Hemostasis is considered the first phase in terminating bleeding and initiating wound healing in the event of vascular injury. Initially, vasoconstriction occurs to reduce blood flow, followed by the aggregation and activation of platelets at the site of damage to form a temporary plug. These platelets release various chemical signals that amplify the hemostatic response. The subsequent formation of a stable fibrin clot reinforces the platelet plug, thereby sealing the wound. During this process, cytokines and growth factors, such as vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF-β) and platelet-derived growth factor (PDGF), are released, preparing the tissue for the subsequent phases of wound healing (14).

The inflammatory phase represents the initial response of the body to tissue injury, lasting from several hours to a few days. Its primary role is to remove debris, pathogens and dead cells, thereby preparing the wound bed for tissue repair. This phase is marked by vasodilation and increased vascular permeability, which facilitates the recruitment of immune cells to the injury site. Neutrophils are the first responders and perform phagocytosis to eliminate microbes and cellular debris. As the phase progresses, macrophages become predominant, releasing pro-inflammatory cytokines, such as interleukin 1 and tumor necrosis factor-α, along with growth factors that initiate the next stage of healing. Clinically, this phase is characterized by the classic signs of inflammation: Redness, swelling, warmth and pain (15).

Following the inflammatory phase is the proliferative phase, which focuses on tissue regeneration and repair. Fibroblasts proliferate and deposit type III collagen, forming a temporary extracellular matrix for tissue repair. Concurrently, neoangiogenesis (the formation of new blood vessels) occurs to restore oxygen and nutrient supply to the healing tissue (16).

Finally, the maturation or remodeling phase occurs, aiming to strengthen and reorganize the newly formed tissue. During this phase, the type III collagen initially deposited is gradually replaced by the stronger and more organized type I collagen. Simultaneously, vascular regression occurs, and a scar forms as excess blood vessels are removed. Over time, the tensile strength of the wound increases, eventually reaching ~80% of that of the original tissue (17).

In recent years, polymeric nanoparticles have received considerable attention in the promising and fast-evolving areas of biomedicine and bioengineering. These novel polymeric devices, when administered in the body or conjugated with target sites, effectively protect drugs from proteolytic attacks in wounds, allowing for controlled and regulated drug delivery, while significantly reducing dosage frequency (19). Nanoparticle applications provide a viable option to meet the growing need for the effective delivery of a wide variety of biomolecules, which may include critical components, such as DNA, growth factors that stimulate healing and highly effective antibacterial agents utilized to avoid infection (20). In the contemporary age, polylactic-co-glycolic acid (PLGA), is one of the most commonly used materials for synthesizing polymeric nanoparticles. Alginate, gelatin, chitosan and several other polymer mixtures are the most commonly used polymers in a vast variety of applications. The synthesis of polymeric nanoparticles capable of effectively encapsulating antimicrobial agents has been explored across a broad spectrum of scientific fields through numerous research studies (21). Antimicrobial peptide LL37-loaded PLGA nanoparticles (PLGA-LL37 NPs) are a biodegradable drug delivery system for healing. The nanoparticles inhibited Escherichia coli in antibacterial activity and caused cell migration, but did not affect the proliferation of keratinocytes. The PLGA-LL37 NPs-treated group exhibited enhanced formation of granulation tissue in the full-thickness excisional wound model, as reflected by significantly enhanced collagen deposition, re-epithelialized content, and neovascularization (21,22). Chitosan, a biopolymer derived from chitin in crustaceans, such as shrimp and crab, has also garnered considerable interest in drug delivery systems. The reason for this is largely due to its remarkable properties, including being mucoid, biodegradable, non-toxic, and biocompatible. Properties, such as this position chitosan in an immensely versatile manner for applications across a wide range of drugs, from lipophilic to hydrophilic drugs (22). Chitosan particles are between 10 and 500 nanometers in diameter, a size that significantly increases their uptake by cells. The presence of amino groups also signifies a positive zeta potential, which increases interaction with mucosal surfaces and negatively charged cell membranes. Chitosan also has the capability of slowing the rate of drug administration through the provision of the potential to regulate how rapidly the drugs are delivered into the system (23). Chitosan-based topical systems have gained attention in chronic wound management due to their film-forming ability, biocompatibility and intrinsic wound-healing potential. In this context, in a previous study, a chitosan–polyvinyl alcohol film-forming solution loaded with doxycycline demonstrated rapid film formation, sustained drug release, and effective matrix metalloproteinase inhibition, highlighting the utility of chitosan in improving healing outcomes in diabetic foot ulcers (24). The different types of polymeric nanoparticles with their distinct features, advantages and disadvantages as drug delivery systems in chronic wound management are summarized Table I (25-30). All the nanoparticle systems have their own merits and demerits; however, they have exhibited promising therapeutic outcomes. Polymeric nanoparticles provide controlled drug release and biodegradability, while lipid nanoparticles provide increased skin penetration and drug retention. Although metallic nanoparticles have an improved antimicrobial activity, there are concerns regarding the long-term toxicity and bioaccumulation. Thus, balancing efficacy, biosafety, scalability and cost is key for successful clinical translation (31).

Solid lipid nanoparticles and nanostructured lipid carriers facilitate skin penetration and drug retention. An intriguing and important class of nanomaterials, known as lipid nanoparticles, finds widespread application in the areas of gene therapy, drug delivery systems and vaccine production. These novel particles consist of several lipids that come together to form nanoscale structures, which have the unique property of encapsulating and delivering drugs or other biological molecules with efficiency and specificity (32). A summary of various lipid nanoparticles utilized in chronic wound management is presented in Table II (21,33-35). All the nanoparticle systems have their own merits and demerits; however, they have shown promising therapeutic outcomes. lipid nanoparticles provide increased skin penetration and drug retention.

Silver and gold nanoparticles exhibit antimicrobial properties, which reduce wound infections and accelerate tissue regeneration. Generally, metallic nanoparticles are tiny particles with dimensions ranging from 1 nanometer to 100 nanometers. These tiny particles are primarily composed of a sequence of metals (36). Unlike bulk metals of larger dimensions, metallic nanoparticles possess exceptional physical, chemical and biological properties, a characteristic attributed to their significantly smaller dimensions and the large surface area they exhibit (37). Surface plasmon resonance and related phenomena are feasible due to their notable capacity to absorb and scatter light in a highly concentrated form. This property renders them extremely effective catalysts for most chemical reactions due to their enormous surface area, which allows for maximum interaction with other reactants (38). Moreover, some metal nanoparticles, such as iron oxide, possess magnetic properties, which can be extremely useful for a wide range of applications, including medical applications and data storage devices. Moreover, electronic devices can improve their performance with higher conductivity, a property that can be achieved with these materials (39). The different types of metallic nanoparticles along with their applications, advantages and disadvantages are presented in Table III (40-47). All the nanoparticle systems have their own merits and demerits; however, they have shown promising therapeutic outcomes. Metallic nanoparticles exhibit an improved antimicrobial activity; however, there are concerns regarding the long-term toxicity and bioaccumulation. Thus, balancing efficacy, biosafety, scalability and cost is key for successful clinical translation. Metallic nanoparticles exhibit strong antimicrobial activity, but their long-term biosafety remains a matter of concern. However, clinical translation is still hampered by challenges, such as bioaccumulation, oxidative stress, inflammatory responses, delayed biodegradation and organ toxicity. Further research is required to focus on detailed in vivo safety evaluation and the development of biodegradable metallic nanoplatforms.

The environmental pH is of utmost relevance to the extent to which the hydrogels will swell. The performance of the materials is markedly effective under acidic conditions, particularly in situations where pH ranges are above what is commonly considered to be normal physiological ranges (55). Such a situation is common in a number of biological surroundings, such as tumor tissues or regions characterized by inflammation. For example, in the cancerous tumor microenvironment, the pH is likely slightly acidic, which allows for the targeted release of pH-sensitive drugs exactly where they are needed. Among all the various forms of stimuli-sensitive hydrogels that have been of interest to both scientists and researchers, one of the most prominent classes is thermosensitive hydrogels (56). This class of hydrogels possesses special characteristics as the hydrophobic groups in its composition undergo a phase transition when subjected to particular temperatures. As such, the structural organization of thermosensitive hydrogels can undergo a drastic change depending on the extent to which they swell upon being subjected to thermal stimuli. The most significant temperatures of relevance to such hydrogels are the lowest critical solution temperature (LCST) and the highest critical solution temperature (HCST), both of which play crucial roles in characterizing their behavior in solutions (57). LCST has become the most widely used form of thermosensitive hydrogel in a variety of applications. When the ambient temperature is below the LCST value, the hydrophobic interactions between the polymer chains decrease considerably, leading to a state where such interactions are considerably weaker. As such, this provides solubility of therapeutic drugs in the solution, thereby enabling direct injection into the target tumor while the drug remains in liquid form. Alternatively, when temperatures are above the LCST value, the polymer chains contained in the hydrogel undergo a drastic rise in hydrophobicity, which alters the manner in which they interact with the immediate environment (58).

Among the different types of stimuli-sensitive hydrogels that have gained the interest of scientists and researchers, thermosensitive hydrogels have been of particular interest. When temperature-sensitive hydrogels are exposed to certain temperature conditions, they undergo spectacular structural and physical property changes. Some hydrogels are better suited for use in injectable drug delivery systems, as they have been specifically engineered to gel at the natural temperature of the body. This feature enables them to set well after injection into the body (59). Furthermore, in the context of localized therapy, these advanced systems are extremely useful in the delivery of medication over a longer duration. This is due to the fact that this type of hydrogel is essential owing to its sensitivity to physical structural transformations caused by temperature variations. This is owing to the fact that the thermosensitive hydrogels contain hydrophobic units that can achieve a high phase transition when they reach a specific temperature level. Such a temperature level is known as the HCST or the LCST. It acts as a decisive factor that determines the behavior exhibited by these hydrogels (60). Out of the two types, the LCST is the most widely used type of thermosensitive hydrogel in experimental and functional operations. When the ambient temperature drops below the LCST, the dominant hydrophobic interactions among the polymer chains are significantly decreased. Due to this decrease in hydrophobic bonding, the therapeutic drugs become easily soluble in the solution and can be delivered directly at the cancer site without being insoluble. When the temperature increases above the LCST, however, the polymer chains in the hydrogel become hydrophobic (61).

Such hydrogels are designed to release drugs under specific conditions upon exposure to certain wavelengths of light. This characteristic renders them highly effective in treatments, such as photodynamic therapy, a well-established form of cancer therapy. The spatial and temporal accuracy provided by these hydrogels significantly improves the efficacy of the therapy by delivering drug release precisely at the correct location and time (62). The osmotic balance of the gel medium is grossly disturbed on ionization of the photosensitive radicals by light. The ionization leads to a permeability imbalance, and hence the entry or exit of ions and water into or out of the gel network. As a direct result of this imbalance, the gel swells or contracts in volume. The role of detecting light signals and transducing them into chemical signals is solely a function of the photosensitive part of the system. As a result of the light-induced reaction, the structure and properties of the hydrogel undergo a radical change, including processes such as isomerization, pyrolysis, and even dimerization, all of which contribute to the overall material alteration. The interference with chemical interactions between hydrogel polymer chains and photosensitive groups leads to the breaking of the photosensitive groups when exposed to ultraviolet or visible light (63). This effect increases the internal osmotic pressure of the hydrogel, allowing water molecules from the surrounding medium to penetrate the structure. The penetration of water enables the opening of pores in the hydrogel, thereby enhancing the release of drugs encapsulated within it. Furthermore, the inclusion of photothermal agents allows the hydrogel to generate heat locally through the effective absorption of light energy. It is also worth noting that the increase in temperature decreases the effect of hydrogen bonds. By contrast, the protophilic effect of hydrogels, which refers to the interactions between the segments of the polymer chain and the temperature-sensitive groups, increases (64). The classification of hydrogels is presented in Table IV (65-71).

Combining nanoparticles with hydrogels improves mechanical strength and drug delivery efficiency. In numerous applications and areas, such as drug delivery, tissue engineering, biomedical engineering, and environmental engineering, this new hybrid system is of immense interest to scientists and professionals alike. Hydrogels are water-friendly polymer networks that possess the unique ability to retain a high-water content. The addition of nanoparticles, such as carbon-based, ceramic, polymeric, or metallic, significantly improves parameters such as mechanical strength, conductivity and biological activity, thereby enhancing the application and efficiency of the materials in their respective fields (72). The different types of nanoparticle-impregnated hydrogels are presented in Table V (73-78).

Hydrogels prepared using biopolymers as formulators are gaining popularity and are increasingly sought after in applications as potential carriers for drug delivery systems. Most of the increase in popularity can be attributed to their superior properties, including biocompatibility, biodegradability and responsiveness to various environmental stresses. These hydrogels possess the unique property of being able to absorb large quantities of water or biological fluids, and they are composed of networks of natural or synthetic polymers (79). Notably, they possess the unique property of being capable of swelling or shrinking reversibly in response to changes in temperature, pH values, ionic strengths, or other essential variables. The majority of naturally occurring polysaccharides used in hydrogel formulations include alginate, chitosan, pectin, hyaluronic acid and carboxymethyl cellulose. These biopolymers are particularly convenient for use in drug delivery due to their abundance in nature, primarily due to their high biocompatibility and biodegradability (80). Natural proteins, such as collagen, fibrin and gelatin, are also used to prepare hydrogels with enhanced mechanical and bioactive properties. These hydrogels are applied in areas where direct tissue contact and controlled release processes are required. In addition to natural polysaccharides and proteins, other biopolymers, including polylactic acid, polyglycolic acid and PLGA, are used in the composition of drug delivery hydrogels (81). This is due to the fact that the mentioned biopolymers are more biodegradable and undergo controlled degradation rates, making them the ideal choice for novel drug delivery systems. Biopolymer hydrogels, a platform for a vital drug delivery system, have numerous benefits, including controlled and targeted drug release, biocompatibility, and biodegradability. They are used more in medicine, and novel and improved formulations for different therapeutic applications are emerging as a result of continuous research into their limitations (82). A summary of biopolymer-based hydrogels, and their applications, properties and key benefits is presented in Table VI (83-91).

Along with current technological advancements in microneedle-based drug delivery systems, this section addresses several forms of microneedles, including dissolvable microneedles (DMNs) and hydrogel-forming microneedles (HFMNs). Based on its composition, mode of action and therapeutic uses, each type is investigated with an eye towards developments that improve transdermal delivery efficiency, patient compliance and formulation stability.

DMNs. DMNs are a cutting-edge and therapeutically feasible microneedle technology, composed entirely of water-soluble polymers infused with medicinal compounds. Microneedles are often composed of biodegradable and biocompatible materials, such as hyaluronic acid, polyvinylpyrrolidone and PLGA, which facilitates safe administration and prolonged drug release (96). One of the primary advantages of DMNs is their substantial drug-loading capacity, allowing for the incorporation of up to 30% w/w of active pharmaceutical ingredients. Upon application to the skin, DMNs rapidly dissolve, typically within 5 to 15 min, facilitating the prompt and efficient medication delivery, while preventing the generation of biohazardous sharp debris (97). Their rapid dissolution characteristics and excellent biocompatibility make DMNs highly promising for various clinical applications, including the administration of antibiotics (e.g., vancomycin for wound infections), growth factors (e.g., VEGF to promote angiogenesis), and anti-inflammatory medications (e.g., dexamethasone) (98). The combination of rapid onset, substantial payload and user-friendly, minimally invasive administration underscores the potential of DMNs as an innovative technique for transdermal drug delivery.

HFMNs. HFMNs are a second-generation microneedle device designed for extended drug administration and enhanced wound care. HFMNs consist of cross-linked hydrophilic polymers such as poly(methyl vinyl ether-co-maleic acid), which rapidly absorb interstitial fluid upon implantation into the skin. The swelling results in the formation of a hydrogel matrix that serves as a drug reservoir, enabling regulated and prolonged drug release (99). Unlike dissolving microneedles, HFMNs have extended drug release patterns ranging from 24 h to 7 days, significantly reducing the necessity for frequent dosing. The hydrogel matrix creates an optimal moisture microenvironment (often 60-70% relative humidity) at the wound site, facilitating improved tissue regeneration, while preventing desiccation and excessive exudate accumulation (100). In addition to regulated medication delivery, HFMNs provide multimodal therapeutic capabilities, including serving as a physical barrier against bacterial infiltration and facilitating autolytic debridement, benefits which are particularly critical in the treatment of chronic and non-healing wounds. The incorporation of prolonged medication release, hydration and infection prevention highlights the utility of HFMNs as a versatile and therapeutically relevant platform for advanced transdermal and wound care (101).

Innovative smart microneedle devices are transforming personalised medicine through the integration of stimulus-responsive drug administration and real-time monitoring capabilities. Notable advancements encompass glucose-responsive microneedles for diabetic wound treatment, pH-sensitive microneedles that activate drug release in infected wounds, and photothermal microneedles that enable on-demand drug release via light stimulation (101,102). These intelligent solutions enhance therapy precision by dynamically responding to pathological variations in the wound microenvironment. Further advancements include sensor microneedle patches that are incorporated into diagnostic and therapeutic functions by continually monitoring wound parameters, such as temperature, pH and exudate biomarkers, in real-time (103). Some of the next-generation devices even incorporate closed-loop feedback systems in which data from sensors automatically drive drug release, maximizing therapeutic effectiveness, while decreasing the need for manual intervention. Collectively, these technologies signify a paradigm change towards intelligent, adaptive wound therapy that integrates diagnostics and treatment: clinical translation and its obstacles (104). However, the practical limitations of microneedle systems in chronic wound treatment are limited due to their advantages. Chronic wounds typically present with large amounts of exudate, necrotic tissue, irregular wound shapes and fragile tissue structures, rendering it difficult to uniformly insert microneedles. Improper application can increase patient discomfort and secondary tissue trauma, limiting clinical applicability.

Contemporary 3D printing techniques enable exceptional control over scaffold architecture, facilitating precise adjustments of pore dimensions (50-500 µm), mechanical characteristics (Young's modulus 1-20 MPa) and drug release kinetics (106). Digital light processing is an intriguing technique that achieves print resolutions of 50 µm using photocrosslinkable hydrogels such as gelatin methacryloyl (107). Recent research has demonstrated that thermoresponsive polymers, such as Pluronic F127, can be utilized in extrusion-based printing, facilitating temperature-regulated drug release kinetics (108). Polycaprolactone scaffolds infused with the dual agents VEGF and ciprofloxacin demonstrate enhanced wound healing efficacy, exhibiting a prolonged release over 14 days that accelerates wound closure by 40% in diabetic mouse models (P<0.01) (109). pH-sensitive hydrogels that preferentially release doxycycline in acidic wound environments (pH <6.5) have demonstrated a 99% reduction in bacterial load (P<0.001) (110). Chou et al (111) demonstrated that lipoic acid-modified gold nanoclusters (AuNCs) incorporated into a silk fibroin scaffold significantly accelerated burn wound healing by enhancing fibroblast proliferation through PI3K/Akt-mediated cell cycle activation, while simultaneously promoting collagen deposition, angiogenesis, and suppressing inflammation and apoptosis. These findings highlight the therapeutic potential of AuNC-based biomaterial scaffolds for regenerative wound healing (111). Silk fibroin/collagen composite scaffolds demonstrate significant efficacy in burn treatment, attaining complete re-epithelialization in full-thickness burns after 21 days, compared to 35 days for conventional dressings (112).

Electrospinning technology has significantly advanced, enabling the fabrication of nanofibers with diameters ranging from 100 to 1,000 nm and exceptionally high surface-area-to-volume ratios, facilitating drug loading efficiencies of 90-100% (113). Recent advancements, such as coaxial electrospinning, enable the creation of core-shell nanofiber structures designed for sequential or sustained drug release (114). Functionalized electrospun systems, such as polyvinyl alcohol/chitosan nanofibers integrated with silver nanoparticles, have demonstrated exceptional efficacy as antimicrobial agents, achieving a 99% inhibition of biofilm formation by Staphylococcus aureus and Pseudomonas aeruginosa (P<0.001), while maintaining cytocompatibility (115). Furthermore, gelatin nanofibers infused with PDGF significantly boosted wound healing in severely diabetic conditions, achieving a 2.5-fold acceleration (P<0.01) in wound closure through improved fibroblast migration and collagen production. This indicates the effectiveness of electrospun nanofiber platforms as multifunctional carriers for targeted medication administration and advanced wound treatment (116).

Collagen scaffolds incorporating fibroblast growth factor-2 and TGF-β3 have exhibited marked scar reduction potential, increasing the collagen III/I ratio by 3-fold (P<0.01) (117). VEGF-encapsulated alginate microspheres embedded in scaffolds have exhibited an enhanced capillary density by 80% (P<0.001) in ischemic wounds (118). Another study demonstrated that mesenchymal stem cell-laden decellularized ECM scaffolds promoted angiogenesis through the 80% upregulation of VEGF secretion in full-thickness burn models (11). It was also previously demonstrated that exosome-loaded hyaluronic acid scaffolds significantly improved fibroblast migration and collagen organization in chronic wounds (P<0.01) (8).

Exosomes are nanosized extracellular vesicles that can deliver proteins, nucleic acids, cytokines and growth factors to target tissues. Exosome-loaded hydrogels and scaffold systems have emerged as promising regenerative platforms for chronic wound healing due to their immunomodulatory, angiogenic and anti-inflammatory properties. Exosomes derived from mesenchymal stem cells significantly enhance fibroblast proliferation, collagen deposition, and neovascularization, while decreasing scar formation and the risk of immune rejection (119).