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Oxygen-Releasing Composites: A Promising Approach in the Management of Diabetic Foot Ulcers

Department of Otolaryngology Head & Neck Surgery, University of Alabama at Birmingham, Birmingham, AL 35294-0012, USA
Department of Internal Medicine, College of Korean Medicine, Woosuk University, Jeonju 54987, Korea
Author to whom correspondence should be addressed.
Polymers 2021, 13(23), 4131;
Submission received: 28 October 2021 / Revised: 23 November 2021 / Accepted: 25 November 2021 / Published: 26 November 2021
(This article belongs to the Special Issue New Composites for Medical Applications)


In diabetes, lower extremity amputation (LEA) is an irreversible diabetic-related complication that easily occurs in patients with diabetic foot ulcers (DFUs). Because DFUs are a clinical outcome of different causes including peripheral hypoxia and diabetic foot infection (DFI), conventional wound dressing materials are often insufficient for supporting the normal wound healing potential in the ulcers. Advanced wound dressing development has recently focused on natural or biocompatible scaffolds or incorporating bioactive molecules. This review directs attention to the potential of oxygenation of diabetic wounds and highlights current fabrication techniques for oxygen-releasing composites and their medical applications. Based on different oxygen-releasable compounds such as liquid peroxides and solid peroxides, for example, a variety of oxygen-releasing composites have been fabricated and evaluated for medical applications. This review provides the challenges and limitations of utilizing current oxygen releasable compounds and provides perspectives on advancing oxygen releasing composites for diabetic-related wounds associated with DFUs.

1. Introduction

Diabetes is a common and growing disease, affecting nearly 415 million people in the world. Among common diabetes-related complications, lower extremity amputation (LEA) has been recognized as an irreversible complication that usually occurs due to the failure of sufficient preventive care [1]. The risk of LEA in diabetic patients is about 10-fold higher than in the general population [2]. Diabetic foot ulcer (DFU), peripheral neuropathy, and ischemia are usually responsible for LEA. LEA leads to poor quality of patient life, while simultaneously increasing mortality rate. Both immobility and a restricted social life are well-known inconveniences of diabetic patients with LEA [3]. According to a recent study, 1 of 10 patients under major LEA procedures died within 30 days, and male patients were more susceptible regarding mortality [4]. To overcome this unfavorable complication associated with diabetes, it is often required to treat DFUs with elaborative measures. However, the complexity and variation in the origin of the diabetic wound has often resulted in following conventional offloading surgical procedures or offloading treatments with either removable or nonremovable knee-high devices without considering the development of new therapeutic composites [5].
Recent advanced biomaterials for regenerative medicine have also been applied to increase the potential efficacy of wound dressing materials for DFUs. For example, a variety of nanoparticles containing growth factors (e.g., vascular endothelial growth factor; VEGF and basic fibroblast growth factor; bFGF), microRNA (miRNA), and antibacterial agents (e.g., ciprofloxacin) showed improved healing potential in diabetic in vivo models [6,7,8,9]. In addition to these typical bioactive agents, antioxidants have also been incorporated into multiple functional composites for chronic wounds, including diabetic wounds [10,11,12]. Because all diabetic-related complications, including DFUs, have multifactorial etiology, oxygen-releasing composites serve as a source of oxygenation for DFUs and would serve as another essential biomaterial for rescuing chronically impaired wounds. Oxygen supports normal wound metabolism, the synthesis of critical extracellular matrices, and the migration and subsequent proliferation of participant cells such as fibroblasts and macrophages [13]. Moreover, oxygen improves the innate defense mechanism against bacterial invasion by supporting the immune cell-mediated generation of bactericidal oxygen free radicals in physiological conditions [14,15].
In this regard, hyperbaric oxygen therapy (HBOT) has received attention for the past decades and shows positive outcomes. Increased collagen deposition, improved immune activity, and enhanced wound healing have been reported in nondiabetics and DFUs [16]. However, currently available data on the efficacy of HBOT also indicates the variability of adjunctive therapy due to the effect of hyperbaric oxygenation on the damaged tissues. In the hyperbaric oxygen therapy (HBOT) setting, patients receive 100% oxygen directly in a pressured environment and are thus likely to be subjected to central nerve system (CNS) oxygen toxicity [17]. Specifically, overproduction of reactive oxygen species (ROS), formation of peroxynitrite (ONOO-) from nitric oxide, and gross retention of carbon oxide (CO2) in the brain are thought to cause the oxygen toxicity seizure. At low concentrations, oxygen is also reported to create ROS-mediated wound healing signals, while over-dosage of oxygen supplements can increase oxygen cytotoxicity [18]. Hence, oxygen composites that deliver concentrated oxygen in the atmosphere would become a critical element of an ideal diabetic wound dressing material. This article is intended to discuss current oxygen-releasable compounds and oxygen-releasing composite materials as well as recent fabrication techniques for oxygen-releasing composites capable of topically providing oxygen on diabetic-related wounds associated with DFU.

1.1. Diabetic Foot Ulcers (DFUs)

DFUs are one of the most significant diabetes-related complications associated with the hyperglycemic crisis, and the rate of occurrence has remained the same for the past two decades [19]. Diabetic foot ulceration (DFU) characterized by full-thickness penetration of the dermis should be closely monitored to prevent LEA. Several grading systems, including the Wagner system, have been used to characterize DFUs [20]. According to anatomical features, the extent of infection, and the presence of gangrene, the Wagner system can distinguish the degree of diabetic foot ulcerations in diabetic patients and provide either preventive treatment or suitable interventions [21]. The prevalence of DFU was reported as 4% to 10%, while the lifetime risk of a diabetic patient increases up to 25% [22]. Moreover, the recurrence rate of DFU was assumed to be as high as 70% within five years [23]. Peripheral neuropathy, excessive plantar pressure, and repetitive trauma are common causative factors that lead to DFU formation [22]. According to a prevalence study, peripheral neuropathy is common in half of the sixty-year-old type 2 diabetic patients [24]. Likewise, diabetic patients within 25 years of diabetic onsets have symptomatic peripheral neuropathy and subsequent sensory neuropathy that causes the malfunction of protective sensation. Hence, diabetic patients with those diabetic-related complications are prone to experience ultimate physical and thermal trauma [25]. Motor neuropathy is another type of peripheral neuropathy found in diabetic patients, resulting in neuropathic DFU [26]. In combination with sensory loss, the weakened muscles in the foot change the typical foot shape, thereby increasing plantar pressure in the foot, a critical parameter for the development of a neuropathic DFU. The high plantar pressure within diabetic patients is a causative factor, and a 30% reduction in maximum plantar pressure can reduce the risk of developing DFUs [27]. The third causative factor, repetitive trauma, can occur from normal walking activities, through which the foot undergoes an undesired pressure change [28]. The high plantar pressure over time results in neuropathy, deformity, and callus formation [29]. Regarding the risk of LEA during a person’s lifetime with diabetes, peripheral arterial disease (PAD) is another substantial contributing factor. Atherosclerosis, created by the blocking of arteries with fatty deposits, contributes to the development of PAD. The narrowed arteries reduce the blood flow of the heart, brain, and limbs, leading to multiple diabetes complications in diabetic patients [30]. When PAD develops, diabetic patients often feel calf and lower extremity pain, called intermittent claudication. Most diabetic patients with PAD, however, are asymptomatic, meaning that early diagnosis is essential to reduce the chance of developing LEA. Although both DFU and PAD increase the possibility of needing LEA, DFUs are a more critical risk factor than PAD in terms of necessitating LEA. Over 80% of LEA were reported because of nonhealing wounds and ulceration [31].

1.1.1. General Pathobiochemical Hallmarks of Chronic Wounds in the DFU

In an acute injury, damaged skin can initiate the normal wound healing phases comprised of hemostasis, inflammation, proliferation, and remodeling phase, whereas lower extremity wounds are characterized by impaired wound healing phases (Figure 1) [32]. Delayed wound healing is associated with several pathophysiological changes in diabetic wounds. Elevated inflammatory cytokines (e.g., IL-1β and TNF-α), lowered circulating endothelial progenitor cells (EPCs), and reduced stromal cell-derived factor 1 (SDF1) were consistently found in diabetic wounds [33,34]. Lack of sufficient concentrations of the growth factor, granulocyte macrophage-colony stimulating factor (GM-CSF), was also observed in diabetic wounds [35]. In addition, Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), which play a significant role in the remodeling of ECM, are not balanced in chronic diabetic wounds [36,37]. Moreover, in the state of diabetic neuropathy, glucose levels in the wound area are likely to rise without sufficient blood supply. High glucose in the wound area delays the re-epithelization stage of wound healing by impairing keratinocyte migration [38]. According to several recent studies, p38/mitogen-activated protein kinase (MAPK), which regulates keratinocyte migration, was altered in high glucose conditions [39,40].

1.1.2. General Risk Factors Associated with DFU for Preventing LEA

To prevent ultimate amputation, the major causes of DFUs should be managed. Both ischemia and infection are considered critical causal factors that unfortunately lead to LEA (Figure 2) [41]. In diabetic ischemic ulcers, hypoxia is responsible for reduction of hypoxia-inducible factor-1 (HIF-1), which is a transcription factor that mediates oxygen homeostasis [42]. This reduction of HIF-1 activation thereafter contributes to the delayed wound healing seen in DFUs [42]. Moreover, hyperglycemia destabilizes HIF-1α, which is the regulatory subunit of HIF-1 [43]. In a recent in vitro study, human dermal fibroblasts (HDFs) and human dermal microvascular endothelial cells (HDMECs) secreted reduced HIF-1α in high glucose media compared to normal cells grown in regular glucose media [44]. The increased pressure of the plantar aspect of the foot observed in diabetic patient groups is another casual factor [45]. High plantar foot pressure leads to ulceration in diabetic populations, regardless of ethnicity, and diabetic neuropathy also independently affects the extent of ulceration [46].
In addition, diabetic foot infection (DFI) is a well-known risk factor for LEA [31]. Multiple causative factors such as diabetic immunopathy, diabetic neuropathy, and diabetic angiopathy, and impaired skin antimicrobial defense mechanisms in both physical and biochemical manner induce the polymicrobial biofilm infections [47]. Following chronic infections associated with reduced blood flow in peripheral artery disease, the normal recruitment of immune cells fails, and high glucose levels in the peripheral blood vessels retard the proper function of neutrophiles, which is a critical step of the proper host antimicrobial defense [48]. Gram-positive bacteria such as Staphylococcus aureus and Streptococcus spp. were commonly found in mid-infected diabetic wounds, while both Gram-positive and Gram-negative bacteria were found in the case of severe infections [49]. Moreover, multidrug-resistant (MDR) microorganisms are easily found in polymicrobial infected DFUs, thereby reducing the efficacy of available antibiotic treatments [50]. Such hard-to-kill pathogens are the primary reason for poor clinical outcomes when treated with conventional antibiotic treatment for DFIs [51].

1.1.3. Topical Ulcer Treatment of Preventing the DFU

While avoiding the risks mentioned above, appropriate topical ulcer treatments are essential to reduce the risk of LEA. To date, commonly utilized topical ulcer treatments include debridement, wound dressing, and antimicrobial wound dressing. All wound dressings can absorb excessive exudates from wounds, creating the favorable microenvironment that initiates the wound healing process. Based on the physical types of wound dressings, four significant forms are currently found in the market: hydrogels, hydrocolloids, foams, and films [52]. However, for treating chronic wounds, including DFUs, more functional wound dressings are more attractive. A variety of wound care products are already commercially available using advanced matrices and bioactive molecules (Table 1). For example, natural polymers such as hyaluronic acid and alginate are frequently used materials. Collagen is also a well-utilized advanced matrix material intended for promoting the wound healing process. Likewise, human cellular wound dressings are used for supporting epidermal reconstitution. The extracellular matrices (ECMs) facilitate the normal wound healing processes. The ECM interacts with cells capable of remodeling the damaged tissues. In addition, recent studies indicate that the fragmented ECM molecules also act as singling cues for governing the healing processes [53,54]. Several bioactive molecules have been widely used in the development of wound dressings for DFUs. For example, inorganic antimicrobial agents such as silver and iodine are utilized without the risk of antibiotic resistance, in contrast to conventional antibiotics which can sometimes be limited by antibiotic resistance.

2. Oxygen Releasable Compounds: Different Approaches for the DFU

Oxygen releasable compounds can achieve a topical oxygen delivery to chronic wounds. In general, oxygen-releasing composites have been fabricated by embedding oxygen releasable compounds such as solid peroxides, liquid peroxides, and fluorinated molecules into biocompatible matrices. Through different triggering mechanisms, these oxygen-carrying compounds can release oxygen (Table 2). This section explains the different types of oxygen releasable compounds commonly used to give an insight on the development of topical oxygen-based methods for diabetic wounds repair.

3. Oxygen in Diabetic Wound Repairs

Oxygen is another critical factor for increasing the successful healing of chronic wounds. The oxygenated microenvironment during angiogenesis improves the wound healing process (Figure 3). Oxygen also promotes procollagen maturation and collagen deposition for proper epithelialization [60,61]. Even at the molecular level, hypoxia in wounds can initially stimulate collagen fiber formation through inactivated HIF-1 mediated procollagen hydroxylases, thus supporting the fact that proper oxygen tension is essential for the completion of the wound-healing process [62]. While promoting the healing process, increased oxygen tension also helps enhance the antibacterial activity of leukocytes recruited near chronic wounds [63].
In this regard, hyperbaric oxygen therapy (HBOT) provides pure oxygen to diabetic patients in a pressurized oxygen chamber and has been clinically used to manage diabetic foot ulcers for the last decades [64,65]. In a randomized, double-blinded, and placebo-controlled clinical trial performed at a Sweden hospital with ninety-four patients with above Wagner grade 2, the HBOT patient group treated with at least 35 HBOT sessions during an eight-week study showed improved healing of ulcers [65]. In another randomized clinical trial, the significant amputation rate in diabetic patients with severe foot ulcer was reduced when treated with systemic HBOT. Only 8.6% of subjects with systemic HBOT led to major amputation compared to 33% in the nontreated group (p = 0.016) [66]. HBOT also demonstrated improved healing rates and quality of life in diabetic foot ulcers when applied for several months [67].
However, HBOT has several drawbacks in terms of clinical complications associated with repetitive use and accessibility. Common difficulties with pressured oxygen chambers include middle ear pain, cranial sinus pain, and teeth pain. Almost 10% of subjected patients had reported such pain, and over half of the patients terminated the HBOT [68]. In addition to the clinical complications, some patients experienced claustrophobia due to the enclosed chamber. Because HBOT affects the whole body during treatment, pressure-associated side effects including middle ear barotrauma (MEB), sinus/paranasal barotrauma, dental barotrauma, and pulmonary barotrauma are common [17]. Moreover, artificial oxygen tension created in the enclosed chamber can induce central nervous system (CNS) oxygen toxicity [69].

4. Examples of Oxygen-Releasing Composites in the Tissue Engineering

Based on the oxygen releasable compounds mentioned above, different types of oxygen-releasing composites have been developed (Table 3). Recent oxygen-releasing composites have mainly been studied to either create a normoxic cellular microenvironment in pathological tissues or sustain oxygen delivery for supporting tissue-engineered constructs.

4.1. Hydrogen Peroxides: Orangic Oxygen Releasing Compounds

A study used a double encapsulated oxygen delivery system to achieve sustained oxygen delivery while reducing the cytotoxicity of hydrogen peroxide [70]. The first encapsulated layer was made from H2O2 and biocompatible poly(D,L-lactide-co-glycolide) (PLGA) polymer. Then, a covalently cross-linked catalase-alginate polymer was used to enclose the shelled H2O2 composite, leading to prolonged oxygen delivery without cellular cytotoxicity. Silica gel, polyvinylpyrrolidone (PVP), and small molecules (e.g., urea, sodium carbonate, and sodium borate) entrapped H2O2 molecules within the composite [79,80]. In such silica-based encapsulation, divalent metal ions, Mg2+ and Ca2+, also contributed to the release of H2O2 from silica hydrogels [81]. Such engineerable characteristics of materials that modulate the extended H2O2 delivery indicate that liquid H2O2 molecules hold great potential for the realization of topical oxygen delivery in diabetic wounds repair.

4.2. Solid Peroxides: Inorangic Oxygen Releasing Compounds

Compared to liquid hydrogen peroxide, solid peroxides are flexible to achieve controlled oxygen delivery through encapsulating them within biocompatible materials such as PLGA and polydimethylsiloxane (PDMS). Harrison et al. created SPC-encapsulated PLGA films that release oxygen for 70 h, contributing to the prevention of graft necrosis as shown in mice skin flaps [82]. An implantable silicone encapsulated CPO, exhibiting much more extended oxygen release for transplanted islets, was developed [83]. In this study, authors fabricated a CPO (25% wt/wt)-embedded PDMS disc to rescue beta-cells, which produced insulin in response to glucose. Because beta-cells reside in the core of islets, they need to receive significant oxygen continuously while responding to physiological glucose levels. A CPO-embedded PDMS disc demonstrated long-term oxygen delivery for four weeks with the highest oxygen delivery in the first week, supporting enhanced viability and functionality of the MIN6 β cell line and rat pancreatic islets in vitro for 14 days [84]. In other studies, antioxidant-doped polyurethane (PU) scaffold (PUAO) encapsulated CPOs were utilized [85,86]. The PUAO-CPO scaffolds released oxygen and prevented skin flip necrosis in mice in vivo model up to nine days.

4.3. Perfluorocarbons: Passive Oxygen Releasing Compounds

Perfluorocarbons are halogen-substituted nonpolar carbon-based oils. Perfluorocarbon (PFC) emulsions are typical forms of enhanced oxygen delivery [87]. For example, Fluosol-DA-20% obtained FDA approval to prevent coronary ischemia and demonstrated enhanced oxygen delivery because of large surface ratios of the PFC emulsions, facilitating oxygen charges subjected to Henry’s Law (in PFCs).

5. Topical Oxygen-Releasing Composites in the Management of the DFU

Based on our previous reviews on oxygen biomaterials, this section describes how such oxygen-releasing composites help heal wounds (e.g., chronic wounds) commonly observed in early LEA. Although most scaffolds are not specific for DFUs, these studies give a perspective on the ongoing development of functional oxygen-releasing composites for diabetic-related complications.

5.1. Topical Delivery of Oxygen: Significance of Repeated Oxygen Supplements

As an alternative to using sophisticated methods involved in HBOT, topical hyperbaric oxygen (THO) treatment using a disposable or reusable limb chamber attached to an oxygen tank has been studied. However, there is controversy regarding the efficacy of THO on diabetic wounds exhibiting delayed healing [88]. Another approach toward improved wound healing is transdermal oxygen therapy (TOT). A portable miniature device (EPIFLO®) capable of producing oxygen from the ambient air delivers nearly pure oxygen around diabetic wounds for 15 days [89]. The concept of TOT was also studied using excisional pig dermal wounds where repeated TOT treatment via topical oxygen device accelerated wound closure in the early post-wound phase [90]. According to a nine-month follow-up study, seven surgeons performed TOT treatment on the wounds (n = 58) of 32 patients. About 73% of the wounds from fifteen participating patients were completely cured. Even though ten wounds resulted in no positive outcome during the TOT treatment, TOT has a beneficial role in facilitating wound healing without complications overall [91].

5.2. Potential Examples of Viable Oxygen-Releasing Composites for the DFU

An oxygen-delivering hydrogel, called methacrylamide chitosan, modified with perfluorocarbon chains (MACF) hydrogel, was fabricated and evaluated for use as a topical oxygen deliverable wound dressing [91]. The MACF hydrogel showed 100% oxygen saturation within 10 min. The oxygenated MACF showed the best re-epithelialization compared to controls (no hydrogel, non-oxygenated MACF, unmodified methaacrylamide (MAC), and non-oxygenated MAC). Further metabolomic analyses also indicated that MACF hydrogel promoted the metabolic expression associated with wound healing, followed by collagen synthesis in the granulation bed. In this study, the MACF hydrogel was replaced every two days and observed for eight days.
Another oxygen-generating hydrogel (OG hydrogel) was developed by incorporating glucose oxidase (GOx, EC and peroxidase (PO, EC within either PVA or PVP-based hydrogel via γ-irradiation cross-linking [92]. The prepared OG hydrogel produced oxygen in response to glucose and released iodine from potassium iodine. This composite contributed to rapid diabetic wound healing while combatting microbial wound infections. A paper-based oxygen-releasing platform was also studied [88]. Using the ability of manganese dioxide (MnO2) to convert H2O2 into oxygen and water, the authors fabricated a PDMS microfluidic device with parchment paper onto which MnO2 were selectively deposited in the designated catalytic regions of the microfluidic device. In this device, generated oxygen from the catalytic regions was freely permeated through the installed parchment paper, supporting cell survival without harmful opposite-side flowing H2O2 cytotoxicity. Because new wound dressings can replace old ones daily, such repetitive replacements would boost the benefits of oxygen therapy while maintaining the advantage of oxygen biomaterials in practical wound management.

5.3. Antibacterial Activities of Oxygen-Releasing Composites

In the process of wound healing, oxygen can contribute not only to the production of energy essential for tissue regeneration, but also to the establishment of anti-microbial defense mechanisms [93]. Not only can solid peroxides provide oxygen in contact with water, but they also exhibit antibacterial activity due H2O2 production. In a study using polycaprolactone (PCL) nanofibers as CPO carriers, the CPO-PCL nanofibers inhibited the growth of Escherichia coli (E. coli) and Staphylococcus epidermidis (S. epidermidis) at the initial incubation period, during which embedded CPOs were rapidly released [94]. Similarly, an oxygen-releasing hybrid polymeric nanofiber scaffold composed of poly(glycerol sebacate) (PGS) and poly(ε-caprolactone) (PCL) was studied [95]. In this study, nanofibers with more fine CPO nanoparticles exhibited a sustainable oxygen release for up to one week. In addition to antibacterial activity against Staphylococcus aureus (S. aureus), the CPO-embedded PGS/PCL nanofibrous also showed gradual viability recovery of primary bone-marrow-derived mesenchymal stem cells (BM-MSCs).

5.4. Perspecitve and Future Directions for Oxygen-Releasing Composites

In the perspective of prolonged topical oxygen delivery for DFUs, it is worth paying attention to recent studies showing both developments of new functional materials and the utilization of new oxygen sources (Figure 4). A study directly fabricated an oxygen-releasing composite by stabilizing the formed CPO nanoparticle with tannic acid (TA) [96]. The authors created spherical CPO aggregates intermingled with tannic acids with sizes of 25–31 nm. Compared to the normal several micrometer sizes of CPO particles, such a stable small size of oxygen-releasing composites increased the application of solid peroxides in the development of functional composites for a variety of tissue-engineering applications including topical oxygen delivery for DFUs. Another strategy that effectively delivers oxygen applies to the concept of on-demand drug delivery, which has been one of the more interesting topics in the field of pharmaceutical sciences. Utilizing the principle of radial extracorporeal shockwave therapy (rESWT), an in vivo study demonstrated that the radial extracorporeal shock wave (rESW) can initiate the release of oxygen from oxygen-loaded nano-perfluorocarbon (Nano-PFC) emulsions [97]. The authors showed rESW-responsive oxygen release from the oxygen-saturated emulsions. Instead of using conventional oxygen-releasable compounds, a recent innovative study employed a living microorganism to serve as an oxygen provider under light [98]. While there are a lot of practical challenges required for becoming a clinically applicable technology, such innovated strategies give us new insight for developing more ideal oxygen-releasing composites that have the potential to manage diabetic chronic wounds.

6. Conclusions

Ineffective management of DFUs can lead to terminal LEA. As previously described, all types of diabetic foot ulcers result from numerous risk factors such as peripheral neuropathy, peripheral vascular disease, foot deformities, arterial insufficiency, trauma, and impaired resistance to infection. However, there is no ideal wound dressing suitable for all diabetic patients suffering from pathologies with different sets of causes. A study indicated that almost 12% of all diabetic patients with DFUs will require amputation, and most patients who have undergone LEA are still at risk of developing ulcers in the contralateral limb [99]. In this regard, there is an ongoing need for developing more functional wound dressings tailored to diabetic patients. Topical ulcer treatment with oxygen would be a potential therapy for treating DFUs in the healing stages, which has already been impaired by diabetes. Because of the unique drawbacks of each oxygen compound, few studies have been reported to develop such functional wound scaffolds with oxygen-releasing composites. Oxygen-carrying perfluorocarbons in lipophilic carriers have limited shelf life, and safety issues associated with both used perfluorocarbons themselves and carriers [56,100]. Meanwhile, solid peroxides cannot avoid undesired byproducts (e.g., hydroxide, H2O2 in high level) during the oxygen generation. Such limitations in oxygen releasing compounds, however, may be resolved by incorporating advanced fabrication techniques and new functional biomaterials that exhibit sustained oxygen delivery from these compounds while minimizing or neutralizing reactants. Further advancement in fabrication techniques as well as in the development of functional materials for oxygen-releasing composites will allow us to present a viable option for better diabetic chronic wound management that recuses vulnerable diabetic patients to both DFUs and LEA.

Author Contributions

Conceptualization, D.-J.L.; writing—original draft preparation, D.-J.L. and I.J.; writing—review and editing, I.J.; project administration and funding acquisition, D.-J.L. and I.J. All authors have read and agreed to the published version of the manuscript.


This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.


  1. Harding, J.L.; Pavkov, M.E.; Magliano, D.J.; Shaw, J.E.; Gregg, E.W. Global trends in diabetes complications: A review of current evidence. Diabetologia 2019, 62, 3–16. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Siitonen, O.I.; Niskanen, L.K.; Laakso, M.; Siitonen, J.T.; Pyörälä, K. Lower-extremity amputations in diabetic and nondiabetic patients. A population-based study in eastern Finland. Diabetes Care 1993, 16, 16–20. [Google Scholar] [CrossRef] [PubMed]
  3. Price, P. The Diabetic Foot: Quality of Life. Clin. Infect. Dis. 2004, 39, S129–S131. [Google Scholar] [CrossRef]
  4. Gurney, J.K.; Stanley, J.; Rumball-Smith, J.; York, S.; Sarfati, D. Postoperative Death After Lower-Limb Amputation in a National Prevalent Cohort of Patients With Diabetes. Diabetes Care 2018, 41, 1204–1211. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. Lazzarini, P.A.; Jarl, G. Knee-High Devices Are Gold in Closing the Foot Ulcer Gap: A Review of Offloading Treatments to Heal Diabetic Foot Ulcers. Medicina 2021, 57, 941. [Google Scholar] [CrossRef]
  6. Chereddy, K.K.; Lopes, A.; Koussoroplis, S.; Payen, V.; Moia, C.; Zhu, H.; Sonveaux, P.; Carmeliet, P.; des Rieux, A.; Vandermeulen, G.; et al. Combined effects of PLGA and vascular endothelial growth factor promote the healing of non-diabetic and diabetic wounds. Nanomed. Nanotechnol. Biol. Med. 2015, 11, 1975–1984. [Google Scholar] [CrossRef]
  7. Losi, P.; Briganti, E.; Errico, C.; Lisella, A.; Sanguinetti, E.; Chiellini, F.; Soldani, G. Fibrin-based scaffold incorporating VEGF- and bFGF-loaded nanoparticles stimulates wound healing in diabetic mice. Acta Biomater. 2013, 9, 7814–7821. [Google Scholar] [CrossRef]
  8. Zgheib, C.; Hilton, S.A.; Dewberry, L.C.; Hodges, M.M.; Ghatak, S.; Xu, J.; Singh, S.; Roy, S.; Sen, C.K.; Seal, S.; et al. Use of Cerium Oxide Nanoparticles Conjugated with MicroRNA-146a to Correct the Diabetic Wound Healing Impairment. J. Am. Coll. Surg. 2019, 228, 107–115. [Google Scholar] [CrossRef] [PubMed]
  9. Wang, T.; Li, Y.; Cornel, E.J.; Li, C.; Du, J. Combined Antioxidant-Antibiotic Treatment for Effectively Healing Infected Diabetic Wounds Based on Polymer Vesicles. ACS Nano 2021, 15, 9027–9038. [Google Scholar] [CrossRef] [PubMed]
  10. Hassan, M.A.; Tamer, T.M.; Valachová, K.; Omer, A.M.; El-Shafeey, M.; Mohy Eldin, M.S.; Šoltés, L. Antioxidant and antibacterial polyelectrolyte wound dressing based on chitosan/hyaluronan/phosphatidylcholine dihydroquercetin. Int. J. Biol. Macromol. 2021, 166, 18–31. [Google Scholar] [CrossRef] [PubMed]
  11. Zhu, Y.; Cankova, Z.; Iwanaszko, M.; Lichtor, S.; Mrksich, M.; Ameer, G.A. Potent laminin-inspired antioxidant regenerative dressing accelerates wound healing in diabetes. Proc. Natl. Acad. Sci. USA 2018, 115, 6816–6821. [Google Scholar] [CrossRef] [Green Version]
  12. Xu, Z.; Han, S.; Gu, Z.; Wu, J. Advances and Impact of Antioxidant Hydrogel in Chronic Wound Healing. Adv. Healthc. Mater. 2020, 9, 1901502. [Google Scholar] [CrossRef]
  13. Sano, H.; Ichioka, S.; Sekiya, N. Influence of Oxygen on Wound Healing Dynamics: Assessment in a Novel Wound Mouse Model under a Variable Oxygen Environment. PLoS ONE 2012, 7, e50212. [Google Scholar] [CrossRef] [Green Version]
  14. Knighton, D.R.; Halliday, B.; Hunt, T.K. Oxygen as an Antibiotic: A Comparison of the Effects of Inspired Oxygen Concentration and Antibiotic Administration on In Vivo Bacterial Clearance. Arch. Surg. 1986, 121, 191–195. [Google Scholar] [CrossRef] [PubMed]
  15. Knighton, D.R.; Halliday, B.; Hunt, T.K. Oxygen as an Antibiotic: The Effect of Inspired Oxygen on Infection. Arch. Surg. 1984, 119, 199–204. [Google Scholar] [CrossRef]
  16. Sharma, R.; Sharma, S.K.; Mudgal, S.K.; Jelly, P.; Thakur, K. Efficacy of hyperbaric oxygen therapy for diabetic foot ulcer, a systematic review and meta-analysis of controlled clinical trials. Sci. Rep. 2021, 11, 2189. [Google Scholar] [CrossRef]
  17. Heyboer, M., 3rd; Sharma, D.; Santiago, W.; McCulloch, N. Hyperbaric Oxygen Therapy: Side Effects Defined and Quantified. Adv Wound Care (New Rochelle) 2017, 6, 210–224. [Google Scholar] [CrossRef] [Green Version]
  18. Gordillo, G.M.; Sen, C.K. Revisiting the essential role of oxygen in wound healing. Am. J. Surg. 2003, 186, 259–263. [Google Scholar] [CrossRef]
  19. Gregg, E.W.; Li, Y.; Wang, J.; Rios Burrows, N.; Ali, M.K.; Rolka, D.; Williams, D.E.; Geiss, L. Changes in Diabetes-Related Complications in the United States, 1990–2010. N. Engl. J. Med. 2014, 370, 1514–1523. [Google Scholar] [CrossRef] [Green Version]
  20. Widatalla, A.H.; Mahadi, S.E.I.; Shawer, M.A.; Elsayem, H.A.; Ahmed, M.E. Implementation of diabetic foot ulcer classification system for research purposes to predict lower extremity amputation. Int. J. Diabetes Dev. Ctries 2009, 29, 1–5. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  21. Wagner, F.W., Jr. The diabetic foot. Orthopedics 1987, 10, 163–172. [Google Scholar] [CrossRef]
  22. Singh, N.; Armstrong, D.G.; Lipsky, B.A. Preventing Foot Ulcers in Patients With Diabetes. JAMA 2005, 293, 217–228. [Google Scholar] [CrossRef]
  23. Boulton, A.J.M.; Vileikyte, L.; Ragnarson-Tennvall, G.; Apelqvist, J. The global burden of diabetic foot disease. Lancet 2005, 366, 1719–1724. [Google Scholar] [CrossRef]
  24. Young, M.J.; Boulton, A.J.M.; Macleod, A.F.; Williams, D.R.R.; Sonksen, P.H. A multicentre study of the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population. Diabetologia 1993, 36, 150–154. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  25. Volmer-Thole, M.; Lobmann, R. Neuropathy and Diabetic Foot Syndrome. Int. J. Mol. Sci. 2016, 17, 917. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  26. Andersen, H. Motor dysfunction in diabetes. Diabetes/Metab. Res. Rev. 2012, 28, 89–92. [Google Scholar] [CrossRef]
  27. Bus, S.A.; Armstrong, D.G.; van Deursen, R.W.; Lewis, J.E.; Caravaggi, C.F.; Cavanagh, P.R. IWGDF guidance on footwear and offloading interventions to prevent and heal foot ulcers in patients with diabetes. Diabetes/Metab. Res. Rev. 2016, 32 (Suppl. s1), 25–36. [Google Scholar] [CrossRef] [Green Version]
  28. Lavery, L.A.; La Fontaine, J.; Kim, P.J. Preventing the first or recurrent ulcers. Med. Clin. N. Am. 2013, 97, 807–820. [Google Scholar] [CrossRef]
  29. Lavery, L.A.; Peters, E.J.; Armstrong, D.G. What are the most effective interventions in preventing diabetic foot ulcers? Int. Wound J. 2008, 5, 425–433. [Google Scholar] [CrossRef] [PubMed]
  30. La Sala, L.; Prattichizzo, F.; Ceriello, A. The link between diabetes and atherosclerosis. Eur. J. Prev. Cardiol. 2019, 26, 15–24. [Google Scholar] [CrossRef]
  31. Pecoraro, R.E.; Reiber, G.E.; Burgess, E.M. Pathways to Diabetic Limb Amputation: Basis for Prevention. Diabetes Care 1990, 13, 513–521. [Google Scholar] [CrossRef]
  32. 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. [Google Scholar] [CrossRef] [Green Version]
  33. Wetzler, C.; Kämpfer, H.; Stallmeyer, B.; Pfeilschifter, J.; Frank, S. Large and Sustained Induction of Chemokines during Impaired Wound Healing in the Genetically Diabetic Mouse: Prolonged Persistence of Neutrophils and Macrophages during the Late Phase of Repair. J. Investig. Dermatol. 2000, 115, 245–253. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Gallagher, K.A.; Liu, Z.J.; Xiao, M.; Chen, H.; Goldstein, L.J.; Buerk, D.G.; Nedeau, A.; Thom, S.R.; Velazquez, O.C. Diabetic impairments in NO-mediated endothelial progenitor cell mobilization and homing are reversed by hyperoxia and SDF-1 alpha. J. Clin. Investig. 2007, 117, 1249–1259. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Bianchi, L.; Ginebri, A.; Hagman, J.; Francesconi, F.; Carboni, I.; Chimenti, S. Local treatment of chronic cutaneous leg ulcers with recombinant human granulocyte-macrophage colony-stimulating factor. J. Eur. Acad. Dermatol. Venereol. 2002, 16, 595–598. [Google Scholar] [CrossRef] [PubMed]
  36. Trengove, N.J.; Stacey, M.C.; Macauley, S.; Bennett, N.; Gibson, J.; Burslem, F.; Murphy, G.; Schultz, G. Analysis of the acute and chronic wound environments: The role of proteases and their inhibitors. Wound Repair Regen. 1999, 7, 442–452. [Google Scholar] [CrossRef]
  37. Ito, A.; Sato, T.; Iga, T.; Mori, Y. Tumor necrosis factor bifunctionally regulates matrix metalloproteinases and tissue inhibitor of metalloproteinases (TIMP) production by human fibroblasts. FEBS Lett. 1990, 269, 93–95. [Google Scholar] [CrossRef] [Green Version]
  38. Hu, S.C.; Lan, C.E. High-glucose environment disturbs the physiologic functions of keratinocytes: Focusing on diabetic wound healing. J. Dermatol. Sci. 2016, 84, 121–127. [Google Scholar] [CrossRef] [PubMed]
  39. Kim, E.K.; Choi, E.-J. Pathological roles of MAPK signaling pathways in human diseases. Biochim. Biophys. Acta (BBA)-Mol. Basis Dis. 2010, 1802, 396–405. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  40. Li, L.; Zhang, J.; Zhang, Q.; Zhang, D.; Xiang, F.; Jia, J.; Wei, P.; Zhang, J.; Hu, J.; Huang, Y. High Glucose Suppresses Keratinocyte Migration Through the Inhibition of p38 MAPK/Autophagy Pathway. Front. Physiol. 2019, 10, 24. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  41. Ulbrecht, J.S.; Cavanagh, P.R.; Caputo, G.M. Foot Problems in Diabetes: An Overview. Clin. Infect. Dis. 2004, 39, S73–S82. [Google Scholar] [CrossRef]
  42. Catrina, S.-B.; Zheng, X. Disturbed hypoxic responses as a pathogenic mechanism of diabetic foot ulcers. Diabetes/Metab. Res. Rev. 2016, 32, 179–185. [Google Scholar] [CrossRef]
  43. Botusan, I.R.; Sunkari, V.G.; Savu, O.; Catrina, A.I.; Grünler, J.; Lindberg, S.; Pereira, T.; Ylä-Herttuala, S.; Poellinger, L.; Brismar, K.; et al. Stabilization of HIF-1α is critical to improve wound healing in diabetic mice. Proc. Natl. Acad. Sci. USA 2008, 105, 19426–19431. [Google Scholar] [CrossRef] [Green Version]
  44. Catrina, S.-B.; Okamoto, K.; Pereira, T.; Brismar, K.; Poellinger, L. Hyperglycemia Regulates Hypoxia-Inducible Factor-1α Protein Stability and Function. Diabetes 2004, 53, 3226–3232. [Google Scholar] [CrossRef] [Green Version]
  45. Bennett, P.J.; Stocks, A.E.; Whittam, D.J. Analysis of risk factors for neuropathic foot ulceration in diabetes mellitus. J. Am. Podiatr. Med Assoc. 1996, 86, 112–116. [Google Scholar] [CrossRef] [PubMed]
  46. Frykberg, R.G.; Lavery, L.A.; Pham, H.; Harvey, C.; Harkless, L.; Veves, A. Role of neuropathy and high foot pressures in diabetic foot ulceration. Diabetes Care 1998, 21, 1714–1719. [Google Scholar] [CrossRef] [PubMed]
  47. Pouget, C.; Dunyach-Remy, C.; Pantel, A.; Schuldiner, S.; Sotto, A.; Lavigne, J.-P. Biofilms in Diabetic Foot Ulcers: Significance and Clinical Relevance. Microorganisms 2020, 8, 1580. [Google Scholar] [CrossRef] [PubMed]
  48. Gallacher, S.J.; Thomson, G.; Fraser, W.D.; Fisher, B.M.; Gemmell, C.G.; MacCuish, A.C. Neutrophil Bactericidal Function in Diabetes Mellitus: Evidence for Association with Blood Glucose Control. Diabet. Med. 1995, 12, 916–920. [Google Scholar] [CrossRef] [PubMed]
  49. Frykberg, R.G. An evidence-based approach to diabetic foot infections. Am. J. Surg. 2003, 186, 44–54. [Google Scholar] [CrossRef] [PubMed]
  50. Hassan, M.A.; Tamer, T.M.; Rageh, A.A.; Abou-Zeid, A.M.; Abd El-Zaher, E.H.F.; Kenawy, E.-R. Insight into multidrug-resistant microorganisms from microbial infected diabetic foot ulcers. Diabetes Metab. Syndr. Clin. Res. Rev. 2019, 13, 1261–1270. [Google Scholar] [CrossRef] [PubMed]
  51. Lipsky, B.A. Diabetic foot infections: Current treatment and delaying the ‘post-antibiotic era’. Diabetes/Metab. Res. Rev. 2016, 32, 246–253. [Google Scholar] [CrossRef]
  52. Moura, L.I.F.; Dias, A.M.A.; Carvalho, E.; de Sousa, H.C. Recent advances on the development of wound dressings for diabetic foot ulcer treatment—A review. Acta Biomater. 2013, 9, 7093–7114. [Google Scholar] [CrossRef] [Green Version]
  53. Maquart, F.X.; Siméon, A.; Pasco, S.; Monboisse, J.C. Regulation of cell activity by the extracellular matrix: The concept of matrikines. J. Soc. Biol. 1999, 193, 423–428. [Google Scholar] [CrossRef]
  54. Duca, L.; Floquet, N.; Alix, A.J.P.; Haye, B.; Debelle, L. Elastin as a matrikine. Crit. Rev. Oncol./Hematol. 2004, 49, 235–244. [Google Scholar] [CrossRef] [PubMed]
  55. Waite, A.J.; Bonner, J.S.; Autenrieth, R. Kinetics and Stoichiometry of Oxygen Release from Solid Peroxides. Environ. Eng. Sci. 1999, 16, 187–199. [Google Scholar] [CrossRef]
  56. Jägers, J.; Wrobeln, A.; Ferenz, K.B. Perfluorocarbon-based oxygen carriers: From physics to physiology. Pflug. Arch 2021, 473, 139–150. [Google Scholar] [CrossRef]
  57. White, D.C.; Teasdale, P.R. The oxygenation of blood by hydrogen peroxide: In vitro studies. Br. J. Anaesth. 1966, 38, 339–344. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  58. George, P. Reaction Between Catalase and Hydrogen Peroxide. Nature 1947, 160, 41–43. [Google Scholar] [CrossRef] [PubMed]
  59. Hiner, A.N.P.; Hernández-Ruiz, J.; Williams, G.A.; Arnao, M.B.; García-Cánovas, F.; Acosta, M. Catalase-like Oxygen Production by Horseradish Peroxidase Must Predominantly Be an Enzyme-Catalyzed Reaction. Arch. Biochem. Biophys. 2001, 392, 295–302. [Google Scholar] [CrossRef]
  60. Jonsson, K.; Jensen, J.A.; Goodson, W.H., 3rd; Scheuenstuhl, H.; West, J.; Hopf, H.W.; Hunt, T.K. Tissue oxygenation, anemia, and perfusion in relation to wound healing in surgical patients. Ann. Surg. 1991, 214, 605–613. [Google Scholar] [CrossRef]
  61. Gottrup, F. Oxygen in Wound Healing and Infection. World J. Surg. 2004, 28, 312–315. [Google Scholar] [CrossRef] [PubMed]
  62. Hofbauer, K.-H.; Gess, B.; Lohaus, C.; Meyer, H.E.; Katschinski, D.; Kurtz, A. Oxygen tension regulates the expression of a group of procollagen hydroxylases. Eur. J. Biochem. 2003, 270, 4515–4522. [Google Scholar] [CrossRef] [PubMed]
  63. Hohn, D.C.; MacKay, R.D.; Halliday, B.; Hunt, T.K. Effect of O2 tension on microbicidal function of leukocytes in wounds and in vitro. Surg. Forum 1976, 27, 18–20. [Google Scholar] [PubMed]
  64. Doctor, N.; Pandya, S.; Supe, A. Hyperbaric oxygen therapy in diabetic foot. J. Postgrad. Med. 1992, 38, 112. [Google Scholar]
  65. Londahl, M.; Katzman, P.; Nilsson, A.; Hammarlund, C. Hyperbaric oxygen therapy facilitates healing of chronic foot ulcers in patients with diabetes. Diabetes Care 2010, 33, 998–1003. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  66. Faglia, E.; Favales, F.; Aldeghi, A.; Calia, P.; Quarantiello, A.; Oriani, G.; Michael, M.; Campagnoli, P.; Morabito, A. Adjunctive systemic hyperbaric oxygen therapy in treatment of severe prevalently ischemic diabetic foot ulcer. A randomized study. Diabetes Care 1996, 19, 1338–1343. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  67. Health Quality, O. Hyperbaric Oxygen Therapy for the Treatment of Diabetic Foot Ulcers: A Health Technology Assessment. Ont. Health Technol. Assess. Ser. 2017, 17, 1–142. [Google Scholar]
  68. Ambiru, S.; Furuyama, N.; Aono, M.; Otsuka, H.; Suzuki, T.; Miyazaki, M. Analysis of risk factors associated with complications of hyperbaric oxygen therapy. J. Crit. Care 2008, 23, 295–300. [Google Scholar] [CrossRef]
  69. Manning, E.P. Central Nervous System Oxygen Toxicity and Hyperbaric Oxygen Seizures. Aerosp. Med. Hum. Perform. 2016, 87, 477–486. [Google Scholar] [CrossRef]
  70. Abdi, S.I.H.; Ng, S.M.; Lim, J.O. An enzyme-modulated oxygen-producing micro-system for regenerative therapeutics. Int. J. Pharm. 2011, 409, 203–205. [Google Scholar] [CrossRef] [PubMed]
  71. Abdi, S.I.H.; Choi, J.Y.; Lau, H.C.; Lim, J.O. Controlled release of oxygen from PLGA-alginate layered matrix and its in vitro characterization on the viability of muscle cells under hypoxic environment. Tissue Eng. Regen. Med. 2013, 10, 131–138. [Google Scholar] [CrossRef]
  72. Montazeri, L.; Hojjati-Emami, S.; Bonakdar, S.; Tahamtani, Y.; Hajizadeh-Saffar, E.; Noori-Keshtkar, M.; Najar-Asl, M.; Ashtiani, M.K.; Baharvand, H. Improvement of islet engrafts by enhanced angiogenesis and microparticle-mediated oxygenation. Biomaterials 2016, 89, 157–165. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Mohseni-Vadeghani, E.; Karimi-Soflou, R.; Khorshidi, S.; Karkhaneh, A. Fabrication of oxygen and calcium releasing microcarriers with different internal structures for bone tissue engineering: Solid filled versus hollow microparticles. Colloids Surf. B Biointerfaces 2021, 197, 111376. [Google Scholar] [CrossRef]
  74. McQuilling, J.P.; Opara, E.C. Methods for Incorporating Oxygen-Generating Biomaterials into Cell Culture and Microcapsule Systems. Methods Mol. Biol. 2017, 1479, 135–141. [Google Scholar] [CrossRef] [PubMed]
  75. Park, S.; Park, K.M. Hyperbaric oxygen-generating hydrogels. Biomaterials 2018, 182, 234–244. [Google Scholar] [CrossRef] [PubMed]
  76. Chandra, P.K.; Ross, C.L.; Smith, L.C.; Jeong, S.S.; Kim, J.; Yoo, J.J.; Harrison, B.S. Peroxide-based oxygen generating topical wound dressing for enhancing healing of dermal wounds. Wound Repair Regen. 2015, 23, 830–841. [Google Scholar] [CrossRef] [PubMed]
  77. Wang, S.; Qiu, J.; Guo, A.; Ren, R.; He, W.; Liu, S.; Liu, Y. Nanoscale perfluorocarbon expediates bone fracture healing through selectively activating osteoblastic differentiation and functions. J. Nanobiotechnol. 2020, 18, 84. [Google Scholar] [CrossRef]
  78. Lowe, K.C. Chapter 25—Fluosol®: The first commercial injectable perfluorocarbon oxygen carrier. In Blood Substitutes; Winslow, R.M., Ed.; Academic Press: Oxford, UK, 2006; pp. 276–287. [Google Scholar] [CrossRef]
  79. Panarin, E.F.; Kalninsh, K.K.; Pestov, D.V. Complexation of hydrogen peroxide with polyvinylpyrrolidone: Ab initio calculations. Eur. Polym. J. 2001, 37, 375–379. [Google Scholar] [CrossRef]
  80. Żeglin’ski, J.; Piotrowski, G.P.; Piękos’, R. A study of interaction between hydrogen peroxide and silica gel by FTIR spectroscopy and quantum chemistry. J. Mol. Struct. 2006, 794, 83–91. [Google Scholar] [CrossRef]
  81. Sudur Zalluhoglu, F.; Dogan, E.M.; Namusuubo, N.P.; Orbey, N.; Jahngen, E. In Situ Encapsulation of Hydrogen Peroxide in a Silica Matrix in the Presence of Divalent Metal Ions (Mg2+ and Ca2+). Ind. Eng. Chem. Res. 2017, 56, 2607–2614. [Google Scholar] [CrossRef]
  82. Harrison, B.S.; Eberli, D.; Lee, S.J.; Atala, A.; Yoo, J.J. Oxygen producing biomaterials for tissue regeneration. Biomaterials 2007, 28, 4628–4634. [Google Scholar] [CrossRef]
  83. Pedraza, E.; Coronel, M.M.; Fraker, C.A.; Ricordi, C.; Stabler, C.L. Preventing hypoxia-induced cell death in beta cells and islets via hydrolytically activated, oxygen-generating biomaterials. Proc. Natl. Acad. Sci. USA 2012, 109, 4245–4250. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  84. Sato, Y.; Endo, H.; Okuyama, H.; Takeda, T.; Iwahashi, H.; Imagawa, A.; Yamagata, K.; Shimomura, I.; Inoue, M. Cellular hypoxia of pancreatic beta-cells due to high levels of oxygen consumption for insulin secretion in vitro. J. Biol. Chem. 2011, 286, 12524–12532. [Google Scholar] [CrossRef] [Green Version]
  85. Shiekh, P.A.; Singh, A.; Kumar, A. Oxygen-Releasing Antioxidant Cryogel Scaffolds with Sustained Oxygen Delivery for Tissue Engineering Applications. ACS Appl. Mater. Interfaces 2018, 10, 18458–18469. [Google Scholar] [CrossRef]
  86. Shiekh, P.A.; Singh, A.; Kumar, A. Engineering Bioinspired Antioxidant Materials Promoting Cardiomyocyte Functionality and Maturation for Tissue Engineering Application. ACS Appl. Mater. Interfaces 2018, 10, 3260–3273. [Google Scholar] [CrossRef] [PubMed]
  87. Spiess, B.D. Perfluorocarbon emulsions as a promising technology: A review of tissue and vascular gas dynamics. J. Appl. Physiol. 2009, 106, 1444–1452. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  88. Ochoa, M.; Rahimi, R.; Huang, T.L.; Alemdar, N.; Khademhosseini, A.; Dokmeci, M.R.; Ziaie, B. A paper-based oxygen generating platform with spatially defined catalytic regions. Sens. Actuators B Chem. 2014, 198, 472–478. [Google Scholar] [CrossRef]
  89. Fries, R.B.; Wallace, W.A.; Roy, S.; Kuppusamy, P.; Bergdall, V.; Gordillo, G.M.; Melvin, W.S.; Sen, C.K. Dermal excisional wound healing in pigs following treatment with topically applied pure oxygen. Mutat. Res./Fundam. Mol. Mech. Mutagenesis 2005, 579, 172–181. [Google Scholar] [CrossRef] [PubMed]
  90. Kalliainen, L.K.; Gordillo, G.M.; Schlanger, R.; Sen, C.K. Topical oxygen as an adjunct to wound healing: A clinical case series. Pathophysiology 2003, 9, 81–87. [Google Scholar] [CrossRef]
  91. Patil, P.S.; Fountas-Davis, N.; Huang, H.; Michelle Evancho-Chapman, M.; Fulton, J.A.; Shriver, L.P.; Leipzig, N.D. Fluorinated methacrylamide chitosan hydrogels enhance collagen synthesis in wound healing through increased oxygen availability. Acta Biomater. 2016, 36, 164–174. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  92. Song, N.-E.; Song, Y.-R.; Gwon, H.-J.; Lim, Y.-M.; Baik, S.-H. Preparation and characterization of oxygen generating (OG) hydrogels using γ-ray irradiation crosslinking. Macromol. Res. 2012, 20, 1137–1143. [Google Scholar] [CrossRef]
  93. Schreml, S.; Szeimies, R.M.; Prantl, L.; Karrer, S.; Landthaler, M.; Babilas, P. Oxygen in acute and chronic wound healing. Br. J. Dermatol. 2010, 163, 257–268. [Google Scholar] [CrossRef]
  94. Wang, J.; Zhu, Y.; Bawa, H.K.; Ng, G.; Wu, Y.; Libera, M.; van der Mei, H.C.; Busscher, H.J.; Yu, X. Oxygen-Generating Nanofiber Cell Scaffolds with Antimicrobial Properties. ACS Appl. Mater. Interfaces 2011, 3, 67–73. [Google Scholar] [CrossRef]
  95. Abudula, T.; Gauthaman, K.; Hammad, A.H.; Joshi Navare, K.; Alshahrie, A.A.; Bencherif, S.A.; Tamayol, A.; Memic, A. Oxygen-Releasing Antibacterial Nanofibrous Scaffolds for Tissue Engineering Applications. Polymers 2020, 12, 1233. [Google Scholar] [CrossRef] [PubMed]
  96. Park, J.S.; Song, Y.J.; Lim, Y.G.; Park, K. Facile Fabrication of Oxygen-Releasing Tannylated Calcium Peroxide Nanoparticles. Materials 2020, 13, 3864. [Google Scholar] [CrossRef] [PubMed]
  97. Wang, S.; Yin, C.; Han, X.; Guo, A.; Chen, X.; Liu, S.; Liu, Y. Improved Healing of Diabetic Foot Ulcer upon Oxygenation Therapeutics through Oxygen-Loading Nanoperfluorocarbon Triggered by Radial Extracorporeal Shock Wave. Oxidative Med. Cell. Longev. 2019, 2019, 5738368. [Google Scholar] [CrossRef] [Green Version]
  98. Chen, H.; Cheng, Y.; Tian, J.; Yang, P.; Zhang, X.; Chen, Y.; Hu, Y.; Wu, J. Dissolved oxygen from microalgae-gel patch promotes chronic wound healing in diabetes. Sci. Adv. 2020, 6, eaba4311. [Google Scholar] [CrossRef]
  99. Sen, C.K.; Gordillo, G.M.; Roy, S.; Kirsner, R.; Lambert, L.; Hunt, T.K.; Gottrup, F.; Gurtner, G.C.; Longaker, M.T. Human skin wounds: A major and snowballing threat to public health and the economy. Wound Repair Regen 2009, 17, 763–771. [Google Scholar] [CrossRef] [Green Version]
  100. Lowe, K.C. Perfluorinated blood substitutes and artificial oxygen carriers. Blood Rev. 1999, 13, 171–184. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Wound healing phases. (a) Normal wound healing phases. In healthy people, wound closure consists of several processes that occur sequentially: rapid hemostasis that involves platelet aggregation to form the platelet plug; an inflammation phase where neutrophils, macrophages, and mast cells release proinflammatory cytokines; wound contraction when inflammation decreases, angiogenesis occurs, keratinocytes and fibroblasts migrate, and the extracellular matrix forms; and, finally, the remodeling phase, where granulation tissue converts into mature scar tissue. (b) Diabetic wound healing phases. The wound healing phases are altered, starting with a decrease in fibrinolysis and an imbalance of cytokines. A decrease in angiogenesis due to hyperglycemia and the migration of cells such as keratinocytes and fibroblasts is diminished, causing deficient re-epithelialization; in the same way, poor production of the ECM by fibroblasts contributes to the emergence of DFUs. Reproduced from [32].
Figure 1. Wound healing phases. (a) Normal wound healing phases. In healthy people, wound closure consists of several processes that occur sequentially: rapid hemostasis that involves platelet aggregation to form the platelet plug; an inflammation phase where neutrophils, macrophages, and mast cells release proinflammatory cytokines; wound contraction when inflammation decreases, angiogenesis occurs, keratinocytes and fibroblasts migrate, and the extracellular matrix forms; and, finally, the remodeling phase, where granulation tissue converts into mature scar tissue. (b) Diabetic wound healing phases. The wound healing phases are altered, starting with a decrease in fibrinolysis and an imbalance of cytokines. A decrease in angiogenesis due to hyperglycemia and the migration of cells such as keratinocytes and fibroblasts is diminished, causing deficient re-epithelialization; in the same way, poor production of the ECM by fibroblasts contributes to the emergence of DFUs. Reproduced from [32].
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Figure 2. Major causal factors that lead to lower extremity amputation in diabetics.
Figure 2. Major causal factors that lead to lower extremity amputation in diabetics.
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Figure 3. Role of oxygen in the management of DFU.
Figure 3. Role of oxygen in the management of DFU.
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Figure 4. Recent development of oxygen-releasing composites applicable for DFU treatments. (A) Tannylated calcium peroxide nanoparticle. In this study, tannic acid was used to coordinate the bridge between calcium ions [96], (B) Novel microalga-gel patch (AGP). The fabricated patch was filled with gel beads containing active Synechococcus elongatus (S. elongatus) PCC7942, a unicellular cyanobacterium that produces oxygen for diabetic chronic wounds [98], and (C) Oxygen-loaded nanperfluorocarbon (Nano-PFC). The radial extracorporeal shock wave (rESW) was employed to trigger the release of oxygen from a human serum albumin (HSA)-stabilized perfluorocarbon (perfluoro-15-crown-5-ether) emulsion [97].
Figure 4. Recent development of oxygen-releasing composites applicable for DFU treatments. (A) Tannylated calcium peroxide nanoparticle. In this study, tannic acid was used to coordinate the bridge between calcium ions [96], (B) Novel microalga-gel patch (AGP). The fabricated patch was filled with gel beads containing active Synechococcus elongatus (S. elongatus) PCC7942, a unicellular cyanobacterium that produces oxygen for diabetic chronic wounds [98], and (C) Oxygen-loaded nanperfluorocarbon (Nano-PFC). The radial extracorporeal shock wave (rESW) was employed to trigger the release of oxygen from a human serum albumin (HSA)-stabilized perfluorocarbon (perfluoro-15-crown-5-ether) emulsion [97].
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Table 1. The typical examples of commercially available topical wound dressings for DFU 1.
Table 1. The typical examples of commercially available topical wound dressings for DFU 1.
Commercial DressingCompanyCompositionMain Characteristics
Bionect®BioScience0.2% of sodium salt of hyaluronic acid
  • Easy to use
  • Reduces the incidence of high-grade skin reactions
  • Reduces wound severity
Unite® BiomatrixSynovis Orthopedic and WoundCare, Inc.Non-reconstituted collagen
  • Collagen dressing helps maintain wound bed in healing phase
  • Allows for healthy granulation tissue and wound closure
  • Absorbs excess exudate, thus reducing dressing changes
  • Easily conforms to the wound bed
  • Strong and durable
BGC Matrix®Mölnlycke Health Care US, LLCCollagen and advanced
carbohydrate beta-glucan
  • Protects underlying tissue from external contamination
  • Provides structural support for new cell growth
  • Adherent, flexible and conformable
  • Minimizes protein and water loss
  • Collagen aids in hemostasis
  • Minimizes pain
Promogran Prisma® MatrixSystagenixCollagen, oxidized regenerated cellulose (ORC), and silver-ORC matrix
  • In the presence of exudate, the matrix transforms into a biodegradable gel
  • Provides protection from infection and an optimal healing environment
  • Designed to “kick start” the healing process in stalled wounds
  • Biodegradable gel is soft and conformable
  • Can be used under compression therapy
  • Nontoxic and non-irritating
  • Easy to use
Dermacol/Ag™ Collagen Matrix
Dressing with Silver
DermaRite IndustriesCollagen, sodium alginate,
carboxyl methyl-cellulose,
ethylenediamine-tetraacetic acid (EDTA) and silver chloride
  • Transforms into a soft gel sheet when in contact with wound exudates
  • Maintains a moist wound environment and creates ideal conditions for healing
  • Antimicrobial silver chloride prevents colonization of the dressing
  • Easy to use
Fibracol® Plus Collagen Wound Dressing with
SystagenixCollagen and calcium alginate fibers wound
  • Structural support of collagen with gel forming properties of alginates
  • Maintains a moist wound environment and creates ideal conditions for healing
  • Adherent, flexible and conformable
  • Sterile and soft
Hydrofiber® Wound Dressing
ConvaTecAntimicrobial hydrofiber
containing carboxymethyl
cellulose with ionic silver
  • Absorbs wound fluid and creates a soft gel, which maintains a moist wound environment
  • Absorbs and retains exudate and harmful components such as bacteria contained within exudate, directly into its fibers
  • Helps reduce pain and trauma upon dressing removal
  • Conforms to the wound surface
  • Used on moderately and highly exuding chronic wounds
Regranex® GelHealthpoint
Human recombinant PDGF-BB 2 incorporated in aqueous sodium carboxymethylcellulose
  • Stimulates wound healing processes and aids in creation of granulation tissue
  • Only FDA-approved topical agent with platelet-derived growth factor
  • Promotes the recruitment and proliferation of chemotactic cells
  • Stimulates wound closure
  • Easy to use
Derma Sciences, Inc.80% active Leptospermum honey with colloidal alginate
  • Maintains effectiveness even in the presence of wound fluid, blood, and tissue
  • For wounds with light to moderate amounts of exudates
  • Pad forms a gel as it warms up and contacts wound fluid
  • Promotes a moisture-balanced environment conducive to wound healing
  • Helps wounds that have stalled healing
  • High osmolarity cleanses
  • Helps lower overall wound pH
  • Non-toxic, natural, safe and low-cost
Calcium Alginate
Derma Sciences, Inc.Contains 95% active
Leptospermum honey with
calcium alginate
  • As wound fluid enters the dressing, honey is released while the dressing forms a gel
  • Maintains effectiveness even in the presence of wound fluid, blood and tissue
  • Promotes a moisture-balanced environment conducive to wound healing
  • Highly osmotic and helps to reduce overall wound pH
  • For wounds with moderate to heavy amounts of exudates
  • Non-toxic, natural, safe, and easy to use
Algisite M Calcium Alginate DressingSmith & Nephew, Inc.Calcium-alginate
  • Forms a gel that absorbs exudate when in contact with wound
  • Helps prevent scar formation and promotes wound contraction
  • Allows gas exchange necessary for a healthy wound bed
  • Low-adherence reduces trauma at dressing changes
  • Conforms to wound contours
  • Low fiber shed
  • Easy to remove
Sorbalgon®Hartman USA, Inc.Calcium alginate
  • Forms a hydrophilic gel on contact with wound exudate
  • Maintains integrity while dry or wet
  • Highly absorbent
  • Easy to remove
  • Latex-free
ConvaTecSodium and calcium salts of
alginic acid
  • In the presence of exudate or other body fluids containing sodium ions, the fibers absorb liquid and swell
  • Calcium ions promote the dressing to take on a gel-like appearance
  • Facilitates wound healing providing a favorable micro-environment
  • Easy to use
Tegaderm™ High Gelling
3 M Health CarePolyurethane dressing containing alginate
  • Forms a gel-like consistency as it absorbs exudate to provide a moist healing environment
  • Completely gels with saturation for easy removal from fragile tissue by gentle irrigation
  • Easily irrigated from the wound bed when saturated
  • Highly absorbent and conformable
Acute Care Solutions, LLCAlginate hydrocolloid with
  • Breathable film membrane surrounds the wound site
  • Promotes wound repair
  • Visually signals dressing changes
  • Water, dirt, and germ proof
  • Reduces dressing changes
  • Extended wear time
  • Prohibits leakage
Biatain® Heel Foam DressingColoplast Corp.3-D non-adhesive foam of
  • Foam absorbs and retains wound exudate to control moisture balance in wound
  • Absorbs low-to-high wound exudate levels and protects the heel
  • Decreases wound area and prevents skin maceration
  • Soft and beveled edges make dressing more comfortable for patient
  • Longer wear time for fewer dressing changes
  • Low risk of leakage or maceration
  • Safe and effective
Biatain Ibu Foam Dressing
Coloplast Corp.Combination of
polyurethane-foam, polyurethane film, polyethylene and ibuprofen
  • Combines moist wound healing with an active pain reliever
  • Releases ibuprofen evenly into the wound
  • Helps to ease pain from the wound during wear and when changing the dressing
  • Promotes wound repair
  • Easy to use
MANUKAhd®ManukaMed USA, Inc.Polyurethane foam and film in backing and an absorbent
dressing pad of polyacrylate
polymers impregnated with
ManukaMed® honey
  • 100% active medical grade Manuka® honey
  • Gentle on wounds promoting wound healing
  • Forms gels in contact with exudate
  • Fluid permeable and dry touch
DuoDERM® CGF®ConvaTecPolyurethane foam
  • Promotes granulation and facilitates autolytic debridement
  • Can be easily and gently molded into place
  • Use on lightly to moderately exuding acute and chronic wounds
  • Minimize skin trauma and disruption of healing
  • Can be worn for up to seven days
  • Allows observation of the healing process due to its transparency
Conformable Wound Gel Dressing
Smith & Nephew, Inc.Polyurethane and polyethylene hydrogel
  • Creates a moist wound healing environment
  • Keeps gel in intimate contact with wound surface
  • Absorbs excess exudate thus reducing dressing changes
  • Noncytotoxic and nonsensitizing
Silverlon® Island Wound DressingArgentum Medical, LLCPolyurethane film containing
  • Non-adherent wound contact layer
  • Provides effective protection against microbial contamination
  • Permits passage of wound exudate
  • Stimulates wound repair
  • Easy to apply
AllevynSmith & Nephew, Inc.Polyurethane films combined with polyurethane foam
containing 5% silver
  • Minimizes pain to the patient and trauma to the wound during dressing changes
  • Rapid and sustained (seven days) antibacterial action
  • Absorbs, retains, and transpires exudate to provide enhanced fluid management
  • Provides a moist wound environment for the promotion of faster closure
  • Stays in place for up to seven days
Meliplex AgMolnlycke Heath CarePolyurethane foam containing a silver compound (silver sulphate)
  • Vapor-permeable
  • Waterproof film to absorb exudate
  • Maintains a moist wound environment
LigasanoLigasanoHoneycomb-polyurethane foam
  • Economic and manageable
  • Absorbs high amounts of exudate without dehydrating the wound bed
  • Creates a moist and warm wound environment
  • Antiseptic and cleans the wound without sticking to the wound
  • Stimulates local blood circulation in the wound
1 This table is reformatted from [52] with permission, copyright Elsevier, 2013. 2 PDGF-BB; Platelet-derived growth factor (PDGF) two B subunits.
Table 2. Examples of oxygen releasable compounds and their characteristics.
Table 2. Examples of oxygen releasable compounds and their characteristics.
Calcium peroxideReleased by hydrolytic decomposition
Reported saturated concentration: 22 mg/L
Magnesium peroxideReleased by hydrolytic decomposition
Reported saturated concentration: 44 mg/L
Sodium percarbonateReleased by hydrolytic decomposition
Reported saturated concentration: 31 mg/L
Perfluorodecalin (PFD)
Oxygen solubility: 403 mL/LPFD[56]
Perfluorooctylbromide (PFOB)
Oxygen solubility: 527 mL/LPFD[56]
Hydrogen peroxideConverted by blood, catalase, and Horseradish peroxidase[57,58,59]
Table 3. The oxygen-releasing composites from different oxygen releasable compounds.
Table 3. The oxygen-releasing composites from different oxygen releasable compounds.
CompoundOxygen-Releasing CompositeDescriptionsRef.
Hydrogen PeroxideH2O2-loading poly(D,L-lactide-co-glycolide) (PLGA) particleCatalase was immobilized alginate used for detoxifying H2O2.[70,71]
H2O2-incoporating polyvinylpyrrolidone (PVP)/poly(D,L-lactide-co-glycolide) (PLGA) core-shell microparticleCatalase was covalently incorporated onto the surface of microparticles.[72]
Calcium Peroxide (CPO)CPO-loading poly (L-lactic acid) (PLLA) nanoparticleCatalase was grafted onto the surface of hollow nanoparticles.
Nano CPOs were loaded.
CPO-encapsulated alginate microcapsuleBecause of calcium, alginates were
immediately cross-linked.
CPO-mediated thiolated gelatinThiolated gelatins formed a
cross-linkable hydrogel due to
CaO2-mediated oxidative cross-linking
Sodium percarbonate (SPO)CPO-loading poly (L-lactic acid) (PLLA) nanoparticleCatalase was grafted onto the surface of hollow nanoparticles.[73]
CPO/SPO-PVA and PCL filmIn the final contrast, a gelatin layer was served as decomposing H2O2 through manganese chloride (MnCl2).[76]
PerfluorocarbonNano-sized perfluorocarbon 1 stabilized by human
serum albumin (HSA)
HSA-stabilized nano-emulsion PFC materials have small size in diameter (~80 nm).[77]
Perfluorodecalin (C10F18) and
perfluoro-n-tripropylamine, (C3F7)3N, based-emulsion
(C3F7)3N was used for stabilizing the
final emulsion
1 Perfluoro-15-crown-5-ether.
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Lim, D.-J.; Jang, I. Oxygen-Releasing Composites: A Promising Approach in the Management of Diabetic Foot Ulcers. Polymers 2021, 13, 4131.

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Lim D-J, Jang I. Oxygen-Releasing Composites: A Promising Approach in the Management of Diabetic Foot Ulcers. Polymers. 2021; 13(23):4131.

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Lim, Dong-Jin, and Insoo Jang. 2021. "Oxygen-Releasing Composites: A Promising Approach in the Management of Diabetic Foot Ulcers" Polymers 13, no. 23: 4131.

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