Advance Institute of Biotech and Paramedical Sciences, Kanpur.
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Non-healing wounds constitute one of the most significant diabetic mellitus complications as they considerably worsen the morbidity, healthcare expenditures, and chances of lower-limb amputation. The wounds of diabetes do not heal effectively; this is a complex of systemic metabolic disorders and local pathology. Chronic low-grade inflammation extends the window of the inflammatory healing phase at the expense of normal healing transition to proliferation [133]. It comes along with the development of excessive production of reactive oxygen species (ROS), which destroy cellular structures, lower growth factor levels and advance cellular senescence in the wound bed. In addition, another signature is impaired angiogenesis, thus restricting delivery of oxygen and nutrients to the healing tissue thus slowing granulation tissue formation and re-epithelialization [2]. Improper collagen turnover also destabilizes the structural architecture of the extra-cellular matrix (ECM), rendering the environment of a wound unfavorable to the migration of any keratinocytes or the fibroblasts. TGF-beta/SMAD improper signaling also promotes pathological fibroblast-to-myofibroblast differentiation and ECM accumulation, which are the limitations of TGF- beta signaling in diabetic wounds [4]. This propensity to fibrosis causes a defective formation of scars and retards closure of an epithelium. Simultaneously, macrophage polarization has been shifted towards the pro-inflammatory M1 subtype and the natural progression to the anti-inflammatory, pro-reparative M2 macrophages becomes delayed or blocked [5]. Pirfenidone (PFD)- small-molecule antifibrotic agent approved to aid the treatment of idiopathic pulmonary fibrosis is currently under consideration as a promising treatment drug in diabetic wounds. PFD multi-pathway modulation, it does not express TGF-B1 [6], decreases the gene expression of ECM-related properties, including collagen type I and collagen type III [7], and also reduces the expression of a pro-inflammatory cytokine, TNF- and IL-1B. Moreover, PFD is antioxidant in nature which alleviates the damage caused by the ROS in microenvironment of a wound [8]. Such pleiotropic effects directly target the mechanisms of pathology of chronic diabetic wounds and PFD can be an appealing choice as a topical delivery system. it has undergone testing by induced diabetic murine study to prove its efficacy prior to clinical translation.
Figure1. Pirfenidone-loaded Hydrogels for Diabetic Wound Healing
There has been a promising sign using pirfenidone (PFD) in chronic diabetic foot ulcers (DFUs) in which randomized controlled and crossover clinical trials were conducted as adjunctive therapies in treating it. PFD was added to topical delivery vehicles like gel dressing or ointment in these studies and applied to the ulcer bed alongside conventional wound care interventions, debridement, infection management, off-loading and moist wound dressing [9,10]. The trial by Janka-Zires et al. showed that patients diagnosed with PFD dressings had significantly higher levels of complete ulcer closure on the study period than the patients with placebo dressings. In addition, the average time to wound area reduction of 50% is less in the PFD group, meaning faster healing kinetics. On the same note, Gasca-Lozano et al. demonstrated that besides increasing the rate of closure, the topical use of PFD also improved the quality of the regenerated tissue in an improved granulation coverage and higher re-epithelialization checking.
A key feature of these trials is the safety profile of topical PFD. Overall in both studies, treatment was well tolerated with no major or systemic adverse effects and lab abnormalities. Incidents of mild, local reactions which did not require the termination of the therapy were also low in frequency and included such changes as fleeting erythema or pruritus. This advantageous tolerability is clinically significant since patients with chronic DFU usually have comorbidities that restrict the use of systemic drugs. These data are consistent with the clinical potential to include PFD in complex wound dressings, especially on fibrotic, chronic non-healing ulcers in which hyper-signaling with TGF- beta and excessive background inflammation are major obstacles to wound closure. Nevertheless, the potential efficacy currently observed in humans cannot be proven; further, multicentric trials with extended follow-ups are important to substantiate the findings as far as the long-term benefits, recurrence rates, and cost-effectiveness are concerned.
Figure 2. Process Depicting
3. Evidence Preclinical and Technological
Despite no published work so far directly testing pirfenidone (PFD)-loaded hydrogels in streptozotocin (STZ)-induced diabetic mouse models, ample preclinical data in related models of cutaneous trauma, diabetic wound models with other drugs and sophisticated drug-delivery technologies could be taken to suggest a high likelihood of achieving this therapeutic concept. The studies show that the pleiotropic pharmacological effects of PFD can overcome several pathological impediments to wounds healing in diabetes, such as fibrosis, chronic inflammation, microbial infection, and oxidative injuries when PFD was used together with a hydrogel-based delivery system.
3.1. Antifibrotic and Anti-inflammatory In Vitro Cutaneous Injury Model
Topical preparations of PFD have been shown to inhibit TGF-beta 1 expression, the key-regulator of fibrotic tissue remodeling, in murine burn and full-thickness excisional wound models [11]. Treatment decreased α-smooth muscle actin (α-SMA)- positive myofibroblasts, causing excessive ECM synthesis and scar contracture, and equalized collagen I/III proportions toward those of pliable tissue to functional tissue, as opposed to dense scar. Following histological studies, it was found that the PFD increased collagen fibers alignment and reconstituted skin appendages indicating that the therapy is not only faster when inducing closure but may also enhance the regenerated tissue quality. Notably, application of PFD greatly reduced the pro-inflammatory cytokines (such as TNF- alpha and IL-1 beta) in the wound bed, diminishing the propagation of an M1-dominated macrophage pattern. Such polarization to M2 macrophage facilitates angiogenesis in ECM remodelling and epithelial migration thus making the microenvironment conducive to regenerative healing.
3.2. Innovations under Drug Delivery System
PFD is hydrophobic with low water solubility; thus, topical application would not be able to maintain optimal local concentration in a local setting over an extended period of time. In a bid to circumvent this challenge, scientists have come up with more sophisticated drug-delivery vehicles that guarantee sustained delivery, targeted delivery and protection of PFD against degradation.
Layer-by-Layer Thin Films: Mandapalli et al. have synthesized polyelectrolyte multilayers which can release the drug in a sustained manner over several days with PFD as the load [11]. These films increased the rates of wound contraction, improved the epithelialization process and ECM was deposited in a better organized manner than a free PFD solution that drained out of the wound promptly.
Double-Layer Hydrogels: In another approach by Zhang et al., a two stage-o-Hydrogel composite was developed where curcumin was encapsulated in the outer layer, so that it could exert instant anti-inflammatory as well as antioxidant activity, and PFD was incorporated in the inner layer of the hydrogel to extend its antifibrotic activity [12]. This successive-release design generated synergy effects of wound healing in rats, growing granulation tissue thickness, larger microvessel density, greater structured collagen fiber form, and scar elasticity than single-drug or whole-group therapy.
3.3. Multifunctional and Stimuli-Responsive Hydrogel platforms
More recent strides have been made towards the development of the concept of smart hydrogels which unlock their therapeutic loads in the presence of certain wound microenvironment signals- e.g., hypocitrusity (bacterial infection) or the high glucose levels in diabetic wounds. Pan et al. (2025) also contributed a pH/glucose dual-responsive hydrogel in which PFD was used in combination with a photothermal/photodynamic antibacterial agent [13]. This multifunctional hydrogel produced the following results in diabetic rat ulcer models: Much more rapid rates of wound healing than are possible with standard dressings Higher CD31 positive capillary density, that is, increased angiogenesis The decrease in viable bacterial count and biofilm growth, which is essential in the treatment of the DFUs More homogenous aligned collagen fibers and better tensile strength Such properties are especially useful in diabetic lesions, in which the threat of infection, prolonged inflammation, and insufficient vascularization are key barriers to recovery.
3.4. Translational Relevance
Although the majority of studies were performed in non-diabetic or chemically driven wound model, the underlining biological processes, which include: suppression of fibrosis, modulation of inflammation, reduction of oxidative stress, and enhanced collagen remodeling are directly applicable to diabetic wound pathophysiology. The hydrogel matrix, in its own right, adds to the therapeutic effects such as mechanical protection against trauma, persistence of a moist wound environment and oxygen and nutrient exchange. Moreover, we can design hydrogels having adjustable crosslink density, degradation rate, and drug release profiles such that they can be optimized to suit and match the density of chronic diabetic wounds because they need longer duration of treatment, weeks, and not days. It will also be important to bridge this drug efficacy in preclinical studies to strictly controlled STZ-induced diabetic murine model. Such studies may lift a mechanistic understanding, dose-response relationship, and safety data and eventually lead to a regulatory approval and clinical translation of PFD-loaded hydrogel dressings as a diabetic wound care product.
4. The benefits of Hydrogel-Based PFD Delivery
There are multiple synergistic benefits of using the hydrogel matrix to deliver pirfenidone (PFD), to treat the diabetic wounds, as it has a complex pathophysiology. Such benefits are across the biological, mechanical and pharmaceutical scales; thus, the hydrogel systems are a very promising approach in translating PFD therapy to chronic wound.
4.1. Biological Advantages
4.1.1. Long term Modulation of wound microenvironment
Chronic TGF-B overexpression and pro-inflammatory signaling are present in diabetic wounds and delay healing [1,4]. Topical delivery of free PFD is removed at a rate of minutes to hours from the wound surface [11]. In comparison, hydrogels can be used to offer controlled release over 2-3 days in which case the levels on PFD in the wound bed can remain at therapeutic levels without the need to frequently re-dress the wound. This prolonged exposure has the maximal PFD anti-fibrotic and anti-inflammatory efficacy, including the attenuation of α-SMA-positive myofibroblasts and M2 macrophage polarization [11,12]. The High Hypocrite:
4.1.2 Angiogenesis and ECM remodeling Stimulation
Some of the hydrogel matrices, like hyaluronic acid (HA) or gelatin methacryloyl (GelMA) are bioactive themselves allowing the growth of fibroblasts, advancement of keratinocytes, and tube formation of endothelial cells [15,16]. These hydrogels when loaded with PFD will enable one to inhibit aberrant fibrosis and simultaneously enable proper organization of the ECM by secretion and neovascularization respectively to restore the functional skin in diabetic ulceration.
4.2. Mechanical Advantages
4.2.1. Wet Healing Atmosphere
Hydrogels absorb a lot of water (as high as 90 percent of their weight), which provides a humid healing environment the speed of epithelialization and reduces the chances of forming a scab [13]. This is important especially in diabetic wounds, in which desiccation and hard eschar structure may impede migration of cells. On the orientation course, check what is the degree or level of loss of relevant knowledge. Conformability and Physical Barrier Hydrogel dressings seal over the surface of irregular wound shapes and prevent secondary trauma and invasion of microorganisms, as well as providing gaseous exchange [10]. This physical barrier accounts to a reduced risk of contamination that is also of utmost importance to immunocompromised diabetic patients who develop infections easily.
4.3. Pharmacy and Engineering Benefits
4.3.1. Adjustable Drug Release Profiles
The crosslink density of hydrogel, the composition of the polymer, and addition of nanocarriers can be manipulated to adjust PFD release characteristics- ranging between an ideal zero-order release or microenvironment-sensitive release that depends on the pH, glucose, or enzyme activity [12]. This enables one to schedule drug delivery according to stages of wound healing with more dose during the inflammatory phase, and less maintenance dose during the remodeling. In fact, 30-40 percent of mothers of school children live in rural areas.
4.3.2. Combination Therapies Compatibility Several possible agents may be held in a hydrogel including antimicrobials or growth factors, oxygen carriers, or photothermal agents as well as PFD [12,13]. As a case in point, a PFD-loaded dual-responsive hydrogel in the study of Pan et al. in 2025 released an antibacterial photographic dynamic agent in addition to simultaneously overcoming infection and fibrosis [13]. More specifically, this type of combination treatment is especially suitable in the case of diabetic wounds since such wounds may occasionally be as multifaceted as multisite intervention itself.
4.3.3. Local Delivery Reduced Whole Body Exposure
PFD administered systemically (oral) has gastrointestinal side effects and in some rare instances has hepatotoxicity [6]. Localized delivery via hydrogel limits systemic absorption of the drug and, thus, the occurrence of adverse effects as high local concentrations are achievable that would not be used on a systemic level.
4.4. Translational Significance
The biologic combination of the pharmacology of PFD and the modifiability of a hydrogel solution presents a precision medicine solution to diabetic wound healing. Combining inhibitory effects on several pathopathogenic pathways--fibrosis inhibition, anti-inflammatory, and anti-infective effects and angiogenesis stimulation, a PFD-containing hydrogel could accelerate healing, enhance scar cosmesis, and lower rates of recurrence of diabetic ulcers. Further, translation to therapy does not need to be highly innovative since hydrogel is already inherently an FDA approved clinical product due to its common clinical utility in moist wound healing, thus serving as a tractable and easily-transferable translational solution with very little incremental patient training being necessary.
Figure 3.Study Timeline
5. The proposed methodology of the study is the STZ-induced diabetic murine study.
This study design aims to determine the therapeutic potential of the hydrogel dressing containing pirfenidone (PFD) in induction of wound healing in streptozotocin (STZ) induced diabetic murine model in terms of encompassing the closure rate, quality of histology, resolution of inflammation and safety.
The proposed preclinical study will shake the scales thoroughly in regard to the therapeutic potential of pirfenidone (PFD)-loaded hydrogel dressing in wound-healing promotion in streptozotocin (STZ)-induced diabetic murine model. The primary hypothesis is that perennially administered, remote controlled administration of PFD will hasten closure and also enhance the quality of the healing process in terms of histology, inflammation, fibrosis, angiogenesis and oxidative stress which are all pathways that become dysregulated in diabetic wounds.
5.1 Ethical issues in the choice of animal models
Eight- to 10-week-old male C57BL/6 mice that weigh 20 to 25 g will be used because of their known genetic background and predictable wound-healing outcome. The Institutional Animal Ethics Committee (IAEC) will approve all procedures carried out in an experiment in accordance with national animal welfare legislation. Animals are going to be maintained in a regulated condition (12 h light/dark, temperature 22 22 22degreesongRef?? spheracy 5060 percent RH) and have free access to normal chow and water. The use of STZ-induced diabetic model was based on its clinical relevance, since it models the chronic hyperglycemic and microvascular-inhibited conditions evident in diabetic wounds in human beings.
5.2 Diabetes induction
A diabetes state similar to type 1 will be induced through the intraperitoneal operation of STZ (5060 mg/kg body weight) into 5 consecutive days, freshly made in citrate buffer (pH 4.5). STZ has the selective ability to kill pancreatic 8-cells producing a chronic state of hyperglycemia. The fasting blood glucose will be assessed by day 7 and 10 after injection using a glucometer and those mice whose blood glucose measures above 250 mg/dL two days in a row will be termed diabetic and used in the wound-healing experiment. It is also during this induction phase that it gives time to stabilize the effects of systemic metabolic changes prior to wound creation.
5.3 Randomization and wound Creation
After diagnosing and proving diabetes, the mice will be anesthetized through the intraperitoneal injection of ketamine (100 mg/kg) and xylazine (10 mg/kg). Dorsal hair will be removed, and the skin will be swabbed with povidone-iodine and 70 percent of ethanol. Full-thickness excisional wounds of 6-mm will be produced on the dorsum; these wounds are to be made with a sterile biopsy punch down to the panniculus carnosus. The very frequent confounding variable, contraction bias of a rodent wound, will be curtailed by placing a silicone splint blocking mechanism upon each wound with the help of cyanoacrylate glue and use of interrupted sutures.
The animals will be subsequently randomly allocated into four treatment groups (n = 1012 wounds per group):
5.4 Treatment Application
PFD stability will be maintained by storing hydrogels under light-protected, refrigerated conditions until use with pre-sterilization of hydrogels by gamma-irradiation. The dressing will be directly placed on the wound immediately after the wound is created and every part of the wound bed fully covered and then covered with a semi-occlusive sterile movie. Referral will be used after every 48-72 hours or earlier in case the dressing is displaced. Hydrogel formulation will be optimized to achieve local PFD concentrations within the wound microenvironment between 13 mM PFD 3 mM which in vitro has dalla shown to suppress endogenous fibroblast TGFb signaling activity, but not reduce the viability of the wound keratinocytes.
5.5 Outcome Measures Primary Endpoint
Wound Closure Kinetics-- Standardized photographs of each wound on day 0, 3, 7, 10 and 14 will be taken with a high-resolution digital camera having a scale in frame. ImageJ software will be used to quantify areas of wound, which would then be represented as a percentage closure in relation to the baseline. The time of 50 per cent/90 per cent closure will be estimated. Secondary Endpoints Histology - hematoxylin and eosin to determine the epithelial thickness and granulation tissue, Masson trichrome to measure collagen deposition and picrosirius red under polarized light to the collagen 1/3 ratio. Immunohistochemistry 1- α-SMA myofibroblast quantitation,2- TGF-β1 fibrotic signalling quantitation, 3-CD86 M1 macrophage quantitation, 4-CD206 M2 macrophage quantitation, 5-CD31 angiogenesis quantitation. Molecular Analysis - qPCR of ECM (Col1a1, Col3a1, and Fn1, inflammatory (Tnfa, Il1b, and Il10) and remodeling (Mmp2, Mmp9) and macrophage polarization markers (Arg1, and Nos2). Cytokine Profiling - ELISA of TNF-a, IL-1b and IL-10 wound tissue homogenates. Oxidative Stress Oxidative Stress- DHE Staining of ROS, and enzymatic measures of SOD, catalase activity and GPx.
5.6 Safety Assessments
The local tolerability will be rated on the erythema, edema and exudate levels at the time of dressing changes. The weight, grooming, activity levels, and fasting blood glucose will be monitored as a measure of systemic safety. The minimal systemic exposure will be ensured by confirming plasma PFD levels on days 3 and 7 measured using LC-MS/MS.
To identify a 20 to 25 percent difference in the first wound area between treatment and control groups at Chen, 2016, there is 0.05 level of significance and 80 percent power is used to calculate sample size. Repeated-measures ANOVA or mixed-effects models will be used in the analysis of the closure kinetics data, one-way ANOVA with Tukey post hoc test would be applied in the analysis of histology and molecular markers, and finally KaplanMeier survival analysis would be used as the analysis of time-to-healing data. The significant level will be p < 0.05.
6. Predicted Results and Translational Value
The outlined investigation aiming to use STZ induced diabetic murine study with hydrogel dressings containing pirfenidone (PFD) molecules is expected to provide convincing preclinical data favouring the local administration of antifibrotic treatment of chronic diabetic wounds. There are a number of primary outcomes based on previous clinical and preclinical results.
The hypothesis is that the wound healing time needed to reach 50 and 90 percent of complete wound closure will be considerably less when using PFD-loaded hydrogels than with blank hydrogels and the ordinary moist gauze. Such enhancement can be explained by a twofold effect: specific prevention of pro-inflammatory cytokines (e.g., TNF-x, IL-1b) and reduced TGF-x-induced fibroblast activation, which allows more quickly switching the process in time to proliferation.
More structured extracellular matrix, equal ratios of collagen I/III, lesser abundance in α-SMA-positive myofibroblasts, and ended re-epithelialization is supposed to be detected in histological analyses. All these characteristics are likely to imply a reduced possibility of hypertrophic scarring and contracture, which are two known issues related to diabetic wounds.
Delivery of PFD in the form of a hydrogel matrix are expected to increase polarization of macrophages towards M2 reparative phenotype, enhance angiogenesis by increasing the CD31+ vessel density, and decreasing the marker of oxidative stress. These modifications of the microenvironment will establish a steady environment to allow long term repair and restoration of tissue functions.
As the delivery will occur locally, it is likely that systemic exposure of PFD will be low, which will prevent the gastrointestinal/hepatic side effects, occasionally observed after oral administration. Hydrogel moist, biocompatible matrix is also likely to reduce any irritation as well as risk of secondary infection particularly with semi-occlusive film dressing.
Such findings in their case would give a pure basis to go ahead onto early-phase clinical testing of fPFD-loaded hydrogel in human DFUs. This would involve testing of optimization of dosing, frequency of administration, and its possible co-delivery with antimicrobials or growth factors to deal with the multifactorial character of DFU pathology.
In addition to DFUs, localised PFD hydrogel therapy may prove useful in other fibrotic and chronic wounds (including post-burn scars and venous leg ulcers, as well as surgical wounds with a predisposition to hypertrophic healing). The flexibility of the formulation of hydrogel enables adjustment to identify-specific clinical cases and compatibility of additional treatment such as photothermal agents, oxygen carriers, or antimicrobial peptides.
Although the therapeutic case of pirfenidone (PFD)-loaded hydrogels in diabetic wound healing holds water, a number of scientific and translation questions have not been answered still. These gaps will have to be overcome in order to leapfrog preclinical validation to regular clinical usage.
As much as different natural and non-natural polymers, hyaluronic acid, gelatin methacryloyl (GelMA), chitosan, and silk fibroin, have presented themselves as promising hydrogel matrices, there is no general agreement regarding the best composition of PFDs to be delivered to diabetic wounds. Subsequent studies need to systematically compare various types of polymer systems as well as cross linking densities and rates of degradation to establish the optimum balance among the desired sustained release of drugs, mechanical stability of the construct and biocompatibility.
Addition of microenvironment-responsive components (e.g., pH- or glucose-sensitive linkers) can further be used to more readily align drug release with stages of wound healing.
Ideal local dosing with PFD in terms of cutaneous application has not been determined yet. Preclinical models ought to explore various concentrations and release patterns and test the therapeutic window of antifibrotic and anti-inflammatory effects without posing any negative effects on the viability of keratinocytes and fibroblasts. These parameters could be informed by real-time in vivo monitoring drug levels with the use of tissue microdialysis or an analysis using LC-MS/MS. Integration with Multifunctional Platforms
7.4 Wounds associated with diabetes can be complicated by infection, hypoxia and biofilm.
The potential to combine PFD with antimicrobial agents, oxygen-delivery systems, or angiogenic factors in the same hydrogel may overcome more than one pathological challenge at a time. Performance of such multifunctional dressings under clinically relevant conditions should be tested in infection-challenged diabetic models to validate their performance.
Long-Term Functional The majority of wound-healing researches are centered on closure statistics and near-term histology. The final aim, however, is repairing functional tissue. To determine that PFD-loaded hydrogels lead not only to faster healing but also to the production of high-quality, long-lasting mechanically sound skin, tensile strength, elasticity, nerve regeneration, and recurrence rate need to be tested in long term studies.
7 5 Human scale-up
Although the STZ-induced diabetic mouse models are useful in understanding the mechanisms, they do not resemble human diabetic ulcers of the foot with respect to size, biomechanics, and chronicity of the wound. The translational gap may be filled in by the intermediate models, semi-human, such as diabetic pigs, with more similar to the human skin architecture. Human-scale prototype dressing prototypes may also be tested in these models and the handling qualities in a surgical environment gauged.
7.6 Regulatory/ Manufacturing
It is natural to expect that the regulatory agencies would categorize hydrogel dressings including such active pharmaceutical ingredient as PFD as combination products. The future work needs to deal with Good Manufacturing Practice (GMP) scale-up, sterilization validation, packaging stability and shelf-life study. The interactions with the regulatory bodies could be simplified through early engagement activities.
CONCLUSION
Diabetic wounds are a significant clinical problem because of chronic inflammation, defective angiogenesis, oxidative stress response and fibrotic signaling all of which slow down the repair. Pirfenidone (PFD) has all the advantages of its documented antifibrotic, anti-inflammatory and antioxidant properties actions directly attack some of these pathophysiological choke points. Although oral PFD is accepted as treatment of idiopathic pulmonary fibrosis, localized application through hydrogels provides a strategic benefit in that its wound bed application will achieve maximum therapeutic concentrations and minimal systemic exposure. Preclinical and clinical observations studied in relevant wound model indicated that hydrogel-mediated depression of macrophage polarization on wound, inhibition of myofibroblast activation and restoration of architecture construct as well as stimulation of re-epithelialization could be done using hydrogel-based PFD administration. Mature hydrogel technologies such as stimuli-responsive and multifunctional platforms can take it a step further, synchronizing drug release with the phases of wound-healing to deliver a personalized treatment option in managing complex diabetic wounds. The proposed streptozotocin (STZ)-induced diabetic murine model described in the current review presents a thorough study that may help determine the mechanistic and functional advantages of PFD-loaded hydrogels. A clinical success in a model with such biological reasoning would not only ratify the biological rationale, but also offer a potent preclinical basis to make a translation into human studies. Finally, the potential of PFD to be incorporated into a next-generation hydrogel dressing may be one of the important milestones toward filling the gap in effective, targeted, and well-tolerated therapies in the field of diabetic foot ulcer management, thus, ultimately potentially improving outcomes, minimizing the risk of amputation, and reducing global healthcare burdens and costs.
REFERENCES
Abhishek Kumar, Dakshina Gupta, To Study About the Therapeutic Potential of a Pirfenidone-Loaded Hydrogel in Accelerating Wound Healing in a Streptozotocin-Induced Diabetic Murine Models, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 8, 1549-1560. https://doi.org/10.5281/zenodo.16875161
10.5281/zenodo.16875161
