Antibacterial

Much importance must be given to the antimicrobial performance of hydrogels when they are used as wound dressings. In wound treatment, hydrogel dressings have gained wide acceptance due to their ability to provide an antimicrobial or bacteriostatic effect. Their key role is to inhibit the spread of unwanted microorganisms and fight against infection in the wound. Hydrogel dressings offer improved coverage of the wound surface to prevent infection, including acting as an effective barrier against external pathogens. Functional modifications of hydrogels are performed to provide enhanced antimicrobial activity by adding antimicrobial agents, including silver nanoparticles or antibiotics15. This increases the hydrogel’s potential to inhibit bacterial growth at the lesion site. Antibacterial interactions can occur by mechanisms such as disruption of the bacterial cell wall/membranes, interference with bacterial replication, or inhibition of bacterial metabolic pathways. Hydrogels have a complex structure that plays a twofold role in protecting against bacterial invasion. The connections in the hydrogel’s structure act like a physical barrier, blocking bacteria from reaching the wound surface.

Conversely, this structure permits the evaporation of water and the penetration of oxygen into the wound, thus providing favorable conditions for wound healing. Importantly, most hydrogel sheets are not intrinsically antimicrobial, although their structure provides a suitable framework for incorporating antimicrobial agents that can be added to achieve the overall antibacterial activity of the hydrogel dressing16. Such flexibility in action makes hydrogel dressings adaptable and powerful tools in medicine, specifically in wound management, where preventing infection is one of the most essential aspects.

There are many ways to impart antibacterial ability to hydrogel bandages, such as using nanoparticles, using antibiotics, using hydrogels with inherent antibacterial properties, or synergistic approaches, . All are shown in Table 1 . Nanotechnology is particularly interesting due to its broad-spectrum antibacterial ability and its lack of drug resistance.

There are several approaches to making hydrogels containing nanoparticles with antibacterial activity. One approach is to expose the hydrogel to different solution conditions that cause it to expand and contract continuously, leading to periodic repackaging of the silver nanoparticles within the gel. The resistance to of the nanosilver-loaded gel increased based on the number of cycles the hydrogel had to undergo34. Another approach is to use NPs during gelation35. Alternatively, silver nitrate can be directly reduced in the gel network36. Another effective method is the incorporation of antibacterial polymers during hydrogel synthesis. Most of these antibacterial polymers have intrinsic antibacterial activity and hence, when blended into the hydrogel matrix, they enhance the hydrogel’s antibacterial properties. Several strategies are used for the development of antibacterial hydrogels, including the integration of antibacterial nanoparticles, surface modification with antibacterial functionalities, encapsulation of antibacterial agents, and incorporation of antibacterial polymers during hydrogel synthesis. Each of these methods has certain advantages, making the field of application versatile and effective.

Other than the use of nanoparticles, antibiotics have long been considered the number-one priority in fighting infections. Although antibiotic resistance is a major drawback, the effectiveness of antibiotics is indisputable. In a rabbit open fracture model, a hydrogel containing gentamicin was shown to be effective in preventing infection37. White blood cell counts in rabbit plasma, 7–18 days after surgery, were 12.3 × 10⁶ WBC/ml in the untreated group, compared to 8.9 × 10⁶ (Collagen Gen) WBC/ml in the treated group. A study by Boo . also demonstrated that this hydrogel, in combination with gentamicin and vancomycin, was effective against methicillin-resistant S. aureus in a large animal (sheep) model38. Vancomycin combined with hydrogel is crucial for treating MRSA infections, with effective dosing confirmed by a target trough concentration of 15–20 μg/ml or a 24-hour AUC of 400 μg·hour/ml. Silk sericin (SS)/poly (vinyl alcohol) (PVA) hydrogel containing azithromycin, synthesized by a freezing/thawing process, has also demonstrated effective antibacterial activity. This product accelerates healing of infected burns while reducing systemic effects such as liver and spleen enlargement compared with the control group39. Agarose containing minocycline or gentamicin has similar effects; it reduces burn depth and bacterial counts as effectively as silver sulfadiazine cream commonly used in large animal (pig) models40.

AMPs are among the most important first-line defense molecules, effective against a wide variety of microorganisms, especially antibiotic-resistant bacteria. Amphiphilic in nature, AMPs generally have a hydrophobic core and a polycationic surface that interacts with negatively charged bacterial membranes. AMPs are short chains of cationic amino acids produced by many organisms, contributing significantly to the innate immune response and showing promise in addressing antibiotic-resistant bacteria. In the work of Ehsan ., AMP combined with hydrogel showed excellent antibacterial activity against Porphyromonas gingivalis. Furthermore, it supported autogenous bone growth following healing of defects in rat calf bones41. Incorporating antibacterial peptides into hydrogels is seen as a future trend because they are safe and avoid unwanted side effects42. In addition, the hydrogel itself may possess natural antibacterial properties. For example, chitosan is an antibacterial cationic polymer whose amino groups in an acidic environment can accept hydrogen ions (H), rendering these groups positively charged. This positive charge can facilitate binding to negatively charged molecules such as DNA and proteins—useful for controlling drug release from chitosan hydrogels—and may also help repel bacteria in wound dressings due to the negative charge on bacterial membranes43. In addition, there are peptides, polymers,.42. The administration of antimicrobials alone lacks the inherent capability to directly facilitate wound healing; their primary function is to prevent infection, which in turn allows cell proliferation, differentiation, and migration to proceed. However, this process can be hampered if immune cells are preoccupied with fighting bacteria.

Promote wound healing

Wound healing depends largely on the proliferation and migration of cells at the wound surface. That is only possible when an extracellular matrix (ECM) is present to help anchor the cells. Hydrogels can serve that role. They possess several properties desirable for tissue engineering, and many are structurally similar to the ECM. One investigation showed that cells from a wound infiltrated the hydrogel matrix up to a depth of 100 µm within the first 24 hours44. Dextran-based hydrogels encouraged significant healing of deep burn wounds by facilitating new blood vessel formation and skin regeneration. Rapid revascularization was observed in mouse burn wounds treated with dextran hydrogel over a 3-week period. By day 7, endothelial cells had settled within the hydrogel, enhancing blood flow; by day 21, treated wounds had developed mature epithelial structures, including hair follicles and sebaceous glands. Within 5 weeks, skin thickness and morphology were nearly indistinguishable from normal mouse skin45.

A hydrogel can also act as a carrier for growth factors, releasing them into regenerating burn or wound tissue. Consequently, most hydrogels have a notable effect on tissue repair and regeneration. This effect can be further boosted by growth factors or cytokines from recombinant proteins or even by mesenchymal stem cells. These induce angiogenesis, skin cell interactions, extracellular matrix remodeling, and other related functions, playing a critical role in all phases of wound healing (inflammation, proliferation, and cellular migration). Examples include fibroblast growth factor, epidermal growth factor, human growth hormone, platelet-derived growth factor, insulin-like growth factor, and transforming growth factor. One recent study reported the preparation of a new chitosan hydrogel containing EGF-loaded CNCs, which accelerated wound healing by promoting granulation tissue formation with significant collagen deposition46. EGF (epidermal growth factor) plays a pivotal role in wound healing, acting as a chemoattractant that guides macrophages and fibroblasts to the wound site, thereby contributing substantially to the inflammatory response—an essential phase of wound healing47. EGF also exerts anti-inflammatory effects by inhibiting the inflammatory response and down-regulating TGF-β1 expression. It is an important modulator of collagen synthesis, thereby influencing healed tissue quality and minimizing scar formation. Its proliferative impact extends to endothelial and epithelial cells, stimulating their division and assisting their migration to the wound surface, actively contributing to wound contraction46, 48. Similar outcomes are reported with the addition of FGF39, PDGF49, PDGF50, 51, . The mechanism of action of a hydrogel, meanwhile, involves retaining growth factors and cytokines at the wound site for an extended period, due to its slow-release capability. This retention supports longer-term cell growth and differentiation, thereby augmenting wound healing and creating highly favorable conditions for native tissue regeneration and recovery. Such benefits help increase performance and durability in hydrogel-based medical applications.

Technical and Preclinical Trials

The use of autologous skin in patients with severe burns for transplantation is limited because of the insufficient amount of healing skin. Moreover, culturing autologous skin takes several weeks before it can be used for transplantation. Such waiting times lead to higher infection rates and increased patient mortality. There are many approaches to wound healing, and one of them is direct aerosol spraying of a cell suspension onto the wound. A comparative study of direct aerosol delivery of a horn cell suspension with an in vitro fibrin delivery system showed that the aerosol approach was 20% more effective than fibrin. After seven days, aerosol-delivered cells expressed cytokeratin K6, indicating that the cells had begun to proliferate52. The same approach, when using a mixture of cells cultured on microporous biodegradable carriers distributed over the wound, also has a positive effect53. This method can be used on a large burn area without causing an immune response because the cells are autologous, and the hydrogel is inert. Patients also do not need anesthesia, and the procedure can be performed directly.

If the burn area is small, skin cells can be applied directly, and the process is quick—taking less than one hour—to produce a spray product, with cell survival rates of more than 75%54. This method can be performed in local hospitals and does not require highly advanced technical resources compared to other methods. The cells are evenly distributed over the wound, and their coverage is 100 times greater than the area from which they were harvested54, 55. If the burn area is large, the cells are cultured in the laboratory to increase their number, then mixed with hydrogel and applied. This process takes about 7–14 days. Another, more complex method is 3D skin generation, in which collagen is commonly used to create scaffolds for cell types. The proportions of substrates, fillers, and cells are accurately distributed by specialized software and machines, and the mechanical properties of this type of product can closely mimic human skin56. However, this approach has not become widespread because the machinery is expensive and requires a highly skilled workforce. In addition, such therapy is currently very costly.

Several preclinical and clinical studies have focused on the multidimensional roles of MSCs in enhancing the wound-healing process, suppressing inflammation, and preventing burn-related injuries. MSCs have also been shown to reduce scar development when burn wounds heal. It therefore follows that MSCs are important for overall improvements in wound healing and could offer potential therapeutic benefits in the management of burn-related complications57, 58. Consequently, using MSCs in combination with hydrogels is still gaining interest. Wei Zeng demonstrated that combining amniotic membranes with human amniotic membrane–derived mesenchymal stem cells improved corneal epithelium faster and with significantly less opacity than the control group in cases of corneal alkaline burns59. The combination of the amniotic membrane with bone marrow mesenchymal stem cells and keratinocytes has also shown a positive effect in a radiation burn model in piglets60. Because stem cells possess reparative and regenerative properties, they have gained much attention in skin care and restoration, especially in treating burns. However, direct stem cell application to injured skin in burn injuries still encounters major challenges due to the limited survival and maintained functionality of the cells in the compromised tissue environment. Important obstacles include ensuring stem cell survival and preserving their repair capacity under harsh conditions (, high temperatures in burn injuries and sunlight exposure).

Advances in technology combined with hydrogel-based techniques have made cell survival in open wounds much more feasible. Nowadays, bioprinting combined with UV irradiation cures the material after printing, enabling the combination of stem cells, growth factors, and media in a spray form61. Using UV irradiation at 700 mW/cm² did not significantly affect cell viability compared to the control group without UV exposure (no statistically significant difference)61. This approach represents a promising future trend for burn treatment and potentially for other solid organs, particularly as therapy costs decrease and adoption becomes more widespread.

Clinical Trials

Clinical trials on treating burns with hydrogels were introduced in 1991 in Russia and Poland62, 63. These have been documented in clinical trials (Table 3). Hydrogel products are easier to apply practically than many drugs because of their biocompatibility and inertness. However, this also means that patented research is proprietary and not publicly accessible.

The mentioned studies positively impact the wound healing process and show statistically significant differences compared to the control group. However, this is just the tip of the iceberg. Most studies on hydrogel dressings are commercialized, so their information is kept confidential within commercial companies.

Current situation and challenges

With the world's increasing demands, numerous new hydrogel technologies are emerging. One of the interesting novelties in advanced hydrogel applications for wound healing is smart hydrogels. These can adhere to the wound and, upon stimulation by various stimuli (such as temperature, humidity, or chemical agents), they will contract. This property gives them exceptional suitability for different types of wounds, including variations in shape and thickness. They are designed based on materials with unique properties and specialized technical methods.

It can be envisioned that a smart hydrogel design would be very flexible, depending on changes in temperature, pH, or the presence of infection in the wound environment. Due to this responsiveness, they can adapt their cohesion mechanism according to the conditions and optimize it. H. Wang's research84 produced an innovative hydrogel, comprising pH-sensitive bromothymol blue and a near-infrared (NIR)-absorbing conjugated polymer integrated into thermosensitive chitosan, which allows for real-time, visual diagnosis and photothermal therapy of bacterial infections. It enables in situ detection of Staphylococcus aureus biofilm and infected wounds through visible color changes displayed by the hydrogel. Further, localized hyperthermia is sequentially triggered with NIR laser irradiation to ensure effective therapy. The hybrid hydrogel presents wide-range antibacterial efficacy with low cytotoxicity, making it a promising platform for the intelligent and convenient diagnosis and treatment of bacterial infection. Moreover, the pH-sensitive nature of the hydrogel enables control over the amount of drug released, as the acidity fluctuates at different stages of wound healing. Asmaa Ahmed Arafa .85 used pH-sensitive natural dye Curcuma longa extract (CLE) as a color indicator. Hydroxyethyl cellulose loaded with CLE and combined with itaconic acid produced a neutral and pH-sensitive dressing. This is highly useful, as the drug release from the dressing increases significantly at pH 7.4, suitable for treating many types of wounds.

In the case of increased temperatures—a clear indicator of inflammation—the hydrogel could self-regulate and deliver anti-inflammatory agents that would dampen inflammatory responses, facilitating an environment more conducive to tissue regeneration. Min .86 focus on a thermo-sensitive methylcellulose (MC) hydrogel containing silver oxide nanoparticles (Ag₂O). The drug release from this hydrogel is temperature-dependent. The silver oxide nanoparticle-loaded MC hydrogel exhibited very good antimicrobial activity and proved useful for treating burn wounds. For wounds susceptible to bacterial infection, such smart hydrogel bandages contain responsive elements capable of initiating the release of an antibacterial agent upon detecting the presence of bacteria. This provides not only a quick physical barrier to infection but also facilitates the general healing process by creating an environment less favorable to bacterial multiplication.

Hydrogel dressings play an important and promising role as biomaterials that act as protective barriers to replace damaged skin tissue, especially from burns. Hydrogel capabilities can also be enhanced by incorporating growth factors or stem cells they can carry. This flexibility is a great advantage of hydrogels, enabling them to be part of most lesion treatments caused by diseases, external factors, or tissue replacement. However, there are significant limitations when incorporating tissue engineering into burn treatment. Hydrogel dressings currently face several challenges, including high costs, low durability, and the risk of infection and allergies. Besides, although hydrogel dressings have proved their effectiveness, their universal efficacy in treating all categories of wounds has not been fully established. Moreover, despite their huge potential, hydrogel dressings are marketed heterogeneously and often require rigorous storage measures, resulting in high medical waste. This is further compounded by the fact that most hospitals and clinics are not equipped to manufacture hydrogel dressings at a clinical level. Therefore, distribution networks should be expanded, and hydrogel development must be done in an eco-friendly way to reduce waste. On the other hand, many studies are needed to address drawbacks such as drug compatibility issues, biofilm formation, and environmental effects—important safety and effectiveness concerns regarding hydrogels used in healthcare (Table 3 ).

The major problem facing hydrogel dressings, which needs to be surmounted, is cost and availability through the healthcare system. First, hydrogel dressings are more expensive compared to other more conventional modes of treatment. This adds a financial burden on health facilities and influences patients’ choices. Another aspect is that hydrogel dressings must be applied effectively by healthcare service providers through training at hospitals and clinics. Third, evaluation related to hydrogel dressings needs to be considered from the patient’s perspective. Promotion of hydrogel dressings should be widened in terms of marketing campaigns. Focusing on the patient’s experience, their quality of life, and pain management outcomes in light of their satisfaction will assist in an appropriate study related to hydrogel dressings. All modes of treatment need to have the patient as the prime focus.