for real-time monitoring wound status and flexible heater for triggering thermo-responsive drug carriers loaded with antibiotics. Reprinted from Ref. [255].
Glucose level is also a key factor of the diabetics. Lipani et al. reported a graphene-based thin film integrated with an electrochemical glucose sensor and proved this assembly platform could be applied as a noninvasive, transdermal glucose monitoring system to track blood sugar in human [250]. Thus, it could be anticipated with the emergence of wound dressing integrated real-time glucose sensing system in the future.
So far, real-time tracking of wound healing has been realized through monitoring the level of several parameters, including physiological signals [168], pH [193, 249, 251, 252, 254], oxygen [19], temperature [239], moisture [256], glucose [193, 250], and uric acid [257]. We envision that more comprehensive portable healthcare devices with high accuracy and precision based on conductive biomaterials will be manufactured, guaranteeing suitable wound care and noninvasive real-time healing measurement with comprehensive adaptivity at the same time.
