Diabetic Foot Ulcers: Promising Biomaterials for Wound Dressings: History
Please note this is an old version of this entry, which may differ significantly from the current revision.

Diabetic Foot Ulcers (DFUs) are deep tissue lesions on the lower extremities, mainly associated with sustained hyperglycemia, peripheral neuropathy, and peripheral arterial disease (PAD). Globally, a lower limb is amputated every 20 to 30 s, with DFU being responsible for 85 to 95% of cases. Furthermore, individuals with DFUs typically display an increased risk of mortality, more than the double risk of those with DM without a DFU.

  • biomaterials
  • chronic wounds
  • clinical translation
  • wound healing

1. Pathophysiology of Diabetic Foot Ulcers

Peripheral neuropathy is the primary predisposing factor in DFU development, due to long-term hyperglycemia, which results in oxidative stress and damages the sensitive, motor, and autonomous nerves [1][2]. Sensory defects manifest as a loss of sensitivity to injury and stimulation in the lower limbs due to small-fiber nerve dysfunction, thereby promoting constant unconscious trauma and subsequent ulceration [1]. These sensory defects may include sensory dullness, numbness, and abnormal pain, among others [1][3]. By generating intrinsic muscle weakness and atrophy, consequently leading to biomechanical anatomical changes in the feet such as hammer toe, Charcot’s ankle, pes-planus, and pes-cavus, motor neuropathy triggers high-pressure zones in the feet [1][2][3][4][5]. This increased shear stress and friction force further promote foot ulceration [1]. Peripheral sympathetic nerves may also be damaged, causing thermoregulatory dysfunction that involves altered sweating, dry skin, cracking, and calluses, subsequently facilitating ulceration [1][3].
PAD is another key factor in ulcer development, characterized as a chronic arterial occlusive disease of the lower extremities [1][2][4]. Specifically, approximately 80% of individuals with DFUs initially experience PAD, resulting in an insufficient blood supply, hypercoagulability, and serious limb ischemia [1][2][4][6]. Tissue ulceration is therefore anticipated due to long-term ischemia and hypoxia, which weaken lower-extremity regions and render them susceptible to secondary infection [1][2][4].
Significantly, 50 to 60% of DFUs become infected, predominantly with bacterial colonies of S. aureus, C. striatum, and P. aeruginosa, and fungal colonies of C. albicans [7][8][9][10][11][12]. Moreover, between 20 and 25% exhibit deep infections with some anaerobic bacteria, such as Bacteroides spp., Prevotella spp., and Clostridium spp., which can spread to the bone, further exacerbating the risk of mortality and the socioeconomic burden [2][5][13].

2. Impaired Healing in Diabetic Foot Ulcers

DFUs may arise from several risk factors that collectively impair the wound healing process of these individuals. Wound healing is a process with four overlapping phases, involving a complex and dynamic sequence of cellular and biochemical events to restore skin integrity and functionality after trauma [7][14][15][16]. The first phase—hemostasis—begins immediately after skin injury with the constriction of the damaged blood vessels and activation of platelets [7][14][17]. This promotes platelet aggregation and the subsequent formation of a fibrin clot, covering the injured endothelium and consequently stopping the bleeding [7][14][17]. The second phase—inflammation—starts with the recruitment of neutrophils to the wound site, as a first line of defense against pathogens [7][14][15][17]. After a peak population between 24 and 48 h post skin injury, the number of neutrophils greatly reduces and pro-inflammatory M1 phenotype macrophages arrive successively at the wound site to continue clearing microbial pathogens and debris [7][14][15]. In detail, M1 macrophages attract different types of adaptive immune system cells to the wound site by the secretion of cytokines and chemokines, either to continue clearing cellular debris or to fight infection [7][14][15][16]. These macrophages then switch from the pro-inflammatory M1 to anti-inflammatory M2 phenotype as inflammation resolves to further foster tissue regeneration, producing anti-inflammatory cytokines and growth factors. The third phase—proliferation—occurs with the formation of granulation tissue to fill the wound, the contraction of the wound borders, wound coverage with epithelial cells (i.e., re-epithelialization), and neovascularization [7][14][15][16][17]. The fourth phase—remodeling—involves collagen fiber reorganization, tissue remodeling and maturation, and an overall increase in tensile strength [7][14][15][17].
Nonetheless, the impairment of local and systemic factors in individuals with DFUs leads to a poorly orchestrated cascade of the four phases, thus delaying or even interrupting the healing process, as per Figure 1. The concurrent presence of DM and DFU stimulates an unbalanced accumulation of immune cells, as well as an increase in the M1/M2 macrophage ratio, reactive oxygen species (ROS), and pro-inflammatory cytokines, together ending in chronic non-healing wounds that remain in a state of low-grade inflammation [3][7][16][18]. In detail, Erem et al. showed that patients with DM exhibited hypercoagulability and decreased fibrinolysis during the hemostasis phase, compared to healthy individuals [19]. Patients with DM have also been associated with an imbalance in cytokine release by neutrophils during the inflammatory phase, thus favoring wound infection [3][20]. Furthermore, fibroblast and keratinocyte migration, as well as their proliferative capacity, is compromised in patients with DM due to hyperglycemia, leading to poor re-epithelialization of the wound [21][22]. On top of this compromised cell migration, angiogenesis is also reduced in patients with DM, resulting in decreased blood supply to the wound site [23]. During the remodeling phase, patients with DM have also shown altered fibroblast function, contributing to flawed closure of the wound [24]. This may probably be explained by an inefficient response to transforming growth factor beta (TGF-β) from fibroblasts, as well as an aberrant production of the extracellular matrix [3][24].
Figure 1. Healthy versus impaired phases of the healing process: the case of diabetic foot ulcers (DFUs) (produced using BioRender). Under DFU conditions, an unbalanced accumulation of immune cells and an increase in the M1/M2 macrophage ratio, reactive oxygen species (ROS), and pro-inflammatory cytokines occur. In addition, re-epithelialization and angiogenesis are scarce, altogether ending in chronic non-healing wounds that remain in a state of low-grade inflammation.

3. Management of Diabetic Foot Ulcer

Current therapeutic approaches for managing DFUs involve multidisciplinary strategies that address key aspects of diabetic wound care, including glycemic control, adequate arterial supply, the debridement of necrotic tissue, pressure offloading, and the treatment of any infection with appropriate broad-spectrum antibiotics [4][18][25][26][27][28][29][30][31]. For example, it was recently reported that the MADADORE acronym corresponds to the recommended DFU management principles: Metabolic control, Assessment of foot, Debridement, Antibiotics, Dressing, Offloading pressure, Referral to multidisciplinary teams, and Education [32]. Metabolic control involves the management of associated medical conditions such as hyperglycemia and hyperlipidemia, through adequate medication and dietary counseling [33]. Assessment of foot concerns the correct evaluation of the associated risk factors and classification of the ulcer according to the perfusion, extent, depth, infection, and sensation (PEDIS) scale [34]. Debridement involves the surgical removal of any necrotic or unhealthy tissue, while treating any infection with appropriate broad-spectrum antibiotics. Furthermore, dressings are needed to foster wound exudate absorption and create a protected environment propitious for tissue regeneration. In turn, offloading through minimally invasive surgery such as the minimally invasive metatarsal osteotomies is essential to reduce plantar pressure, while supporting minimal tissue damage, immediate post-operative weight bearing, and a lower risk of potential infections, consequently preventing recurrent ulceration [35][36]. Last but not least, referral to multidisciplinary teams means the indication of appropriate adjuvant therapies for the optimal management of DFUs, such as stress-reducing approaches [37][38], while education is fundamental to improve DFU health literacy for the prevention of future ulcers.
However, despite these efforts, the efficient management of DFUs remain a clinical challenge, with limited success rates in treating severe infections [39][40]. Indeed, current DFU treatments still exhibit a huge recurrence rate of 40% within one year, 60% within three years, and 65% within five years [2][5][29][41], due to persistent risk factors even after the former ulcer has healed [42]. Consequently, there is a crucial need for novel strategies that can successfully address the multifactorial etiology of DFUs.

4. Biomaterials as a Promising Therapeutic Platform for Wound Dressings

A therapeutic strategy with rising potential to handle the challenging macro and micro wound environment of individuals with DM involves the use of biomaterials as wound dressings. Biomaterials have long been related to unique versatility, biocompatibility, biodegradability, and hydrophilicity, characteristics that make them ideal candidates for therapeutic applications [43][44][45]. Furthermore, biomaterials have also been explored for their innate properties for wound healing [43][44][45][46]. An ideal wound dressing for the management of DFUs should present several key features. Firstly, it must demonstrate excellent biocompatibility and biodegradability to ensure tissue healing. Secondly, it should create a moist and warm environment conducive to tissue regeneration. Thirdly, the dressing should prevent polymicrobial infections to ensure proper wound healing. Finally, it should exhibit adequate porosity that enables gas exchange, and stimulate cell migration, proliferation, and neovascularization, as depicted in Figure 2 [43][46].

Figure 2. Potential features of functional biomaterials as ideal wound dressings for diabetic foot ulcer (DFU) healing (produced using BioRender). ↑ represents an increase.

This entry is adapted from the peer-reviewed paper 10.3390/ijms24129900

References

  1. Yang, L.; Rong, G.; Wu, Q. Diabetic foot ulcer: Challenges and future. World J. Diabetes 2022, 13, 1014–1034.
  2. Baig, M.S.; Banu, A.; Zehravi, M.; Rana, R.; Burle, S.S.; Khan, S.L.; Islam, F.; Siddiqui, F.A.; Massoud, E.E.S.; Rahman, M.H.; et al. An Overview of Diabetic Foot Ulcers and Associated Problems with Special Emphasis on Treatments with Antimicrobials. Life 2022, 12, 1054.
  3. Srivastava, P.; Sondak, T.; Sivashanmugam, K.; Kim, K. A Review of Immunomodulatory Reprogramming by Probiotics in Combating Chronic and Acute Diabetic Foot Ulcers (DFUs). Pharmaceutics 2022, 14, 2436.
  4. Akkus, G.; Sert, M. Diabetic foot ulcers: A devastating complication of diabetes mellitus continues non-stop in spite of new medical treatment modalities. World J. Diabetes 2022, 13, 1106–1121.
  5. Edmonds, M.; Manu, C.; Vas, P. The current burden of diabetic foot disease. J. Clin. Orthop. Trauma 2021, 17, 88–93.
  6. Megallaa, M.H.; Ismail, A.A.; Zeitoun, M.H.; Khalifa, M.S. Association of diabetic foot ulcers with chronic vascular diabetic complications in patients with type 2 diabetes. Diabetes Metab. Syndr. Clin. Res. Rev. 2019, 13, 1287–1292.
  7. Da Silva, J.; Leal, E.C.; Carvalho, E. Bioactive antimicrobial peptides as therapeutic agents for infected diabetic foot ulcers. Biomolecules 2021, 11, 1894.
  8. Kalan, L.R.; Meisel, J.S.; Loesche, M.A.; Horwinski, J.; Soaita, I.; Chen, X.; Uberoi, A.; Gardner, S.E.; Grice, E.A. Strain- and Species-Level Variation in the Microbiome of Diabetic Wounds Is Associated with Clinical Outcomes and Therapeutic Efficacy. Cell Host Microbe 2019, 25, 641–655.e5.
  9. Kareliya, H.; Bichile, L.; Bal, A.; Varaiya, A.; Bhalekar, P. Fungal Infection in Diabetic Foot a Clinicomicrobiological Study. Acta Sci. Mcrobiol. 2019, 2, 49–55.
  10. Kalshetti, V.T.; Wadile, R.; Bothikar, S.T.; Ambade, V.; Bhate, V.M. Study of fungal infections in diabetic foot Ulcer. Indian J. Microbiol. Res. 2017, 4, 87–89.
  11. Raiesi, O.; Shabandoust, H.; Dehghan, P.; Shamsaei, S.; Soleimani, A. Fungal infection in foot diabetic patients. J. Basic Res. Med. Sci. 2018, 5, 47–51.
  12. Chellan, G.; Shivaprakash, S.; Ramaiyar, S.K.; Varma, A.K.; Varma, N.; Sukumaran, M.T.; Vasukutty, J.R.; Bal, A.; Kumar, H. Spectrum and prevalence of fungi infecting deep tissues of lower-limb wounds in patients with type 2 diabetes. J. Clin. Microbiol. 2010, 48, 2097–2102.
  13. Ibrahim, A.; Berkache, M.; Morency-Potvin, P.; Juneau, D.; Koenig, M.; Bourduas, K.; Freire, V. Diabetic foot infections: How to investigate more efficiently? A retrospective study in a quaternary university center. Insights Imaging 2022, 13, 88.
  14. Rodrigues, M.; Kosaric, N.; Bonham, C.A.; Gurtner, G.C. Wound healing: A cellular perspective. Physiol. Rev. 2019, 99, 665–706.
  15. Childs, D.R.; Murthy, A.S. Overview of Wound Healing and Management. Surg. Clin. N. Am. 2017, 97, 189–207.
  16. Petkovic, M.; Sørensen, A.E.; Leal, E.C.; Carvalho, E.; Dalgaard, L.T. Mechanistic Actions of microRNAs in Diabetic Wound Healing. Cells 2020, 9, 2228.
  17. Petkovic, M.; Vangmouritzen, M.; Mojsoska, B.; Jenssen, H. Immunomodulatory properties of host defence peptides in skin wound healing. Biomolecules 2021, 11, 952.
  18. Perez-Favila, A.; Martinez-Fierro, M.L.; Rodriguez-Lazalde, J.G.; Cid-Baez, M.A.; Zamudio-Osuna, M.D.J.; Martinez-Blanco, M.D.R.; Mollinedo-Montaño, F.E.; Rodriguez-Sanchez, I.P.; Castañeda-Miranda, R.; Garza-Veloz, I. Current therapeutic strategies in diabetic foot ulcers. Medicina 2019, 55, 714.
  19. Erem, C.; Hacıhasanoğlu, A.; Çelik, Ş.; Ovalı, E.; Ersöz, H.Ö.; Ukinç, K.; Deger, O.; Telatar, M. Coagulation and Fibrinolysis Parameters in Type 2 Diabetic Patients with and without Diabetic Vascular Complications. Med. Princ. Pract. 2005, 14, 22–30.
  20. Xiao, J.; Li, J.; Cai, L.; Chakrabarti, S.; Li, X. Cytokines and Diabetes Research. J. Diabetes Res. 2014, 2014, 920613.
  21. Santoro, M.M.; Gaudino, G. Cellular and molecular facets of keratinocyte reepithelization during wound healing. Exp. Cell Res. 2005, 304, 274–286.
  22. Lan, C.E.; Liu, I.; Fang, A.; Wen, C.; Wu, C. Hyperglycaemic conditions decrease cultured keratinocyte mobility: Implications for impaired wound healing in patients with diabetes. Br. J. Dermatol. 2008, 159, 1103–1115.
  23. Galiano, R.D.; Tepper, O.M.; Pelo, C.R.; Bhatt, K.A.; Callaghan, M.; Bastidas, N.; Bunting, S.; Steinmetz, H.G.; Gurtner, G.C. Topical Vascular Endothelial Growth Factor Accelerates Diabetic Wound Healing through Increased Angiogenesis and by Mobilizing and Recruiting Bone Marrow-Derived Cells. Am. J. Pathol. 2004, 164, 1935–1947.
  24. Maione, A.G.; Smith, A.; Kashpur, O.; Yanez, V.; Knight, E.; Mooney, D.J.; Veves, A.; Tomic-Canic, M.; Garlick, J.A. Altered ECM deposition by diabetic foot ulcer-derived fibroblasts implicates fibronectin in chronic wound repair. Wound Repair Regen. 2016, 24, 630–643.
  25. Brocco, E.; Ninkovic, S.; Marin, M.; Whisstock, C.; Bruseghin, M.; Boschetti, G.; Viti, R.; Forlini, W.; Volpe, A. Diabetic foot management: Multidisciplinary approach for advanced lesion rescue. J. Cardiovasc. Surg. 2018, 59, 670–684.
  26. Uivaraseanu, B.; Bungau, S.; Tit, D.M.; Fratila, O.; Rus, M.; Maghiar, T.A.; Maghiar, O.; Pantis, C.; Vesa, C.M.; Zaha, D.C. Clinical, Pathological and Microbiological Evaluation of Diabetic Foot Syndrome. Medicina 2020, 56, 380.
  27. Ramirez-Acuña, J.M.; Cardenas-Cadena, S.A.; Marquez-Salas, P.A.; Garza-Veloz, I.; Perez-Favila, A.; Cid-Baez, M.A.; Flores-Morales, V.; Martinez-Fierro, M.L. Diabetic foot ulcers: Current advances in antimicrobial therapies and emerging treatments. Antibiotics 2019, 8, 193.
  28. Apelqvist, J. Diagnostics and treatment of the diabetic foot. Endocrine 2012, 41, 384–397.
  29. Reardon, R.; Simring, D.; Kim, B.; Mortensen, J.; Williams, D.; Leslie, A. The diabetic foot ulcer. Aust. J. Gen. Pract. 2020, 49, 250–255.
  30. Musuuza, J.; Sutherland, B.L.; Kurter, S.; Balasubramanian, P.; Bartels, C.M.; Brennan, M.B. A systematic review of multidisciplinary teams to reduce major amputations for patients with diabetic foot ulcers. J. Vasc. Surg. 2020, 71, 1433–1446.e3.
  31. Wang, A.; Lv, G.; Cheng, X.; Ma, X.; Wang, W.; Gui, J.; Hu, J.; Lu, M.; Chu, G.; Jin’an, C.; et al. Guidelines on multidisciplinary approaches for the prevention and management of diabetic foot disease (2020 edition). Burn. Trauma 2020, 8, tkaa017.
  32. Lazzarini, P.; Fernando, M.; Van Netten, J. Diabetic foot ulcers: Is remission a realistic goal? Endocrinol. Today 2019, 8, 22–26.
  33. Da Porto, A.; Miranda, C.; Brosolo, G.; Zanette, G.; Michelli, A.; Ros, R. Da Nutritional supplementation on wound healing in diabetic foot: What is known and what is new? World J. Diabetes 2022, 13, 940–948.
  34. Chuan, F.; Tang, K.; Jiang, P.; Zhou, B.; He, X. Reliability and Validity of the Perfusion, Extent, Depth, Infection and Sensation (PEDIS) Classification System and Score in Patients with Diabetic Foot Ulcer. PLoS ONE 2015, 10, e0124739.
  35. Biz, C.; Ruggieri, P. Minimally Invasive Surgery: Osteotomies for Diabetic Foot Disease. Foot Ankle Clin. 2023, 25, 441–460.
  36. Biz, C.; Belluzzi, E.; Crimì, A.; Bragazzi, N.L.; Nicoletti, P.; Mori, F.; Ruggieri, P. Minimally Invasive Metatarsal Osteotomies (MIMOs) for the Treatment of Plantar Diabetic Forefoot Ulcers (PDFUs): A Systematic Review and Meta-Analysis with Meta-Regressions. Appl. Sci. 2021, 11, 9628.
  37. Pombeiro, I.; Moura, J.; Pereira, M.G.; Carvalho, E. Stress-Reducing Psychological Interventions as Adjuvant Therapies for Diabetic Chronic Wounds. Curr. Diabetes Rev. 2022, 18, e060821195361.
  38. Pereira, M.G.; Vilaça, M.; Carvalho, E. Effectiveness of Two Stress Reduction Interventions in Patients with Chronic Diabetic Foot Ulcers (PSY-DFU): Protocol for a Longitudinal RCT with a Nested Qualitative Study Involving Family Caregivers. Int. J. Environ. Res. Public Health 2022, 19, 8556.
  39. Sen, P.; Demirdal, T.; Emir, B. Meta-analysis of risk factors for amputation in diabetic foot infections. Diabetes. Metab. Res. Rev. 2019, 35, e3165.
  40. Dörr, S.; Freier, F.; Schlecht, M.; Lobmann, R. Bacterial diversity and inflammatory response at first-time visit in younger and older individuals with diabetic foot infection (DFI). Acta Diabetol. 2021, 58, 181–189.
  41. Armstrong, D.G.; Boulton, A.J.M.; Bus, S.A. Diabetic Foot Ulcers and Their Recurrence. N. Engl. J. Med. 2017, 376, 2367–2375.
  42. Fu, X.-L.; Ding, H.; Miao, W.-W.; Mao, C.-X.; Zhan, M.-Q.; Chen, H.-L. Global recurrence rates in diabetic foot ulcers: A systematic review and meta-analysis. Diabetes. Metab. Res. Rev. 2019, 35, e3160.
  43. Güiza-Argüello, V.R.; Solarte-David, V.A.; Pinzón-Mora, A.V.; Ávila-Quiroga, J.E.; Becerra-Bayona, S.M. Current Advances in the Development of Hydrogel-Based Wound Dressings for Diabetic Foot Ulcer Treatment. Polymers 2022, 14, 2764.
  44. Alven, S.; Peter, S.; Mbese, Z.; Aderibigbe, B.A. Polymer-Based Wound Dressing Materials Loaded with Bioactive Agents: Potential Materials for the Treatment of Diabetic Wounds. Polymers 2022, 14, 724.
  45. Bardill, J.R.; Laughter, M.R.; Stager, M.; Liechty, K.W.; Krebs, M.D.; Zgheib, C. Topical gel-based biomaterials for the treatment of diabetic foot ulcers. Acta Biomater. 2022, 138, 73–91.
  46. Divyashri, G.; Badhe, R.V.; Sadanandan, B.; Vijayalakshmi, V.; Kumari, M.; Ashrit, P.; Bijukumar, D.; Mathew, M.T.; Shetty, K.; Raghu, A.V. Applications of hydrogel-based delivery systems in wound care and treatment: An up-to-date review. Polym. Adv. Technol. 2022, 33, 2025–2043.
More
This entry is offline, you can click here to edit this entry!
Video Production Service