Abstract
Diabetic wounds are among the most common complications in patients with diabetes, often occurring in the lower extremities and manifesting as diabetic foot ulcers. These wounds are often associated with issues such as infection, peripheral artery disease, hyperglycemia, and hypoxia, making them difficult to heal and prone to becoming chronic wounds. MNs enable painless, controlled transdermal drug delivery, overcoming limitations of traditional methods such as poor permeability and short drug duration. Stimuli-responsive microneedles targeting specific triggers have developed rapidly in recent years and are expected to contribute to the realization of precision medicine. Diabetic wounds are often accompanied by microenvironmental imbalance, and this complex wound milieu frequently causes them to progress into refractory wounds. Stimuli-responsive microneedles therefore represent a promising therapeutic strategy. Current studies in this field are still mainly limited to single-stimulus-responsive microneedles, whereas multifunctional microneedles capable of responding to multiple stimuli have not yet been fully developed. This review summarizes the research foundation and current progress of stimuli-responsive microneedles for the treatment of diabetic wounds, and further discusses the future prospects and potential directions of multi-stimuli-responsive microneedles. In addition, this review clarifies the conceptual boundary between truly stimuli-responsive microneedles and microenvironment-associated therapeutic platforms, compares major responsive strategies and microneedle platforms, and discusses key translational barriers including mechanical robustness, manufacturing scalability, cargo stability, model relevance, and regulatory considerations.
1. Introduction
Diabetes has emerged as one of the most rapidly spreading health crises globally, with a total of 537 million of the world’s population living with diabetes, more than tripling from 151 million in 2000. By 2045, this number is expected to reach 783 million. 1 About 30% of diabetic patients are complicated by diabetic foot ulcers (DFUs). Diabetes causes neuropathy, which makes the patient’s skin sensation dull and muscles atrophy. 2 In this case, changes in the way patients stand and work alter the distribution of forces on the foot, ultimately contributing to the development of ulcers. 3 Diabetes also causes peripheral arterial disease (PAD), which leads to ischemia of the foot and induces ischemic ulcers. 4 Normal wound healing consists of three stages. The first stage is inflammation, the second is tissue formation, and the last one is remodeling. 5 However, the healing process of DFUs often stalls in the inflammatory stage, resulting in delayed healing, challenges in management, and, in severe cases, the necessity for amputation. 1
Clinical treatment of DFUs mainly includes dressing change, surgical debridement, skin and flap grafts. Patients with severe DFUs may even require amputation. A suitable dressing is important for the treatment of DFUs. It should have excellent breathability, water control and antimicrobial capacity to balance the wound microenvironment and promote granulation growth and tissue healing. Unlike other common chronic wounds, DFUs are often accompanied by a high-glycemic environment, so managing both tissue glucose levels and blood glucose should also be considered. A number of dressings have been developed for the treatment of diabetic feet, such as hydrogels, electrospun membranes, and microneedle-based systems, each of which has its own advantages and disadvantages.6,7
As an emerging transdermal drug delivery method, microneedles have the advantages of being painless, convenient and continuous administration.8,9 They can achieve precise and continuous transdermal drug delivery, solving the problem of poor transdermal permeability of certain drugs. Conventional microneedles primarily rely on passive diffusion, dissolution, or matrix degradation, and their release kinetics are therefore generally pre-programmed rather than feedback-regulated.
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In contrast, stimuli-responsive microneedles are designed to couple pathological cues, such as glucose, pH, ROS, enzymes, or temperature, with material-level changes and regulated drug release.11,12 Because DFUs are characterized by a dynamic and heterogeneous microenvironment, such feedback-regulated systems may offer advantages for pathology-matched therapy (Scheme 1). Stimuli-responsive microneedles exhibit excellent biocompatibility and transdermal drug delivery capabilities, enabling sustained drug release with minimal tissue damage, demonstrating outstanding potential in wound treatment.
In this review, stimuli-responsive microneedles are conceptualized as dynamic therapeutic interfaces that couple pathological cues in DFUs with material-level responses and therapeutic outputs. This framework includes four interconnected layers: wound-derived stimuli, responsive material transformations, regulated drug-release behavior, and therapeutic reconstruction of the diabetic wound microenvironment. By organizing existing studies according to this stimulus–material–release–therapy axis, this review aims to clarify the mechanistic rationale, comparative advantages, and translational limitations of stimuli-responsive microneedles for DFU treatment. A structured literature search was conducted using PubMed and Web of Science to identify relevant studies published up to February 2026. The search terms included combinations of the following keywords: “diabetic wound”, “diabetic foot ulcer”, “microneedle”, “stimuli-responsive microneedle”, “smart microneedle”, “glucose-responsive microneedle”, “pH-responsive microneedle”, “ROS-responsive microneedle”, “temperature-responsive microneedle”, “enzyme-responsive microneedle”, and “multi-stimuli-responsive microneedle”. Additional relevant articles were identified by manually screening the reference lists of selected publications.3,10,13
Original research articles, representative translational studies, and highly relevant review articles were included if they focused on microneedle-based drug delivery, stimuli-responsive materials, diabetic wound healing, or wound microenvironment regulation. Studies were excluded if they were unrelated to microneedles, lacked a clear stimulus-responsive mechanism, focused only on general biomaterial synthesis without wound-healing relevance, or did not provide sufficient mechanistic or therapeutic information. Because this article aims to provide a critical overview rather than a systematic review, the selected literature was analyzed narratively with emphasis on stimulus–material interactions, release mechanisms, therapeutic rationale, fabrication strategies, and translational potential.
Compared with previous reviews that mainly summarize microneedle materials or diabetic wound dressings, this review emphasizes the coupling relationship between pathological stimuli, responsive material transformations, and therapeutic outputs. 14 It further distinguishes truly stimuli-responsive systems from microenvironment-associated therapeutic platforms and critically discusses the translational barriers that must be addressed before stimuli-responsive microneedles can be advanced toward clinical DFU treatment.
2. Basic physiology of the DFUs
2.1. Physiologic response to wound healing
DFUs are one of the complications that most often occur in patients with diabetes. They can cause pain and inconvenience. DFUs usually begin with a wound. The first thing that occurs after an injury is the inflammatory phase. After a brief period of vasoconstriction, the vasculature of the wound dilates and permeability increases, followed by platelet aggregation and the release of growth factors and vasoactive substances such as PDGF, TGF-β, thromboxane and histamine.
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If there is bacterial colonization of the wound during this period, it can lead to a prolonged inflammatory phase, which makes the wound difficult to heal.
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The period lasts for about 48 hours, after which fibroblasts become predominant in the wound healing process.
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During this period, new capillaries are generated and grow into the wound, providing substances necessary for wound healing. It also includes activation of fibroblasts, fiber deposition, and epithelialization.
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If capillaries are obstructed or growth is arrested, ischemic ulcers can develop and transform into chronic wounds, as typified by occlusive atherosclerotic ulcers.
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Three weeks after injury, the remodeling phase begins and can last for up to two years. It includes reactions such as epithelialization, wound contraction, and granulation tissue production.
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Diabetic patients have a higher risk of PAD, tissue hypoxia and inflammation than healthy people. They are more likely to develop chronic wounds when they suffer trauma or pressure injuries (Figure 1(a)).
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Such injuries often occur in the feet, namely diabetic foot. The inflammatory phase of DFUs is prolonged and the healing process is stagnant. It brings great economic and living burden to patients (Figure 1(b)). (a) Risk factors such as cardiovascular diseases, kidney diseases, smoking, PAD, and abnormal foot pressure interactions collectively increase the risk of DFUs. (b) Copyright 2023, Diabetes Care. Clinically, DFUs are commonly seen at pressure points, often accompanied by bacterial infections, and in some patients, complications like gangrene may occur.
2.2. Peripheral arterial disease (PAD)
PAD can be caused by atherosclerosis, embolism, thrombosis, fibromuscular dysplasia or vasculitis of the vascular wall. Intermittent claudication (IC), lower limb vessels, and ankle brachial index (ABI) can help diagnose the disease. 20 As early as 1959, scientists suggested that structural occlusion of small arteries was responsible for ischemic lesions in diabetic patients. Diabetes affects vessel wall function and hemodynamics, leading to an increased risk of PAD. 21 A 2007 European study showed that PAD was diagnosed in 49% of the DFU patients tested. 22 Factors that cause PAD in diabetes include platelet aggregation, inflammation and dysfunction of vascular smooth muscle cells and endothelial cells. PAD restricts blood flow to the wound, triggering a cascade of effects such as hypoxia and malnutrition. In severe cases, it can lead to limb cyanosis, tissue necrosis, and even amputation. 23
2.3. Hypoxia
Higher trauma oxygenation has a positive effect on wound healing. 24 PAD is common in diabetes and often results in inadequate blood supply to wounds, leading to hypoxia. Persistent hyperglycemia-induced inflammation further aggravates oxidative stress and exacerbates tissue hypoxia. 25 Unlike ordinary acute wounds, DFU tissues remain in a prolonged hypoxic environment. Under normal circumstances, hypoxia-inducible factor 1 (HIF-1) is activated in response to hypoxia as a kind of crucial regulatory element. This activation promotes the release of growth factors and regulates the body’s responses to hypoxic conditions. However, under hyperglycemic and stress conditions, the expression of HIF-1 and VEGF in the wound is downregulated, angiogenesis is impaired, and the healing process becomes stagnant. 26
2.4. Inflammation
Unlike inflammation in other wounds, DFUs present a chronic low-grade inflammatory state. 27 The wounds of patients with DFUs often exhibit an accumulation and infiltration of inflammatory cells. In the skin of diabetic rabbits, an increased proportion of both pro-inflammatory and anti-inflammatory macrophages (a marker of chronic inflammation) was observed. 28 In diabetic patients, there was heightened immune cell infiltration, along with elevated expression of MMP-9 and protein tyrosine phosphatase-1B (PTP1B). It inhibits the signaling pathways of insulin, leptin, and growth factors. 29 Persistently elevated levels of chemokines are also observed in patients with DFUs, including interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). 30 Infectious Diseases Society of America recommends the use of antibiotics to control inflammation in all infected DFUs. 31
2.5. Effect of persistent hyperglycemia on DFUs
Chronic hyperglycemia is closely related to the onset and development of peripheral neuropathy. 32 Furthermore, there are strong correlations between precursors of advanced glycation end-products (AGEs), dyslipidemia markers, and acute-phase proteins. Programmed cell death (PCD) refers to the regulated process of cell death controlled by genetic mechanisms. 33 The most widely studied PCD forms includes apoptosis and autophagy. Endogenous apoptosis is promoted by BAK and BAX, while exogenous apoptosis is initiated by membrane receptors. 34 In diabetic wound healing, the abnormal high-glucose environment induces dysregulated apoptosis in various cell types, such as fibroblasts, neutrophils, and macrophages. This dysregulation exacerbates persistent inflammation, impairs angiogenesis, and hinders epithelialization. 35 Additionally, the high-glucose environment leads to impaired autophagy. Impaired autophagy in fibroblasts reduces collagen synthesis, while in macrophages, it increases susceptibility to infection, further delaying wound healing. 36 Therefore, controlling blood glucose is crucial in the treatment of diabetic DFUs.
3. Microneedles and drug delivery
3.1. Transdermal drug delivery
The most common mode of clinical administration is oral administration, which is non-invasive and convenient, but because of the first pass metabolism, oral administration always leads to lower blood concentrations. 37 Intravenous administration, while avoiding first pass metabolism, is more cumbersome and painful. Thus, transdermal administration becomes an attractive option, and many efforts have been made in this regard. Examples include traditional herbal plasters used in Chinese medicine. Patches are also non-invasive and easy to use. Therefore, they are still popular with patients. 38 The first-generation transdermal delivery system includes most of the early available patches. They were mainly used for the delivery of small lipophilic drugs, such as steroids. 39 Next, people started to develop methods to enhance transdermal delivery. 40 Enhancing skin permeability was a good choice. Then scientists developed conventional chemical enhancers, 41 iontophoresis, 42 etc. They are the second-generation transdermal delivery system. They have improved ability of small-molecule delivery. 39 The third-generation transdermal delivery system involves microneedles, thermal ablation and nanoparticles.43–45 They have solved the problem of delivering macromolecules, making transdermal delivery system can be used in more areas, even vaccine production. 46 Traditional drug delivery methods such as patching have low drug utilization, difficult transdermal delivery, and cannot maintain a stable drug release curve. Therefore, microneedles, which perform well in drug delivery and controlled release, have become a new research focus.
3.2. Microneedles
Here are the components of skin. The epidermis is the outermost layer of the skin, consisting of the stratum corneum (10-20 μm), stratum lucidum, stratum granulosum, stratum spinosum, and stratum basale. Below the epidermis lies the dermis (0.05-0.2 mm), which is composed of the papillary and reticular layers. The innermost layer is the subcutaneous tissue (1.5-3 mm).
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Stratum corneum is one of the hindrances that affects the absorption of transdermal administration delivery. Microneedles can transport drugs through the epidermis to accomplish controlled drug release.
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Microneedles are miniature needles that are part of the third-generation transdermal delivery systems. In the 1970s, researchers proposed the use of microneedles to reduce the cost of drug delivery.
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In the beginning, microneedles were fabricated out of silicon.
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With the advancement of technology, more kinds of microneedles have been developed, such as polymer,
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glass,
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metal
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microneedles and so on. Simply put, microneedles can be classified as coated microneedles, solid microneedles, dissolving microneedles and hollow microneedles.
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There are many processes to make microneedles. These include etching,
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electroplating,
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laser,
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photolithography
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and injection molding (Figure 2).
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(a) Microneedles for wound treatment. Several common microneedle preparation processes. (b) Copyright 2022, J Control Release.
4. Classification of microneedles
Solid microneedles can deliver drugs by piercing the stratum corneum with a sharp tip. It can serve as both a topical drug delivery method and a means of systemic drug administration via vascular absorption. Additionally, it can be combined with ointments, gels, and other medications as part of a transdermal drug delivery system. 58 Common raw materials for solid microneedles include silicon, polymers, glass, metals, and maltose. For example, three-dimensional arrays of sharp-tipped, solid tetrahedral microneedles can be fabricated using micro-molding technology. The micro-molds are produced through etching techniques, allowing the length of the microneedles to be adjusted according to specific requirements. 59
Coated microneedles are produced by applying a layer of the drug onto the surface of the microneedles, forming a coating. 60 The process is divided into two steps: the first step is dipping and withdrawal, the second step is drying. Drugs can not only be coated onto the needle surface but also be loaded into cavities within the microneedles. 61 It has been reported that coated microneedles can transport proteins and peptides into the skin.62,63
Unlike solid microneedles, hollow microneedles have hollow tips that can be made by laser, etching, or other methods. It has the dual properties of transdermal and injectable drug delivery. When loaded with liquid, the drug is first loaded in the pores and can diffuse from the microneedle backing plate when the drug is depleted. When loaded with dry formulations, the drug is first dried in the pores and is activated to act after the needle is pierced into the skin and comes into contact with tissue fluid. 64 Gupta, J et al. are the first to demonstrate that hollow microneedles can effectively deliver insulin into diabetic patients. 65 In addition, hollow microneedle patches with a glucose detection and monitoring function and an electroosmotic pump have been developed to control blood glucose at a stable level in diabetic rats, providing a cost-effective, sensitive, and safe method of drug delivery. 66
Dissolving microneedles, composed of water-soluble matrix materials such as carboxymethylcellulose, hyaluronic acid, and polyvinylpyrrolidone, offer better biocompatibility compared to the previously mentioned types of microneedles.67,68 Preparation methods for dissolving microneedles include the two-step casting technique, centrifugal lithography, photopolymerization, droplet-born air-blowing method, and drawing lithography, among others.
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In 2013, Ling et al. investigated dissolvable microneedles loaded with insulin composed of starch and gelatin, manufactured using a two-step casting method. Microneedles not only effectively control blood glucose levels in diabetic rats but also dissolve within the skin after just five minutes of contact with tissue fluid, thereby minimizing the required application time (Figure 3).
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(a) The preparation of a kind of dissolvable microneedle-based wound dressing (PLT-Exos@ADMMA-MN), along with the morphological images and SEM images. (b) and (c) In the in vivo experiment of diabetic rat wound model, the microneedle group showed a faster healing speed and longer drug retention time. (d) The wounds treated with microneedles have higher epithelial transformation rate, that is, better healing. Copyright 2024, Bioact Mater.
From the above introduction to microneedles, it is evident that, while microneedles are commonly used as a convenient and painless method for administering insulin to control blood glucose, their application in wound treatment has been less frequently explored. In reality, microneedles are a class of products that are exceptionally well-suited for the treatment of chronic wounds, including DFUs.
5. Classification of stimuli-responsive microneedles
It should be noted that not all microneedle systems designed for diabetic or inflammatory wound microenvironments can be regarded as truly stimuli-responsive systems. 14 In this review, truly stimuli-responsive microneedles are defined as systems in which a specific endogenous or exogenous stimulus induces a verifiable physicochemical change in the microneedle matrix or interface, thereby regulating drug release, degradation, swelling, crosslink density, phase transition, or therapeutic activity. This definition is consistent with the general design principle of stimuli-responsive biomaterials, in which environmental triggers induce changes in swelling, degradation, phase transition, or molecular interactions. 70 In contrast, microneedle systems that merely deliver therapeutic agents to a pathological wound environment, or passively scavenge pathological byproducts without stimulus-triggered material transformation, are considered microenvironment-associated therapeutic platforms rather than strictly stimuli-responsive microneedles. 71
5.1. Glucose-responsive microneedles
Major well-characterized stimulus-responsive systems. Enzyme- and inflammation-related systems are discussed in the text but are not included as separate columns because strictly enzyme- or cytokine-triggered stimuli-responsive microneedles for DFUs remain relatively limited.
Glucose-responsive mechanisms can generally be categorized into phenylboronic acid (PBA)-mediated reversible binding, glucose oxidase (GOx)-triggered enzymatic reactions, and competitive dynamic covalent bonding systems. For example, researchers constructed a hydrogel network without the need for external crosslinking by combining phenylboronic acid-modified oligochitosan with dopamine-grafted aldehyde-functionalized dextran. Through the interplay between glucose-insensitive imine bonds and glucose-sensitive boronate ester bonds, this system achieved basal drug release under hypoglycemic conditions and therapeutic release under hyperglycemic conditions, thereby maintaining glycemic stability and promoting wound healing. 83 Another notable feature of DFUs is their highly complex and dynamic microenvironment. Therefore, beyond systemic glycemic regulation, glucose-responsive microneedles designed for local wound application are also of considerable research value, as they can release therapeutics according to local wound conditions and enable precise treatment. For instance, microneedles fabricated using amyloid fibrils as templates in combination with polyphenols and glucose oxidase can reduce glucose levels in the wound microenvironment while simultaneously scavenging reactive oxygen species and alleviating tissue hypoxia, thereby promoting wound healing. 78
5.2. pH-responsive microneedles
The surface of normal human skin is weakly acidic, with a pH ranging from 4.8 to 6.0. After injury, the pH of the exuded tissue fluid is approximately 7.4, creating a transient weakly alkaline environment. 88 During the healing process, wound pH is determined by multiple factors, including metabolism, infection, inflammation, and oxygen concentration, making it a complexly regulated parameter. 81 Following normal healing of an acute wound, the skin gradually returns to its original weakly acidic state. However, when the wound progresses to a non-infected chronic wound, the accumulation of blood, interstitial fluid, and ammonia results in a weakly alkaline wound environment. Although transient acidification may occur during early inflammatory and hypoxic stages because of increased glycolysis and lactate accumulation, chronic and infected wounds are more commonly reported to exhibit neutral-to-alkaline pH values overall. 81
pH-triggered microneedles typically exploit acid-labile dynamic covalent bonds that undergo cleavage or structural rearrangement under mildly acidic or alkaline conditions. Common chemical bonds used in such systems include Schiff bases, acetal bonds, hydrazone bonds, and boronate esters. Huaqian Xue et al. developed a pH-responsive hydrogel microneedle based on laminarin-polysaccharide stearic acid micelles (LSI-GCA). By coating a complex prepared from anthocyanins and chitosan on the back side of the microneedles, the system was able to monitor wound pH in real time. 84
5.3. ROS-responsive microneedles
One of the major sources of reactive oxygen species (ROS) is the mitochondrial respiratory process. During electron transfer to O2, a portion of O2 is partially reduced to O2- or H2O2, among which O2- serves as the precursor of most ROS. After skin injury, macrophages are activated and generate large amounts of ROS, a process that plays a beneficial role during the early stage of wound healing. However, when the wound develops into a chronic wound, persistent infection and inflammation continuously activate macrophages, leading to excessive ROS accumulation. 89 This in turn damages proteins and nucleic acids, inhibits angiogenesis, and impairs wound repair. DFUs are often accompanied by tissue hypoxia, infection, and abnormal ROS levels. Therefore, strategies aimed at restoring redox balance have therefore been widely explored for diabetic wound repair. 80
ROS-responsive microneedles generally rely on oxidation-sensitive linkers such as thioketal bonds or boronic ester crosslinkers, enabling ROS-triggered network degradation and on-demand drug release. For example, a degradable boronate ester-crosslinked network was constructed by incorporating the ROS-responsive crosslinker TSPBA into a PVA/PVP matrix. When ROS levels increase in the tissue, the crosslinking bonds undergo oxidation and hydrolytic cleavage, accelerating hydrogel degradation and releasing the encapsulated metformin-CeO2 nanoparticles. This system reduces intracellular ROS generation and accelerates extracellular ROS scavenging, thereby overall lowering ROS levels in the wound. 89 Li et al. adopted a core–shell structure in which the outer layer was designed as a rapidly degradable CeO2-containing layer. Through dissolution of the outer layer, ROS levels in the wound were directly reduced first, followed by sustained mitochondrial regulation. This reflects a sequential therapeutic strategy rather than direct ROS-triggered material degradation. 85
5.4. Enzyme-responsive microneedles
Diabetic foot wounds are often accompanied by the abnormal expression of enzymes such as matrix metalloproteinases (MMPs), collagenase, and hyaluronidase. 26 This disruption of enzymatic homeostasis affects physiological processes including cell migration and differentiation, collagen deposition, and proteolysis, thereby causing the wound to remain in a chronic non-healing state. Enzyme-responsive microneedles rely on enzyme-sensitive linkages, degradable matrices, or peptide sequences to achieve stimulus-triggered responses, thereby enabling precise regulation of the wound microenvironment. However, in current studies on DFUs, strictly enzyme-triggered responses remain relatively limited, and more attention has been directed toward enzyme-involved synergistic therapies.
5.5. Temperature-responsive microneedles
Chronic wounds usually exhibit a relatively low temperature because of impaired blood perfusion and oxygen supply. However, under pathological conditions such as infection and inflammation, local temperature may increase as a result of inflammatory responses, enhanced local blood circulation, and accelerated cellular metabolism. A low temperature is unfavorable for neovascular ingrowth, whereas an excessively high temperature may lead to tissue edema and exudation, thereby aggravating infection. In addition, a series of enzymes involved in processes such as cell migration and collagen synthesis require an appropriate temperature for effective activation. Therefore, maintaining a normal wound temperature is beneficial for tissue repair. 90 In one study, the inner layer of the microneedles was composed of sodium alginate–poly (N-isopropylacrylamide) (SA-PNIPAM) containing sucrose octasulfate sodium salt (SOS), in which the volume phase transition of PNIPAM was utilized to accelerate the drug response to temperature changes. The outer layer consisted of polyethylene glycol/poly (lactic-co-glycolic acid) (PEG-PLGA) loaded with urea, which underwent a gel–sol transition to promote the controlled release of urea and wound cooling, thereby achieving dual thermo-responsive drug release and improving release efficiency. 86
5.6. Inflammation-responsive microneedles
Persistent abnormal inflammation is one of the hallmark features of DFUs and is characterized by markedly elevated levels of inflammatory cells and cytokines in wound tissue. To date, only a limited number of DFU-oriented microneedle studies have explicitly used enzyme-cleavable linkages or inflammatory cytokines as direct release triggers. 91 Most current approaches instead target inflammation-related byproducts, such as ROS, pH, and enzymes, to achieve wound treatment. In one study, PLGA-thioketal-polyethylene glycol microneedles were used to encapsulate metronidazole, enabling responsiveness to the high ROS levels in the wound microenvironment and thereby allowing the precise release of metronidazole for anti-inflammatory therapy. 92 Research on the detection of inflammatory factors and the development of responsive materials for them is still insufficient, and how to accurately and rapidly reflect inflammatory changes in wounds remains one of the greatest challenges.
6. Mechanism of action
Stimuli-responsive microneedles function through a sequential process involving stimulus recognition, physicochemical transformation of the matrix, and modulation of drug release kinetics, ultimately enabling feedback-regulated therapy. 13
6.1. Stimulus sensing
There is a wide variety of stimuli signals. In DFUs, common chemical stimuli include glucose, ROS, GOx, metabolites, pH, and temperature.
PBA is widely utilized in glucose-responsive systems due to its ability to form reversible boronate ester bonds with cis-diol groups in glucose molecules. This dynamic covalent interaction enables glucose-dependent crosslink rearrangement within the hydrogel matrix, thereby regulating drug release. 72
GOx catalyzes the reaction of β-D-glucose with oxygen to generate gluconic acid and hydrogen peroxide through its key cofactor FAD, and is therefore an important oxidoreductase in biological processes. Owing to its high sensitivity, GOx has been widely used for glucose detection. 93 In DFUs, glucose oxidase can precisely and efficiently ameliorate the hyperglycemic microenvironment while being relatively less affected by other metabolites. 74
Wound pH changes in response to multiple factors, including inflammation, metabolism, and bacterial products, and is therefore one of the key indicators for monitoring wound status. Many studies have employed colorimetric reagents (such as litmus) to monitor wound pH in real time. In contrast to these approaches, pH-responsive microneedles typically regulate drug release through acid- or alkali-cleavable dynamic covalent bonds, protonation-induced structural transitions, or charge-based swelling behavior. By coupling pathological pH changes with matrix degradation or structural swelling, pH-responsive microneedles can achieve infection-adaptive or inflammation-sensitive drug release. However, the relatively narrow pH range observed in DFUs may limit response specificity, thus requiring precise material design to achieve clinically meaningful responsiveness. 84
As one of the indicators reflecting wound infection, metabolism, and inflammation, temperature influences a series of biochemical processes, including vascular ingrowth, fibroblast-mediated repair, and metabolic activity. Current approaches for monitoring wound temperature include infrared imaging, thermometric devices, and wearable sensor patches. However, these methods are often delayed and operationally complex. In contrast, temperature-responsive microneedles exploit changes in the physicochemical properties of polymers at different temperatures to achieve real-time controlled drug release. 94 Thermo-responsive hydrogels are generally categorized into lower critical solution temperature (LCST)-type and upper critical solution temperature (UCST)-type systems. LCST-type polymers (e.g., PNIPAM) remain hydrophilic and swollen below the LCST but undergo hydrophobic collapse and network contraction when the temperature rises above the transition threshold. 44 This volume shrinkage can accelerate drug release through matrix densification or expulsion effects. In contrast, UCST-type polymers dissolve above their critical temperature and aggregate below it, enabling alternative release modulation mechanisms.
6.2. Material structural transformation
These structural transformations directly alter mesh size, crosslink density, or matrix integrity, thereby modulating drug diffusion pathways. Upon exposure to specific stimuli, microneedles achieve controlled drug release through four principal mechanisms: swelling, degradation, crosslink breaking, and phase transition. In general, swelling and dissolution are often associated with diffusion- or degradation-governed release, whereas dynamic bond cleavage and phase-transition mechanisms are more directly associated with stimulus-coupled release regulation.
Swelling-based microneedles rely on water uptake upon contact with interstitial fluid, leading to expansion of the polymer network without complete structural disintegration. This process increases mesh size and enhances molecular diffusion, enabling sustained drug release or interstitial fluid extraction while maintaining mechanical integrity. 95
Dissolving microneedles are typically fabricated from biodegradable polymers such as hyaluronic acid. Upon insertion into the skin, the matrix gradually dissolves in the presence of tissue fluid, resulting in complete structural disintegration and rapid drug release. While this approach minimizes residual needle fragments and tissue trauma, the release kinetics are largely predetermined and lack feedback regulation due to the irreversible nature of matrix dissolution. 96
Crosslink-breaking represents a central mechanism in stimuli-responsive microneedles. In these systems, dynamic covalent bonds or stimulus-labile linkers are incorporated into the hydrogel network. Upon exposure to specific stimuli such as elevated glucose levels, reactive oxygen species, or pH shifts, these bonds undergo cleavage, leading to reduced crosslink density, matrix softening, and enhanced drug diffusion. Unlike simple swelling-based systems, crosslink-breaking enables stimulus-dependent modulation of release kinetics, thereby offering a more precise and adaptive therapeutic response. 85
Phase transition mechanisms are typically observed in thermo-responsive polymers such as PNIPAM. When the environmental temperature exceeds the LCST, the polymer undergoes a hydrophilic-to-hydrophobic transition, resulting in network collapse and volume shrinkage. 97 This conformational change reduces pore size and can expel encapsulated drugs, thereby enabling temperature-triggered release. Importantly, this process is reversible, allowing dynamic modulation of drug delivery in response to fluctuating thermal conditions.
6.3. Controlled drug release kinetics
In passive microneedle systems, drug release is primarily governed by concentration-gradient-driven diffusion or time-dependent matrix degradation, resulting in relatively fixed release kinetics. However, in stimuli-responsive systems, structural transformations such as crosslink cleavage or phase transition dynamically alter diffusion pathways and matrix permeability. More importantly, feedback-controlled microneedles establish a direct coupling between stimulus intensity and drug release rate, enabling self-regulated therapeutic delivery. For example, elevated glucose levels accelerate matrix dissociation and drug diffusion, whereas reduced glucose concentrations slow the release process. This closed-loop regulation distinguishes stimuli-responsive microneedles from conventional time-programmed systems and represents a key advancement for precision treatment of DFUs. 74
7. Advanced fabrication strategies for stimuli-responsive microneedles
As a precise transdermal drug delivery technology, one of the key factors affecting the performance of microneedle products is the fabrication method. These methods include micro-molding, 3D printing, lithography, hybrid fabrication, microfluidic-assisted fabrication, and layer-by-layer assembly. Among them, micro-molding is the most mature and broadly compatible fabrication method, and it has been widely applied in the preparation of various types of microneedles.
7.1. Micro-molding
In the micro-molding method, a polymer solution is cast into a pre-fabricated mold, and the liquid is driven to completely fill the needle cavities by centrifugation, pressurization, or other means. This is followed by drying, crosslinking, or curing to obtain the final microneedle product. This method is simple to perform, highly reproducible, and cost-effective, and the molds can be reused repeatedly. It is particularly suitable for hydrogel systems such as HA, PVP, and PVA, and is also applicable to the fabrication of core-shell microneedles. 98 However, it has certain limitations in terms of internal structural control and therefore cannot fully meet the fabrication requirements of microneedles with more complex architectures.
7.2. 3D printing
Microneedles fabricated by 3D printing rely on digital manufacturing equipment and computer-aided design to achieve precise printing of microneedle structures. A major advantage of this fabrication approach is its high parameter tunability, which allows rapid optimization of variables such as needle length, angle, and base geometry, making it particularly suitable for microneedle design refinement. In addition to directly printing microneedles, 3D printing can also be used to fabricate molds, which can then be employed for microneedle production through other methods. 99 However, 3D printing also has notable limitations. The range of printable materials remains relatively restricted, with resin-based materials being the most commonly used. Moreover, the layer-by-layer printing pattern can significantly affect microneedle performance and therefore requires further optimization.
7.3. Lithography
Lithography refers to a technique in which patterns from a template are transferred onto a substrate by means of light exposure and photoresist. It has been extensively and maturely studied in the fabrication of chips, sensors, and semiconductors. In the field of microneedles, the fabrication of templates through lithography and soft etching, followed by replication of molds or microneedles, represents a production strategy well suited for high-precision design. As a classical microfabrication method, lithography offers several prominent advantages, including high precision, excellent array uniformity, suitability for standardized manufacturing, and compatibility with microstructure processing. Therefore, lithography is a promising approach for studies involving highly precise structural design. However, in microneedle fabrication, its long process chain, high equipment threshold, and considerable cost limit its broader application. In addition, the raw materials currently used in lithographic processes are mainly silicon-based, making lithography unsuitable for the direct fabrication of polymeric microneedles. Similar to 3D printing, it is more suitable for the design of high-precision templates and mold fabrication, which can then be followed by micro-molding or layer-by-layer assembly. 100
7.4. Layer-by-layer assembly
Layer-by-layer (LBL) assembly involves the sequential deposition of different drugs or raw materials in distinct layers to achieve on-demand controlled release. This fabrication strategy is well suited for the design and preparation of multifunctional microneedles, particularly those intended for sequential release, stimuli-responsive release, and multilayer functional partitioning. For example, a rigid polymer may be used to fabricate the needle tip to penetrate the stratum corneum, after which therapeutic agents loaded in the base can be released to treat the wound.
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However, the fabrication of such microneedles is relatively complex, requires stringent process control, and is generally time-consuming. In addition, because multiple raw materials are involved, the interlayer structure may be unstable, which can adversely affect microneedle performance. Overall, this fabrication method expands material diversity and provides greater possibilities for microneedle design (Figure 4). (a) Schematic diagram of the micro-molding fabrication process. Copyright2019, Acta Biomater. (b) Schematic illustration of 3D-printed microneedles. Copyright2019, Microsyst Nanoeng. (c) Principle of the lithography process. Copyright 2019, Plasma Sources Science and Technology. (d) Microstructure of layer-by-layer (LBL) assembly. Copyright 2024, J Transl Med.
8. Material platforms enabling stimuli-responsive microneedles
8.1. Hydrogels as major matrices for stimuli-responsive microneedles
Hydrogel is a porous 3D mesh polymer, in which the -CONH2, CONH-, -OH, -COOH, -SO3H and other groups make it highly hydrophilic, but the material that constitutes the 3D mesh itself cannot dissolve in water, so water molecules can penetrate into the mesh, and then the volume of the hydrogel expands greatly, gaining a strong water absorption capacity. 102 Their excellent biocompatibility, biodegradability, and modifiability make hydrogels highly suitable as drug carriers. Hydrogel-forming microneedles (HFMs) have achieved significant progress in the treatment of DFUs, and a variety of responsive microneedle systems have also been developed.
Manxuan Liu developed a self-healing, double-layered, drug-loaded microneedle (SDDMN) for the purpose of diabetic wound healing. The researchers used 3-amino-1,2-propanediol (POGa) and insulin-modified gallium porphyrin to simulate hemoglobin, allowing it to enter the cell in the form of a special ‘Trojan horse’, hindering the iron metabolism of bacteria and achieving an antibacterial effect. The microneedle is a double-layer structure, with quaternary ammonium chitosan cografted with Da and Larginine (QDL) oxidized HA-DA. Methacrylated poly (vinyl alcohol) (methacrylated PVA) and phenylboronic acid (PBA) are used as the main part of the MN. The antibacterial properties of quaternary ammonium chitosan and the healing effects of HA help accelerate wound healing in the base. The microneedle network, composed of PBA and PVAMA, facilitates the release of POGa and insulin by forming a glucose-boric acid complex. This complex helps achieve a hypoglycemic effect in the high-sugar environment of the wound, thereby promoting the healing of DFUs. 103
Silk fibroin is a natural biomaterial that can be extracted from silk. It has excellent biocompatibility and mechanical strength and can be purified using alkali or enzyme-based degumming procedures. 104 Silk fibroin can be used to make hydrogels, scaffolds and fiber mats, and has shown potential for application in tissue repair. How to increase the functionality of silk fibroin products and improve their strength has always been the focus of current research. 105
In order to increase the oxygen content of the wound and promote wound healing, relevant materials have been under development. The hydrogel material containing calcium peroxide (CaO2) can prolong the release time of O2, but the H2O2 generated by the reaction of CaO2 and water molecules in the tissue is a kind of ROS, which will aggravate the tissue damage. As a result, Mengli Sun and colleagues created a new type of silk fibroin protein methacryloyl hydrogel microneedle patch that produces antibacterial oxygen. The patch’s base was coated with Ag nanoparticles for antibacterial properties, while its tip was loaded with CaO2 and catalase. Catalase reduces tissue damage caused by ROS by decomposing H2O2 into H2O and O2, while also mitigating the oxidation of Ag particles and enhancing antibacterial activity. In the MN@CaO2-AgNP system, oxygen released by the patch reaches its peak on the third day and continues to be released until the seventh day. 106
The biodegradability and modifiability of hydrogels enable prolonged, controllable, and sequential drug release. Because the fabrication of multi-responsive microneedles often requires the incorporation of multiple materials to respond to different stimuli, hydrogels may serve as one of the fundamental material platforms for the development of multi-responsive microneedle systems.
To address the issues of narrow antibacterial spectrum, short antibacterial duration, increased drug resistance, and poor efficacy against drug-resistant strains associated with traditional materials, nitric oxide (NO) gas has emerged as a promising solution. NO is a signaling molecule produced by endothelial cells that performs various functions, including regulating vasodilation, signal transmission and integration, infection elimination, and immune modulation.
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Tannic acid (TA), a natural polyphenolic compound, exhibits strong antioxidant and antibacterial properties.
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The phenolic hydroxyl groups in its side chain can chelate with iron ions to form iron/tannic (FeIIITA) particles, converting 808nm laser into thermal energy, killing bacteria through local thermal effect (Figure 5(b) and (c)). Penghui Wang et al. used the amidotransferase reaction triggered by TG enzyme to cross-link the glutamine residues of gelatin and the primary amino groups of polylysine side chains to prepare FeIIITA-containing hydrogels. They used the mold casting method to prepare microneedles loaded with Gel/PL@FeIIITA to achieve NO release in deep tissues. TG can catalyze the amidotransfer reaction between glutamine residues in gelatin and the free amino groups of ε-polylysine, leading to the release of ammonia, and then generate NO gas through NO cycle or urea cycle, which is precisely delivered to the wound surface. This type of microneedle degrades in about 96 hours after entering the wound tissue, releasing nitrogen oxides in deep tissues to achieve anti-infection and anti-inflammatory effects (Figure 5(d) and (e)).
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Different roles of microneedles in promoting wound healing. (a) GelMA/PGDA microneedles were shown to enhance angiogenesis at the wound site. Copyright 2021, Int J Biol Macromol. (b) and (c) Gel/PL@FEIIITA microneedles exhibited bactericidal effects against E. coli and S. aureus, causing surface shrinkage, rupture, and eventual bacterial death. (d) and (e) In addition, microneedles were able to reduce the release of TNF-α and IL-6. Copyright 2023, Int J Biol Macromol.
8.2. PNIPAM-based thermo-responsive systems
Poly (N-isopropylacrylamide) (PNIPAM), a thermo-responsive polymer, is a negatively temperature-sensitive polymer. Its structure contains both hydrophobic isopropyl (-CH(CH3)2) side-chain groups and hydrophilic amide (-CONH-) groups, enabling it to form an elastic helical structure in aqueous media. The sharp phase transition around physiological temperature (32–34°C) makes PNIPAM particularly attractive for fine-tuned, externally controllable drug delivery systems. 76 PNIPAM is hydrophilic and swollen below its lower critical solution temperature (LCST), whereas it undergoes hydrophobic collapse above the LCST; this transition process is reversible. PNIPAM-based systems offer a reversible and precisely tunable thermo-responsive platform, which may enable externally controllable drug release in smart microneedle applications. 110 Although PNIPAM exhibits precise thermo-responsive behavior, its relatively low mechanical strength and limited biodegradability restrict its direct application as a standalone microneedle matrix. Researchers have adopted a variety of engineering strategies to optimize the performance of PNIPAM. One strategy is to crosslink PNIPAM with other polymers, while another is to compensate for these limitations through structural design optimization. In Hu’s study, the physical properties were improved through microneedle structural design: rigid porous gelatin was used to fabricate the needle tips, which penetrated the corneal barrier and subsequently released riboflavin loaded in PNIPAM/GO, thereby overcoming the problem of insufficient mechanical strength. 111 In summary, although research on PNIPAM-related microneedles is still at an early stage due to limitations in mechanical strength, PNIPAM remains a promising thermo-responsive polymer for smart drug delivery, although its application as a standalone microneedle matrix remains limited.
8.3. Nanozyme-integrated systems
DFUs are often complicated by bacterial infections. Wei Liu et al. used centrifugation to prepare double-layer microneedles loaded with tetracycline hydrochloride (TH) and human epidermal growth factor (rh-EGF) to achieve both bactericidal and anti-infective functions. The needle tip is composed of gelatin carboxymethyl chitosan loaded with rh-EGF, while the basal layer consists of HA loaded with TH, allowing for the local, sequential release of the two drugs. Although rh-EGF is released slowly into the deeper tissue, it promotes the formation of vascular networks during the later stages of wound healing, thereby accelerating the healing process. The microneedle tip of DMN@TH/rh-EGF can smoothly penetrate rat skin and pig skin, and it bends rather than breaks at the force limit, and skin healing is observed within 4 minutes after being pulled out. The above results show that it has sufficient mechanical strength and causes no damage to the human body, making it suitable for wound drug delivery. rh-EGF can promote wound angiogenesis, and DMN degrades and breaks after contacting a large amount of collagenase in DFUs, releasing drugs. HA loaded with TH shows antibacterial ability against Staphylococcus aureus and Escherichia coli. In addition, the wound tissue of rats treated with DMN@TH/rh-EGF showed lower inflammatory response and faster wound healing. 112
9. Preclinical progress and translational outlook
At present, experimental studies on multifunctional stimuli-responsive microneedles remain largely at the animal-testing stage. Certain progress has been achieved in applications such as scalp drug delivery, scar reduction, and wound repair; however, research data specifically targeting DFUs are still lacking. In comparison, studies on single-stimulus-responsive microneedles or multifunctional microneedles are relatively more mature.71,113
Single-stimulus-responsive microneedles are designed to respond to a specific target signal and have already demonstrated desirable therapeutic effects. For example, Yang et al. developed separable microneedles responsive to the overexpression of MMP5 and ROS in the wound microenvironment. These microneedles were composed of photocrosslinked GelMA and the 5-FuA-Pep-MA prodrug, and were able to inhibit hypertrophic scar formation by modulating inflammatory responses and keratinocyte differentiation. 114
Although research on multi-responsive microneedles for DFUs remains limited, dual-responsive microneedles have already been developed for glycemic control. In one study, dual responsiveness to glucose and H2O2 was achieved by integrating glucose-sensitive polyethylene glycol, poly (phenylboronic acid), and H2O2-responsive polymeric vesicles composed of poly (phenylboronic acid pinacol ester). In this system, the drug-loaded vesicles continuously released insulin under basal conditions, while responding rapidly in a hyperglycemic environment to accelerate the release rate. The incorporated GOx further promoted insulin release by generating H2O2 under high-glucose conditions, which accelerated the cleavage of the chemical bonds in the phenylboronic acid pinacol ester groups. 115 The synergistic action of these two components enhances the glucose-lowering effect, thereby providing a potential direction for the development of microneedles for diabetic wound applications. Single-stimulus-responsive microneedles possess well-defined mechanisms and are relatively easy to fabricate, but their capacity to address the complex microenvironment of diabetic ulcers remains limited. These findings indicate that multi-responsive microneedles provide a promising conceptual direction, but their therapeutic superiority over simpler MN platforms remains insufficiently established because of limited DFU-specific studies, heterogeneous evaluation criteria, and the lack of clinically oriented validation.
10. Challenges and limitations
Although stimuli-responsive microneedles have shown considerable promise in preclinical diabetic wound studies, their clinical translation remains constrained by several interrelated engineering, biological, and regulatory challenges. First, a fundamental design trade-off exists between mechanical robustness and rapid responsiveness. Microneedles must possess sufficient puncture strength to penetrate the skin or wound-associated barrier, whereas highly swellable, degradable, or dynamically crosslinked matrices may undergo premature softening or structural failure under physiological conditions. Therefore, puncture performance, delivered dose, dissolution behavior, and release kinetics should be considered as critical quality attributes during product development. 116
Second, the structural complexity of stimuli-responsive and multi-stimuli-responsive systems increases the difficulty of batch-to-batch consistency, scalable manufacturing, and quality control. Compared with conventional microneedles, these systems often require precise integration of responsive polymers, dynamic covalent linkers, enzymes, nanozymes, biologics, or multilayer architectures. Such complexity may affect needle geometry, drug loading, response threshold, release reproducibility, and long-term storage stability. In addition, fabrication, drying, storage, and sterilization processes may compromise sensitive therapeutic cargos, such as proteins, enzymes, peptides, nucleic acids, or living-cell-derived products. 117
Third, the predictive value of animal models remains limited. Human DFUs are clinically heterogeneous and often involve neuropathy, ischemia, infection, pressure loading, impaired angiogenesis, and chronic inflammation. In contrast, commonly used diabetic wound models usually reproduce only part of this pathological spectrum. Therefore, therapeutic efficacy observed in rodent models should be interpreted cautiously and further validated in clinically relevant models before human translation. 118
Finally, stimuli-responsive microneedles may face complex regulatory pathways because they often function as drug-device or biologic-device combination products. In such systems, the interaction between the microneedle matrix, therapeutic cargo, responsive component, and delivery site must be systematically evaluated, as these interactions may influence product stability, dose delivery, safety, and therapeutic performance. Therefore, future development should place greater emphasis on standardized characterization, scalable fabrication, clinically relevant efficacy models, and early regulatory considerations.
In recent years, the development of artificial intelligence has provided a potential solution to these challenges. Rapidly advancing artificial intelligence possesses unique advantages in data prediction and structural optimization, enabling the rapid refinement of structural design and prediction of microneedle strength. Artificial intelligence systems with image-recognition capabilities, such as neural networks, can also be integrated with wound images to help analyze wound changes during microneedle treatment. Another promising direction is to use microneedles as sensors and combine them with artificial intelligence to analyze wound data for diagnostic purposes. Among these research directions, the most promising is the application of artificial intelligence to optimize microneedle formulations and structures, thereby greatly reducing research and development costs and time. In the design and improvement of hydrogels, artificial intelligence has already demonstrated remarkable capability, including screening potential therapeutic agents from large datasets, identifying binding sites, and enhancing adhesion. 119
At present, studies on artificial intelligence-designed microneedles are still in the developmental stage. Future directions with strong potential include optimizing microneedle composition and structure, predicting microneedle degradation time, estimating drug release profiles, and performing drug screening in combination with molecular docking techniques. Machine learning is becoming increasingly widespread in data analysis and prediction. By integrating finite element methods with machine learning algorithms, it is possible to optimize the geometric and physical parameters of microneedles and design microneedles capable of maximizing interstitial fluid extraction during insertion. 120 In combination with 3D printing technology, integrated systems may eventually enable the autonomous 3D printing of microneedles. 121 In one study, biodegradable PLA microneedles were fabricated by combining machine learning with 3D printing to optimize and predict printing strategies. The researchers first used potassium hydroxide solution etching to obtain different geometric features as baseline data, and then processed these data using machine learning to determine the optimal formulation. Artificial intelligence greatly accelerated the research process and demonstrated a promising pathway toward more convenient and advanced medical research. 122 However, artificial intelligence at its current stage still faces certain limitations. The insufficient amount of available data on multi-stimuli-responsive microneedles may lead to instability in model accuracy and predictive performance. Moreover, the optimization strategies proposed by artificial intelligence are often confined to the theoretical level and may encounter practical obstacles during implementation. Therefore, only by identifying appropriate ways to apply this technology can its advantages be maximized.
11. Conclusion
Although multi-stimuli-responsive microneedles hold broad promise for the treatment of DFUs, their development is still restricted by multiple factors. Among these, the most important is the technological barrier. At present, multi-stimuli-responsive microneedles require a relatively high level of technical expertise in the selection of stimuli, fabrication processes, and structural design. 123 If incompatibility arises during material integration, defects in mechanical strength, biocompatibility, and other properties may occur, necessitating repeated optimization. However, the optimization process is complex, time-consuming, labor-intensive, and prone to failure. As a result, most multi-stimuli-responsive microneedles remain at the animal experiment stage, and very few have progressed beyond preclinical validation. With the continuous development of materials science, suitable materials, emerging fabrication technologies, and novel research approaches may provide potential solutions to the current challenges facing multi-stimuli-responsive microneedles. Based on currently available preclinical evidence, multi-stimuli-responsive microneedles represent a promising but still early-stage strategy for DFU treatment.
Footnotes
Ethical considerations
This study does not involve human participants or their data, ethics approval.
Consent to participate
Consent to participate were not required.
Author contributions
Funding
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Natural Science Foundation of China (82203961), China Postdoctoral Science Foundation funded project (2023M730588).
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.