1. Introduction
Diabetes is a metabolic disorder that is triggered by genetic and environmental factors. Recognized as one of the most prevalent chronic diseases worldwide, it affects nearly 537 million people. Forecasts estimate that the diabetic population will rise to 643 million by 2030 and 783 million by 2045 [
1]. Diabetic wounds (DWs), such as diabetic foot ulcers, represent one of the common complications associated with this condition. The lifetime risk of developing DW for those living with diabetes ranges from 19% to 34%. Recurrence of DW is common, with approximately 40% of patients experiencing a recurrence within one year of initial healing. Nearly 60% of patients experience a recurrence within three years and 65% within five years. Additionally, patients with DW face a five-year mortality rate that is 2.5 times greater than those patients without foot ulcers [
2],[
3].
Despite years of exploration and development of minimally invasive therapeutic formulations for managing DW, practical treatments still lack strategies that adapt to varying wound conditions. Furthermore, these therapies often exhibit broad mechanisms of action that can adversely affect systemic health and lead to potentially toxic side effects. These limitations hinder the efficiency of targeted management. Bioactive dressings offer promising clinical applications for personalized therapy by integrating interdisciplinary approaches encompassing polymer materials, nanoscience, and engineering sciences. They confer several therapeutic advantages: ① The dressings provide excellent patient compliance and comfort [
4]. ② They establish a continuous and stable drug delivery system capable of tailoring release efficiency, half-life, and loading rates to fit specific clinical situations [
5],[
6]. ③ Functional design enables targeting of biomarkers and environmental conditions, facilitating demand-driven cargo release [
7],[
8]. ④ Surface modifications enhance their affinity for components of the extracellular matrix, promoting cellular migration and proliferation [
9],[
10]. ⑤ Integration with indicators enables the visualization of treatment efficacy and real-time monitoring of the treatment progress [
11],[
12].
As our understanding of the recalcitrant healing mechanisms of DW has deepened, researchers have developed various bioactive dressings based on synthetic polymers, polysaccharides, and peptides
[13],
[14],
[15]. An exhaustive review spanning the past 30 years reveals that over 3000 patents and 300 scholarly manuscripts on bioactive dressings for DW management have been published globally. Additionally, a clear upward trajectory in the output number is evident, marked by a consistent year-on-year increase in patent filings and publications (
Figs. 1(a) and (b)). Previous research reports that patients with DW have a five-year mortality rate that is 2.5 times greater than that of diabetic patients with diabetes without foot ulcers, underscoring the immense challenges in healing [
2]. Although reviews have elucidated the pathological characteristics of DW and the progress in treating DW with various bioactive dressings, as our understanding of DW challenges deepens, there is an ever-present need to continually update the mechanisms of its management [
16]. This is crucial for microenvironment-sensitive modulation and vital for the precise and on-demand design of bioactive dressings. Currently, there is a lack of comprehensive literature that systematically reviews the advantages, disadvantages, and challenges of treating DW with different bioactive dressings; this includes a systematic investigation on active and passive methods that provide on-demand management and modulation of the complex and dysregulated microenvironment of DW
[17],
[18],
[19].
This review commences by examining the historical context of wound management, emphasizing a comprehensive analysis of the pathophysiological distinctions between DW and acute wounds. Subsequently, we identify the potentially harmful elements inherent in the DW microenvironment and examine strategies relevant to both active and passive on-demand responses utilizing bioactive dressings. Furthermore, this study discusses the potential challenges associated with the application of bioactive dressings in the treatment of DW. In addition, future research trajectories aimed at refining targeted therapeutic strategies for DW using bioactive dressings are outlined.
2. Evolution history of wound management
The history of wound management is ancient, with the Egyptians and Chinese pioneering natural remedies around 2000 before Common Era (BCE). The Egyptians used honey, while the Chinese relied on herbal treatments, such as those described in
Shennong Bencao Jing [
20],[
21] (
Fig. 1(c)). Advancements in medical knowledge transformed wound care in the 19th century following Louis Pasteur’s introduction of the theory of dry wound healing (DWH) in 1859
[22],
[23],
[24] (
Fig. 1(d)). In the mid-20th century, George Winter pioneered a paradigm shift by demonstrating that moist conditions accelerate wound healing, thereby establishing the concept of moist wound healing (MWH). This radical change, focusing on maintaining optimal moisture at wound sites, considerably improved healing outcomes and transformed clinical wound management practices
[25],
[26],
[27] (
Fig. 1(e)).
Many MWH-related products for DW management have been tested in clinical trials (
Table 1). Breakthroughs in biomanufacturing and material sciences have introduced an era of bioactive dressings that can respond to the dynamic changes within the wound microenvironment
[28],
[29],
[30],
[31]. Bioactive dressings utilize both active and passive on-demand mechanisms to enhance wound management. Passive on-demand dressings use natural environmental changes or biomarkers within the wound for treatment, eliminating the need for external manipulation. This approach delivers therapy directly to the wound site without additional intervention; it offers a more natural, efficient, and biocompatible alternative to traditional methods. In contrast, active on-demand dressings are designed to react to specific external stimuli, enabling precise control of drug release and therapeutic responses. This strategy enhances the treatment efficiency and specificity by delivering a stronger effect exactly when and where needed. This trend indicates a future in which wound care can be personalized through intelligent dressings sensitive to the wound microenvironment and capable of responding to dynamic demands (
Fig. 1(f)).
3. Healing mechanisms: Acute vs DW
The repair of injured tissues constitutes a sophisticated biological mechanism regulated by both intrinsic and extrinsic elements, progressing through sequentially overlapping phases including hemostasis, inflammatory response, cellular proliferation, and extracellular matrix remodeling. Various cell types, including platelets, neutrophils, macrophages, and fibroblasts, along with associated biomolecules, work synergistically to affect healing [
32] (
Fig. 2). The collective goal is to repair damaged skin tissue and restore its structural integrity [
33],[
34].
As shown in
Fig. 2(b), during the initial phases of wound injury (hemostasis phase), the tissue blood vessels are quickly constricted. Activated platelets interact with extracellular matrix (ECM) proteins to form a fibrin clot, which serves to stem excessive bleeding and provides a protective barrier against the invasion of bacteria and other external pathogens. Additionally, platelets enhance immune responses by releasing chemotactic factors that attract more immune cells to the wound site, facilitating the transition to the inflammatory phase
[35],
[36],
[37].
During the inflammatory response phase, injured cells promote the aggregation and migration of leukocytes, particularly neutrophils, and monocytes, by increasing the concentrations of damage-associated molecular patterns (DAMPs). Additionally, macrophages, which differentiate from monocytes, predominantly exhibit an M1 phenotype. These M1 macrophages release substantial amounts of pro-inflammatory cytokines that aid in initiating and sustaining the inflammatory response. They also help in clearing dead cells, debris, and any potential pathogens from the wound site
[38],
[39],
[40] (
Fig. 2(c)).
As the wound progresses into the proliferative phase, extensive activation and synergistic interactions occur among keratinocytes, fibroblasts, M2 macrophages, and endothelial cells. This coordinated activity promotes angiogenesis and cellular migration, which are essential for granulation tissue formation and collagen synthesis. On the one hand, keratinocytes respond to various stimuli by undergoing epithelial-to-mesenchymal transition, which enhances their migratory capabilities and facilitates the reconstruction of the epidermal layer
[41],
[42],
[43]. On the other hand, fibroblasts differentiate into pro-fibrotic phenotypes and myofibroblasts, driving wound contraction while promoting extracellular matrix deposition. During this phase, the granulation tissue utilizes fibrin clots as a scaffold for the growth of macrophages or newly formed blood vessels [
36],[
44]. Endothelial cells, stimulated by moderate hypoxia and cytokines, proliferate and migrate toward signals that promote angiogenesis. Myofibroblasts, secreting α-smooth muscle actin (α-SMA), effectively enhance neovascularization and maturation. Moreover, during this stage, there is a substantial generation of M2 macrophages that release healing factors such as transforming growth factor-β (TGF-β) and vascular endothelial growth factor (VEGF) to assist the functions of the aforementioned cells
[44],
[45],
[46],
[47] (
Fig. 2(e)).
Subsequently, the wound progresses to the remodeling phase, in which fibroblasts and myofibroblasts remain key players. Initially, fibroblasts replace the fibrin clots formed in the early stages of the wound with mature collagen fibers, gradually transitioning from type III to type I collagen and creating a structurally stronger mature scar [
48],[
49]. Additionally, the high expression of TGF-β and mechanical tension stimulates the generation of myofibroblasts, which secrete α-SMA, endowing these cells with contractile capabilities. By adhering to cellular adhesion sites, particularly by linking to fibronectin and other ECM components, the α-SMA protein assembly enables myofibroblasts to exert tension on the ECM, further promoting wound contraction and compaction [
50],[
51]. Eventually, as the healing process concludes, the involved cells undergo apoptosis or migrate from the wound site, forming the final scar tissue [
44] (
Fig. 2(f)).
However, the wound healing process is profoundly influenced by the wound microenvironment, which encompasses external and internal conditions such as temperature, pH, humidity, bacterial load, and oxygen levels. These factors intricately and complexly affect the behavior of key cells within the internal wound microenvironment, such as macrophages, fibroblasts, and endothelial cells, as well as the levels of ECM [
52]. Although the healing processes of acute wounds and DWs are broadly similar in their overall trajectories, a DW is a form of chronic wound. A detailed comparison of the differences between these two types of wounds at each stage of healing is shown in
Table 2 [35],
[36],
[37],[
39],[
40],[
43],[
45],[
48],[
49],[
[53],
[54],
[55],
[56],
[57],
[58],
[59],
[60],
[61],
[62],
[63],
[64],
[65],
[66],
[67].
4. Microenvironmental characteristics of DW
As mentioned, the DW exhibits a complex microenvironment that impedes healing. This microenvironment is characterized by persistent inflammatory responses, consistently elevated blood glucose levels, elevated concentrations of reactive oxygen species (ROS), fluctuating pH levels, and sustained hypoxia, distinguishing it from acute wounds. Together, these factors increase the risk of infection, hinder proper angiogenesis, and impair the overall healing process. In stark contrast, the microenvironment of acute wounds is considerably simpler and lacks these compounded challenges, which enables quicker and more effective healing. Understanding the complex dynamics involved in DW healing is essential for designing bioactive dressings. The importance of managing these specific environmental aspects during the design of bioactive dressings cannot be overstated. These dressings can dramatically improve the healing process by focusing on each unique challenge posed by DWs, such as inflammation, glucose levels, oxidative stress, pH balance, and oxygen supply.
The next section delves into the key characteristics that define the DW microenvironment, highlighting the importance of this understanding for developing targeted therapeutic strategies (
Fig. 3).
4.1. High glucose
The compromised healing capacity in DW primarily stems from advanced glycation end-products (AGEs) accumulation-induced pathophysiological cascades, with hyperglycemia serving as the predominant driver of AGEs formation. The excessive generation of AGEs promotes a substantial increase in cytosolic ROS, leading to elevated expression levels of pro-inflammatory mediators such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and results in the activation of the nucleotide oligomerization domain (NOD)-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome. This cascade extends the inflammatory response and complicates it, further complicating wound healing
[68],
[69],
[70].
Moreover, numerous studies have found that the excessive production of AGEs can adversely affect the migration and proliferation abilities of key healing cells, including fibroblasts, keratinocytes, and endothelial cells. These cellular activities are crucial for the formation of new tissues and wound closure
[71],
[72],
[73],
[74],
[75]. Additionally, AGEs can interfere with collagen synthesis and crosslinking, further hindering the fibrous restructuring of tissues. This interference can adversely affect the structure and strength of the newly formed tissues in wound areas
[76],
[77],
[78].
Furthermore, the extensive accumulation of AGEs results in microvascular complications, reducing blood supply to the injured tissue. This diminishes the transport of oxygen and nutrients and directly impedes the healing process
[79],
[80],
[81]. These mechanisms interact with each other to create a negative feedback loop, significantly delaying the natural healing process of DW.
4.2. Persistent inflammation
Sustained inflammatory responses are closely linked to healing challenges, with a disrupted immune microenvironment playing a central role in this process. This disruption involves multiple processes, including excessive production of ROS, imbalanced macrophage polarization, and pyroptosis. These factors collectively constitute a complex network, interacting with and influencing each other, creating a disordered immune microenvironment at the wound site in patients with diabetes. As previously noted, the formation of AGEs in the DW microenvironment exacerbates cellular oxidative stress and the release of ROS. Additionally, in this microenvironment, the efficiency of endogenous antioxidant systems, such as superoxide dismutase (SOD) enzymes, is reduced, leading to further elevation of ROS levels in the immune microenvironment. Excessive ROS disrupts cellular functions, inhibits cell proliferation and differentiation, and affects the normal structure and function of tissues; it, therefore, exacerbates inflammatory responses, thereby impeding normal wound healing
[82],
[83],
[84].
Macrophages play a critical role in the immunological dysregulation of DW environments. Under the hyperglycemic and oxidative stress conditions characteristic of DW, macrophages tend to polarize toward the pro-inflammatory M1 phenotype, releasing large quantities of inflammatory mediators and cytokines, intensifying the inflammatory response. Conversely, the generation of reparative M2 macrophages is diminished, leading to the inadequate secretion of anti-inflammatory and reparative mediators. Consequently, this failure to effectively control inflammation prolongs the inflammatory phase of the wound and subsequently impairs wound healing [
56],[
85]. However, recent research has also identified the presence of four distinct types of macrophages within DW, including those highly expressing osteoclast-related genes, which do not entirely fit into the traditional macrophage classification schema [
86]. Finally, the excessive activation of M1 macrophages can increase the risk of pyroptosis, further inducing disorders in the immune microenvironment. For instance, the activation of the NLRP3 inflammasome is associated with M1 macrophage polarization, which promotes both pyroptosis and the release of the pro-inflammatory cytokine IL-1β. This not only exacerbates the inflammatory response but perpetuates a vicious cycle of inflammation
[87],
[88],
[89].
4.3. Persistent infection
Researchers collected wound swab samples from 50 diabetic patients with diabetes and observed multiple microbial infections in DW [
90]. Patients with diabetes often experience diminished immune function, which can lead to an increased risk of bacterial infections during the wound-healing process. Recurrent bacterial infections further negatively affect the healing of DWs, thereby delaying the healing process at multiple levels [
91],[
92]. First, bacterial infections trigger an immune response that leads to the overexpression of pro-inflammatory cytokines, intensifying the inflammatory response [
93]. Second, bacteria and their toxins can directly damage key components of the ECM, such as collagen and elastin, which are crucial for maintaining the structural integrity and quality of wound healing [
94],[
95]. Additionally, bacterial infections promote the upregulation of matrix metalloproteinases (MMPs) and inhibit their natural inhibitors, such as tissue inhibitors of metalloproteinases (TIMPs), further disrupting the balance between ECM degradation and regeneration and severely impairing tissue repair at the wound site. Furthermore, the production of bacterial metabolites and toxins consumes oxygen and nutrients within the wound microenvironment, increasing the metabolic burden required for wound healing
[96],
[97],
[98],
[99],
[100].
However, some studies emphasize that the aggregation and adhesion of various microbes to the wound tissue, which ultimately leads to biofilm formation, is a more severe problem than microbial infection [
101],[
102]. This complex microbial community within the biofilm is typically attached to the tissue surface and encapsulated by a protective layer of extracellular matrix. The structure gives the biofilm a high level of resistance to antibiotics and immune responses, causing the infection to persist and become difficult to eradicate. Consequently, the presence of biofilms not only complicates the treatment of wound infections but also significantly increases the risk of treatment failure [
103].
4.4. Hypoxia
Oxygen plays a pivotal role in wound healing, and its effects are particularly pronounced during the initial phases of wound formation. Newly formed acute wounds are typically exposed to a hypoxic environment that facilitates the initiation of the healing process by activating inflammatory responses and promoting angiogenesis [
104],[
105]. However, unlike the transient hypoxia experienced in acute wounds, the DW endures prolonged chronic hypoxia, posing several persistent challenges to the healing process. First, prolonged chronic hypoxia affects the functionality of cellular populations. Research has indicated that under chronic hypoxic conditions, endothelial cells exhibit enhanced vasoconstriction and adhesion capabilities, thereby increasing the risk of vascular pathology. Furthermore, the combined effects of hyperglycemia and hypoxia can sustain a chronic inflammatory state in macrophages [
106],[
107]. Second, under hypoxic conditions, hypoxia-inducible factor-1 (HIF-1), which plays a pivotal role in regulating oxygen homeostasis, orchestrates several biological processes, such as cell proliferation, migration, and angiogenesis, to adapt to low oxygen levels [
108], is activated. During acute wound healing, HIF-1 activation stimulates the production of various growth factors, including VEGF, thus enhancing angiogenesis. However, in DW, high glucose levels promote the hydroxylation of HIF-1α and inhibition of HIF-1 activity in hypoxic cells through a mechanism dependent on prolyl hydroxylase domain-containing proteins. This leads to reduced expression of key HIF-1 target genes, such as
VEGF, exacerbating vascular formation obstacles and tissue ischemia and severely impairing the healing process of DW
[109],
[110],
[111]. Additionally, with HIF-1 inhibited, there is a further decrease in macrophage migratory activity and the bactericidal capability of natural killer cells, potentially increasing the risk of wound infection
[112],
[113],
[114].
Hyperbaric oxygen therapy (HBOT) has emerged as a potential treatment modality for DW that focuses on enhancing oxygen delivery to damaged tissues by increasing oxygen concentrations at the wound site. Clinical studies have demonstrated that HBOT significantly contributes to DW healing by increasing VEGF levels and suppressing TNF-α [
115]. Huang et al. [
116] found that HBOT promoted fibroblast proliferation and endothelial cell angiogenesis, aiding in DW healing. However, its indications are relatively stringent. Clinical practice guidelines indicate that not all types of DW are suitable for HBOT. Particularly, HBOT is more suitable for DW at Wagner stage 3 or above or for those that have recently undergone debridement surgery. HBOT does not significantly reduce the amputation rate or improve the healing rate for DW at Wagner stage 2 or below. Therefore, its use is not recommended. Moreover, Lalieu et al. [
117] conducted a systematic review, revealing that the HBOT demonstrates suboptimal effects in non-ischemic DW and does not prevent amputations in diabetic patients without peripheral arterial occlusive disease, thereby limiting its indications. Additionally, some studies argue that HBOT cannot achieve sustained oxygenation [
118]; this inadequate performance is primarily due to the limitation of HBOT in consistently delivering sufficient oxygen to the wounds, as the oxygen levels in poorly vascularized wounds rapidly decline after treatment [
119]. While HBOT functions as a systemic oxygenation modality, its administration has been associated with hyperoxic tissue damage through multiple pathways, including neurotoxic manifestations (e.g., seizure induction), barometric stress-induced injuries, metabolic dysregulation, and ophthalmic complications
[119],
[120],
[121],
[122],
[123],
[124]. HBOT is generally held to have an inconsistent and unsatisfactory therapeutic efficacy [
125].
4.5. Disordered factors
In the DW microenvironment, the healing process is significantly affected by the disruption of pathological, biological, and cytokine factors, manifesting in several key ways. First, there is an excessive accumulation of harmful factors, which is primarily evident in the build-up of AGEs, ROS, and MMPs. In a high-glucose environment, surplus glucose reacts with proteins via a non-enzymatic glycation reaction to form AGEs. This not only triggers the activation of inflammatory signaling pathways such as nuclear factor-κB (NF-κB) but also stimulates the aggregation of inflammatory cells and the release of related cytokines. Additionally, AGEs enhance ROS production by binding to the receptor for advanced glycation end products (RAGE) receptors on cell surfaces [
68],[
126]. The increase in ROS within the wound tissues of diabetic patients further disrupts the balance between MMPs and tissue inhibitors of TIMPs, stimulating the overproduction of MMPs and downregulation of TIMP expression
[127],
[128],
[129]. MMPs are a diverse and extensive group of enzymes, with at least 23 different types identified in the human body, each showing specificity toward a particular substrate. These enzymes play a dual role in the healing process of DW [
130]. Under normal conditions, MMPs facilitate tissue reconstruction during wound healing. However, when overproduced, they can excessively degrade collagen and other matrix components, thereby compromising the structural integrity of the wound and causing delayed healing [
127].
Second, there is a disruption in cytokine expression, primarily reflected in the overactivation of pro-inflammatory factors such as TNF-α and IL-1β. This leads to abnormally enhanced and prolonged inflammatory responses, while low levels of the anti-inflammatory cytokine IL-10 hinder the progression of the healing process to later stages [
131]. Moreover, through the analysis of clinical tissue samples, Wang et al. [
132] have identified that key growth and repair factors such as TGF-β and VEGF show diminished activity or reduced expression in DW compared to normal skin tissue. This impairment affects collagen deposition and angiogenesis, further delaying wound recovery. Additionally, the reduced expression of antimicrobial peptides weakens the resistance of DW to bacterial infections, increasing the risk of infection. Studies have also shown that epidermal cells from DW exhibit lower levels of the antimicrobial peptide LL-37 than those from healthy skin [
133]. This collective disruption of cytokines delays the normal wound-healing process of wounds in patients with diabetes, underscoring the importance of restoring the balance between these factors to promote wound healing.
4.6. Dynamic pH disruption
The natural pH of the skin typically remains within the mildly acidic range of 4 to 6. This is predominantly due to the action of organic acids secreted by the epidermal cells, which form a natural barrier. The acidic environment protects against microbial invasion [
134]. Traditional research posits that the pH of acute wounds progressively transitions from alkaline to acidic during the healing process, eventually stabilizing to the skin’s normal acidic state [
135]. This shift aids in promoting cellular proliferation and tissue reconstruction. In contrast, chronic or infected wounds typically present with persistent alkaline conditions, generally ranging from 7.15 to 8.90 [
136]. However, Strohal et al. [
137] found that, when measuring the pH of various types of chronic wounds in a study involving 30 patients, the average pH could be as high as 9.25. This elevated level may result from multiple factors, such as different microbial colonization patterns and bacterial metabolic products, such as urease, which likely contribute to the typically alkaline environment of chronic wounds. In a study of 137 wounds, 121 (88.3%) contained significant amounts of ammonia in their dressings, likely resulting from the catalysis of urea by urease, thus releasing ammonia [
138]. Furthermore, the higher pH values in wound environments promote bacterial growth and proliferation, exacerbating a vicious cycle that increases the risk of bacterial infections in the wounds [
139].
However, there are differing views regarding the responsiveness of pH-sensitive wound dressing management specifically designed for chronic wounds, such as those associated with diabetes, under acidic or basic conditions. Currently, most reported bioactive dressings intended for DW treatment are designed to degrade in acidic conditions. This contradiction might stem from discrepancies between diabetic animal wound studies and the actual conditions of wounds in patients with diabetes. In animal experiments, research on wound dressing treatments often starts from the initial stages of the wound, when the primary responsive phase may still predominantly occur during the initial inflammatory period (acidic environment) of wound healing. Notably, the pH levels of wounds are highly variable and depend on factors such as the progression of wound healing, the diversity and variability of microbial colonization, the presence of infection, and the level of inflammatory responses. For instance, chronic wounds can exhibit a transient acidic pH during the early stages of healing. In contrast, infected wounds tend to maintain a more continuously alkaline environment than non-infected wounds [
140]. Furthermore, if a wound exhibits a significant local inflammatory response, this can also substantially lower the pH of the microenvironment.
5. Bioactive dressing strategies for on-demand management of DW
Previously, management strategies for DW were often limited to fragmented treatments that only addressed surface symptoms. However, with the advancement of bioactive dressing technologies and a deeper understanding of the DW microenvironment, management strategies have evolved toward both microenvironment-sensitive passive and active on-demand management approaches (
Fig. 4). This review covers microenvironment-sensitive active on-demand management strategies that enable bioactive dressings to proactively regulate the DW microenvironment through external stimuli-responsive techniques such as temperature, light, ultrasound, and magnetic fields. Conversely, microenvironment-sensitive passive on-demand management strategies leverage physical and chemical principles to adapt automatically to changes in the wound environment. For instance, some dressings contain smart materials that adjust their drug-release behavior under specific temperature or humidity conditions, thereby adaptively releasing therapeutic agents in response to natural variations in the wound environment, such as high glucose, hypoxia, or pH, while maintaining consistent therapeutic efficacy. These sophisticated management strategies significantly enhance DW treatment by minimizing tissue toxicity and side effects while achieving on-demand, precise control tailored to the unique wound conditions. In contrast to traditional DW management, this innovative approach has considerable benefits, including superior drug release efficacy, customization, reduced patient burden, and improved treatment outcomes and compliance. Despite these significant advantages, a thorough evaluation of the strengths, weaknesses, and potential adverse effects of each dressing’s materials and strategy is essential.
Table 3 [140],
[141],
[142],
[143],
[144],
[145],
[146],
[147],
[148],
[149],
[150],
[151],
[152],
[153],
[154],
[155],
[156],
[157],
[158],
[159],
[160],
[161] provides a comprehensive comparison of the results.
5.1. Microenvironment-sensitive passive on-demand management
5.1.1. Glucose-sensitive management
High glucose levels are a crucial factor complicating DW healing. Existing dressings tend to have limited functionalities and respond slowly to the complex wound microenvironment, resulting in suboptimal treatment outcomes. A major focus in DW dressing research is incorporating glucose-sensitive materials into polymeric dressings to enhance their responsiveness to glucose levels in the wound environment. Traditional glucose-sensitive materials are primarily based on concanavalin A (Con A), glucose oxidase (GOx), and phenylboronic acid (PBA) derivatives. Con A, a plant lectin extracted from jack beans, exhibits reversible high affinity for unmodified hydroxyl groups at the C-3, C-4, and C-6 positions of non-reducing α-
D-mannose, α-
D-glucose,
N-acetyl-
D-glucosamine, and polysaccharides. Researchers, including Mansoor et al. [
162], have combined pluronic F-127, chitosan, and Con A to develop a closed-loop polymer system for the glucose-responsive delivery of rapid-acting insulin. In this design, the glucose-responsive characteristics of Con A function as a “monitor,” sensing changes in external glucose concentrations [
162]. However, the limited biocompatibility of Con A restricts its clinical application. Therefore, enhancing the biosafety of Con A while maintaining its bioactivity remains a key direction for future research [
163],[
164]. Molecular modification and surface modifications are potential strategies for addressing these challenges.
GOx catalyzes the reaction between glucose and oxygen to produce gluconic acid and hydrogen peroxide (H
2O
2). Studies have suggested that the H
2O
2 generated during this reaction may damage wound tissues. Therefore, effectively managing and utilizing the H
2O
2 produced by GOx is crucial for the design of glucose-responsive hydrogels for wound-dressing applications. Ren et al. [
141] proposed a bioactive dressing with a dual-layer structure. The exterior layer of the dressing comprised a hydrogel rich in sodium alginate, GOx, and a bromelain substrate, capable of generating oxygen through photosynthesis, ensuring that GOx catalyzed the glucose in the wound area to produce H
2O
2, thus functioning as an antibacterial agent. The inner layer featured a microneedle layer infused with catalase (CAT), which reduces tissue oxidative stress caused by H
2O
2 accumulation, suppresses the polarization of macrophages toward a pro-inflammatory phenotype, and promotes fibroblast proliferation and angiogenesis, ultimately enhancing DW healing. Notably, the DW model used in this study was non-bacterially infected (
Fig. 5(a)). Therefore, some researchers believe that for DW with bacterial infections, H
2O
2 produced by the catalytic action of GOx can further promote healing. For example, Zhou et al. [
142] designed a bioactive dressing characterized by high glucose responsiveness and consistent nitric oxide (NO) release. This dressing, shown in
Fig. 5(b), utilized chitosan coupled with
L-arginine and HA modified with GOx as raw materials. The dressing, named CAHG dressing, was formed via
in situ crosslinking based on Schiff base reactions. In the high-glucose microenvironment of the wound, CAHG initiated a cascade reaction in which H
2O
2 generated by GOx-mediated glucose consumption oxidizes the
L-arginine-coupled chitosan, inducing the release of NO.
In vitro and
in vivo studies have demonstrated that the synergistic release of H
2O
2 and NO from CAHG can inhibit bacterial proliferation and pro-inflammatory cytokines, foster the production of anti-inflammatory M2 macrophages, and ultimately enhance the healing of bacterially-infected DW.
In fluids, phenylboronic acid derivatives exhibit tunable ionization equilibrium properties, and their ionization states are significantly influenced by the surrounding glucose concentration. Specifically, these derivatives could stably bind to glucose molecules, altering their ionization equilibrium. Under certain pH conditions, phenylboronic acid derivatives with lower pKa (pKa: negative base 10 logarithm of the acid dissociation constant) values are more likely to release protons, creating negatively charged active sites that are more likely to interact effectively with the hydroxyl groups in glucose. Consequently, studies have attempted to enhance the glucose responsiveness of phenylboronic acid derivatives through modifications with electrophilic groups [
165]. For instance, in a polymer dressing system developed by Lu et al. [
143], the introduction of fluorophenylboronic acid (FPBA) bearing electrophilic groups as glucose-sensitive components demonstrated excellent glucose detection capabilities (
Fig. 5(c)). In future research on bioactive dressings for DW management, exploring advanced modification strategies for phenylboronic acids will be a crucial direction. In addition to incorporating the electrophilic groups mentioned previously, the precise tuning of phenylboronic acid derivatives to introduce functional groups that can engage in dynamic, synergistic interactions with multiple sites on glucose molecules, such as hydroxyl and amino groups, will be key to enhancing their glucose detection sensitivity and specificity. The affinity between the phenylboronic acid derivatives and glucose can be significantly enhanced through multipoint and non-covalent interaction mechanisms, including hydrogen bonding and van der Waals forces.
5.1.2. pH-sensitive management
As the wound heals, the pH of the wound bed may change. Consequently, the pH value can serve as a precise and dynamic indicator of cargo release from bioactive dressings. This enables a reduced frequency and surge in medication administration and minimizes the range of associated side effects, ultimately enhancing the therapeutic efficacy of DW management. Thus, studies have developed a pH-regulated dressing by crosslinking gelatin- and benzaldehyde-modified Pluronic F-127 drug-loaded micelles using dynamic Schiff base linkages [
144]. This bioactive dressing exhibits pH sensitivity, self-healing properties, and injectability, enabling targeted drug delivery directly to DW sites. By encapsulating curcumin, which has antioxidant, anti-inflammatory, and antimicrobial effects within these micelles, and including magnesium-based micromotors within the polymer system, the formulation actively generates hydrogen to scavenge ROS and mitigate inflammation. Therefore, the dressing effectively re-engineers the DW microenvironment (
Fig. 6(a)). In addition, studies have also skillfully utilized the dynamically changing pH of DW to design a dressing with pH colorimetric indicator functions. Xu et al. [
145] developed a Janus dressing composed of a hydrophilic cellulose layer containing antioxidants, pH-sensitive red cabbage anthocyanins, and a hydrophobic polycaprolactone layer infused with the antimicrobial agent chlorhexidine. Incorporating pH-sensitive red cabbage anthocyanins enables the dressing to respond dynamically to changes in the microenvironmental pH during the DW healing process. Furthermore, this color change could be digitally analyzed using a Python Red Green Blue (RGB) program and transmitted to a smartphone, providing real-time monitoring of the wound for both patients and healthcare providers (
Fig. 6(b)).
Finally, the design and study of hydrogels that respond to the dynamic pH changes in DW and subsequently provide feedback on pH regulation is a major focal point in research. Cui et al. [
140] employed microfluidic techniques to design a bioactive dressing capable of responding to and regulating the pH within the DW microenvironment of a DW. This dressing primarily consists of –COOH-containing hydrogel microspheres and –NH
2 components, capable of releasing or adsorbing hydrogen ions in the moist environment of a DW, thereby enabling dynamic adjustment of wound pH. This bioactive dressing can maintain a low pH microenvironment during the early hemostasis and inflammation stages of wound healing, inhibiting bacterial infection and promoting angiogenesis. During the later proliferation and remodeling phases, it adjusts wound pH to a more alkaline environment, thereby facilitating cell proliferation and tissue remodeling (
Fig. 7(a)). Moreover, Xia et al. [
146] developed a glycopeptide-based pH-regulated dressing, including HA modified with diacylhydrazine adipate (HA-ADH) or aldehyde (OHA), and dopamine (DOPA)-modified poly(6-aminohexanoic acid) (PADA). This dressing was synthesized via Schiff base crosslinking between the –NH
2 and –CHO groups, complemented by metal complexation between –COOH, phenol hydroxyl groups, and metal ions. In the initial stages of a DW, in a neutral to slightly alkaline microenvironment, the dressing facilitates substantial deprotonation of carboxyl groups, releasing H
+ and thereby lowering the environmental pH to a mildly acidic level. Subsequently, owing to the swelling of the dressing, a large number of hydrazide groups within are exposed. This results in the gradual adsorption of free H
+ from the wound microenvironment, forming NH
3+ structures and causing a slow rise in the environmental pH toward neutrality. The researchers employed a DW mouse model and discovered that, during the early inflammatory phase of wound healing, the bioactive dressings facilitated a shift in the wound microenvironment from slightly alkaline to slightly acidic. This pH change enables macrophages in the wound microenvironment to undergo polarization toward the M2 type, thereby accelerating the resolution of inflammation. In the middle and later stages of healing, the wound microenvironment transitions from slightly acidic to neutral, which enhances fibroblast recruitment and collagen remodeling. Furthermore, this dynamic shift from alkaline to acidic to neutral pH in the wound environment favors angiogenesis, ultimately accelerating the healing (
Fig. 7(b)).
5.1.3. Antioxidant, anti-inflammation, and anti-infection management
Excessive build-up of ROS presents a significant oxidative stress challenge in DW, complicating both anti-inflammation and anti-infection efforts. This issue has become a major research focus on bioactive medical strategies for treating DW. Shi et al. [
147] aimed to modulate oxidative stress in DW by modifying hyperbranched polyethylene glycol diacrylate (HB-PEGDA) with disulfide to create a disulfide-bonded hyperbranched polyethylene glycol (HB-PBHE) (
Fig. 8(a-I)), thereby endowing the polymer system with a ROS-responsive antioxidant capacity. Furthermore, using a Michael addition reaction, thiolated hyaluronic acid (SH-HA) and HB-PBHE were crosslinked (
Fig. 8(a-II)), and both curcumin liposomes and silver nanoparticles (AgNPs) were incorporated, culminating in the synthesis of a multifunctional bioactive dressing (
Fig. 8(a-III)), HA@Cur@Ag, which was characterized by its ROS responsiveness and dual antioxidant, antimicrobial, and anti-inflammatory properties (
Fig. 8(a-IV)). Both
in vivo and
in vitro experiments demonstrated the excellent biocompatibility of the polymer system, its capability to effectively load and release curcumin liposomes and silver ions, and its promotion of DW healing via multiple mechanisms like scavenging ROS, bactericidal activity, exerting anti-inflammatory effects and angiogenesis promotion.
Meanwhile, Jia et al. [
148] developed a ROS-responsive supramolecular polymer system constructed from a simple hexapeptide, glutamate–phenylalanine–methionine–glutamate–methionine–glutamate (EFM), synthesized via solid-phase peptide synthesis (SPPS) without the need for additional ROS-responsive linkers or modifications. The peptide EFM was designed to incorporate specific amino acids, each conferring the essential physicochemical attributes required for its functionality. Within this hexapeptide, glutamic acid residues impart hydrophilicity, enhancing solubility in water; phenylalanine residues provide hydrophobicity crucial for driving the π−π stacking interactions that facilitate self-assembly of the system. Methionine residues respond to ROS, endowing the system with the capacity for ROS responsiveness and antioxidative activity through ROS scavenging. As discussed in
Fig. 8(b-I), this hexapeptide supramolecular hydrogel can encapsulate therapeutics such as VEGF and curcumin and undergo self-assembly. Upon exposure to ROS, the methionine residues are oxidized to methionine sulfoxide (MetO), disrupting the hydrophobic interactions within the hydrogel and leading to the degradation of the hydrogel and release of the encapsulated drugs.
In vitro and
in vivo studies have demonstrated that this dressing possesses dual functionalities as an ROS scavenger and a drug delivery vehicle, efficiently facilitating DW healing (
Fig. 8(b-II)). Moreover, Li et al. [
149] developed a bioactive dressing, fabricated using a modified electrospinning strategy, which enables the incorporation of
Salvia miltiorrhiza Bunge–
Radix Puerariae herbal compound (SRHC) into gelatin (Gel)/poly(
L-lactic acid) (PLLA) nanofibrous yarns during the electrospinning process. This innovative approach enables the dressing patch to possess both the advantageous microstructure of electrospun nanofibers and the robust mechanical properties of woven textiles (
Fig. 8(c)). The anti-inflammatory properties exhibited by the dressing patches can be primarily ascribed to the presence of SRHC, which has been proven to possess excellent anti-inflammatory and antioxidant properties. According to studies, the incorporation of SRHC into the Gel/PLLA nanofibrous yarns not only significantly promotes the attachment and proliferation of human dermal fibroblasts (HDFs) but also markedly inhibits the levels of secretion of pro-inflammatory factors from M1 macrophages.
In pursuit of a more precise targeted antimicrobial therapy, Yang et al. [
150] devised a strategic approach for fabricating bioactive dressings featuring bacteria-responsive self-activating antimicrobial properties and multiple nanozymatic functionalities. They synthesized a pH-responsive H
2O
2 self-replenishing composite nanozyme (MSCO) and pH/enzyme-sensitive bacteria-responsive triblock micelles loaded with lactate oxidase (PPEL). Subsequently, these components were encapsulated within hydrogels composed of
L-arginine-modified chitosan (CA) and phenylboronic acid-modified oxidized dextran (ODP), resulting in a cascading bacteria-responsive self-activating antimicrobial composite platform. Engineered to detect and respond to various factors in the bacterial metabolic microenvironment, these hydrogels enable targeted antibacterial action and biofilm elimination via bacterial metabolite conversion (
Fig. 9(a)). Non-antibiotic dressings for infection management are currently a significant area of research. Pranantyo et al. [
151] engineered a bioactive dressing devoid of antibiotics, metallic compounds, or nanoparticles. They synthesized a polyethylene glycol (PEG)-based hydrogel with antibiofilm and antioxidant properties by incorporating a cationic polyimidazolium–maleimide (PIM–Mal) backbone and
N-acetylcysteine (NAC). Both PIM–Mal and NAC were covalently bonded into the hydrogel matrix via thiol-maleimide click chemistry. PIM–Mal was initially synthesized using the poly-Radziszewski reaction to form a diamine-terminated PIM, which was subsequently modified with maleic anhydride. The resulting hydrogel was fabricated as a film hydrogel, designated as PPN (
Fig. 9(b)), and was produced by crosslinking a four-arm PEG-thiol (PEG-4SH) with a four-arm PEG-maleimide (PEG-4Mal), supplemented with PIM–Mal and NAC.
5.1.4. Factors-sensitive management
As previously discussed, DW, characterized by the excessive accumulation of AGEs and MMPs, exhibits a more complex and challenging healing process than normal wounds. AGEs activate inflammatory signaling pathways, thereby escalating inflammation and impairing tissue repair. However, when present in excess, MMPs degrade collagen and other extracellular matrix proteins, thereby impeding normal cellular migration and wound healing. Given these characteristics, designing dressings with specific responsiveness to these molecular disturbances is an effective strategy for accelerating DW healing.
Inspired by the multiple chiral sites present in AGEs, Xing et al. [
152] designed a bioactive dressing rich in chiral structural features, which was peptide-modified to specifically bind and remove AGEs as a therapeutic strategy. The fundamental material of this dressing consists of self-assembling nanofibers of
L/
D-phenylalanine derivatives (LM2/DM2) that physically cross-link with HA via hydrogen bonding to form a final chiral bioactive dressing (HA-LM2-RMR). In addition, antimicrobial peptides have been incorporated to produce dressings with substantial antibacterial properties. This dressing engages in stereoselective interactions with the chiral sites on AGEs, enhancing the capacity of the dressing for the
in situ adsorption of AGEs. The aim was to remove AGEs from DW
in situ while providing antimicrobial treatment. Experiments demonstrated that using the HA-LM2-RMR chiral dressing helped reduce AGEs, eradicated multidrug-resistant bacteria, decreased inflammation, promoted cell migration, and stimulated angiogenesis. This enabled complete healing of infected DW within 14 days, offering a promising therapeutic approach for wound healing (
Fig. 10(a)). Sonamuthu et al. [
153] developed an MMPs-regulated dressing primarily composed of a metal-chelating dipeptide (
L-carnosine), curcumin nanoparticles, and a biocompatible silk protein (SF) (
Fig. 10(b-I)). In this composite, the histidine residue of the
L-carnosine dipeptide (β-alanine-histidine) can chelate and deactivate the Zn
2+ ion in the active site of MMP-9 (
Fig. 10(b-II)). Additionally, the curcumin nanoparticles strongly interact with the silk protein through hydrophobic interactions facilitated by the phenolic groups of curcumin and the beta-sheet structure of the silk protein, delivering antimicrobial activity when applied to wounds. This MMPs-regulated bioactive dressing has been shown to effectively inactivate MMP-9 and inhibit bacterial growth
in vivo DW models, thereby enhancing DW healing efficiency.
5.1.5. Temperature- and moisture-sensitive management
Temperature changes around DW are key indicators of inflammation, infection, and healing. Temperature-regulated dressings can adjust their properties in response to these changes, transitioning between states, providing mechanical stimulation, or delivering drugs precisely. These dressings enhance wound care by responding in real-time, promoting faster and more effective healing. One commonly used material in these dressings is poly(
N-isopropylacrylamide) (PNIPAm), which is synthesized through free-radical polymerization of the monomer
N-isopropylacrylamide (NIPAm). PNIPAm molecules contain hydrophilic amide groups (–CONH–) and hydrophobic isopropyl groups (–CH(CH
3)
2–). They exhibit a lower critical solution temperature (LCST) of approximately 33 °C. Below this temperature, PNIPAm maintains its interactions with water molecules through hydrogen bonding, keeping the polymer chains in an extended state. However, when the environmental temperature exceeds the LCST, such as at a body temperature of 37 °C, the hydrogen bonds between the water molecules and the amide groups break. This event causes the isopropyl groups to approach each other, forming hydrophobic regions. The enhanced hydrophobic interactions cause the polymer chains to contract, leading to a gelation phase transition [
166],[
167]. Based on this characteristic, PNIPAm is utilized in the treatment of DW primarily because of its temperature-responsive properties, which facilitate the mechanical closure of wounds while concurrently delivering therapeutics to promote healing. Sun et al. [
154] exploited the phase transition properties of PNIPAm to develop a semi-interpenetrating polymer network composed of PNIPAm and calcium-crosslinked sodium alginate, incorporating antioxidative amino- and hydroxyl-modified C70 fullerene (AHF) particles as immunomodulatory components in these bioactive dressings. Both
in vitro and
in vivo studies have demonstrated that these bioactive dressings exhibit excellent biocompatibility and respond well to thermal stimuli with significant thermally responsive contraction capabilities, effectively accelerating the mechanical closure of DW. Furthermore, the inclusion of AHF imparts anti-inflammatory properties and enhances tissue repair and regeneration, ultimately promoting DW healing (
Fig. 11(a)). Pluronic F-127, a nonionic triblock copolymer, is also suitable for preparing temperature-regulated dressings for DW (
Fig. 11(b)). Chen et al. [
155] developed a bioactive dressing based on Pluronic F-127 grafted with dopamine (PDA) that encapsulates live algae and
Bacillus subtilis (
Fig. 11(b-I)). Given that the LCST of Pluronic F-127 is near body temperature, this hydrogel dressing remains in a liquid state at lower temperatures and rapidly solidifies upon application to the wound. The PDA grafting enables the dressing to adhere quickly and tightly to the wound surface. Additionally, the presence of live algae, which provide sustained oxygen delivery, along with probiotics known for their anti-infective properties, facilitated the rapid healing of infected DW (
Fig. 11(b-II)).
DW sites often suffer from issues such as excessive exudates, which hinder the performance of conventional wound care products. Current dressings and bandages struggle to maintain adhesion and control contraction in a moist environment. They typically offer only passive coverage, and do not effectively facilitate wound closure. Addressing this, Theocharidis et al. [
156] have developed a new type of dressing that responds to the moisture levels within the wound environment to promote healing through mechanical contraction. This innovative dressing comprises two distinct layers: ① a non-adhesive backing made of hydrophilic polyurethane and ② a bioadhesive layer formed from a crosslinked network of poly(acrylic acid) grafted with
N-hydroxysuccinimide (PAA-NHS) ester and chitosan. This strain-programmed patch uniquely integrates a dry-crosslinking mechanism with a hydration-responsive shape-memory feature. When applied to moist DW, it delivers strong, durable, and selectively detachable adhesion while also enabling precise mechanical modulation of the wounds, alleviating stress concentration at the edges, and fostering wound contraction (
Fig. 11(c)).
5.2. Microenvironment-sensitive active management
5.2.1. Ultrasound-sensitive management
Ultrasound-guided targeted local drug delivery techniques have advantages such as targeted therapy, on-demand release, non-invasive approaches, and precise spatial and temporal control through non-thermal mechanisms. Based on this, Huang et al. [
157] developed an ultrasound-triggered dressing that incorporates anthocyanin as a visual pH indicator and degradable PLLA microcapsules as an ultrasound-responsive drug delivery system for antibiotics, embedded in an injectable polyethylene glycol (PEG) hydrogel matrix. As shown in
Fig. 12(a), the anthocyanin/cefazolin sodium (CS)-loaded PLLA microcapsules/PEG (ACPP) hydrogel was prepared by embedding anthocyanin- and CS-loaded PLLA microcapsules in a hydrogel crosslinked with amino-functionalized tetra-PEG (Tera-PEG-NH
2) and
N-hydroxysuccinimide-functionalized tetra-PEG (Tera-PEG-NHS). Hydrogels containing anthocyanin enable visual pH monitoring of infections and chronic wounds by analyzing RGB signals collected from images. Upon detection of an infection, ultrasound can trigger on-demand treatment. Furthermore, owing to the focusing ability of ultrasound, the release of antibiotics can be spatially and temporally controlled.
5.2.2. Magnetic-sensitive management
Magnetic fields are non-invasive and highly adaptable physical intervention tools with significant potential for clinical therapeutic applications. Building on this, He et al. [
158] developed a magnetically-triggered dressing designed to treat infected DW (
Fig. 12(b)). This dressing demonstrated excellent magnetothermal conversion capabilities and the ability to continuously release antioxidant particles, enabling effective magnetothermal therapy for DW with deep-seated infections and promoting the remodeling of the wound microenvironment. This dressing primarily takes the form of microneedles, which can penetrate hard scabs and bacterial biofilms, delivering loaded therapeutic nanoparticles into the deep layers of the infected tissue. Moreover, under the influence of an electromagnetic field, the ferromagnetic nanoparticles at the head of the dressing can generate heat through magnetothermal conversion, clearing the wound biofilms and ultimately promoting the healing of infected DW. Additionally, Shou et al. [
159] have incorporated thiol-coated magnetic particles (TMP), Food and Drug Administration (FDA)-approved fibroblasts and keratinocytes, and insulin into a poly(ethylene glycol) diacrylate (PEGDA)-based polymer system enhanced with the cell-adhesion arginine–glycine–aspartate (RGD) (
Fig. 12(c-I)).
In vitro and
in vivo experiments demonstrated that under the influence of a dynamic magnetic field, this magnetic-triggered dressing significantly increased cell proliferation, ECM deposition, and neovascularization, thereby mechanically regulating cellular biofunctional activities. Moreover, as illustrated in
Figs. 12(c-II) and
(c-III), the magnetic-triggered dressing can also utilize a dynamic magnetic field generated by a moving magnet to control insulin release, thereby regulating glucose levels in the wound environments to enhance healing outcomes.
5.2.3. Light-sensitive management
Bioactive dressings that integrate photocatalytic and photothermal technologies not only possess excellent moist healing properties but also enable precise control over therapeutic outcomes by regulating light exposure duration and intensity. This capability significantly enhances healing efficiency while minimizing side effects, showcasing considerable potential for treating DW. Building on this, Chen et al. [
160] designed a visible-light-triggered dressing for treating DW, primarily composed of hydrogen-incorporated titanium oxide nanorods (HTON) embedded in a chitosan/hyaluronate gel matrix. During treatment, the HTON loaded within this light-triggered dressing utilized glucose from the high-sugar microenvironment of DW as a sacrificial agent. Under visible-light catalysis, this leads to sustained hydrogen generation and local glucose consumption, thereby suppressing the synthesis of AGEs and the expression of their receptors within the tissue (
Fig. 13(a-I)). This promotes tissue repair and regeneration, offering a promising strategy for enhancing DW healing (
Figs. 13(a-II)–(a-IV)). Furthermore, Zhu et al. [
161] developed a near-infrared (NIR) light-triggered dressing, primarily composed of a matrix gel that included copper-dopamine polydopamine nanoparticles (CuPDA NPs) and metformin as the active agents, along with hyaluronic acid modified by phenylboronic acid (HA-PBA) and gelatin modified by dopamine (Gel-DA), which are key components sensitive to both pH and glucose levels. The CuPDA NPs confer excellent NIR light responsiveness to the dressing, being capable of killing over 95% of the bacteria within minutes and facilitating the slow release of Cu
2+ ions to promote angiogenesis in tissues. Both
in vivo and
in vitro experiments demonstrated that this NIR light-triggered bioactive dressing significantly promoted DW healing by controlling infection, managing inflammation, enhancing angiogenesis, and accelerating ECM deposition, showcasing significant potential for application (
Fig. 13(b)).
6. Summary and outlook
Given the intricate microenvironment of DW and the substantial challenges it presents in treatment, bioactive dressings have emerged as a key focus of the medical and materials science communities. To enable these dressings to be dynamically sensitive to changes in the wound-healing environment and perform on-demand management to achieve personalized, efficient, and patient-friendly treatments, future research should continue to focus on the following key elements:
(1) Smart response mechanisms: These bioactive dressings are equipped with sensitive monitoring systems capable of detecting and responding to one or more environmental changes, such as the photothermal effects, pH fluctuations, and glucose levels. This capability enables them to automatically adjust and release therapeutic agents specifically tailored to the wound’s conditions, thereby enhancing their effectiveness and adaptability [
11],[
12],[
14],[
168],[
169];
(2) Delivery system construction and integration: Utilizing a polymeric matrix, which includes structures such as metal–organic frameworks, liposomes, and inorganic nanoparticles, these dressings are engineered to precisely transport and release essential therapeutic components such as drugs, cells, growth factors, and enzymes. Advanced micro- and nano-delivery systems ensure that drugs are dispensed at controlled times and dosages, aligning with the wound’s healing stages and specific needs
[170],
[171],
[172],
[173],
[174]. Furthermore, three-dimensional (3D) printing technology can be employed to ensure personalized customization based on the specific shape, size, and depth of the patient’s wound. This precise geometric matching enhances the conformity of the dressing to the wound surface, thereby improving therapeutic efficacy
[175],
[176],
[177]. Moreover, it enables the creation of complex internal structures that are difficult to achieve using traditional manufacturing methods, such as microchannels, porosity, or specific drug release patterns. These structures can be utilized to control the rate of drug release
[178],
[179],
[180];
(3) Biocompatibility and biodegradability: It is essential that the materials used are harmless to the human body and degradable after use to minimize the environmental impact. This consideration was extended to their chemical properties and degradation rates
[181],
[182],
[183],
[184];
(4) Mechanical property optimization: Enhancing properties such as elasticity, flexibility, and strength is crucial to dressing performance. These characteristics significantly influence the comfort and suitability of dressings, particularly for wounds with irregularly shaped wounds or those located in actively moving areas. For instance, incorporating hydrogen bonding and metal-ligand coordination into the design can endow the dressings with enhanced adhesive properties, self-healing capabilities, and fatigue resistance. This would enable the dressings to more dynamically and flexibly conform to the wound surface, thereby improving the overall therapeutic outcomes
[185],
[186],
[187],
[188],
[189]. Electrospun nanofiber technology can also be utilized to create nanofiber-enhanced composite bioactive dressings, which possess advanced characteristics derived from nanofiber materials. These include the ability to mimic the morphology and structure of ECM fibers, such as flexibility, elasticity, and high specific surface area, ultimately enabling improved conformity to the wound surface [
190],[
191];
(5) Integration of sensors and monitoring functions: Development of dressings containing micro-sensors to monitor vital physiological indicators such as humidity, temperature, and pH levels. This technology facilitates dynamic treatment adjustments and real-time communication with healthcare professionals, thereby ensuring personalized and immediate patient care
[192],
[193],
[194];
(6) Multifunctional design: This enhances medical efficiency and reduces costs by incorporating functionalities such as hemostasis, tissue growth promotion, and infection prevention. This approach requires a multidisciplinary collaboration across materials science, biomedical science, and chemistry in the future [
195],[
196].
Although bioactive dressings offer advanced therapeutic solutions, their clinical application faces several challenges. First, the incorporation of innovative materials such as nano-delivery systems or biological agents poses significant biosafety challenges and requires rigorous analysis and compliance with regulatory standards. The choice of the FDA approval pathway depends substantially on the specific characteristics of the dressings and how they differ from existing medical devices. Dressings that utilize standard or commonly used materials might qualify for a 510(k) clearance, which is used for medical devices that are substantially equivalent to already legally marketed devices (
Fig. 14(a)). However, if the dressings incorporate innovative elements not classified under current regulatory frameworks, they may be subject to the
De Novo classification pathway (
Fig. 14(b)). This process was designed for novel low- to moderate-risk medical devices without legally marketed predicates. For dressings that are particularly complex and present a higher risk, such as those involving drug delivery mechanisms, a pre-market approval (PMA) might be necessary. The PMA process is the most stringent regulatory pathway of the FDA and involves comprehensive clinical and laboratory evaluations [
197] (
Fig. 14(c)). Furthermore, detailed studies on their performance inside the body are necessary, including their degradation, drug release, and effects on healing and inflammation
[198],
[199],
[200]. Future research should include broader studies involving animal models and human trials to evaluate long-term impacts
[201],
[202],
[203]. Additionally, more efficient and cost-effective manufacturing techniques and innovative delivery methods that meet patient needs are crucial for enhancing the clinical utility and patient compliance with bioactive dressings [
204],[
205].
Since the approval of becaplermin gel (RegranexTM), the FDA has not cleared any new DW care products. This may be because of the complexity of wound healing, which requires interventions that act across various cell types and pathways, unlike cancer treatments that typically target a single molecule. Moreover, wound care research is significantly underfunded compared to cancer research, which hampers innovation [
206]. However, with advancements in biomanufacturing and synthetic biology, future dressings will be able to precisely target wound-specific physiological and chemical signals, resulting in improved therapeutic outcomes. Bioactive dressings have considerable potential for DW care. Developers can use synthetic biology to create genetically modified microbes that produce specific bioactive molecules, such as antibiotics or growth factors, which can be incorporated directly into dressings [
207]. These molecules can be programmed to be released automatically under certain conditions to optimize the treatment and speed up healing. Looking ahead, DW care will lean toward more efficient and intelligent solutions, offering safer, more targeted, and more convenient options for patients and paving the way for personalized medicine in diabetes management.
CRediT authorship contribution statement
Yanan Xue: Formal analysis, Data curation, Conceptualization. Junping Zhou: Formal analysis, Data curation, Conceptualization. Ying Lu: Investigation. Huiling Zhang: Investigation. Bailin Chen: Investigation. Shaoan Dong: Investigation. Yawen Xue: Investigation. Kan Zhan: Resources. Cheng Chen: Investigation, Conceptualization. Yi Sun: Investigation. Sufan Wu: Validation. Liqun Jin: Supervision. Zhiqiang Liu: Supervision. Yuguo Zheng: Writing – review & editing, Visualization, Validation, Supervision, Funding acquisition.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
This work was financially supported by the National Natural Science Foundation of China (22408078, 82401057, and 32101170) and the Zhejiang Province Postdoctoral Excellence Funding Program-Special Support (ZJ2024004).
PDF
(9862KB)
