STANDARD CARE PRACTICES FOR DFUs

Pressure Relief aims to alleviate abnormal pressure and shear stress at the ulcer site. Debridement, the removal of necrotic, damaged, or infected tissue, optimizes healing. Surgical debridement, utilizes a scalpel blade to swiftly eliminate nonviable tissue. Mechanical debridement, involves moist dressings, and enzymatic debridement, utilizing chemical agents. Autolytic debridement, harnesses the body's enzymatic processes, and biologic debridement, utilizes sterile maggots, presents alternative approaches with distinct indications and considerations.¹⁴

Infection Management is crucial, as more than half of DFUs exhibit signs of infection at presentation. Culturing and treating infected wounds with antibiotics are recommended, with mild to moderate infections targeted by agents focusing on Gram-positive cocci¹⁵. Severe infections require broad-spectrum empiric therapy, which is then tailored based on pathogen identification and sensitivities¹⁶. Since antibiotics address infection complications and do not directly contribute to wound healing, hence combining antibiotic therapy with other treatment and management aspects is imperative¹⁷.

Dressings and wound care techniques

Low-cost non-adherent dressings have limitations in managing infected diabetic wounds. They necessitate daily changes and are often recommended in combination with antibiotic treatments to address the challenges posed by infection. Regular wound dressings maintain a humid wound environment, facilitating exudates absorption, preventing infections, and promoting ulcer healing.

Hydrocolloids, recognized as the second most popular choice for DFU dressings, are subject to controversy in infected wounds due to their hypoxic and moist nature, which may initiate autolysis of necrotic material. Despite in vitro studies suggesting hydrogels do not support bacterial growth, concerns persist regarding their use in the presence of infections¹⁸.

Alginates demonstrated to have bacteriostatic properties inhibiting the growth of bacteria involved in DFU infections, are recommended for infected foot ulcers. However, their application requires regular dressing changes, which may elevate the risk of infection. Silver-impregnated dressings emerge as more effective in controlling the microbiological burden of wounds, promoting tissue granulation. However, the absence of randomized controlled trials for silver-impregnated dressings in DFUs underscores the need for further research to validate their efficacy^19-20.

Foam dressings, particularly those with bactericidal silver, have demonstrated the ability to prevent infections with daily changes. Their superior absorbency, exemplified by innovations like Biatain Ag, makes them cost-effective and efficient in managing infected wounds^{21, 22}. Iodine-based dressings face concerns about their toxicity to fibroblasts and keratinocytes, limiting their advisability for wound treatment in DFUs. However, clinical studies suggest that iodine-based dressings, while not universally recommended, may show effectiveness in specific cases²³.

Collagen dressings, known for reducing collagenase-like activity and promoting tissue healing, have shown promise in cases of neuro-ischaemic DFUs. It is reported that collagen implants impregnated with gentamicin sulfate contribute to granulation tissue formation, microcirculation improvement, and reduced bacterial load^24-25.

Recombinant human growth factors, such as Heberprot-P and Becaplermin gel, address the decreased growth factor concentrations in diabetic tissues, enhancing wound healing by encouraging tissue growth and cell proliferation.²⁶

Dakin solution and honey dressing, though backed by some clinical studies, require further analysis to determine their efficacy in treating DFUs. The meta-analysis of randomized controlled trials and quasi-experimental studies indicates that the use of honey dressing was associated with shortened wound debridement time, accelerated wound healing, faster bacterial clearance, and increased rates of wound healing and bacterial clearance during the initial one to two weeks of application^27-28.

CHALLENGES IN TREATMENT

Antibiotic resistance and infection control

Antibiotic resistance and infection control pose complications affecting around 15% of individuals with diabetes. DFU patients are predominant in the elderly, with an average age of 60.2 ± 10.1 years, and often have a prolonged history of diabetes²⁹. The prevalence of pathogens on foot ulcers varies, with some studies reporting a dominance of gram-positive (GP) bacteria over gram-negative (GN), while others observe a shift where GN bacteria replace GP bacteria as the primary pathogens. This changing trend in infective organisms, particularly in developing countries, underscores the complexity of DFU infections³⁰. Climate differences explain geographic variations in bacterial infections on foot ulcers, with an increase in temperature and humidity correlating with a higher proportion of GN bacteria on DFUs³¹.

A study reveals that multidrug-resistant organisms (MDRO) account for approximately one-fifth of the isolated pathogens, with about one-third of MDRO being Staphylococcus aureus. The prevalence of methicillin-resistant Staphylococcus aureus (MRSA) colonization among diabetic patients has been reported to be 4.75% higher than in non-diabetics, although recent studies suggest a potential decrease in MRSA prevalence globally. These superbugs, resistant to all available antibiotics compounded by biofilm formation on DFUs contribute to antibiotic resistance. Effective debridement is highlighted as crucial for biofilm removal in DFU treatment. Emerging treatments such as recurrent autologous platelet-rich gel (APG), negative pressure wound therapy (NPWT), and S. nux-vomica–ZnO nanocomposite are proposed as potential strategies for managing multidrug-resistant bacteria in DFU patients³².

Fungal infections particularly Candida infection vary globally, with reported rates of 7% in Kuwait and 4.3% in Croatia. Recent studies utilizing high-throughput sequencing suggest that up to 80% of non-healing DFUs may contain fungi, with Cladosporidium herbarum and Candida albicans being the most abundant species.

The latest research findings underscore the persistent challenges posed by the recurrence and chronicity of ulcers in DFU treatment and highlight the need for further research and the development of targeted interventions to improve patient outcomes³³.

ADVANCES IN PHARMACOTHERAPY: NOVEL AGENTS AND DELIVERY SYSTEMS

Ciprofloxacin-loaded calcium alginate wafer is reported to inhibit and prevent re-infection caused by both GP and GN bacteria. The wafer also showed biocompatibility with human adult keratinocytes³⁴.

Deferoxamine (DFO) induces hypoxia-inducible factor 1-alpha (HIF-1α) accumulation under normoxia, which mediates various processes, including cell metabolism, proliferation, survival, and angiogenesis. It increases neovascularization through the upregulation of HIF-1α and target genes, including vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1α (SDF-1α). The administration of DFO to diabetic wounds has been shown to improve wound healing, along with enhanced granulation tissue formation, re-epithelization, and neovascularization^{35, 36}.

An emerging drug treatment is WF10, an aqueous solution of the chlorite drug OXO-K99, having anti-inflammatory and antiseptic properties that boost the phagocytic activity of macrophages through the myeloperoxidase–hydrogen peroxide–halide system. It stimulates keratinocytes to produce laminin and other constituents of the normal basement membrane, which can help in the healing of DFUs³⁷.

Nitroglycerine (Isosorbide Dinitrate),is an effective donor of nitric oxide (NO) to diabetic wounds, leading to increased blood flow and biochemical activity of the ulcers and facilitating wound healing³⁸.

Pirfenidone (PFD) has antioxidant and anti-inflammatory properties and reduces secreted and cell-associated tumor necrosis factor-alpha (TNF-α) levels. In a randomized double-blind trial, the efficacy of topical PFD + M-DDO (an antimicrobial and antiseptic agent) versus ketanserin, a serotonin antagonist of 5-HTR2, with no agonistic properties, was evaluated in the treatment of non-infected chronic DFUs. Patients receiving PFD treatment had improved levels of TGF-β1, which promotes the differentiation of fibroblasts to myofibroblasts and cell proliferation and stimulates keratinocytes to produce laminin and other constituents of the normal basement membrane³⁹.

Polymers like gelatin microspheres carrying FGFb and curcumin have reduced infection rates and improved wound closure rates⁴⁰.

Silver nanoparticles exhibit antimicrobial properties by disrupting the respiratory chain at the cytochromes, and their anti-inflammatory characteristics aid in wound healing by reducing cytokine release and diminishing lymphocyte and mast cell infiltration. They expedite wound healing through dermal contraction and epidermal re-epithelialization with low systemic toxicity, although confirmation is needed regarding their cytotoxicity on fibroblasts and keratinocytes^{41, 42}.

NO-releasing nanoparticles play a vital role in wound oxygenation for faster healing and preventing DFU-related amputations. Increased levels of nitric oxide (NO) in foot ulcers contribute to healing by regulating re-epithelialization, angiogenesis, fibroblast and collagen synthesis, and enhancing inflammatory cells' growth factor, blood flow, and circulation. However further research on cell cytotoxicity is essential for evaluating their efficient usage in clinical settings^{43, 44}.

Zinc oxide nanoparticles (ZnO NPs), in vitro and in vivo studies revealed their anti-diabetic effects, improving glucose tolerance, insulin levels, and superoxide dismutase activity. ZnO NPs demonstrate promise as an anti-diabetic agent, warranting further investigation. Bandages with ZnO exhibit reduced bacterial cell viability without causing cell toxicity^45,
46.

Electrospun polymeric nanofibrous meshes show promise in wound dressing materials for DFU treatment. Recognizing the optimal moist wound environment for healing, these nanofibrous meshes prevent microbial infiltration, maintain moisture balance, and allow gas exchange. Soft, cost-effective, and easily handled, these nanofibers promote cell respiration, skin regeneration, moisture retention, and support tissue formation, offering potential solutions for chronic wounds like DFU⁴⁷.

REGENERATIVE MEDICINE APPROACHES: GROWTH FACTORS AND PROTEINS, STEM CELL THERAPY

Growth factors

Growth factors such as platelet-derived growth factor-BB (PDGF-BB), fibroblast growth factor β (FGFb), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and granulocyte colony-stimulating factor (G-CSF) have been studied for their efficacy in promoting the healing of DFUs⁴⁸.

Platelet-derived growth factor-BB (PDGF-BB)is approved by the FDA for the treatment of neuropathic ulcers when there is a lack of response to standard wound care⁴⁹.

Epidermal Growth Factor (EGF) shows promising results in the formation of granulation tissue and the prevention of amputation in patients. Intra-lesion injection of recombinant EGF directly at the wound site demonstrated a greater pharmacodynamic response in terms of granulation tissue growth and wound closure⁵⁰.

A double-blind study compared the efficacy of Vascular Endothelial Growth Factor(VEGF) against a placebo in the treatment of DFUs. The study reported a more significant DFU reduction (60%) in patients treated with VEGF than in those treated with a placebo. VEGF in combination with other growth factors and molecules enhances its therapeutic potential. For example, a study hypothesized that local sustained release of VEGF using an adenovirus vector (ADV)-mediated gene therapy approach could improve the healing of DFUs. Another study investigated the role of VEGF, platelet-derived growth factor (PDGF), and interleukin-6 (IL-6) in the treatment of DFUs after platelet-rich fibrin (PRF) and hyaluronic therapy^{51, 52}.

Granulocyte Colony-Stimulating Factor (G-CSF) emerges as a promising therapy for diabetic foot ulcers (DFUs) reducing surgical interventions, especially amputations, and shortening hospitalization duration. Further research and clinical trials are imperative to establish G-CSF's widespread applicability and optimize its therapeutic potential when combined with other growth factors and molecules⁵³.

Biological Peptides

Alpha Connexin Carboxy-Terminal (ACT1) is a peptide displaying potential in the treatment of diabetic foot ulcers (DFUs). It specifically targets connexin43 (Cx43), a gap-junctional protein crucial in dermal wound healing. Studies indicate that focusing on Cx43 can expedite the healing process of chronic neuropathic DFUs. In a prospective, randomized, multicenter clinical trial, the incorporation of ACT1 into standard wound care demonstrated enhanced healing for chronic neuropathic DFUs, leading to accelerated complete reepithelization and reduced healing time. Additionally, ACT1 has been incorporated into hydroxyethyl cellulose gels like Granexin® for diabetic wound treatment. Further research is necessary to establish the safety and effectiveness of ACT1 in DFU management⁵⁴.

Antimicrobial peptides (AMPs) have a broad spectrum of activity, comprising antiviral, antifungal, antibacterial, and antitumor activity. AMPs are being explored for their use as monotherapy for infection management, in combination with conventional antibiotics for synergistic purposes, as immunomodulators, and as neutralizing endotoxins⁵⁵.

Human LL-37 cathelicidin, a powerful endogenous peptide, has shown promise in improving re-epithelialization and granulated tissue development in diabetic wounds⁵⁶.

IDR-1018 has been shown to stimulate the healing of non-diabetic murine and porcine-infected wounds with S. aureus while Pexiganan (MSI-78) has been internationally accepted for the topical treatment of mild-to-moderate DFUs. Furthermore, a multi-center, double-blind clinical trial confirmed the effectiveness of the antimicrobial peptide SR-0379 in closing diabetic wounds⁵⁷.

Stem cells and gene therapy

Placenta-derived mesenchymal stem cells have proven to be particularly successful in the treatment of DFU due to their ability to produce and release a variety of regenerative growth factors that promote wound healing. Autologous stem cell therapy (ASCT) has shown positive benefits in wound healing, and mesenchymal stem cells (MSCs) in a collagen matrix have been found to significantly improve DFU healing in the preclinical model. Adipose stem cell sheets and stem cell secretome have also been shown to accelerate diabetic ulcer healing by upregulating local growth factors^{58, 59}.

Recent meta-analyses have reported that stem cells have better efficacy in the treatment of diabetic foot ulcers compared to traditional treatments, although high-quality clinical studies are still needed to explore the specific therapeutic effects of different types of stem cells.

Other emerging therapies and innovations for DFU treatment include fibroblast cultures, grafting, bovine fluid collagen, acellular dermal matrix, and human amniotic membrane. These approaches have shown promise in improving DFU treatments and promoting wound healing. Here is a brief overview of each of the mentioned therapies:

· Human Amniotic Membrane: The human amniotic membrane is already used as a wound covering for more than 100 years and produces biologically activated cells and powerful regenerative molecules together with structural support for the extracellular matrix (ECM)⁶⁰.

· Acellular Dermal Matrix (ADM): ADM, commercially known as Dermacell, is practiced for many years for wound healing, tissue repairing, and reconstruction. The dermis of the decellularized donor retains bioactive agents and acts as a scaffold for the repopulation of the host cell⁶¹.

· Bovine Fluid Collagen: Bovine fluid collagen fluid that contains fibrillar collagen (non-cross-linked collagen) and is the most advanced wound care matrix⁶².

· Grafting (Bioengineering): Grafting can be used to reconstruct skin defects at higher activation rates, but its application is restricted to external injuries that barely affects the skin and not the soft tissues, muscles, joints, or bones⁶³.

· Fibroblast Cultures: Fibroblast cultures employ dermal fibroblasts, secretory collagen, matrix proteins, growth factors, and cytokines capable of generating a three-dimensional dermis substituted as a graft. An analysis of fibroblasts/keratinocytes (Apligraf®, Graftskin®) reported satisfactory results⁶⁴.

TECHNOLOGY-BASED TREATMENT STRATEGIES

Photodynamic therapy (PDT)

PDT involves the topical application of a photosensitizer into the tissue, followed by illumination that induces the formation of reactive oxygen species (ROS).PDT provides bacterial inactivation and promotes wound healing. Studies have shown that PDT with RLP068, an antimicrobial photosensitizer, reduces the microbial load of diabetic ulcers in patients with DFU^{65, 66}.

Another study evaluated the safety and efficacy of 5-aminolevulinic acid PDT (ALA-PDT) in the treatment of DFUs and found it to be effective and safe⁶⁷.

However, further research is needed to fully understand its efficacy and safety in clinical settings.

Hyperbaric oxygen therapy (HBOT)

Luinio Tongson et al. demonstrated an 88% improvement in foot ulcers of diabetic patients with Wagner grade 2 and 3 wounds who had undergone HBOT treatment, with only 12% undergoing major amputation⁶⁸. A 2018 study reported that HBOT was effective in treating 74.2% of diabetic foot ulcer cases, dramatically improving the foot. Additionally, a 2020 systematic review and meta-analysis found that HBOT can help reduce serious adverse events, such as amputation and wound infection, and improve the quality of life. HBOT is an effective treatment option for the management of DFU and it is approved by the FDA for treating non-healing wounds, such as diabetic foot ulcers. It involves a person entering a pressurized room and breathing almost pure oxygen, which increases the amount of oxygen in the blood, boosting the oxygen flow to the wound, thus promoting healing⁶⁹.

Vacuum Assisted Closure (VAC) therapy

VAC is a device used for promoting wound healing through Negative Pressure Wound Therapy (NPWT). A randomized clinical trial study on partial foot amputation wounds up to the transmetatarsal level and evidence of adequate perfusion showed 56% of wounds healing in VAC treated group compared to 39% in the conventional therapy group. The median time for complete closure of the wound was 56 days in the VAC-treated group compared to 77 days in the conventionally treated group⁷⁰. Another multicenter randomized controlled study in stage II or III on DFU patients showed that VAC therapy induces a complete closure of the wound in comparison with moist wound therapy. VAC devices are designed to clean wounds and, at the same time, provide an opportunity for deep wounds to fill in with healthy tissue⁷¹.

Telemedicine and remote monitoring

Telemedicine and remote monitoring technologies enable early detection and management of chronic conditions such as DFU, reducing the physical burden on patients and improving overall quality of life. It effectively reduces physical hospital visits and outpatient consultations, particularly benefiting patients in remote areas. Enhanced communication among different levels of care increases the efficiency of diabetic foot care management providing regular clinical follow-up and improving patient outcomes⁷². A randomized controlled trial comparing tele-medical and standard outpatient monitoring of DFUs demonstrated the potential benefits of telemedicine in reducing hospital stays and costs, further supporting its effectiveness in the management of DFU⁷³.

Super oxidized solution (SOS)

As a safe and effective in treating infected DFU in humans and animals, SOS exhibits antimicrobial activity against antibiotic-resistant strains. In a 20-week study, SOS treatment significantly reduced cellulitis by 81%, surpassing the control group at 44%. Additionally, SOS-treated patients showed a 100% reduction in odor compared to the control group's 25%. Studies indicate better outcomes, faster healing times, and reduced bacterial strains compared to traditional treatments, making SOS therapy a valuable option for DFU healing and amputation prevention⁷⁴.

Smart dressings and bandages

Incorporating wireless technology and sensors, smart dressings enable real-time monitoring of wounds, providing comprehensive insights into the healing process. Smart dressings use optimal material combinations in a specific multi-layered design, effectively manage exudates, and promote re-epithelialization while maintaining an ideal moisture environment. Composites of natural and synthetic polymers can mimic extracellular matrix (ECM) composition. Researchers at the University of Nottingham have received a major grant to develop a smart wound dressing integrating optical fiber sensors. This innovation will remotely monitor humidity and pH levels, contributing to a holistic understanding of the healing process. Enhanced wound monitoring has the potential to significantly decrease the 7,000 lower limb amputations associated with DFU. In essence, smart dressings and bandages represent a noteworthy advancement in chronic wound care, particularly for diabetic foot ulcers, providing valuable solutions to enhance patient outcomes and alleviate the strain on healthcare systems⁷⁵.

Ozone therapy

Ozone therapy is considered for DFU treatment due to the lack of oxygenation in the injuries. It can be administered in various forms, such as ozonized oils (e.g., sunflower or olive oil) or a mixture of oxygen and ozone directly applied to the wound. Ozone exhibits antimicrobial activities and can activate endogenous growth factors, supporting wound healing. However, excessive application of ozone therapy can lead to unfavorable effects, as reported in clinical cases and more research is needed to precisely define the success rate of ozone therapy^{76, 77}.

PREVENTION STRATEGIES

Importance of Early Detection and Proactive Care

Early detection and proactive care are key preventive strategies improving patient well-being, and being cost-effective. Strategies, including patient education and innovative technologies, increase awareness and enable timely intervention, reducing the risk of complications and amputations.

Early detection strategies to prevent DFUs involve various interventions and technologies aimed at identifying individuals at risk and implementing timely preventive measures.

· Sensor-Equipped Devices: Research has explored the use of sensor-equipped devices, such as a device consisting of a sensor array for plantar pressure, temperature, and photoplethysmography (PPG), to enable early detection of DFU. These devices can help in the early identification of foot complications due to diabetes, such as neuropathy, and facilitate timely intervention to prevent ulceration⁷⁸.

· Multi-Intervention Approaches: A multi-intervention review highlighted the importance of multiple elements, including the identification of feet at risk, regular examinations, and patient education, in preventing foot ulceration among individuals with type 2 diabetes mellitus. This comprehensive approach aims to overcome the severity and prevent new wounds through early detection interventions⁷⁹.

· Telemedicine and Remote Monitoring: The use of telemedicine combined with sensor-equipped insoles and photo documentation is proposed as a preventive strategy for diabetic foot ulceration. It aims early detection of foot ulcers through remote monitoring to avoid or delay the progression of ulcers into more severe stages, ultimately preventing the need for limb amputation or infectious sequels⁸⁰.

Additionally, DFU prevention programs incorporating foot temperature monitoring may lower foot ulcer recurrence rates in high-risk patients. Automated home foot temperature monitoring is needed to improve self-care and patient active participation. Frykberg et al. developed a wireless thermometric foot mat called Podimetrics mat in 2017 to encourage daily foot-temperature monitoring in patients with diabetes and prior DFU. This method accurately measures temperature over the range of 15 to 40 ◦C and transmits data securely to an approved server. Continuous and simultaneous measurement of temperature and pressure may assist in determining digital biomarkers of DFU, such as thermal stress response, which is associated with shear and vascular health and maybe a strong predictor of foot complications like acute Charcot foot⁸¹.

Patient Education Programs and Self-Care Practices

Patient education programs and self-care practices help patients conduct foot self-examinations, identify risk factors, and provide appropriate self-care for feet with any signs of pre-ulceration. They are advised to avoid walking barefoot and wearing sandals, which can expose their feet to injuries. Being overweight or obese can also increase the risk of DFUs. Smoking cessation is recommended as tobacco products contain chemicals that slow healing and may prevent a full recovery from a foot ulcer. Additionally, for diabetic people with peripheral neuropathy, it is essential to conduct regular foot examinations⁸². Regular foot screening and follow-up have significantly decreased the incidence of DFUs and amputation rates.

Role of Multidisciplinary Teams in Prevention

Multidisciplinary teams offer collaborative and specialized care. These teams, composed of healthcare professionals from various disciplines, work together to address the complex needs of patients with diabetes. Collaborative care ensures that patients receive comprehensive and tailored treatment. Studies indicate that this approach can significantly reduce the occurrence of diabetic foot ulcerations and lower extremity amputations, attributed to the holistic care provided by the team. Podiatrists, considered "gatekeepers" in the multidisciplinary approach, focus on preventive screening, education, offloading, and foot care. Additionally, addressing comorbidities associated with diabetes, such as peripheral neuropathy, is strength of multidisciplinary teams, contributing to improved ulcer healing and reduced care gaps⁸³.

A comprehensive management approach includes various elements such as DFU education, blood glucose control, PAD management, regular foot inspection, and long-term use of appropriate shoes. Overall, the involvement of multidisciplinary teams is essential in providing integrated care, addressing co-morbidities, and reducing the overall incidence of DFUs and amputations.

The table below enlists various nanotechnology-based research strategies for the healing of DFUs.

CONCLUSION:

Challenges in DFU treatment include antibiotic resistance, infection control, recurrence, chronicity of ulcers, and patient compliance barriers. Emerging therapies such as regenerative medicine approaches and technology-based interventions show promise in the management of DFUs. Prevention strategies emphasize the importance of early detection, patient education, self-care practices, and multidisciplinary teamwork. Future research and treatment directions focus on novel therapeutic development with drug candidates, personalized medicine, and global health initiatives. In the technology era, treatment and management of DFU can be conveniently done by technology assisted therapy options. The conclusion of the review article highlights the multifactorial nature of DFUs and the need for a comprehensive approach that addresses the underlying pathophysiology, early diagnosis, effective management strategies, and preventive measures. It also emphasizes the potential of emerging therapies and the importance of ongoing research to improve the outcomes for patients with DFUs. We find immense research opportunities in the treatment and mitigation of DFU to minimize LLA.

ACKNOWLEDGEMENTS:

The authors are thankful to the authorities of their respective affiliation universities namely Silver Oak University, India and RAK Medical and Health Sciences University, UAE for their support in terms of infrastructure.

CONFLICT OF INTEREST:

None.

REFERENCES:

1. Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA; IWGDF Editorial Board. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020 Mar; 36 Suppl 1:e3266. doi: 10.1002/dmrr.3266. PMID: 32176447.

2. Doğruel H, Aydemir M, Balci MK. Management of diabetic foot ulcers and the challenging points: An endocrine view. World J Diabetes. 2022 Jan 15; 13(1): 27-36. doi: 10.4239/wjd.v13.i1.27. PMID: 35070057; PMCID: PMC8771264.

3. IDF Diabetes Atlas report on diabetes foot-related complications – 2022, https://diabetesatlas.org/atlas/diabetic-foot-2022/

4. Eleftheriadou I, Samakidou G, Tentolouris A, Papanas N, Tentolouris N. Nonpharmacological Management of Diabetic Foot Ulcers: An Update. Int J Low Extrem Wounds. 2021 Sep;20(3):188-197. doi: 10.1177/1534734620963561. Epub 2020 Oct 19. PMID: 33073653.

5. Jalilian M, Ahmadi Sarbarzeh P, Oubari S. Factors Related to Severity of Diabetic Foot Ulcer: A Systematic Review. Diabetes Metab Syndr Obes. 2020 May 25; 13: 1835-1842. doi: 10.2147/DMSO.S256243. PMID: 32547145; PMCID: PMC7259447.

6. Yazdanpanah L, Nasiri M, Adarvishi S. Literature review on the management of diabetic foot ulcer. World J Diabetes. 2015 Feb 15;6(1):37-53. doi: 10.4239/wjd.v6.i1.37. PMID: 25685277; PMCID: PMC4317316.

7. Whiting DR, Guariguata L, Weil C, Shaw J. IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract. 2011 Dec; 94(3): 311-21. doi: 10.1016/j.diabres.2011.10.029. Epub 2011 Nov 12. PMID: 22079683.

8. https://vascularsocietyofindia.com/wp-content/uploads/2021/01/LBL-9-Diabetic-foot-Vascular-AW-LQ.pdf

9. Rastogi A, Goyal G, Kesavan R, Bal A, Kumar H, Mangalanadanam, Kamath P, Jude EB, Armstrong DG, Bhansali A. Long term outcomes after incident diabetic foot ulcer: Multicenter large cohort prospective study (EDI-FOCUS investigators) epidemiology of diabetic foot complications study: Epidemiology of diabetic foot complications study. Diabetes Res Clin Pract. 2020 Apr; 162: 108113. doi: 10.1016/j.diabres.2020.108113. Epub 2020 Mar 9. PMID: 32165163.

10. McDermott K, Fang M, Boulton AJM, Selvin E, Hicks CW. Etiology, Epidemiology, and Disparities in the Burden of Diabetic Foot Ulcers. Diabetes Care. 2023 Jan 1;46(1):209-221. doi: 10.2337/dci22-0043. PMID: 36548709; PMCID: PMC9797649.

11. Boyko EJ, Zelnick LR, Braffett BH, Pop-Busui R, Cowie CC, Lorenzi GM, Gubitosi-Klug R, Zinman B, de Boer IH. Risk of Foot Ulcer and Lower-Extremity Amputation Among Participants in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study. Diabetes Care. 2022 Feb 1; 45(2): 357-364. doi: 10.2337/dc21-1816. PMID: 35007329; PMCID: PMC8914413.

12. Aumiller WD, Dollahite HA. Pathogenesis and management of diabetic foot ulcers. JAAPA. 2015 May;28(5):28-34. doi: 10.1097/01.JAA.0000464276.44117.b1. PMID: 25853673.

13. Armstrong DG, Boulton AJM, Bus SA. Diabetic Foot Ulcers and Their Recurrence. N Engl J Med. 2017 Jun 15;376(24):2367-2375. doi: 10.1056/NEJMra1615439. PMID: 28614678.

14. Kim J, Nomkhondorj O, An CY, Choi YC, Cho J. Management of diabetic foot ulcers: a narrative review. J Yeungnam Med Sci. 2023 Oct;40(4):335-342. doi: 10.12701/jyms.2023.00682. Epub 2023 Sep 22. PMID: 37735855; PMCID: PMC10626295.

15. Najari HR, Karimian T, Parsa H, QasemiBarqi R, Allami A. Bacteriology of moderate-to-severe diabetic foot infections in two tertiary hospitals of Iran. Foot (Edinb). 2019 Sep;40:54-58. doi: 10.1016/j.foot.2019.05.001. Epub 2019 May 10. PMID: 31102964.

16. Selva Olid A, Solà I, Barajas-Nava LA, Gianneo OD, Bonfill Cosp X, Lipsky BA. Systemic antibiotics for treating diabetic foot infections. Cochrane Database Syst Rev. 2015 Sep 4;2015(9):CD009061. doi: 10.1002/14651858.CD009061.pub2. PMID: 26337865; PMCID: PMC8504988.

17. Ramirez-Acuña JM, Cardenas-Cadena SA, Marquez-Salas PA, Garza-Veloz I, Perez-Favila A, Cid-Baez MA, Flores-Morales V, Martinez-Fierro ML. Diabetic Foot Ulcers: Current Advances in Antimicrobial Therapies and Emerging Treatments. Antibiotics (Basel). 2019 Oct 24;8(4):193. doi: 10.3390/antibiotics8040193. PMID: 31652990; PMCID: PMC6963879.

18. Su J, Li J, Liang J, Zhang K, Li J. Hydrogel Preparation Methods and Biomaterials for Wound Dressing. Life (Basel). 2021 Sep 27;11(10):1016. doi: 10.3390/life11101016. PMID: 34685387; PMCID: PMC8540918.

19. Felgueiras HP. Emerging Antimicrobial and Immunomodulatory Fiber-Based Scaffolding Systems for Treating Diabetic Foot Ulcers. Pharmaceutics. 2023 Jan 11;15(1):258. doi: 10.3390/pharmaceutics15010258. PMID: 36678887; PMCID: PMC9861857.

20. Huang C, Wang R, Yan Z. Silver dressing in the treatment of diabetic foot: A protocol for systematic review and meta-analysis. Medicine (Baltimore). 2021 Feb 19;100(7):e24876. doi: 10.1097/MD.0000000000024876. PMID: 33607864; PMCID: PMC7899903.

21. Yang B, Wang X, Li Z, Qu Q, Qiu Y. Beneficial effects of silver foam dressing on healing of wounds with ulcers and infection control of burn patients. Pak J Med Sci. 2015 Nov-Dec;31(6):1334-9. doi: 10.12669/pjms.316.7734. PMID: 26870092; PMCID: PMC4744277.

22. Shi C, Wang C, Liu H, Li Q, Li R, Zhang Y, Liu Y, Shao Y, Wang J. Selection of Appropriate Wound Dressing for Various Wounds. Front Bioeng Biotechnol. 2020 Mar 19;8:182. doi: 10.3389/fbioe.2020.00182. PMID: 32266224; PMCID: PMC7096556.

23. Gwak HC, Han SH, Lee J, Park S, Sung KS, Kim HJ, Chun D, Lee K, Ahn JH, Kwak K, Chung HJ. Efficacy of a povidone-iodine foam dressing (Betafoam) on diabetic foot ulcer. Int Wound J. 2020 Feb;17(1):91-99. doi: 10.1111/iwj.13236. Epub 2019 Nov 26. PMID: 31773882; PMCID: PMC7949421.

24. Mathew-Steiner SS, Roy S, Sen CK. Collagen in Wound Healing. Bioengineering. 2021; 8(5):63. https://doi.org/10.3390/bioengineering8050063

25. Wang H. A Review of the Effects of Collagen Treatment in Clinical Studies. Polymers (Basel). 2021 Nov 9;13(22):3868. doi: 10.3390/polym13223868. PMID: 34833168; PMCID: PMC8620403.

26. Martí-Carvajal AJ, Gluud C, Nicola S, Simancas-Racines D, Reveiz L, Oliva P, Cedeño-Taborda J. Growth factors for treating diabetic foot ulcers. Cochrane Database Syst Rev. 2015 Oct 28;2015(10):CD008548. doi: 10.1002/14651858.CD008548.pub2. PMID: 26509249; PMCID: PMC8665376.

27. Wang C, Guo M, Zhang N, Wang G. Effectiveness of honey dressing in the treatment of diabetic foot ulcers: A systematic review and meta-analysis. Complement Ther Clin Pract. 2019 Feb;34:123-131. doi: 10.1016/j.ctcp.2018.09.004. Epub 2018 Sep 21. PMID: 30712715

28. Li S, Xiao T, Ye N, Yang G, Chen H, Liang X, Li T, Wang J, Peng Y, Li Y, Liu Y. Effect of honey dressing in the management of diabetic foot ulcers: A meta-analysis. Int Wound J. 2023 Sep;20(7):2626-2633. doi: 10.1111/iwj.14135. Epub 2023 Mar 30. PMID: 36994798; PMCID: PMC10410322.

29. Wada FW, Mekonnen MF, Sawiso ED, Kolato S, Woldegiorgis L, Kera GK, El-Khatib Z, Ashuro AA, Biru M, Boltena MT. Bacterial profile and antimicrobial resistance patterns of infected diabetic foot ulcers in sub-Saharan Africa: a systematic review and meta-analysis. Sci Rep. 2023 Sep 5;13(1):14655. doi: 10.1038/s41598-023-41882-z. PMID: 37670001; PMCID: PMC10480146.

30. Moya-Salazar J, Chamana JM, Porras-Rivera D, Goicochea-Palomino EA, Salazar CR, Contreras-Pulache H. Increase in antibiotic resistance in diabetic foot infections among peruvian patients: a single-center cross-sectional study. Front Endocrinol (Lausanne). 2023 Dec 5;14:1267699. doi: 10.3389/fendo.2023.1267699. PMID: 38116313; PMCID: PMC10728874.

31. Liu X, Ren Q, Zhai Y, Kong Y, Chen D, Chang B. Risk Factors for Multidrug-Resistant Organisms Infection in Diabetic Foot Ulcer. Infect Drug Resist. 2022 Apr 7;15:1627-1635. doi: 10.2147/IDR.S359157. PMID: 35418765; PMCID: PMC8999704

32. Caruso P, Maiorino MI, Macera M, Signoriello G, Castellano L, Scappaticcio L, Longo M, Gicchino M, Campitiello F, Bellastella G, Coppola N, Esposito K. Antibiotic resistance in diabetic foot infection: how it changed with COVID-19 pandemic in a tertiary care center. Diabetes Res Clin Pract. 2021 May;175:108797. doi: 10.1016/j.diabres.2021.108797. Epub 2021 Apr 15. PMID: 33845049; PMCID: PMC8047299.

33. Untari EK, Andayani TM, Yasin NM, Asdie RH. A Review of Patient's Knowledge and Practice of Diabetic Foot Self-Care. Malays J Med Sci. 2024 Feb;31(1):33-50. doi: 10.21315/mjms2024.31.1.3. Epub 2024 Feb 20. PMID: 38456109; PMCID: PMC10917598.

34. Huang F, Lu X, Yang Y, Yang Y, Li Y, Kuai L, Li B, Dong H, Shi J. Microenvironment-Based Diabetic Foot Ulcer Nanomedicine. Adv Sci (Weinh). 2023 Jan;10(2):e2203308. doi: 10.1002/advs.202203308. Epub 2022 Nov 24. PMID: 36424137; PMCID: PMC9839871.

35. You J, Liu M, Li M, Zhai S, Quni S, Zhang L, Liu X, Jia K, Zhang Y, Zhou Y. The Role of HIF-1α in Bone Regeneration: A New Direction and Challenge in Bone Tissue Engineering. Int J Mol Sci. 2023 Apr 28;24(9):8029. doi: 10.3390/ijms24098029. PMID: 37175732; PMCID: PMC10179302.

36. Zhu Y, Chang B, Pang Y, Wang H, Zhou Y. Advances in Hypoxia-Inducible Factor-1α Stabilizer Deferoxamine in Tissue Engineering. Tissue Eng Part B Rev. 2023 Aug;29(4):347-357. doi: 10.1089/ten.TEB.2022.0168. Epub 2023 Feb 1. PMID: 36475887.

37. Awasthi A, Singh SK, Kumar B, Gulati M, Kumar R, Wadhwa S, Khursheed R, Corrie L, Kr A, Kumar R, Patni P, Kaur J, Vishwas S, Yadav A. Treatment Strategies Against Diabetic Foot Ulcer: Success so Far and the Road Ahead. Curr Diabetes Rev. 2021;17(4):421-436. doi: 10.2174/1573399816999201102125537. PMID: 33143613.

38. Hotkar MS, Avachat AM, Bhosale SS, Oswal YM. Preliminary investigation of topical nitroglycerin formulations containing natural wound healing agent in diabetes-induced foot ulcer. Int Wound J. 2015 Apr;12(2):210-7. doi: 10.1111/iwj.12084. Epub 2013 Jun 3. PMID: 23731451; PMCID: PMC7950354.

39. Lopez-de la Mora DA, Sanchez-Roque C, Montoya-Buelna M, Sanchez-Enriquez S, Lucano-Landeros S, Macias-Barragan J, Armendariz-Borunda J. Role and New Insights of Pirfenidone in Fibrotic Diseases. Int J Med Sci. 2015 Oct 14;12(11):840-7. doi: 10.7150/ijms.11579. PMID: 26640402; PMCID: PMC4643073.

40. Bardill JR, Laughter MR, Stager M, Liechty KW, Krebs MD, Zgheib C. Topical gel-based biomaterials for the treatment of diabetic foot ulcers. Acta Biomater. 2022 Jan 15;138:73-91. doi: 10.1016/j.actbio.2021.10.045. Epub 2021 Oct 30. PMID: 34728428; PMCID: PMC8738150.

41. Rosenkranz HS, Rosenkranz S. Silver sulfadiazine: interaction with isolated deoxyribonucleic acid. Antimicrob Agents Chemother. 1972 Nov;2(5):373-83. doi: 10.1128/AAC.2.5.373. PMID: 4677596; PMCID: PMC444323.

42. Tian J, Wong KK, Ho CM, Lok CN, Yu WY, Che CM, Chiu JF, Tam PK. Topical delivery of silver nanoparticles promotes wound healing. ChemMedChem. 2007 Jan;2(1):129-36. doi: 10.1002/cmdc.200600171. PMID: 17075952.

43. Tavares G, Alves P, Simões P. Recent Advances in Hydrogel-Mediated Nitric Oxide Delivery Systems Targeted for Wound Healing Applications. Pharmaceutics. 2022 Jun 29;14(7):1377. doi: 10.3390/pharmaceutics14071377. PMID: 35890273; PMCID: PMC9315818.

44. Seabra AB, de Lima R, Calderón M. Nitric oxide releasing nanomaterials for cancer treatment: current status and perspectives. Curr Top Med Chem. 2015;15(4):298-308. doi: 10.2174/1568026615666150108122918. PMID: 25579351.

45. Nazarizadeh A, Asri-Rezaie S. Comparative Study of Antidiabetic Activity and Oxidative Stress Induced by Zinc Oxide Nanoparticles and Zinc Sulfate in Diabetic Rats. AAPS PharmSciTech. 2016 Aug;17(4):834-43. doi: 10.1208/s12249-015-0405-y. Epub 2015 Sep 8. PMID: 26349687.

46. Shen C, James SA, de Jonge MD, Turney TW, Wright PF, Feltis BN. Relating cytotoxicity, zinc ions, and reactive oxygen in ZnO nanoparticle-exposed human immune cells. Toxicol Sci. 2013 Nov;136(1):120-30. doi: 10.1093/toxsci/kft187. Epub 2013 Aug 31. PMID: 23997113.

47. Fu K, Zheng X, Chen Y, Wu L, Yang Z, Chen X, Song W. Role of matrix metalloproteinases in diabetic foot ulcers: Potential therapeutic targets. Front Pharmacol. 2022 Oct 20;13:1050630. doi: 10.3389/fphar.2022.1050630. PMID: 36339630; PMCID: PMC9631429.

48. Sridharan K, Sivaramakrishnan G. Growth factors for diabetic foot ulcers: mixed treatment comparison analysis of randomized clinical trials. Br J Clin Pharmacol. 2018 Mar;84(3):434-444. doi: 10.1111/bcp.13470. Epub 2018 Jan 5. PMID: 29148070; PMCID: PMC5809344.

49. Gonchar IV, Lipunov AR, Afanasov IM, Larina V, Faller AP, Kibardin AV. Platelet rich plasma and growth factors cocktails for diabetic foot ulcers treatment: State of art developments and future prospects. Diabetes Metab Syndr. 2018 Apr-Jun;12(2):189-194. doi: 10.1016/j.dsx.2017.09.007. Epub 2017 Sep 21. PMID: 29050916.

50. Bui TQ, Bui QVP, Németh D, Hegyi P, Szakács Z, Rumbus Z, Tóth B, Emri G, Párniczky A, Sarlós P, Varga O. Epidermal Growth Factor is Effective in the Treatment of Diabetic Foot Ulcers: Meta-Analysis and Systematic Review. Int J Environ Res Public Health. 2019 Jul 19;16(14):2584. doi: 10.3390/ijerph16142584. PMID: 31331038; PMCID: PMC6678975.

51. Zhao DY, Su YN, Li YH, Yu TQ, Li J, Tu CQ. Efficacy and safety of recombinant human epidermal growth factor for diabetic foot ulcers: A systematic review and meta-analysis of randomised controlled trials. Int Wound J. 2020 Aug;17(4):1062-1073. doi: 10.1111/iwj.13377. Epub 2020 Apr 28. PMID: 32343054; PMCID: PMC7948637.

52. Thanigaimani S, Jin H, Ahmad U, Anbalagan R, Golledge J. Comparative efficacy of growth factor therapy in healing diabetes-related foot ulcers: A network meta-analysis of randomized controlled trials. Diabetes Metab Res Rev. 2023 Jul;39(5):e3670. doi: 10.1002/dmrr.3670. Epub 2023 Jun 5. PMID: 37277960; PMCID: PMC10909411.

53. Zubair M, Ahmad J. Role of growth factors and cytokines in diabetic foot ulcer healing: A detailed review. Rev Endocr Metab Disord. 2019 Jun;20(2):207-217. doi: 10.1007/s11154-019-09492-1. PMID: 30937614.

54. Lopes L, Setia O, Aurshina A, Liu S, Hu H, Isaji T, Liu H, Wang T, Ono S, Guo X, Yatsula B, Guo J, Gu Y, Navarro T, Dardik A. Stem cell therapy for diabetic foot ulcers: a review of preclinical and clinical research. Stem Cell Res Ther. 2018 Jul 11;9(1):188. doi: 10.1186/s13287-018-0938-6. PMID: 29996912; PMCID: PMC6042254.

55. Da Silva J, Leal EC, Carvalho E. Bioactive Antimicrobial Peptides as Therapeutic Agents for Infected Diabetic Foot Ulcers. Biomolecules. 2021 Dec 17;11(12):1894. doi: 10.3390/biom11121894. PMID: 34944538; PMCID: PMC8699205.

56. Haidari H, Melguizo-Rodríguez L, Cowin AJ, Kopecki Z. Therapeutic potential of antimicrobial peptides for treatment of wound infection. Am J Physiol Cell Physiol. 2023 Jan 1;324(1):C29-C38. doi: 10.1152/ajpcell.00080.2022. Epub 2022 Nov 21. PMID: 36409176.

57. Gomes A, Teixeira C, Ferraz R, Prudêncio C, Gomes P. Wound-Healing Peptides for Treatment of Chronic Diabetic Foot Ulcers and Other Infected Skin Injuries. Molecules. 2017 Oct 18;22(10):1743. doi: 10.3390/molecules22101743. PMID: 29057807; PMCID: PMC6151519.

58. El Hage R, Knippschild U, Arnold T, Hinterseher I. Stem Cell-Based Therapy: A Promising Treatment for Diabetic Foot Ulcer. Biomedicines. 2022 Jun 25;10(7):1507. doi: 10.3390/biomedicines10071507. PMID: 35884812; PMCID: PMC9312797.

59. Heublein H, Bader A, Giri S. Preclinical and clinical evidence for stem cell therapies as treatment for diabetic wounds. Drug Discov Today. 2015 Jun;20(6):703-17. doi: 10.1016/j.drudis.2015.01.005. Epub 2015 Jan 17. PMID: 25603421.

60. Cao Y, Gang X, Sun C, Wang G. Mesenchymal Stem Cells Improve Healing of Diabetic Foot Ulcer. J Diabetes Res. 2017;2017:9328347. doi: 10.1155/2017/9328347. Epub 2017 Mar 12. PMID: 28386568; PMCID: PMC5366201.

61. Mohammed YA, Farouk HK, Gbreel MI, Ali AM, Salah AA, Nourelden AZ, Gawad MMA. Human amniotic membrane products for patients with diabetic foot ulcers. do they help? a systematic review and meta-analysis. J Foot Ankle Res. 2022 Sep 14;15(1):71. doi: 10.1186/s13047-022-00575-y. PMID: 36104736; PMCID: PMC9472416.

62. Reyzelman AM, Bazarov I. Human acellular dermal wound matrix for treatment of DFU: literature review and analysis. J Wound Care. 2015 Mar;24(3):128; 129-34. doi: 10.12968/jowc.2015.24.3.128. PMID: 25764957.

63. Veves A, Falanga V, Armstrong DG, Sabolinski ML; Apligraf Diabetic Foot Ulcer Study. Graftskin, a human skin equivalent, is effective in the management of noninfected neuropathic diabetic foot ulcers: a prospective randomized multicenter clinical trial. Diabetes Care. 2001 Feb;24(2):290-5. doi: 10.2337/diacare.24.2.290. PMID: 11213881.

64. Marston WA, Hanft J, Norwood P, Pollak R; Dermagraft Diabetic Foot Ulcer Study Group. The efficacy and safety of Dermagraft in improving the healing of chronic diabetic foot ulcers: results of a prospective randomized trial. Diabetes Care. 2003 Jun;26(6):1701-5. doi: 10.2337/diacare.26.6.1701. PMID: 12766097.

65. Pantò F, Adamo L, Giordano C, Licciardello C. Efficacy and safety of photodynamic therapy with RLP068 for diabetic foot ulcers: a review of the literature and clinical experience. Drugs Context. 2020 Feb 10;9:2019-10-3. doi: 10.7573/dic.2019-10-3. Erratum in: Drugs Context. 2020 Apr 21;9: PMID: 32158488; PMCID: PMC7048156.

66. Brandão MGSA, Ximenes MAM, Sousa DF, Veras VS, Barros LM, Rabeh SAN, Costa IG, Araújo TM. Photodynamic therapy for infected foot ulcers in people with diabetes mellitus: a systematic review. Sao Paulo Med J. 2023 May 12;141(6):e2022476. doi: 10.1590/1516-3180.2022.0476.27022023. PMID: 37194764; PMCID: PMC10181837.

67. Ning X, He G, Zeng W, Xia Y. The photosensitizer-based therapies enhance the repairing of skin wounds. Front Med (Lausanne). 2022 Aug 11;9:915548. doi: 10.3389/fmed.2022.915548. PMID: 36035433; PMCID: PMC9403269.

68. Kessler L, Bilbault P, Ortéga F, Grasso C, Passemard R, Stephan D, Pinget M, Schneider F. Hyperbaric oxygenation accelerates the healing rate of nonischemic chronic diabetic foot ulcers: a prospective randomized study. Diabetes Care. 2003 Aug;26(8):2378-82. doi: 10.2337/diacare.26.8.2378. PMID: 12882865.

69. Löndahl M. Hyperbaric oxygen therapy as adjunctive treatment for diabetic foot ulcers. Int J Low Extrem Wounds. 2013 Jun;12(2):152-7. doi: 10.1177/1534734613486154. Epub 2013 May 9. PMID: 23667103.

70. Armstrong DG, Lavery LA; Diabetic Foot Study Consortium. Negative pressure wound therapy after partial diabetic foot amputation: a multicentre, randomised controlled trial. Lancet. 2005 Nov 12;366(9498):1704-10. doi: 10.1016/S0140-6736(05)67695-7. PMID: 16291063.

71. Plikaitis CM, Molnar JA. Subatmospheric pressure wound therapy and the vacuum-assisted closure device: basic science and current clinical successes. Expert Rev Med Devices. 2006 Mar;3(2):175-84. doi: 10.1586/17434440.3.2.175. PMID: 16515384.

72. Najafi B, Mishra R. Harnessing Digital Health Technologies to Remotely Manage Diabetic Foot Syndrome: A Narrative Review. Medicina (Kaunas). 2021 Apr 14;57(4):377. doi: 10.3390/medicina57040377. PMID: 33919683; PMCID: PMC8069817

73. Rasmussen BS, Froekjaer J, Bjerregaard MR, Lauritsen J, Hangaard J, Henriksen CW, Halekoh U, Yderstraede KB. A Randomized Controlled Trial Comparing Telemedical and Standard Outpatient Monitoring of Diabetic Foot Ulcers. Diabetes Care. 2015 Sep;38(9):1723-9. doi: 10.2337/dc15-0332. Epub 2015 Jun 26. PMID: 26116717.

74. Jiang P, Li Q, Luo Y, Luo F, Che Q, Lu Z, Yang S, Yang Y, Chen X, Cai Y. Current status and progress in research on dressing management for diabetic foot ulcer. Front Endocrinol (Lausanne). 2023 Aug 17;14:1221705. doi: 10.3389/fendo.2023.1221705. PMID: 37664860; PMCID: PMC10470649.

75. Gianino E, Miller C, Gilmore J. Smart Wound Dressings for Diabetic Chronic Wounds. Bioengineering (Basel). 2018 Jun 26;5(3):51. doi: 10.3390/bioengineering5030051. PMID: 29949930; PMCID: PMC6163915.

76. Fitzpatrick E, Holland OJ, Vanderlelie JJ. Ozone therapy for the treatment of chronic wounds: A systematic review. Int Wound J. 2018 Aug;15(4):633-644. doi: 10.1111/iwj.12907. Epub 2018 Mar 13. PMID: 29536625; PMCID: PMC7949634.

77. Kushmakov R, Gandhi J, Seyam O, Jiang W, Joshi G, Smith NL, Khan SA. Ozone therapy for diabetic foot. Med Gas Res. 2018 Sep 25;8(3):111-115. doi: 10.4103/2045-9912.241076. PMID: 30319766; PMCID: PMC6178637.

78. Dabó SG; Brandão MGSA; Araújo TM; Frota NM; Veras VS. Tecnologias digitais na prevenção de pé diabético: uma revisão sobre aplicativos móveis. ESTIMA, Braz. J. Enterostomal Ther., 18, 2020: e1420. https://doi.org/10.30886/estima.v18.870_IN

79. Yang L, Rong GC, Wu QN. Diabetic foot ulcer: Challenges and future. World J Diabetes. 2022 Dec 15;13(12):1014-1034. doi: 10.4239/wjd.v13.i12.1014. PMID: 36578870; PMCID: PMC9791573.

80. Chatwin KE, Abbott CA, Boulton AJM, Bowling FL, Reeves ND. The role of foot pressure measurement in the prediction and prevention of diabetic foot ulceration-A comprehensive review. Diabetes Metab Res Rev. 2020 May;36(4):e3258. doi: 10.1002/dmrr.3258. Epub 2019 Dec 11. PMID: 31825163; PMCID: PMC7317473.

81. Xia N, Morteza A, Yang F, Cao H, Wang A. Review of the role of cigarette smoking in diabetic foot. J Diabetes Investig. 2019 Mar;10(2):202-215. doi: 10.1111/jdi.12952. Epub 2018 Nov 12. PMID: 30300476; PMCID: PMC6400172.

82. Sorber R, Abularrage CJ. Diabetic foot ulcers: Epidemiology and the role of multidisciplinary care teams. Semin Vasc Surg. 2021 Mar;34(1):47-53. doi: 10.1053/j.semvascsurg.2021.02.006. Epub 2021 Feb 5. PMID: 33757635.

83. Wang A, Lv G, Cheng X, Ma X, Wang W, Gui J, Hu J, Lu M, Chu G, Chen J, Zhang H, Jiang Y, Chen Y, Yang W, Jiang L, Geng H, Zheng R, Li Y, Feng W, Johnson B, Wang W, Zhu D, Hu Y. Guidelines on multidisciplinary approaches for the prevention and management of diabetic foot disease (2020 edition). Burns Trauma. 2020 Jul 6;8:tkaa017. doi: 10.1093/burnst/tkaa017. PMID: 32685563; PMCID: PMC7336185.

84. Gallelli G, Cione E, Serra R, Leo A, Citraro R, Matricardi P, Di Meo C, Bisceglia F, Caroleo MC, Basile S, Gallelli L. Nano-hydrogel embedded with quercetin and oleic acid as a new formulation in the treatment of diabetic foot ulcer: A pilot study. Int Wound J. 2020 Apr;17(2):485-490. doi: 10.1111/iwj.13299. Epub 2019 Dec 25. PMID: 31876118; PMCID: PMC7948574.

85. Gourishetti K, Keni R, Nayak PG, Jitta SR, Bhaskaran NA, Kumar L, Kumar N, Krishnadas N, Shenoy RR. Sesamol-Loaded PLGA Nanosuspension for Accelerating Wound Healing in Diabetic Foot Ulcer in Rats. Int J Nanomedicine. 2020 Nov 23;15:9265-9282. doi: 10.2147/IJN.S268941. PMID: 33262587; PMCID: PMC7695744.

86. Sheir MM, Nasra MMA, Abdallah OY. Chitosan alginate nanoparticles as a platform for the treatment of diabetic and non-diabetic pressure ulcers: Formulation and in vitro/in vivo evaluation. Int J Pharm. 2021 Sep 25;607:120963. doi: 10.1016/j.ijpharm.2021.120963. Epub 2021 Aug 4. PMID: 34363919.

87. Bairagi U, Mittal P, Singh J, Mishra B. Preparation, characterization, and in vivo evaluation of nano formulations of ferulic acid in diabetic wound healing. Drug Dev Ind Pharm. 2018 Nov;44(11):1783-1796. doi: 10.1080/03639045.2018.1496448. Epub 2018 Aug 31. PMID: 29973105.

88. Felgueiras HP. Emerging Antimicrobial and Immunomodulatory Fiber-Based Scaffolding Systems for Treating Diabetic Foot Ulcers. Pharmaceutics. 2023 Jan 11;15(1):258. doi: 10.3390/pharmaceutics15010258. PMID: 36678887; PMCID: PMC9861857.

89. Chakraborty, Tulshi and Gupta, Dr. Sumeet and Nair, Anroop and Chauhan, Samrat and Saini, Vipin. (2021). Wound healing potential of insulin-loaded nanoemulsion with Aloe vera gel in diabetic rats. Journal of Drug Delivery Science and Technology. 64. 102601. 10.1016/j.jddst.2021.102601.

90. Yeo E, Yew Chieng CJ, Choudhury H, Pandey M, Gorain B. Tocotrienols-rich naringenin nanoemulgel for the management of diabetic wound: Fabrication, characterization and comparative in vitro evaluations. Curr Res Pharmacol Drug Discov. 2021 Mar 14;2:100019. doi: 10.1016/j.crphar.2021.100019. PMID: 34909654; PMCID: PMC8663980.

91. Nor Azlan AYH, Katas H, Mohamad Zin N, Fauzi MB. Dual action gels containing DsiRNA loaded gold nanoparticles: Augmenting diabetic wound healing by promoting angiogenesis and inhibiting infection. Eur J Pharm Biopharm. 2021 Dec;169:78-90. doi: 10.1016/j.ejpb.2021.09.007. Epub 2021 Sep 25. PMID: 34582971.

92. Eid HM, Ali AA, Ali AMA, Eissa EM, Hassan RM, Abo El-Ela FI, Hassan AH. Potential Use of Tailored Citicoline Chitosan-Coated Liposomes for Effective Wound Healing in Diabetic Rat Model. Int J Nanomedicine. 2022 Feb 5;17:555-575. doi: 10.2147/IJN.S342504. PMID: 35153481; PMCID: PMC8828492.

93. Meamar R, Chegini S, Varshosaz J, Aminorroaya A, Amini M, Siavosh M. Alleviating neuropathy of diabetic foot ulcer by co-delivery of venlafaxine and matrix metalloproteinase drug-loaded cellulose nanofiber sheets: production, in vitro characterization and clinical trial. Pharmacol Rep. 2021 Jun;73(3):806-819. doi: 10.1007/s43440-021-00220-8. Epub 2021 Apr 7. PMID: 33826133.

94. Anand S, Rajinikanth PS, Arya DK, Pandey P, Gupta RK, Sankhwar R, Chidambaram K. Multifunctional Biomimetic Nanofibrous Scaffold Loaded with Asiaticoside for Rapid Diabetic Wound Healing. Pharmaceutics. 2022 Jan 24;14(2):273. doi: 10.3390/pharmaceutics14020273. PMID: 35214006; PMCID: PMC8875374.

95. Ardeshirzadeh A, Ahmadi H, Mirzaei M, Omidi H, Mostafavinia A, Amini A, Bayat S, Fridoni M, Chien S, Bayat M. The combined use of photobiomodulation and curcumin-loaded iron oxide nanoparticles significantly improved wound healing in diabetic rats compared to either treatment alone. Lasers Med Sci. 2022 Dec;37(9):3601-3611. doi: 10.1007/s10103-022-03639-4. Epub 2022 Sep 2. PMID: 36053389.

96. Dubey, K. Sunil,Alexander, Amit,Sivaram, Munnangi,Agrawal, Mukta,Singhvi, Gautam,Sharma, Swapnil, Dayaramani, Richa, Uncovering the Diversification of Tissue Engineering on the Emergent Areas of Stem Cells, Nanotechnology and Biomaterials,Current Stem Cell Research and Therapy, volume 15, issue 3, pages 187-201, year 2020, issn 1574-888X/2212-3946, doi 10.2174/1574888X15666200103124821, (http://www.eurekaselect.com/article/103458, Stem cell tissue engineering nano technology regenerative medicine scaffold transplantation.

97. Saporito F, Sandri G, Bonferoni MC, Rossi S, Boselli C, Icaro Cornaglia A, Mannucci B, Grisoli P, Vigani B, Ferrari F. Essential oil-loaded lipid nanoparticles for wound healing. Int J Nanomedicine. 2017 Dec 27;13:175-186. doi: 10.2147/IJN.S152529. PMID: 29343956; PMCID: PMC5747963.

98. Thattaruparambil Raveendran N, Mohandas A, Ramachandran Menon R, Somasekharan Menon A, Biswas R, Jayakumar R. Ciprofloxacin- and Fluconazole-Containing Fibrin-Nanoparticle-Incorporated Chitosan Bandages for the Treatment of Polymicrobial Wound Infections. ACS Appl Bio Mater. 2019 Jan 22;2(1):243-254. doi: 10.1021/acsabm.8b00585. Epub 2019 Jan 7. PMID: 35016347.

99. Saha K, Ghosh A, Bhattacharya T, Ghosh S, Dey S, Chattopadhyay D. Ameliorative effects of clindamycin - nanoceria conjugate: A ROS responsive smart drug delivery system for diabetic wound healing study. J Trace Elem Med Biol. 2023 Jan;75:127107. doi: 10.1016/j.jtemb.2022.127107. Epub 2022 Nov 12. PMID: 36427436.

100.Zhang P, He L, Zhang J, Mei X, Zhang Y, Tian H, Chen Z. Preparation of novel berberine nano-colloids for improving wound healing of diabetic rats by acting Sirt1/NF-κB pathway. Colloids Surf B Biointerfaces. 2020 Mar;187:110647. doi: 10.1016/j.colsurfb.2019.110647. Epub 2019 Nov 14. PMID: 31761520.

101.Zhu W, Dong Y, Xu P, Pan Q, Jia K, Jin P, Zhou M, Xu Y, Guo R, Cheng B. A composite hydrogel containing resveratrol-laden nanoparticles and platelet-derived extracellular vesicles promotes wound healing in diabetic mice. Acta Biomater. 2022 Dec;154:212-230. doi: 10.1016/j.actbio.2022.10.038. Epub 2022 Oct 27. PMID: 36309190.

Received on 20.05.2024 Modified on 09.08.2024

Research J. Pharm. and Tech 2024; 17(10):5141-5153.

DOI: 10.52711/0974-360X.2024.00788

	African countries	South East Asia	Europe	United States	Middle East and North Africa	Brazil	Reference
DFU	10.0% - 30.0%	<15.0%	1.0% - 17.0%	8.0% - 52.0%	5.0% -20.0%	21.0%	3
LLA	3.0% to 35.0%				0.2% to 60.0%	10.0% to 13.0%	3

Sr. No.	Active Ingredient	Carrier Molecule	Formulation	Ref
1	Quercetin and oleic acid	-	Nano-Hydrogel	84
2	Sesamol	PLGA	Nanosuspension	85
3	Chitosan -Alginate	-	Nanoparticles	86
4	Ferulic acid	PLGA	Nanoparticle	87
5	Deferoxamine	Chitosan, sodium alginate, and polyvinyl alcohol	Nanofiber	88
6	Aloe Vera	Polyethylene glycol 400 and Tween 80	Nanoemulsion	89
7	Naringenin	Capryol 90 and tocotrienols, Solutol HS15, and Transcutol P	Nanoemulgel	90
8	Lignosus Rhinocerotis	AuNPs/PF127	Nanoparticles	91
9	Citicoline	Chitosan-coated	Liposomes	92
10	Venlafaxinand Doxycycline	Bacterial cellulose	Nanofiber	93
11	Asiaticoside	Polyvinyl alcohol-silk fibroin -sodium alginate	Nanofiber	94
12	Curcumin	Iron Oxide	Nanoparticle	95
13	Naringenin and Ferulic Acid	Beeswax-based nanostructured lipid carriers	Nanoparticle	96
14	Essential oil incorporated in SLN and NLC	Nanoparticles made up of lecithin, cocoa butter, olive oil/sesame oilloaded witheucalyptus or rosemaryessential oils as therapeutic agents for DFUs	Nanoparticles	97
15	Chitosan bandages using fibrin nanoparticles	Chitosan (CH) bandages using fibrin nanoparticles (FNPs) encapsulated with antimicrobial agents, such as ciprofloxacin and fluconazole	Nanoparticles	98
16	Clindamycin- Ceria Nanoparticles	ROS responsive Clindamycin conjugated Nanoparticles to combat DFU	Nanoparticles	99
17	Berberine	Polyvinyl alcohol (PVA), sodium alginate (Alg) based nano-colloids hydrogel	Nano-colloids hydrogel	100
18	Resveratrol	Composite hydrogel containing Resveratrol-laden nanoparticles and platelet-derived extracellular vesicles	Composite hydrogel	101