Abstract
Tissue hypoxia represents a major challenge in regenerative medicine because it may impair wound healing and contribute to tissue necrosis and eventually reconstructive failure. To overcome this problem, topically applied oxygen carriers have emerged as a promising strategy to enhance tissue oxygenation independently of vascular function. This narrative review summarizes the clinical evidence for the use of oxygen carriers in plastic, reconstructive and aesthetic surgery. Four principal categories were identified, including hemoglobin-, peroxide-, and microalgae-based oxygen carriers as well as physical oxygen carriers. Hemoglobin- and peroxide-based oxygen carriers have shown beneficial effects on wound healing. However, evidence from randomized controlled trials remains inconsistent and large-scale studies for other indications are limited. In an early clinical study, microalgae-seeded scaffolds enabled controlled in situ oxygen production and provided structural support for full-thickness skin defects. Physical oxygen carriers have demonstrated positive preliminary results in promoting re-epithelialization of donor sites of split-thickness skin grafts but otherwise remain insufficiently investigated. Taken together, oxygen carriers represent a biologically plausible strategy to prevent tissue hypoxia. Although current clinical evidence suggests potential benefits, the literature on oxygen carriers remains limited by small patient cohorts, heterogeneous methodologies, and retrospective study designs. Therefore, future research should prioritize randomized controlled trials with standardized outcome measures and direct comparisons with established treatment modalities.
1 Introduction
Hypoxia occurs when oxygen delivery into the tissue is insufficient to maintain cellular homeostasis. It is characterized by impaired mitochondrial function, leading to an anaerobic shift in cellular metabolism, resulting in reduced adenosine triphosphate production and lactic acid accumulation. If not controlled, these processes ultimately result in cell death and organ dysfunction (). Tissue hypoxia may result from several mechanisms, among which ischemia represents the predominant cause in surgical settings. Ischemia is defined as a restricted or absent blood flow, thereby impairing oxygen delivery into tissues ().
The susceptibility of tissues to acute and persistent ischemia varies according to their metabolic demand. Metabolically highly active tissues, such as the nervous system, are particularly vulnerable to hypoxic injury and sustain irreversible damage earlier than tissues like muscle or skin (; Picard-Ami et al., 1990). In plastic, reconstructive, and aesthetic surgery, acute ischemia is frequently encountered, for instance in traumatic injuries with acutely damaged vessels or vascular complications after flap surgery. In such circumstances, the surgeon must balance tissue preservation against the risk of ischemia and select reconstructive measures accordingly. When this balance is disrupted, the resulting hypoxia may lead to impaired wound healing, necrosis, and subsequent complications ().
In addition to acute ischemia, many tissues relevant to reconstructive surgery exist in a state of chronic hypoxia or critically insufficient tissue perfusion, as observed in chronic wounds or otherwise altered tissues, such as irradiated skin. Similar to acute ischemia, chronic ischemia is often associated with micro- and/or macrovascular dysfunction (). Conventional approaches for the improvement of tissue oxygenation, such as pharmacological vasodilation, may be insufficient or ineffective when vascular integrity is compromised or absent, highlighting the need for alternative methods of oxygen delivery (). Established interventions, such as hyperbaric or topical oxygen therapy, provide effective means of enhancing tissue oxygenation (Ortega et al., 2021). However, these approaches are associated with significant limitations, including the need for a complex infrastructure, anatomical restrictions, and potential adverse effects (Ortega et al., 2021).
Oxygen carriers (OCs) represent a promising alternative strategy for topical oxygen delivery. OCs consist of varying substances capable of transporting or generating oxygen molecules. Initially developed as blood substitutes for managing hemorrhagic shock, they offer advantages, such as improved storability and independence from human donors. Although their clinical application as blood substitutes was discontinued, recent advances have renewed interest in their therapeutic potential and led to novel applications, such as organ preservation (Zhang et al., 2023; ). In fact, topically applied OCs directly address the limitations of conventional approaches by enabling oxygen supply independent of a functional vasculature and, thus, must be viewed separately from blood substitutes. Accordingly, they are gaining increasing attention for the treatment of acute and chronic wounds, ischemic flaps, burn wounds, and split-thickness skin grafts (Figure 1). This narrative review provides a concise overview of topically applied OCs in plastic, reconstructive, and aesthetic surgery. By consolidating the currently available clinical evidence, we aim to highlight significant developments in the field and discuss potential future applications of these technologies.
FIGURE 1
2 Methods
A literature search was performed using PubMed/MEDLINE and Web of Science with the following search strategy (“oxygen carrier*” OR “oxygenating dressing*” OR “oxygen diffusion dressing*” OR “oxygen-releasing dressing*” OR “topical oxygen therap*” OR “topical oxygenation” OR “hemoglobin spray” OR “topical hemoglobin” OR “hemoglobin-based oxygen carrier*” OR HBOC* OR M101 OR “Arenicola marina hemoglobin” OR “extracellular hemoglobin” OR Granulox OR HEMHealing OR “oxygen-generating dressing*” OR “photosynthetic therap*” OR “oxygen producing scaffold*”) AND (wound* OR ulcer* OR burn* OR “diabetic foot” OR “venous leg ulcer” OR “skin necrosis” OR “skin wound*” OR “surgical wound*” OR “chronic wound*”). Only clinical studies published in English or German until the 1st of June 2026 that evaluated the topical application of OCs in wound healing of soft tissues were assessed. Original articles, case reports, and clinical trials were included, whereas review articles, book chapters, and abstracts without complete data were excluded (Figure 2).
FIGURE 2
3 OC categories
Several categories of OCs have been described in the literature. However, only few have been translated to clinical practice until now, i.e., hemoglobin-based, peroxide-based, microalgae-based, and physical OCs (Table 1; Figure 3).
TABLE 1
| Category | Oxygen delivery mechanism | Control of oxygen release | Duration of oxygenation | Dependence on external sources | ROS generation | Antimicrobial effects | Structural support |
|---|---|---|---|---|---|---|---|
| Hemoglobin-based | Heme group within hemoglobin binds and releases oxygen depending on the oxygen partial pressure | Regulated by oxygen gradient | Depending on degradation rate | Atmospheric oxygen | Hemoglobin may oxidize to methemoglobin – M101 as notable exception with intrinsic antioxidant activities | No | No |
| Peroxide-based | Chemical decomposition of peroxide group | Controllable through encapsulation, layered design, and addition of a catalyst | Depending on formulation and peroxide reserve | Generally independent but enzymatic systems may rely on atmospheric oxygen as a substrate | Presence or generation of H2O2 can be cytotoxic if not controlled – regulation through controlled release or enzymatic activity | Intrinsic activity from H2O2 and downstream products; additionally, through iodine in Oxyzyme®/Iodozyme® | No |
| Microalgae-based | Photosynthetic oxygen production under illumination | Externally modifiable by intensity and duration of illumination | Depending on microalgae viability | External light source | Minimal under controlled illumination – microalgae may have inherent antioxidant properties | Some microalgae may produce antimicrobial metabolites | Seeded onto dermal scaffold |
| Physical | Oxygen is physically entrapped or dissolved and released by diffusion along a concentration gradient | Limited control through material permeability | Depending on reservoir size | No | Minimal | No | No |
Characteristics of oxygen carriers in plastic, reconstructive, and aesthetic surgery, as included in the present review.
ROS, reactive oxygen species.
FIGURE 3
Hemoglobin, the primary physiological oxygen carrier in vertebrates binds and releases oxygen in a controlled manner, depending on the demand of the surrounding tissue (). Two types of hemoglobin are currently applied in patients, including porcine hemoglobin and the extracellular hemoglobin M101. Porcine hemoglobin contains four heme groups and exhibits properties comparable to those of human hemoglobin (). M101 is extracted from the marine lugworm Arenicola marina and owing to its high oxygen-carrying capacity of up to 156 oxygen molecules per hemoglobin (Figure 4), M101 represents a promising candidate for topical oxygen delivery (). Hemoglobin-based OCs bind and release oxygen depending on the surrounding oxygen partial pressure and thus rely on the supply of atmospheric oxygen. While they may not directly produce reactive oxygen species, hemoglobin can be oxidized to methemoglobin which in turn generates reactive oxygen species and releases free iron (Rifkind et al., 2015). Notably, M101 is mentioned as an exception as it has demonstrated antioxidant properties due to an intrinsic superoxide dismutase-like activity (Rousselot et al., 2006).
FIGURE 4
An alternative approach to local oxygen delivery involves the use of peroxides that are characterized by two oxygen atoms connected through a covalent bond and interposed between varying atoms or molecules (). These attached atoms and molecules determine certain properties of the peroxide and allow for further classification into liquid peroxides, including hydrogen peroxide, and solid peroxides. The latter include metal peroxides, such as calcium peroxide, that have gained increasing attention in wound healing applications (; ). The peroxide bond is inherently unstable and readily decomposes into molecular oxygen and a second product, such as water in the case of hydrogen peroxide or calcium oxide in the case of calcium peroxide (). This decomposition can be exploited in wound dressings to provide a sustained local oxygen supply. In addition, peroxides exhibit antimicrobial activity, by generating reactive oxygen species and are therefore already in clinical use as disinfectants, making them particularly attractive for the treatment of infected wounds (). Though this generation of reactive oxygen species can be advantageous due to its antimicrobial activity, regulation through controlled release or enzymatic regulators is necessary to prevent cytotoxic effects on the wound tissue.
Photosynthetic biomaterials, specifically microalgae-based biomaterials, represent a promising strategy to address oxygen-deficient conditions across various clinical scenarios, including organ transplantation, tissue infarction, tumor therapy, and wound healing (). The potential advantage of photosynthetic scaffolds is their ability to provide sustained oxygen delivery that can be regulated through in situ illumination without requiring frequent dressing changes. While the production of reactive oxygen species is inherent to the generation of oxygen molecules, certain microalgae may present inherent antioxidative properties and additionally may produce antimicrobial metabolites exerting an antimicrobial effect on the wound ().
Physical OCs allow the topical delivery of oxygen by physically entrapping oxygen without chemically binding it to a carrier molecule or generating it de novo in situ. The entrapped oxygen can then be released into the wound through diffusion, modifiable by differing permeabilities of the interfacing layer. Due to their design, physical OCs also do not rely on a continuous external oxygen supply.
4 Hemoglobin-based topical OCs
As previously described, two types of hemoglobin are currently in use for the treatment of patients with varying types of wounds. Granulox® (Mölnlycke Healthcare AB, Mölndal, Sweden) is a spray containing porcine hemoglobin that was developed for topical use in chronic wounds, such as diabetic foot ulcers, venous ulcers, and pressure sores. Unlike other clinically applied OCs, Granulox® has been extensively investigated in several case reports, case series, and randomized controlled trials (RCTs) examining its effects on wound healing Table 2.
TABLE 2
| Category | Oxygen carrier | Study type | Year | Number of patients | Target tissue | Regulatory status | Outcome | References |
|---|---|---|---|---|---|---|---|---|
| Hemoglobin-based | Porcine hemoglobin | Cohort | 2016 | 15 control, 20 case | Diabetic foot ulcer | Postmarketing study | ↑ Mean wound size reduction (95% vs. 63% after 26 weeks) ↓ Pain | () |
| Hemoglobin-based | Porcine hemoglobin | Case series | 2016 | 17 | Diabetic foot ulcer | Postmarketing study | Mean wound size reduction of 54% after 4 weeks Positive rating by clinicians | () |
| Hemoglobin-based | Porcine hemoglobin | Case series | 2016 | 13 | Diabetic foot ulcer | Postmarketing study | Mean wound size reduction of 39% after 12 weeks | () |
| Hemoglobin-based | Porcine hemoglobin | Case series | 2023 | 12 | Diabetes-related foot ulcer | Postmarketing study | Wound size reduction of 87%–100% (varying time points) Positive rating by clinicians | () |
| Hemoglobin-based | Porcine hemoglobin | Case report | 2024 | 1 | Diabetic foot ulcer | Postmarketing study | Successful wound healing after resistance to initial treatment | (Siafarikas et al., 2026) |
| Hemoglobin-based | Porcine hemoglobin | RCT | 2021 | 14 control, 15 case | Foot ulcers of mixed etiology | Postmarketing study | No difference in wound size reduction | () |
| Hemoglobin-based | Porcine hemoglobin | RCT | 2013 | 31 control, 34 case | Venous ulcer | Postmarketing study | ↑ Mean wound size reduction (53% vs. −21% after 13 weeks) ↑ Wound quality ↓ Pain | () |
| Hemoglobin-based | Porcine hemoglobin | Case report | 2021 | 2 | Venous ulcer | Postmarketing study | Successful wound healing as adjunct after interventions to treat underlying cause | () |
| Hemoglobin-based | Porcine hemoglobin | Mixed (RCT, case series, case reports) | 2011 | 62 | Chronic wounds of mixed etiology | Postmarketing study | RCT: ↑ wound healing (93% vs. 7% after 26 weeks); 39/42 (93%) with subsequent treatment of all patients after the study was closed Case series: Successful wound healing after 10 (8–12), 11 (4–20), and 17 (2-53) weeks | () |
| Hemoglobin-based | Porcine hemoglobin | Cohort | 2018 | 95 control, 100 case | Sloughy chronic wounds of mixed etiology | Postmarketing study | ↑ Wound healing (94% vs. 63% after 26 weeks) ↑ Early mean wound size reduction (52% vs. 11% after 1 week) ↑ Wound quality ↓ Pain | () |
| Hemoglobin-based | Porcine hemoglobin | Cohort | 2017 | 50 control, 50 case | Chronic wounds of mixed etiology | Postmarketing study | ↑ Wound healing (90% vs. 38% after 26 weeks) ↓ Mean time to wound healing (7 weeks (3-22) vs. 11 weeks (3-25)) ↑ Wound quality ↓ Pain | () |
| Hemoglobin-based | Porcine hemoglobin | Case-control | 2026 | 31 control, 28 case | Burns (2nd degree) | Off-label use | Faster re-epithelialization Fewer dressing changes ↓ Late complications | () |
| Hemoglobin-based | M101 | Case report | 2024 | 1 | Burns (3rd degree) | Compassionate use | Successful re-epithelialization (fingertips) | () |
| Hemoglobin-based | M101 | Case report | 2025 | 1 | Burns (2nd degree) | Compassionate use | Reduction of burn area to <2% after 6 weeks without skin grafts (trunk and abdomen) | () |
| Hemoglobin-based | M101 | Case report | 2026 | 2 | Mastectomy skin flap necrosis | Compassionate use | Aversion of full-thickness skin necrosis without surgical debridement | () |
| Peroxide-based | Glucose oxidase | Case series | 2007 | 4 | Venous ulcer | Postmarketing study | Successful wound healing in all patients within 5 weeks | () |
| Peroxide-based | Glucose oxidase | Case series | 2009 | 100 | Chronic wounds of mixed etiology | Postmarketing study | Mean wound size reduction of 35% after 6 weeks Positive rating by clinicians | () |
| Peroxide-based | Glucose oxidase | Case series | 2010 | 45 | Chronic wounds of mixed etiology | Postmarketing study | Mean wound size reduction of 20% after 6 weeks Positive rating by clinicians | (Wood et al., 2010) |
| Peroxide-based | Glucose oxidase | Case series | 2011 | 11 | Chronic wounds of mixed etiology | Postmarketing study | Mean wound size reduction of 52% after 6 weeks, 79% after 12 weeks, and 88% after 20 weeks Cost analysis suggests £23,036 savings over 52 weeks compared to standard treatment | () |
| Peroxide-based | Glucose oxidase | RCT | 2014 | 53 control, 47 case | Chronic wound of vascular origin | Postmarketing study | No difference in wound size reduction Fewer dressing changes in case group | () |
| Peroxide-based | Sodium percarbonate and calcium peroxide | RCT | 2026 | 69 control, 68 case | Skin graft donor site | Premarketing study | ↓ Time until complete wound healing (11 days vs. 15 days) ↑ Wound healing rate in first 2 weeks ↓ Pain | (Tong et al., 2026) |
| Microalgae-based | Chlamydomonas reinhardtii | Phase 1 clinical trial | 2021 | 8 | Full-thickness skin defects | Experimental modification/early clinical investigation | Successful integration of the scaffold and overlying skin grafts No significant adverse events | (Obaíd et al., 2021) |
| Microalgae-based | Chlamydomonas reinhardtii | Case report | 2022 | 1 | Full-thickness skin defect | Experimental modification/early clinical investigation | Positive long-term outcome (17 months) | (Obaíd et al., 2022) |
| Physical | Gas reservoir | RCT | 2014 | 17 | Skin graft donor site | Postmarketing study | ↓ Time until complete wound healing (9 days vs. 12 days) ↓ Pain | () |
| Physical | Closed cell foam hydrogel (Polyacrylamide polymer) | RCT | 2017 | 8 | Abdominoplasty scar | Postmarketing study/discontinued product | No differences in any outcome | () |
Overview of clinical studies on the application of oxygen carriers in plastic, reconstructive, and aesthetic surgery, as included in the present review.
RCT, randomized controlled trial; ↑, increased; ↓, decreased.
Diabetic foot ulcers represent an interesting target for OC-based therapies, because of their high prevalence and underlying microvascular dysfunction (). A retrospective study by Hunt and Elg () compared two cohorts of patients with non-healing diabetic foot ulcers, defined as <40% wound size reduction in 12 weeks, and a SINBAD () score of ≤2. A control group of 15 patients received standard wound care, including surgical debridement, standard wound dressings, and off-loading devices as required. Another group of 20 patients received identical standard treatment with the addition of Granulox® twice weekly, combined with dressing changes until wound closure was achieved. Wound size changes, complete wound healing, pain level, exudate quantity, and other factors were assessed over a 6-month period. Of interest, the study showed a significant 95% reduction in mean wound size in the Granulox® group, compared to 63% in the control group. Furthermore, the group treated with Granulox® showed an increased number of completely healed wounds and reduced pain scores (). Haycocks et al. () evaluated 17 patients with diabetic foot ulcers in a retrospective case series who underwent the same treatment regimen as described above, showing a mean wound size reduction of 54% after 4 weeks. Thirteen patients continued the treatment for an additional 8 weeks, resulting in a mean wound size reduction of 39% after a total treatment duration of 12 weeks (). Similar findings were reported in more recent retrospective studies, which show improved healing rates and positive clinician ratings, although not compared with a control group (; Siafarikas et al., 2026). Conversely, the only prospective RCT in patients with foot ulcers conducted by Jonker et al. () showed no improvement when comparing standard care alone, including surgical debridement, infection management, and offloading, with standard care plus Granulox® therapy. Patients with an ulcer present for at least 4 weeks and a healing rate of less than 50% were enrolled into the study, of which 14 patients were allocated to the control arm and 15 patients to the Granulox® arm. Throughout the study and after conclusion of treatment at 12 weeks, no significant differences in wound size could be observed between the groups (). The interpretation of these findings is complicated by the increased baseline wound chronicity in the Granulox® arm, which may influence the final outcome. However, this was not statistically analyzed in the study.
In addition to its use in diabetic foot ulcers, Granulox® was investigated for the treatment of other types of chronic wounds, such as venous and arterial ulcers and chronic wounds of mixed etiology. Arenbergerova et al. () conducted a prospective RCT investigating the use of Granulox® in venous leg ulcers. Initial enrollment included patients with venous leg ulcers present for over 8 weeks and a wound size of 2–50 cm2, resulting in 36 patients allocated to each of the control and Granulox® arm. Both groups received compression therapy, starting 2 weeks prior to trial initiation and were hospitalized during the first 2 weeks of the trial for daily dressing changes. The patients in the treatment group received Granulox® during dressing changes, whereas the control group received sham treatment with a saline spray. Of the 72 patients, 31 in the control arm and 34 in the Granulox® arm completed the study. The results show a significant 53% reduction in wound size after 13 weeks in the Granulox® group, compared with no change in wound size in the control group. Furthermore, the Granulox® group exhibited an improved wound quality, as indicated by reduced necrotic tissue, fibrin slough, and an increase in granulation tissue, as well as improvements in pain intensity compared to the control group (). Similar outcomes were described in subsequent case reports of two patients with venous and mixed arterial-venous ulcers, respectively, who achieved successful healing after Granulox® therapy (). Further studies investigated patient populations with chronic wounds of diverse etiologies, including diabetic and vascular causes as well as traumatic wounds or pressure ulcers. Arenberger et al. () reported cumulated retrospective data from several centers in Mexico, Germany, and the Czech Republic, evaluating a hemoglobin spray in chronic wound care. Although all centers followed a similar application protocol of the hemoglobin spray, substantial variability in adjacent standard wound care and study design can be observed. One center in Mexico conducted a prospective RCT comparing hemoglobin spray in 14 patients with a local standard treatment using a sterile petroleum jelly bandage in 14 control patients. After 6 months, the trial was discontinued due to distinct positive results. In the hemoglobin spray group, 13 of 14 patients healed successfully, compared with only one of 14 in the control group. Subsequently, all patients, including previously excluded patients, received the hemoglobin spray therapy and were enrolled in an observation study with complete healing in 39 out of 42 patients. Data from the other three centers consist mainly of individual cases, cumulating to a total of 20 patients. From these cases, all wounds healed completely with an average time until wound healing of 10 (8-12), 11 (4-20), and 17 weeks (2-53) at the three centers, respectively (). A separate study by Hunt et al. () investigated the use of Granulox® in chronic and sloughy wounds. In this cohort study, a group of 100 patients with any wound showing evidence of slough without requiring immediate hospitalization was trained on the at-home application of Granulox®, which they performed twice weekly until complete wound healing was achieved. This group was compared to 95 control patients receiving individual standard wound care that was not further specified. After a follow-up of 26 weeks, 94% of patients treated with Granulox® had healed completely compared to 63% in the control group. Furthermore, a more rapid wound size reduction and reduced pain during the first 8 weeks was observed in the Granulox® group (). However, significant differences in pain and slough coverage between the two groups with higher presence in the Granulox® group were observed, potentially affecting the outcome. In 2017, Hunt and Elg () performed a similar cohort study with the same methodology, albeit on patients with chronic wounds that did not show fibrin coverage and failed to respond after 2–4 weeks of standard wound treatment. A group of 50 patients receiving Granulox® therapy was compared with 50 control patients, identified retrospectively, who received only standard treatment. This study showed similar results, with 90% of patients in the Granulox® group achieving complete wound healing after 26 weeks, compared with 38% in the control group. Furthermore, the time to complete wound healing was shorter in the Granulox® group with an average of 7 weeks compared to 11 weeks in the control group (). Taken together, the available evidence indicates a potential benefit for the local application of Granulox® as an adjunct in the treatment of chronic wounds. However, the interpretation of these findings is limited by methodological weaknesses and the retrospective design of most studies. Furthermore, substantial variation in patient populations, follow-up durations, and control treatments limit cross-study comparability.
Recently, a case-control study by Kulice () investigated a novel application of Granulox® in pediatric patients with second-degree burns. In one group, 28 patients received Granulox® in addition to standard burn wound dressings at each dressing change compared with 31 patients in a control group who received standard wound care with paraffin-impregnated gauzes only. This study could show that treatment with Granulox® results in faster re-epithelialization, earlier hospital discharge, reduced need for dressing changes, and decreased incidence of long-term complications, including itching, inhomogeneous pigmentation, hypertrophic scarring, and epithelialization defects (). These findings suggest the potential applicability of Granulox® beyond chronic wound care.
In theory, burn wounds seem particularly well suited for topical oxygen therapy due to acutely impaired microvascular perfusion in superficial soft tissue layers, such as dermis and subcutaneous fat, and large wound areas. In this context, M101 has recently gained attention. Two recent case reports evaluated the use of HEMHealing® (HEMARINA S.A., Morlaix, France), a novel M101-containing hydrogel, in burn wounds. Awan et al. () reported complete re-epithelialization of third-degree fingertip burns in a 22-year-old woman treated with HEMHealing®. Lancien et al. () reported the case of a 34-year-old man presenting with burns involving 85% of the total body surface area. Due to limited donor sites, HEMHealing® was applied to second-degree burns on the chest, abdomen, and back every other day for 47 days, with successful reduction of the burn area in these regions to less than 2% by week 6 (). More recently, Lhuaire et al. () applied HEMHealing® in a different setting to treat acute persistent ischemia of the adipo-cutaneous skin flap following nipple-sparing mastectomy in two patients, with successful healing by 21 and 76 days without requiring additional debridement in the operating room.
Taken together, hemoglobin-based OCs have shown encouraging results across a variety of acute and chronic wounds. While numerous case series and cohort studies report improved outcomes, including reduced wound size and pain, evidence from RCTs remains inconsistent. M101 represents an emerging alternative due to its superior oxygen-carrying capacity with promising early clinical observations, particularly in burn care. Nonetheless, the current body of evidence is limited by heterogeneity in study designs and methodologies, underscoring the need for large-scale RCTs to better define the clinical efficacy and optimal application protocols.
5 Peroxide-based topical OCs
The first commercialized peroxide-based OC was Oxyzyme® (Crawford Healthcare Ltd., Loughborough, UK), which employed a layered enzymatic system to manage the unstable nature of peroxides and prevent excessive decomposition. The dressing contains glucose and potassium iodide in an inner layer and glucose oxidase in an outer layer. This allows for the continued production of hydrogen peroxide, which in turn reacts with potassium iodide to generate oxygen and iodine. A variation of this dressing marketed as Iodozyme® (Crawford Healthcare Ltd., Loughborough, UK), releases higher concentrations of iodine and is intended for use in infected wounds. Ivins et al. () presented the first application of Oxyzyme® in a case series including 4 patients suffering from chronic venous ulcers. In this series, all wounds healed completely within 5 weeks, suggesting therapeutic potential, although limited by the small sample size and lack of untreated control patients. Similar findings were subsequently reported in a larger case series conducted by Davis et al. (). The authors collected data from several centers across Europe, evaluating Oxyzyme® in superficial non-infected, chronic, hard-to-heal wounds defined as static or deteriorating during the previous 4 weeks under standard treatment, including compression bandaging, offloading, and other dressings. The dressing was applied after wound cleaning and was changed according to the state of the wound for 6 weeks or until complete healing, if occurring sooner. A total of 100 patients, of which 38 were excluded from the study prior to its conclusion due to infection, deterioration, pain, and/or other reasons, were analyzed and showed complete healing in 10%, improvement in 63%, unchanged wound conditions in 16%, and deterioration in 11%, with an overall mean wound area reduction of 35%. Subgroup analyses showed the largest reduction (54%) among patients with diabetic foot ulcers. However, the substantial dropout rate of 38% limits the interpretation of these results. Additionally, clinicians were asked for their subjective assessment of the dressing, resulting in 82% rating it as better or much better than standard dressings (). Another case series by the same authors investigated the use of Iodozyme® in 45 patients with 51 chronic wounds following the same methodology without differentiating infection status of the wound (Wood et al., 2010). Data from 30 wound care locations across England showed complete healing in 12%, improvement in 72%, no change in 14%, and deterioration in 2%, with an overall mean reduction in wound area of 20%. The most pronounced reduction in wound area was observed in surgical wounds (46%). Clinicians rated the dressing in 87% as better or much better than standard dressings (Wood et al., 2010). Although the mean wound area reduction was lower compared to the Oxyzyme® study, overall outcomes appeared preferable with 84% of wounds improving or healing completely compared to 73% in the Oxyzyme® study. However, no statistical analyses were performed. Although this mechanism was not directly evaluated, the authors suggest that the increased iodine concentration may not only exert an antimicrobial effect but also reduce inflammation. An additional case series by Lafferty et al. () investigated 11 patients with chronic wounds of mixed etiology applying Iodozyme® to infected wounds and Oxyzyme® to non-infected wounds. While the presented effects in wound healing are comparable to the previously mentioned case series, this study provided additional cost analyses for the 8 patients that completed 20 weeks of treatment to evaluate whether the increased cost of the dressing could be compensated by improved healing rates. With an average treatment cost of £85.40 per week per wound, Oxyzyme®/Iodozyme® treatment was approximately 11% more expensive than standard treatment with £76.80 per week per wound. However, according to the presented results with a complete healing rate of 60% over 20 weeks, 52-week total costs were calculated and compared to total costs under standard treatment with a healing rate of 8% over 24 weeks observed at the same center. This resulted in total savings of £23,036 for the cohort over 52 weeks, assuming the observed healing rate was consistent (). Despite indicating a potential benefit, these calculations are subject to several limitations, including study design, the lack of a control group, and reliance on multiple assumptions, which reduce clinical validity. The highest level of evidence is provided by Moffatt et al. () in an RCT investigating the application of Oxyzyme® in venous and mixed venous-arterial ulcers compared to standard wound dressing. A total of 100 patients were recruited, all of which received concurrent compression therapy. Out of these, 47 were allocated to the experimental arm receiving Oxyzyme® or Iodozyme®, without defining indications for specific dressing choice and regular interchange between the two being mentioned. The remaining 53 patients were allocated to the control arm and received standard wound care, i.e., continuation of their previous treatment regimen. All patients were seen weekly, with additional dressing changes performed as needed. Wound assessment was performed after 12 weeks of treatment and repeated after 24 weeks. No statistically significant improvements in wound healing rates, quality of life, or pain reduction were observed in the experimental group. However, patients in the experimental arm required an average of 10 dressing changes over 12 weeks compared to an average of 15 for patients in the control arm, potentially improving cost-effectiveness for the experimental arm (). Thus, high-level evidence failed to corroborate the positive effects on wound healing reported in earlier case series.
A more recent variation of peroxide dressings employs a different design, using a polymer containing sodium percarbonate and calcium peroxide as oxygen sources. This polymer is enclosed by an outer patch containing a hydrated gel layer required for the chemical reaction and a sealing polyurethane adhesive film. The inner layer consists of an alginate patch in contact with the oxygen-releasing polymer and a release paper ensuring diffusion into the wound. Tong et al. (Tong et al., 2026) performed a phase III randomized clinical trial evaluating this dressing for the healing of split-thickness skin graft donor sites in patients with burns of less than 30% total body surface area. The treatment group consisting of 68 patients received the oxygen-generating dressing and was compared to 69 patients receiving conventional petroleum jelly gauze dressings. All patients were followed for 21 days, with assessment of complete wound closure, wound healing rate, inflammation, infection, and pain. The oxygen-generating alginate dressing group exhibited faster wound healing rates during the first two postoperative weeks, after which the differences were no longer significant. However, time to complete re-epithelialization was significantly reduced in this group at 11 days compared with 15 days in the control group. Although the incidence of pain did not differ between the groups, the group receiving the oxygen-generating alginate dressing demonstrated significantly lower pain intensity scores than the control group. Moreover, inflammation and infection did not differ between the two groups (Tong et al., 2026). Despite these promising outcomes, the oxygen-generating alginate dressing required more frequent dressing changes, increased the workload for care personnel, and was eventually associated with higher treatment costs, thus limiting clinical applicability in its current form.
Taken together, peroxide-based dressings represent a promising approach to topical oxygen delivery by generating and releasing oxygen directly at the wound site while simultaneously exerting an antimicrobial effect. Early enzyme-based systems, such as Oxyzyme® and Iodozyme®, showed promising outcomes in several case series. However, these findings were not supported by subsequent higher-level evidence, although some cost-reduction advantages were observed. With more recent developments employing solid peroxides as an oxygen source, clinical applications have expanded from chronic wounds to acute superficial wounds undergoing persistent ischemia, particularly in burn care. Initial data from a phase III clinical trial demonstrates accelerated healing and a reduced time to re-epithelialization in split-thickness skin graft donor sites. Nevertheless, these advantages are offset by practical limitations, most notably increased demands on healthcare personnel and higher associated costs. Ultimately, peroxide-based dressings represent a biologically plausible approach for local oxygen delivery. However, current evidence remains inconsistent and largely indication-specific. High-quality data are lacking and cost-effectiveness remains uncertain, underscoring the need for well-designed RCTs. Consequently, widespread clinical adoption cannot currently be justified.
6 Microalgae-based OCs
Microalgae offer the potential for sustained oxygen delivery through in situ illumination. Moreover, incorporating microalgae into a biocompatible scaffold capable of integrating with the surrounding tissue permits subsequent skin grafting without necessitating scaffold removal. Such photosynthetic scaffolds were first demonstrated to generate oxygen under light stimulation in vitro and were subsequently validated in full-thickness skin defect animal models (; Schenck et al., 2015).
To evaluate clinical feasibility, Obaíd et al. (Obaíd et al., 2021) conducted a phase 1 clinical trial using porcine-derived decellularized dermal matrices (Integra®; Integra Life Science Corporation, Plainsboro, NJ, United States of America) seeded with C. reinhardtii that were implanted in 8 patients with full-thickness skin defects due to various causes, including trauma, pathological scarring, and tissue necrosis. After initial surgical debridement, the scaffolds were fixed to the defect and illuminated in short dark/light cycles over 7 days with split-thickness skin grafting performed after adequate integration of the scaffold, usually after 21 days. Patients were then kept in hospital for an additional 6 days and follow-up was performed for at least 3 months. Successful integration of the scaffold and overlying skin grafts could be observed in all patients. Self-evaluation regarding pain, burning, itching, and smell yielded favorable results. Furthermore, blood samples collected throughout the follow-up period showed no abnormalities, other than a slight elevation in C-reactive protein in the first few days after surgery, most probably a consequence of the surgical trauma. Histological analyses of the adjacent tissue showed adequate integration of the scaffold without any overwhelming foreign body reaction as well as organized formation of neo-dermis on day 21 and successful integration of the skin graft on day 27. Microalgae showed an orderly structure and presence within the scaffold on day 7 and disappeared by days 21–27. Progressive neovascularization was observed in the adjacent dermis, and early blood vessels could be observed within the scaffold, however, without any vascular lumen. Thus, this study indicates successful scaffold integration and early vascularization (Obaíd et al., 2021). A longer 17-month follow-up was described in a case report following the original study, reporting the outcomes of a patient following correction of a contracted scar in the cubital fossa (Obaíd et al., 2022). At 17 months, the new tissue exhibited positive characteristics in hydration, trans-epidermal water loss, and flexibility, allowing for complete arm extension. Furthermore, favorable results in patient-reported outcomes for this patient could be shown using the SCAR-Q questionnaire (). However, this patient also received negative pressure wound therapy following skin graft surgery and further local vacuum therapy in five weekly sessions 16 months after graft surgery, potentially influencing the outcome (Obaíd et al., 2022).
In summary, microalgae-seeded scaffolds represent an innovative approach to local oxygen delivery, offering the unique capability of externally controlled oxygen generation. The available evidence is encouraging regarding safety and feasibility, with a key advantage being the combination of oxygen delivery and structural support. This may reduce the need for frequent dressing changes and facilitate the transition to definitive wound closure in full-thickness skin defects. However, evidence is currently restricted to a single phase 1 trial with heterogenous wound etiologies and a limited cohort size and a subsequent case report with additional, potentially confounding, treatments. Long-term outcomes, scalability, cost-effectiveness, comparison with current standard-of-care treatment, and potential applicability to other types of wounds remain to be explored in future studies.
7 Physical OCs
In an RCT conducted in a military setting, Lairet et al. () investigated the application of OxyBand™ (OxyBand Technologies Inc., California, United States of America) on donor sites of split-thickness skin grafts. Oxyband™ is a dressing employing a central layer containing a gaseous oxygen reservoir enclosed by an occlusive outer layer and a high-transfer inner film allowing for continued oxygen diffusion. A total of 17 patients with burn wounds of less than 30% total body surface area requiring surgical management and at least two donor sites were included, allowing each patient to serve as their own control. After hemostasis, the donor sites were randomly assigned by means of a randomization table and treated with either Oxyband™ or standard antimicrobial bismuth tribromophenate dressing. The donor sites were inspected daily for 4 days and then every other day until healing, defined as ≥90% re-epithelialization, was achieved. They observed significantly faster healing times of 9 days in the donor sites treated with Oxyband™ compared to 12 days in control sites. Furthermore, early pain scores were significantly lower at the donor sites treated with Oxyband™ than at the control sites. Aesthetic outcomes were assessed between days 30–45 and did not show significant differences between the groups ().
A different wound dressing, which was later discontinued, employed a similar principle by encapsulating oxygen within a closed-cell foam hydrogel. Its effects on scar quality after abdominoplasty were assessed in a clinical trial without producing a final publication (). A small cohort of 8 patients with 4 wounds per patient was enrolled. The left and right side of the patient served as intraindividual case and control wounds and were randomized prior to treatment. Re-epithelialization and pain level were assessed 14 days after surgery and did not show any significant differences between the groups. Furthermore, scar quality was assessed at 42 days post-op, with no significant differences observed (). To date, no further clinical studies of this dressing have been reported.
Taken together, these findings suggest that physical OCs may represent a simple method of local oxygen delivery in selected patient groups. However, the very limited number of clinical studies with varying patient groups and mixed outcomes warrants further investigation before widespread clinical implementation could be considered.
8 Future directions
Promising avenues for the use of OCs in plastic surgery include multienzyme-mediated peroxide systems, nanoparticle-based carriers and novel types of OCs, such as perfluorocarbons (PFCs).
Enzyme-based systems often use enzymes with a catalase-like activity. Catalase converts hydrogen peroxide into oxygen and water without generating reactive oxygen species, thereby oxygenating the surrounding tissue and acting as an antioxidant (Steg et al., 2015). These systems may be particularly useful in chronic or infected wounds, such as diabetic foot ulcers. However, the availability of hydrogen peroxide within these types of wounds is limited, thus reducing the oxygenating effect of exogenous catalase only. The addition of peroxides within polymer matrices or nanoparticles to enable controlled release (Steg et al., 2015; ), or the incorporation of multi-enzyme cascades represent promising approaches. Preclinical studies of such methods report positive outcomes in wound healing applications (Wang et al., 2022), however, clinical studies have not yet been reported. A further approach involves the direct encapsulation of oxygen within a nanoparticle, commonly known as “nanobubbles”. These systems have demonstrated encouraging effects on wound healing in preclinical studies and may enable additional modifications, such as integrating exosomes into the “nanobubble” capsule (; Ren et al., 2023).
PFCs represent a novel type of OC-based on fluorinated carbon chains capable of binding and releasing nonpolar gases, such as oxygen and carbon dioxide, according to the partial pressure gradients (Wijekoon et al., 2013). However, PFCs are hydrophobic and, thus, cannot be dissolved in water, limiting their clinical applicability. To circumvent this, PFCs have been encapsulated in nanoparticles, conjugated to polymers or other nanomaterial surfaces, and incorporated in hydrogels to enable cellular oxygen delivery (Wijekoon et al., 2013; Wrobeln et al., 2017; Patil et al., 2016; ; ; Yang et al., 2022). PFCs have been clinically employed as blood substitutes, although their FDA approval was later revoked due to unforeseen side effects (). Modern variations are currently under investigation for human use in myocardial infarction and stroke (), but their application in wound healing currently remains preclinical. Despite the fact that none of these emerging OCs have yet established clinical efficacy in wound healing, several preclinical studies have demonstrated encouraging results. The future clinical translation of these methods will depend on demonstrating safety, controlled oxygen release, scalability, and practical superiority over existing systems.
9 Conclusion
OCs represent an encouraging strategy based on fundamental biological principles to address persistent tissue hypoxia in a variety of situations encountered in plastic, reconstructive, and aesthetic surgery. By enabling oxygen delivery independent of vascular perfusion, they may complement conventional therapies for the management of acute and chronic wounds. Hemoglobin-based OCs, particularly Granulox®, have the most extensive clinical evidence in chronic wound healing. The discussed M101-based product HEMHealing® is comparatively less established with evidence currently limited to case reports in the treatment of burn wounds and flap necrosis. However, its markedly elevated oxygen-carrying capacity positions it as the most promising candidate for further clinical development within this category. Peroxide-based systems provide an alternative method of local oxygen delivery through in situ oxygen generation with additional antimicrobial properties. Despite their mechanistic appeal, the highest-quality evidence failed to demonstrate a benefit over standard care, and clinical adoption of early enzyme-based systems has been limited accordingly. More recent formulations, however, have shown promising results for split-thickness skin graft donor-site wounds, suggesting a potentially improved suitability for acute, time-limited applications rather than for chronic wound management. Recently, microalgae-seeded scaffolds have introduced the unique ability to externally control oxygen production while providing structural tissue support, with early studies supporting feasibility and safety. Physical OCs offer a mechanistically simple approach through sustained oxygen diffusion and have shown potential benefits in selected clinical applications, however, so far only in small trials and with mixed outcomes.
Despite these exciting developments, the overall clinical evidence for the efficacy of OCs remains limited by small patient cohorts, heterogeneous methodologies, and retrospective designs. High-level evidence could not consistently support the positive results observed in retrospective studies of chronic wound treatment. Consequently, definitive conclusions regarding the comparative efficacy and optimal indications of OCs in chronic wounds cannot yet be drawn. Nonetheless, the application of OCs as an adjunct to standard treatment in selected patient groups may provide clinically relevant improvements. Conversely, preliminary studies in acute wound settings, such as burn wounds, skin graft donor sites, and full-thickness skin defects, have generally reported positive outcomes, albeit large RCTs are still lacking to confirm these results.
Overall, the heterogeneity of evidence did not allow for a quantitative evaluation, such as a meta-analysis. However, to facilitate comparison and clinical interpretation, the products mentioned in this review article and their corresponding indications, reported adverse events, and commercial maturity are presented in Table 3. Furthermore, the authors give a recommendation for their clinical implementation specific to each indication based on the presented literature (Table 3).
TABLE 3
| Category | Product | Indication | Reported adverse events | Commercial maturity | Recommendation |
|---|---|---|---|---|---|
| Hemoglobin-based | Granulox® | Foot ulcers | None related to treatment | Commercialized | Insufficient evidence for routine use with inconsistent findings in RCT; may be considered for adjunctive use |
| Other chronic wounds | None related to treatment | Commercialized | Conditional recommendation for adjunctive use in selected patients | ||
| Burns | None reported | Commercialized, off-label | May be considered as adjunctive therapy in pediatric patients with <30% TBSA | ||
| HEMHealing® | Burns | None reported | Commercialized | Insufficient evidence for routine use; may be considered as adjunctive therapy | |
| Skin flap necrosis | None reported | Commercialized | Insufficient evidence for routine use; may be considered as adjunctive therapy | ||
| Peroxide-based | Oxyzyme®/Iodozyme® | Chronic wound | Might cause inflammatory reaction and encourage autolytic debridement with increased exudate and pain | Commercialized | Insufficient evidence for routine use; may be considered in selected patients with the risk of increased discomfort/pain |
| Polymer oxygenated alginate dressing | Skin graft donor site | None related to treatment | Investigational | Conditional recommendation for adjunctive use though not currently commercially available | |
| Microalgae-based | Integra® + C. reinhardtii | Full-thickness skin defect | None reported | Investigational | Insufficient evidence for routine use; evidence suggests feasibility and safety though not currently commercially available |
| Physical | OxyBand™ | Skin graft donor site | None related to treatment | Commercialized | Conditional recommendation for adjunctive use in selected patients |
| OxyGenesys™ | Scar formation | None related to treatment | Discontinued | No recommendation |
Comparison of different oxygen carrier products, as included in the present review.
RCT, randomized controlled trial; TBSA, total body surface area.
Future advances in biomaterials, nanotechnology, and bioengineering may expand the therapeutic potential of OCs. Emerging strategies, such as enzyme-based systems and PFC-based formulations, may allow OCs to overcome current limitations and broaden clinical applicability. To facilitate translation into clinical practice, future research should focus on larger studies with standardized outcome measures, long-term assessments, and direct comparisons with established treatment modalities. Overall, OCs represent an evolving field with growing clinical interest and the potential to improve patient outcomes in plastic, reconstructive, and aesthetic surgery by addressing one of the fundamental challenges of tissue repair: providing a breath of fresh air by adequate oxygenation.
Statements
Author contributions
LG: Writing – original draft, Formal Analysis, Writing – review and editing, Investigation, Data curation, Methodology, Conceptualization. VP: Writing – review and editing, Formal Analysis, Writing – original draft. FB: Writing – original draft, Formal Analysis, Writing – review and editing. EL: Writing – original draft, Formal Analysis, Writing – review and editing. AW: Writing – review and editing, Formal Analysis, Writing – original draft. ML: Methodology, Investigation, Supervision, Conceptualization, Writing – review and editing, Writing – original draft, Formal Analysis. YH: Formal Analysis, Conceptualization, Writing – review and editing, Methodology, Writing – original draft, Supervision.
Funding
The author(s) declared that financial support was not received for this work and/or its publication.
Acknowledgments
The authors thank Servier Medical Art for providing access to designed medical elements (https://smart.servier.com/), supporting the generation of graphical items in this publication.
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declared that generative AI was not used in the creation of this manuscript.
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Abbreviations
OC, Oxygen carrier; PFC, Perfluorocarbon; RCT, Randomized controlled trial.
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Summary
Keywords
burn care, ischemia, oxygen carrier, plastic surgery, tissue hypoxia, wound healing
Citation
Guggenheim L, Pruzzo V, Bonomi F, Limido E, Weinzierl A, Laschke MW and Harder Y (2026) A breath of fresh air: the role of oxygen carriers in plastic surgery. Front. Bioeng. Biotechnol. 14:1938458. doi: 10.3389/fbioe.2026.1938458
Received
15 July 2026
Revised
10 August 2026
Accepted
11 August 2026
Published
02 September 2026
Volume
14 - 2026
Edited by
Bruce Alan Bunnell, University of Illinois at Urbana–Champaign, United States
Updates
Copyright
© 2026 Guggenheim, Pruzzo, Bonomi, Limido, Weinzierl, Laschke and Harder.
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*Correspondence: Leon Guggenheim, leon.guggenheim@gmx.ch
† These authors have contributed equally to this work
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