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.

 

      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 1h every two days via wound contraction analysis and histopathologic evaluations, as illustrated in Fig. 13. 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 [54, 236, 237]. Wound infection is one of these tough issues [238]. Microorganisms can invade wounds and induce inflammation. Rapid colonization and the biofilms would prevent re-epithelization, and prolong wound healing process, and eventually lead to chronic bacterial-infected wounds [10]. Besides, another issue antibiotics suffering is that they could hardly penetrate biofilms, thus resulting in poor antibacterial efficiency [239]. Fortunately, conductive substances including CPs [201, 240], carbon nanomaterials [177, 180, 183], metals and metal oxides [123], MXene [143], and BP [177] exhibiting intrinsic antibacterial and photothermal antibacterial activities are all good alternatives for antibiotics, because they are less prone to induce bacterial resistance. Commonly, they can be solely incorporated into nonconductive polymeric matrix, exerting excellent bacterial killing effect and promotion toward infected wounds [143, 177, 201, 241]. Among various matrix materials, chitosan and its derivatives have been frequently selected for their synergistic intrinsic antibacterial effect. Chitosan derivatives as N-carboxyethyl chitosan and quaternized chitosan have also been combined with GO [187] or CNT[183] in designing conductive hydrogel-based wound dressings. These conductive dressings demonstrated multifunctional features and realized higher degrees of wound closure and skin regeneration within 14 days.

      Conductive materials with nanostructure morphology owning increased membrane permeability and multiple antibacterial actions, are other preferential choices to deal with infected wounds [242]. In addition to the above -mentioned carbon-based nanomaterials that have been widely applied in infected wound management, nanometer-scaled conductive materials including CPs, metals and metal oxides, and semiconductors also show great value in promoted antibacterial efficiency. However, free nanomaterials are likely to be cleared rapidly from the interstices of tissues once being implanted owing to their small size [243]. Sung group reported chitosan derivatives containing self-doped polyaniline could self-assemble into nanostructures [240]. As shown in Fig.14, polyaniline-conjugated glycol chitosan (PAN-GCS) could spontaneously form nanoparticles in aqueous solution. Since the surface charge of PANI-GCS NPs was sensitive to surrounding environment, these PANI-GCS NPs suffered a bacterium-specific aggregation induced
by localized skin infections which possessing acidic pus, while exerting no influence toward healthy tissues. By this method, the retention capability of PANI-GCS NPs at the injection area was significantly improved. Moreover, under NIR irradiation, there exhibited specific heating of PANI- GCS NPs/bacteria aggregates, the temperature dramatically reached 55 ℃, whereas a slight increase to 33 C of the surrounding normal tissue. Presently, the encapsulation of conductive nanomaterials into multifunctional platform and combination with other bioactive agents have become necessary to implement their application in vivo.

      Compared with antibacterial agents including Zn2+ and Cu2+ with narrow antibacterial spectrum, short-term durability, low heat resistance and stability, metal oxides as ZnO and CuO in nanostructure exhibit improved antibacterial capability, thereby possess great potential in curing infected wounds. Besides, due to the excellent antibacterial ability and extraordinary photothermal effect, Au NPs have excellent performance in killing bacteria. Wang et al. developed a polyvinyl alcohol composite film embedded with hybrid multi-shelled nanoparticles (ZnO@CuO@ Au NPs) [123]. Under NIR laser irradiation, this composite film demonstrated enhanced ROS generation, destruction of bacterial cell membranes, and antibacterial efficacy, ascribing to the photothermal and photodynamic effect, and sustainably released Zn2+/Cu2+. Excitingly, MXene nanosheet as a novel class of 2D inorganic compounds of metal carbides and carbonatites with excellent conductivity, biocompatibility, and antibacterial ability, has shed light on the treatment of infected wounds, as reported by Zhang group [143]. Also, a BPs nanosheets- incorporated chitosan hydrogel has proved its effectiveness in treating S. aureus-infected skin wounds due to the production of singlet oxygen under simulated visible light, compared with pure chitosan hydrogel [177].

      Combination of conductive materials and antibiotics is also a commonly used strategy for managing infected wounds. The synergistic effect from different antibacterial materials can not only reduce the drug resistance and ensure the antibacterial performance, but also alleviate the abuse of antibiotics. The drug -resistant methicillin resistant staphylococcus aureus (MRSA)-infected wound model is well established to evaluate the efficiency of conductive biomaterials. Antibiotics, as doxycycline [180, 187] and moxifloxacin hydrochloride [183] with resistance toward MRSA have been combined with GO or CNT. The hydrogel
matrices allowed for controlled and sustained release profile of antibiotics. Moreover, due to the efficient penetration of nanomaterials through biofilm, the antibiotic-loaded hybrid nanomaterials would largely increase the local concentration of antibiotics in the biofilm. Altinbasak et al. presented a rGO embedded PAA nanofiber mat, and antibiotics were simply loaded through immersion. This composite mat exhibited low passive diffusion-based release at ambient environment, whereas realized “on-demand" release tuned by power density of applied irradiation. Indeed, these hybrid nanofiber mats with photothermal assistance demonstrated the supreme wound healing capability of MRSA- infected wounds. Despite the promising achievement in infected wounds, the fact should not be overlooked that conductive biomaterials are usually synergistically combined with antibiotics and photothermal therapy. Moreover, whether conductive biomaterials are effective enough to severely infected wounds with biofilms still needs further investigation.

5.2.2 Diabetic Wound

      Compared with acute wounds, diabetic wounds exhibited prolonged infection, abnormal angiogenesis, and delayed reepithelization. Therefore, the general principle of designing wound dressings and scaffolds for diabetic wounds is to prevent bacterial infection, control wound infection, induce angiogenesis, enhance collagen deposition, and promote cell proliferation [10, 74]. Even though conductive biomaterials have achieved excellent treatment effects on acute wounds and infected wounds, they are rarely used alone when dealing with diabetic wounds [1 82, 219]. Notably, conductive biomaterials encapsulated with insulin and fibroblast [244], or with mesenchymal stem cells have demonstrated enhanced diabetic wound healing performance [206, 207, 245]. Jin et al. presented an injectable conductive hydrogel based on aniline tetramer which could promote diabetic wound healing by incorporation of laccase to cast a hypoxic microenvironment maintaining for 13 h [184]. Such a hypoxia- pretreatment would largely enhance the effectiveness of adipose- derived mesenchymal stem cells when treating diabetic wounds. Subsequent adequate oxygen supply is essential for diabetic wound healing; thus, it is highly necessary to delivery oxygen to wound sites in a sustained and controlled manner. Zhang et al. developed BP contained thermo-responsive microneedles composing of polyvinyl acetate film as the backing layer and gelatin hydrogel loaded with BP quantum dots and hemoglobin as the tip, as shown in Fig. 15 [191]. Combining the photo thermal effect of BP quantum dots and reversible oxygen binding property of hemoglobin, these microneedles realized NIR-controlled oxygen delivery. Under programmed intermitted NIR irradiation, these microneedles could support adequate oxygen supply lasted for 24 h. Indeed, these multifunctional microneedles demonstrated enhanced wound healing when treating full-thickness diabetic wound. On day 9, the group treated with BP quantum dots and NIR irradiation demonstrated most advanced healing performance, in terms of wound closure, granulation tissue width, epithelial thickness, and blood vessel density.

      Electrotherapy has positive effects to treat chronic wounds but is still limited by small area of electrodes and uneven distribution of ES. Lu et al. have proved that applying conductive biomaterials as the electrodes in ES strategies could drastically improve the efficiency of electrotherapy [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 of3 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 stimuliresponsiveness 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, AgNPs, 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 ranging5.5- 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.

      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 compre-hensive adaptivity at the same time.

6 Summary and Perspectives

      This review summarizes the application and achievement of conductive biomaterials in wound healing and skin tissue engineering. Conductive substances including CPs and their oligomers, carbon nanomaterials, metals and metal oxides, and novel 2D inorganic nanomaterials all have great advantages and serious drawbacks. CPs are limited by the poor processability, mechanical brittleness and nonbiodegradability, and the conductive oligomers benefit manufacture process and good biodegradability, but their conductivity under physiological conditions restricts further practical applications. Carbon nanomaterials and metals and metal oxides tend to aggregate in solution, and the homogeneous dispersion always requires aid from other polymers or techniques. The cytotoxicity of carbon nanomaterials and metals and metals oxides also matters their applications, especially in some researches that they are modified with CPs. More importantly, the conductivity of these materials dependeds on many factors, including pH value, dopant, and adjacent environment. But, in most articles, the measurement for the conductivity of biomaterials was taken place at specific conditions, which are totally different from the real conditions. BPs and MXene with great opportunities in wound healing are still facing a myriad of challenges before fulfilling application in wound healing.

      Conductive biomaterials can be fabricated into diverse forms to meet the requirements of different types of wounds. 2D biomaterials as films, micro- and nanofibers, and membranes can treat acute wounds with fewer exudates, while 3D hydrogels and scaffolds with ECM-like structures are widely used in more complicated wounds and skin substitutes. Amidst, conductive thin films and hydrogel membranes can also work as substrates for bioelectronics, due to the soft feature, flexibility, and suitable mechanical properties [258- -260]. Conductive film and micro-/nanofibers commonly possess much limited water-uptake ability,
and the conductivity is always measured in the dry state. Therefore, they are suitable for wounds with low exudates. Conductive hydrogels and 3D porous scaffolds have high water-uptake ability, and the conductivity in dry and wet states both should be measured because of the ionic conductivity dominating in the wet state. Conductive hydrogels fit for wounds with moderate exudates, while 3D porous scaffolds can manage significant exudates. Moreover, conductive fibers, hydrogel, and 3D porous scaffolds can be loaded with drugs, growth factors, and cells, thus demonstrating great competitiveness in the multifunctional platform and even engineered skin substitutes.

      Conductive biomaterials realize their applications in promoting wound healing via three strategies. First, they can be applied as compliant electrodes for electrotherapy. In general, the conductive wound dressings can facilitate ES to be well and uniformly conducted onto the wounds promoting the efficacy of electrotherapy [50, 109, 120, 225,226]. Second, they can be used alone as wound dressings
or tissue engineering scaffolds, demonstrating similar conductivity to human skin and supporting cellular activities, to accelerate wound healing performance. In addition, some conductive wound dressings loaded with bioactive agents have achieved controlled drug release assisted by an external circuit, realizing long-term treatment and lowering the initial burst and side effects [130, 131, 261- 266]. In the absence of
external ES, these conductive biomaterials still demonstrate enhanced cell attachment and proliferation, and promoted wound healing performance [37]. Also, the effectiveness of conductive biomaterials in promoting wound healing can be attributed to the inherent antibacterial and antioxidant capacities and photothermal properties of these conductive substances [77, 139, 149, 267]. Third, conductive biomaterials could be manufactured into stretchable and flexible electronics for real-time monitoring of wound status. With the significant progress and achievement of flexible electronics and wearable smart biomedical devices, scientists have managed to integrate conductive wound dressing with wound diagnosis and monitoring capacity [249, 255]. Such advance has extremely facilitated wound healing, because it can avoid frequent removal and replacement for closer observation.

      In contrast to visual and subjective observation, the instant automated evaluation with objective standards throws light on a more systematic analysis of wound healing and communication between patients and doctors. In many cases, bioactive agents, including drugs, proteins, and growth factors have been incorporated into conductive biomaterials to enhance wound healing performance through versatile methods. The synergistic effects vary and should be discussed in the specific situation by considering the inherent properties of these bioactive agents, the interactions between bioactive agents and conductive materials or the polymeric matrixes, and the external conditions. Fibronectin as cell- adhesive glycoprotein was incorporated into PPy/PLLA film to endow the conductive film with enhanced fibroblasts adhesion and migration, while incorporation of BSA leading to reduced cell adhesion [106]. The analgesic and anti-inflammatory drug ibuprofen has been loaded into a PPy-based conductive film through electro-chemical polymerization and realized on-demand, electronically controlled release under an electrical potential [130]. Curcumin, an effective drug demonstrating antioxidant, anti-inflammatory and antimicrobial activities, has long been limited by its hydrophobic nature [268]. Through the π - π interaction with aromatic ring in PANI, curcumin was entrapped within PHBV-g PANI composite film [114]. This curcumin entrapped conductive film does not only reveal small burst release and controlled drug release profile due to the noncovalent interaction, but also demonstrate enhanced differentiation, proliferation, and migration of fibroblast cells ascribing to the incorporation of curcumin. Stem cells exhibited self- renewal ability and could differentiate into multiple types of cells, and their availability in promoting wound healing and skin tissue engineering has been widely validated [269]. Bone marrow derived mesenchymal stem cells have been loaded with a graphene foam [205]. The conductive scaffold was biocompatible and conducive for growth and proliferation of bone marrow derived mesenchymal stem cells. Eventually, the cell-loaded conductive foam was found upregulating vascular endothelial growth factor and basic fibroblast growth factor resulting in reduced scar formation in full- thickness defect experiment. The wound-specific delivery of growth factor is of great value in promoting wound healing efficiency, because the low concentration and excessive degradation of growth factor on wound site would delay the healing process [270]. Metal ions are of great value in maintaining human activities, wound healing process included. Copper ions and zinc ions have been incorporated into PEDOT-cellulose polymer composite through doping mechanism without affecting roughness topography of the substrate and realized controlled release. The combination of PEDOT with metal ions on cellulose substrate eventually contributed to enhanced attachment and proliferation of human keratinocytes [119]. Growth factors modulate a series of cellular activities for many types of cells, which is crucial in wound healing [64, 271]. Human keratinocytes' directional migration under electric fields requires several growth factors, particularly epidermal growth factor [39]. In contrast to plenty of works about growth factors loaded conductive biomaterials for cardiac, muscle, and nerve tissue engineering [14, 270, 272, 273], the application of growth factors loaded conductive biomaterials in wound healing and skin tissue engineering has not been widely reported yet [274, 275]. Epidermal growth factor was loaded into a conductive polyacrylamide/chitosan hydrogel. Due to the coexistence of PPy nanorods and epidermal growth factor, the composite hydrogel demonstrated the optimal wound healing effects [176] Based on the above facts, the combination of growth factors and conductive biomaterials is highly appreciated. The ways by which growth factors and conductive biomaterials combined, the interactions between them, and their application in specific types of wound healing need to be further explored.

      In addition, the applications of conductive biomaterials are still in the preliminary stage, limited in acute wound, infected wound and diabetic wound. Whether conductive biomaterials wound promote the healing process for other types of wounds needs to be explored in the next, as well as the detailed mechanisms. Furthermore, there have not established some standard principles to compare the wound
healing effects of these conductive biomaterials, as there are various animal models and different types of wounds. Even if in some works, the selected control groups as traditional passive wound dressings seem not convincing enough, because the chosen control group should be in the same morphology as the designed conductive biomaterials. Another issue is about the manufacturing process. The synthesis and incorporation of conductive substance are often complicated and sometimes require harsh conditions, which would restrict their further application and induce environment issues. Conductive substances are always combined with other functional materials. The interactions including synergistic effect or related side effects also should be fully evaluated.
      So far, there are several commercially available health care products that contains silver ions, such as ACTICOAT antimicrobial silver dressing, AQUACEL@ Ag foam, Biatain Silicone Ag, and SILVERCELTM nonadherent dressing. But, these commercial dressings are mainly claimed for the antimicrobial capability. PosiFect RD@ and Procellera@ are wearable bioelectric dressings and have received FDA approval. They can provide electrical stimulation to wound. However, there are no commercially available conductive biomaterials based on other conductive agents for wound healing and skin tissue engineering. Since the application of conductive biomaterials as wound dressings for wound healing and skin tissue engineering is in the very preliminary stage, there are still many challenges for the further application in practice and clinic. Biocompatibility is one of the important criteria for biomaterials. In vitro short-term blood compatibility and cytotoxicity to different fibroblasts and keratinocytes are the most frequently used methods to evaluate their biocompatibility. However, there lacks the study of long-term histocompatibility of these conductive biomaterials. The biodegradation mechanisms of these conductive biomaterials under physiological environment are not all clear yet. The stability of MXene nanosheets and BP nanosheet under physiological environment is questionable. The conductivity of these conductive biomaterials is always measured under an ideal stable condition that is totally distinct from the real physiological environment. The real conductivity of these conductive biomaterials under practical conditions, how the conductivity would change along with the degradation and upon hydration or dehydration, whether the conductivity would surpass the safe range are still under question. Beyond that, surface modification is indispensable for majority conductive materials. However, it would significantly alter the properties of conductive nanomaterials, including conductivity, hydrophilicity, surface morphology, and photothermal effect, which are all crucial in wound healing. Even worse, metal and metal oxides, BP, and MXene lack of functional surface groups, which make this issue challenging. Moreover, almost all in vivo experiments were conducted on murine defects. But there exists great difference between human and murine skin. Even though the current research results on murine are encouraging, more systematic study and exploration must be conducted for the detailed mechanism in terms of each wound healing phase, while employing other large animal models to further verify the potential application in clinic.

      In summary, the general method to fabricate conductive biomaterials is to incorporate small amount of conductive substance within other nonconducting polymers, and the properties of conductive biomaterials are mainly depended on the selection of the matrix polymers and crosslinking methods. Meanwhile, to accelerate the wound healing process in multiple channels, combination conductive biomaterials with other bioactive agents and cells is an effective method and needs more exploration. Moreover, with the development of nanogenerators and bioelectronics, electrotherapy and real-time wound assessment assisted by conductive biomaterials will make significant progress in the next decades. Working as wound dressing or electrode, conductive biomaterials have made significant achievement in wound healing, skin tissue regeneration and real-time wound diagnosis. Based on these achievements and the booming development of new technology, we expect that conductive biomaterials would make more advanced development for wound healing.

      Acknowledgements This work was jointly supported by the National Natural Science Foundation of China (Grant Numbers: 51973172, and 51673155), the Natural Science Foundation of Shaanxi Province (No.2020JC-03 and 2019TD-020), State Key Laboratory for Mechanical Behavior of Materials, and the Fun-damental Research Funds for the Central Universities, and the World-Class Universities (Disciplines) and the Characteristic Development Guidance Funds for the Central Universities, and Opening Project of Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology,
Xi' an Jiaotong University (No. 2019LHM-KFKT008, and No. 2021LHM-KFKT005).

      Funding Open access funding provided by Shanghai Jiao Tong University.

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 This  article  is  excerpted from the Nano-Micro Letters by Wound World.

4. 3D Conductive Biomaterials for Wound Healing
      2D conductive biomaterials have made great achievement in wound healing. Through adopting multiple functions, they can promote cell attachment, proliferation, differentiation, and further the whole wound healing process. However, they are still restrained on thin and superficial wounds. In contrast, 3D biomaterials such as hydrogels, foams, and sponges possessing high water absorbance capacity can deal with wounds with high exudate [67]. On the other hand, deep wounds and chronic wounds have poor regenerative capacity due to versatile mechanism, such as lack of cell sources, severe infection, limited blood supply, immunosuppression or immunodeficiency, metabolic diseases, and other environmental factors [13]. Fortunately, 3D biomaterials possessing ECM-mimicking architecture could be utilized as scaffolds for these issues, which could not only support the integrity of dermis, but also act as carriers for bioactive reagents and cells [63].

4.1 Hydrogel
      Due to the porous 3D interconnected structure and highwater content, hydrogel owns a lot of advantages as wound dressing [35, 145, 169]. Hydrogel allows oxygen and water vapor to pass through, maintains a humid environment, lowers the wound temperature, and relieves pain [170]. The soft nature, flexibility, and stretchability support hydrogel being compliant with human skin under ceaseless movement [171, 172]. Moreover, hydrogel has great tolerance to integrate multiple functions, including mechanical properties and additional therapeutic effects [173]. Correspondingly, hydrogel wound dressings have attracted most intensive attention in the past few years. Recently developed conductive hydro- gel-based wound dressings are summarized in Table 3.

      So far, versatile conductive hydrogels with different conductive components have been developed. In contrast to most 2D biomaterials-based wound dressings which validate their potential in wound dressing by in vitro cell culture assay, the wound healing efficacy of most conductive hydrogels has been proved both by in vitro and in vivo animal assays. However, unlike the situations of film wound dressings where electrical activities of conductive substances can be isolated to prove their effects on cellular activities, the wound healing performance is always enhanced through synergistic effects from electrical activities, antioxidant, and antibacterial activities of hydrogel-based wound dressings. In 2015, Hsiao et al. synthesized a chitosan derivate with self- doped PANI which could form colloidal gels induced by pH increase and explored the photothermal antibacterial activities in vitro and on subcutaneous abscess [201]. But the conductivity and the electroactivity were not examined in this work. Since then, these relevant features of the conductive substances were comprehensively evaluated via standard protocols. Our group has designed multifunctional conductive hydrogel-based wound dressings and proven their positive performance in accelerating wound healing process [165, 179 -181, 183, 185, 187]. Chitosan, a natural polysaccharide, has been utilized in wound dressing for a long time, owing to its inherent antibacterial, analgesic effect and hemostatic activity [202]. However, the poor solubility of chitosan under neutral and constrained antibacterial effectiveness under nonacidic environments extremely limit its application and efficacy of wound healing. Fortunately, the abundant active amino groups enable further modification. Quaternized chitosan (QCS) is a better choice for its excellent antibacterial activities and improved solubility. Our group not only solves the above issues, but also broadens its derivates and applications as wound dressing.

      As shown in Fig. 8, quaternized chitosan-g-polyaniline (QCSP) synthesized and demonstrated good water solubility and enhanced antibacterial activity and biocompatibility than pure chitosan [203]. Meanwhile, the residue active amino groups remained potential to react with other groups. In this work, QCSP was then crosslinked with benzaldehyde group functionalized poly (ethylene glycol)-Co-poly (glycerol sebacate) via Schiff base forming the hydrogel network [174]. The optimal hydrogel dressing showed an ionic conductivity of 2.37 mS cm-1 that is close to that of human dermis, thus owning the ability to transfer bioelectrical signals for accelerating wound healing. Overall, com- pared with Tegaderm™  film, the optimal hydrogel dressing performed excellent enhanced wound healing covering all stages, including in vivo blood clotting capacity, promoted ECM synthesis, collagen deposition, granulation tissue thickness, and promoted remolding phase. We also developed a supramolecular conductive hydrogel based on QCS and graphene oxide graft-cyclodextrin [189]. The dynamic host-guest interactions were employed as crosslinkers endowing the hydrogel with self- healing and injectability. Considering the antibacterial activity, cell proliferation, and hemocompatibility, the hydrogel with 0.4 wt% of rGO was selected as the optimal dressing. Indeed, this conductive hydrogel dressing exhibited enhanced wound healing on full-thickness wounds. It is worthy to mention that , we validated that Pluronic F127 and polydopamine are of great advantages in designing carbon nanomaterials incorporated hydrogels, including assisting homogeneous dispersion, improving mechanical properties and tissue adhesiveness [183, 185].

 

      In addition, conductive hydrogels can promote the efficiency of electrotherapy. Commonly in clinic, small metal electrodes were attached on human body near the wounds; thus, ES could not directly cover the whole wound [194]. As the large impedance of human skin, it is only possible to apply ES on every inch of wounds under high voltage, which may threat more danger to the patients [24, 204]. In scientific research, conductive films and fabrics have been justified to promote wound healing under ES for covering the whole wound bed [42, 115, 155, 157]. Reasonably, conductive hydrogel is another good choice, in terms of conductivity, softness, stretchability, and flexibility. Recently, a conductive hydrogel containing poly(2-hydroxyethyl methacrylate) and PPy has justified superior to commercial hydrogel dressing considering the antibacterial capacity and alleviated secondary damage during removal. Moreover, the significance of this work was that the replacement of traditional separate electrodes with one integral conductive hydrogel can extremely promote the efficacy of 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- 207]. Conductive hydrogel has been employed as scaffold for the treatment of diabetic wounds. Jin et al. recently reported a conductive hydrogel scaffold based on AT, hyaluronic acid and gelatin [184]. Compared with nonconductive hydrogel, the conductive hydrogel was found to upregulate the level of Cx43, owing to better transport of molecules and ions between cells. What's even more impressive, O2-consuming enzyme laccase was introduced to cast a hypoxic microenvironment, and this hypoxic environment could maintain for almost 12 h. Furthermoe, adipose-derived mesenchymal  stem cells were loaded for direct delivery to the hostile wound, while relative cell activity remained higher than 85% within 2 days. Thus, this conductive hydrogel could act as a multifunctional scaffold for chronic wounds. Overall, conductive hydrogels could promote wound healing process via diversiform approaches, thus being regarded as valuable candidates for wound healing, particularly for complicated chronic wounds. On the other hand, the excellent conductivity, easy fabrication method, and facile surface modification enable conductive hydrogels with great potential in health care devices for wound diagnosis. But , the long-term durability of hydrogel may impede this progress.

4.2 Fibrous Scaffold

      Even though electrospun scaffolds have been reckoned as promising candidates for tissue engineering, their applications still constrained by several factors, such as pore size and pore interconnectivity that all affect cellular infiltration and tissue ingrowth into the scaffold. Small pore size did not hinder the application for nanofibers as wound dressing, but cell attachment and proliferation might be restrained on the surface of nanofibers [162, 1 64]. Nanofibers with too compact structures could not fulfill the requirements of porous scaffolds for tissue engineering applications [208]. A nonwoven conductive web composed of PEDOT and PLLA was fabricated by melt-spinning. After culture for 48 h, human dermal fibroblasts appeared throughout the scaffold, indicating the web permitted cell infiltration [156]. Another interesting work is about a polyaniline-multi-walled carbon nanotube/PNIPAm composite electrospun nanofibers-based “smart”scaffold with temperature responsiveness for cell delivery [159]. Above LCST, this conductive nanofibrous
scaffolds demonstrated enhanced fibroblast attachment and proliferation, while below LCST, the encapsulated cells would detach and been delivered to human body. Moreover, this stimuli-responsive nanofiber network was inflammation-sensitive, and can deal with loco-regional acidosis, which helps to pass through the inflammation phase. Therefore, conductive nanofibrous scaffold could be envisioned with great value in skin tissue engineering with deliberate design.

4.3 Sponge, Foam, and Acellular Dermal Matrix

      Hydrogel-derived aerogel and cryogel have sponge-like structures and high polarity for water absorption and thus could not only manage with a large amount of water, but also permit water to flow out/in freely [209- 213]. Foam also has an interconnected porous structure and is commonly manufactured from polyurethane or silicone [9, 15]. Without further modifications with a hydrophilic surface, the pure foam demonstrates hydrophobicity, thus benefiting inherent antibacterial properties [33]. The subtle difference between sponge and foam is that foam usually exhibited more enhanced mechanical properties than sponge [33]. Generally, foam and sponge dressings can be used for various types of wounds, including burn, ulcer, skin donor area, and transplant. Also, they are lightweight, elastic, and easy to use in practice. As the second layer of skin, the dermis consists of a connective ECM with fibroblasts, endothelial cells, smooth muscle cells, and mast cells [214, 215]. ECM supports the main structure of skin tissue, develops interactions with versatile growth factors, and modulates cellular activities [63]. Acellular dermal matrix (ADM) derived from human or animal skin has been widely used in tissue engineering and wound healing as tissue replacement, graft and wound dressing [216, 217] The currently developed 3D conductive wound dressings are listed in Table 4.

      Our group developed a conductive cryogel composed of chitosan and PF127- assisted homodispersed CNT, while CNT providing conductivity and reinforcement toward the mechanical properties, as shown in Fig. 9 [221]. Com- pared with cryogel from pure natural polymers, commercial gelatin hemostatic sponge, and Combat Gauze, this CNT hybrid cryogel (QCSG/CNT) demonstrated rapid blood- triggered shape recovery and absorption speed, high blood uptake capacity, and hemostatic capability. Moreover, CNT provided this cryogel with photothermal effect and NIR- assisted photothermal antibacterial activity. Compared with commercial Tegaderm™ film and nonconductive cryogel, the conductive cryogel demonstrated better wound healing performance with the least inflammatory infiltration, and the highest vascularization by 15 days.

      The ADM comprised of extracellular matrix proteins and collagen demonstrates excellent biocompatibility, suitable mechanical properties, and bioactivity which is ideal for skin tissue scaffold. Fu et al. developed a rGO incorporated ADM-based scaffold via simple solution immersion process in which ADM was crosslinked with EDC and NHS [223]. The topology and structural integrity preserved after loading with rGO. Compared with the primitive scaffold and scaffold loaded with GO, ADM-rGO demonstrated superior cell attachment and proliferation for mesenchymal stem cells and human skin fibroblasts. Eventually, acting as a transplanting platform for mesenchymal stem ells, this conductive scaffold demonstrated enhanced therapeutic effect toward diabetic wounds. Based on the above, 3D conductive biomaterials have demonstrated encouraging results in promoting loaded with GO, ADM-rGO demonstrated superior cell attachment and proliferation for mesenchymal stem cells and human skin fibroblasts. Eventually, acting as a transplanting platform for mesenchymal stem cells, this conductive scaffold demonstrated enhanced therapeutic effect toward diabetic wounds. Based on the above, 3D conductive biomaterials have demonstrated encouraging results in promoting wound healing by working as wound dressings.

      3D conductive biomaterials demonstrate promising potential in electrodes for electrotherapy and scaffolds for skin tissue engineering. Chen et al. reported an Ag nanowiresloaded foam demonstrating flexibility, enhanced conductivity, and long-term stability under physiological environment [226]. Due to the inherent antibacterial activity, good water-uptake capability, and electrical conductivity, the conductive foam could not only prevent infection and manage necrosis, but also implement annular oriented electrical field to wounds assisted by exogenous electrical fields. In the in vivo experiment on full-thickness pig skin wound, compared with control group treated with gauze, wounds treated with the conductive foam absent from exogenous electrical fields demonstrated enhanced wound healing performance for smaller wound residual area, controlled inflammation, better neovascularization, and advanced re- epithelialization. More excitingly, when applying the conductive foam with exogenous electrical fields, wounds demonstrated the most superior wound healing effect and therefore proved the great value of 3D conductive biomaterials in wound dressing, as well as their application in electrotherapy. Furthermore, the intrinsic feature of the highly porous structure enabled this conductive foam to connect with negative-pressure drainage closure device, thus simultaneously promote the wound healing process. Especially, since the structure, composition, appendages, and healing mechanism of porcine skin are closer to human skin, these results are more convincing.

5. Application of Conductive Biomaterials in Wound Healing

      Regardless of different types of the wounds, the healing process occurs in a similar systematic manner including four distinct phases, as illustrated in Fig.10 [227]. Ideally, hemostasis occurs immediately after injury and would complete within seconds or hours depending on wound size, depth, and wound location. Then, inflammation begins and lasts for several days and reaches the highest level by 72 h. The third phase, proliferation is more complicated. Angiogenesis, fibroblast migration, granulation tissue formation, collagen deposition, epithelialization, and wound contraction take place simultaneously. Finally, the last remodeling phase allowing granulation tissue to develop into mature connective tissue may last for several months to years. With standard wound care, acute wounds can progress through the healing routine steadily. However, in practice, normal wound healing would be affected and disrupted by many factors, including nutrition, oxygen supply, infection, aging, chronic disease, wound treatment, and even genetics. Extensive tissue damage, necrotic debris, and diseases often make wounds suffer from such issues, thus leading to prolonged inflammation and delayed proliferation and remodeling. Wound with delayed healing more than 3 months would be referred to as chronic wound [10, 228, 229]. In detail, chronic wounds with impaired regenerative capacity demonstrate high levels of proinflammatory cytokines, persistent infections, and drug resistance. Apparently, chronic wounds need specific treatment including tissue debridement, infection clearance, moisture balance, mechanical support, and management of comorbidities according to the etiology and real-time diagnosis.

      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 Tegaderm™ film, the electroactive nanofibers exhibited improved wound healing efficiency with rapid wound contraction, higher collagen depostion, lower production of TGF-a, 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 t/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.

      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.

The literature  is  to be continued……

This  article  is  excerpted from the Nano-Micro Letters by Wound World.