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Review

Evaluating the Role of Hyperbaric Oxygen Therapy in Enhancing Skin Graft Outcomes: Mechanisms, Clinical Evidence, and Comparative Efficacy

by
Omer A. Idris
1,2,*,
Alexandra L. Uridge
1,
Syann Hollins
3 and
Kyle Ver Steeg II
4
1
Department of Biological Sciences, Western Michigan University, Kalamazoo, MI 49008, USA
2
Malate Institute for Medical Research, Malate Inc., P.O. Box 23, Grandville, MI 49468, USA
3
Department of Psychology, DePaul University, Chicago, IL 60614, USA
4
Bronson Methodist Hospital Plastic Surgery Specialists, Portage, MI 49024, USA
*
Author to whom correspondence should be addressed.
Oxygen 2024, 4(4), 377-388; https://doi.org/10.3390/oxygen4040023
Submission received: 12 October 2024 / Revised: 24 October 2024 / Accepted: 24 October 2024 / Published: 28 October 2024
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Abstract

:
Skin grafting is a critical procedure for treating skin defects from burns, trauma, and surgical interventions, yet complications such as ischemia, necrosis, and infection can limit graft success. Hyperbaric Oxygen Therapy (HBOT) has emerged as a promising adjunctive treatment that enhances skin graft viability through mechanisms including enhanced oxygenation, angiogenesis, reduced inflammation, and anti-infective effects. This review synthesizes findings from clinical studies, comparative analyses, and case reports to clarify HBOT’s efficacy in improving skin graft outcomes. Methods include a comprehensive analysis of HBOT’s impact on graft take rates, healing times, and complication rates. Results indicate that HBOT significantly improves graft survival by mitigating ischemia and infection, while comparative studies show a reduction in major amputations and improved healing in complex cases, such as diabetic foot ulcers and traumatic injuries. These findings suggest that HBOT can serve as a valuable adjunct to standard grafting procedures, offering a multifaceted approach to improve graft viability, especially in high-risk cases. This review highlights HBOT’s potential for integration into wound management protocols, providing a foundation for further exploration into its efficacy and applications in reconstructive surgery.

Graphical Abstract

1. Introduction

Skin grafting is a crucial surgical technique employed to treat various skin defects, including those resulting from burns, trauma, or surgical excisions. The procedure involves transferring skin from a donor site to a recipient site, where the skin is either partially or completely missing. There are two primary types of skin grafts: split-thickness skin grafts (STSGs) and full-thickness skin grafts (FTSGs). STSGs consist of the epidermis and a portion of the dermis, making them suitable for larger areas due to their ability to re-epithelialize quickly. In contrast, FTSGs include the entire dermis and epidermis, providing better cosmetic results but requiring a more extensive donor site and longer healing time [1,2]. The indications for skin grafting are diverse, ranging from acute injuries like burns to chronic wounds that fail to heal through conventional methods. Common indications include extensive burns, chronic ulcers, surgical defects, and traumatic injuries [3,4]. The success of skin grafting is primarily determined by graft take rates, which refer to the percentage of grafts that successfully adhere and integrate into the recipient site. High graft take rates are essential for achieving optimal healing and aesthetic outcomes, as they reduce the likelihood of complications and the need for additional surgeries [5]. However, graft failure remains a significant challenge, often resulting from inadequate blood supply, which leads to necrosis, infection, or delayed healing. Factors such as patient comorbidities (e.g., obesity and diabetes) can further exacerbate these complications, necessitating innovative approaches to improve skin graft outcomes [6,7]. Hyperbaric Oxygen Therapy (HBOT) has emerged as a problem-solving adjunctive treatment in wound healing and skin grafting. HBOT involves the inhalation of 100% oxygen in a pressurized environment, which enhances oxygen delivery to tissues, promotes angiogenesis, and reduces edema [8]. In skin grafting, HBOT has demonstrated its potential to address specific clinical problems, such as graft necrosis and infection, by improving oxygenation in compromised tissues. This improved oxygenation facilitates graft integration and reduces the risk of complications, directly addressing the clinical challenges that contribute to graft failure [5,8]. The objective of this review is to evaluate the role of HBOT in solving the clinical problems associated with skin graft failures. By synthesizing the current literature, this review aims to elucidate the mechanisms through which HBOT not only enhances graft take rates but also mitigates complications like necrosis and infection, which are significant causes of graft failure. In doing so, this review will highlight the potential of HBOT to solve unmet clinical needs in skin grafting, contributing to more effective wound management strategies. Skin grafting remains a vital component of reconstructive surgery, but challenges such as graft failure and infection continue to necessitate innovative solutions. HBOT represents a promising avenue for addressing these specific problems and improving graft success, warranting further investigation into its efficacy in clinical practice.

2. Mechanisms of Actions HBOT in Skin Grafting

2.1. Enhanced Oxygenation and Promotion of Angiogenesis

Hyperbaric Oxygen Therapy (HBOT) has emerged as a significant adjunctive treatment in the field of skin grafting, primarily due to its mechanisms of enhancing oxygenation and promoting angiogenesis. The therapeutic effects of HBOT are largely attributed to its ability to increase the partial pressure of oxygen in the blood and tissues, which is crucial for the survival and integration of skin grafts.

2.1.1. Enhanced Oxygenation

HBOT significantly elevates the oxygen levels in hypoxic tissues, which is particularly beneficial for skin grafts that are often in a state of low oxygen tension immediately postsurgery. This increased oxygen delivery facilitates essential biological processes such as cellular proliferation and collagen synthesis, both of which are critical for graft adherence and integration into the surrounding tissue [9]. For instance, Zhou and Wang demonstrated that HBOT enhances the oxygen content in the blood, thereby improving the oxygen supply to the grafted tissue at the wound site, which is vital for graft survival [9]. Furthermore, Halbach et al. noted that HBOT has been shown to increase subcutaneous tissue oxygenation, which is essential for the healing process [10]. The promotion of angiogenesis is another critical aspect of HBOT’s mechanism of action. Elevated oxygen levels stimulate endothelial cell proliferation and enhance the expression of angiogenic factors such as vascular endothelial growth factor (VEGF) [11,12]. This is crucial for establishing blood flow within the graft, which facilitates nutrient delivery and ensures long-term graft survival. Studies have indicated that HBOT can lead to increased VEGF expression through various signaling pathways, including the activation of ERK and JNK pathways in endothelial cells [12]. Additionally, the work of Hopf et al. supports the notion that oxygen not only promotes VEGF production but also plays a role in the hydroxylation of proline, which is necessary for collagen synthesis [11].

2.1.2. Promotion of Angiogenesis

The angiogenic response induced by HBOT is vital for the successful integration of skin grafts. Kalns et al. found that HBOT prevents the upregulation of angiogenesis following partial-thickness skin grafts, indicating its role in modulating the angiogenic response [13]. While this finding may appear contradictory to the broader literature, which generally supports HBOT’s role in promoting angiogenesis, this effect may be context dependent. In some cases, particularly with partial-thickness grafts, excessive angiogenesis may not be beneficial. Further studies are needed to understand the varying effects of HBOT on angiogenesis depending on graft type and wound environment. Moreover, studies have shown that sustained oxygenation from HBOT accelerates wound healing by promoting epithelialization and angiogenesis while simultaneously reducing inflammation [14]. This is particularly important in the context of diabetic wounds, where impaired angiogenesis can hinder healing [15]. Furthermore, the systemic delivery of oxygen through HBOT has been shown to mobilize endothelial progenitor cells, which are essential for neovascularization [16]. This mobilization is facilitated by the increased levels of nitric oxide and reactive oxygen species, which play a role in enhancing the wound healing process [17,18].

2.2. Reduction in Ischemia and Necrosis

Hyperbaric Oxygen Therapy (HBOT) plays a critical role in the management of skin grafts by mitigating ischemia and preventing necrosis, two significant challenges in the postoperative care of grafted tissues. The mechanisms through which HBOT achieves these outcomes are multifaceted, primarily involving enhanced oxygen delivery and improved cellular repair processes.

2.2.1. Ischemia Mitigation

HBOT effectively mitigates ischemic conditions by increasing the amount of dissolved oxygen in the plasma, which is particularly beneficial in areas with compromised blood flow. This increased oxygen availability is crucial for preventing tissue hypoxia, a common complication in skin grafting procedures. Studies have shown that HBOT can significantly enhance oxygen levels in tissues, thereby improving the viability of skin grafts in ischemic environments [9,19]. For instance, Zografou et al. demonstrated that the application of HBOT in conjunction with autologous stem cell transplantation improved skin graft survival in diabetic rats, highlighting the therapy’s potential to enhance graft viability under ischemic conditions [19]. Furthermore, Zhou and Wang reported that HBOT increases the oxygen content in the blood, which is vital for supporting the metabolic needs of grafted tissues [9]. The ability of HBOT to penetrate hypoxic tissues and deliver oxygen where it is most needed is essential for reducing the risk of ischemia-induced complications. This is particularly relevant in cases where blood supply is compromised, as seen in patients with diabetes or peripheral vascular disease [20].

2.2.2. Prevention of Necrosis

In addition to mitigating ischemia, HBOT plays a vital role in preventing necrosis by enhancing cellular repair mechanisms and reducing oxidative stress in grafted tissues. The improved oxygenation provided by HBOT not only supports metabolic processes but also promotes the activation of various growth factors and cytokines that are essential for tissue repair and regeneration [21]. For example, Mukundan et al. highlighted that HBOT, when used early in the treatment of soft tissue infections, significantly improved the integration of skin grafts and reduced the incidence of necrosis [21]. Moreover, HBOT has been shown to decrease oxidative stress, which is a contributing factor to tissue damage and necrosis. By enhancing antioxidant defenses and promoting a favorable oxidative balance, HBOT aids in the preservation of graft viability [22]. The study by Kang et al. indicated that preconditioning with HBOT protects skin flap grafts against ischemia/reperfusion injury, which is a common cause of necrosis following grafting procedures [23]. This protective effect is crucial for ensuring better graft integration and reducing the need for revision surgeries, which can be both costly and burdensome for patients [5]. In summary, the mechanisms by which HBOT reduces ischemia and necrosis in skin grafting are centered around enhanced oxygen delivery and improved cellular repair processes. By addressing the challenges of tissue hypoxia and oxidative stress, HBOT significantly contributes to the success of skin grafts, promoting better healing outcomes and reducing complications.

2.3. Anti-Inflammatory Effects

Hyperbaric Oxygen Therapy (HBOT) has been recognized for its anti-inflammatory effects, which are particularly beneficial in the context of skin grafting. The mechanisms through which HBOT exerts these effects include the reduction in inflammatory markers and enhanced cellular recovery, both of which contribute to improved graft survival and integration.

2.3.1. Reduction in Inflammatory Markers

HBOT has been shown to downregulate pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1), which are typically elevated following grafting procedures. This reduction in inflammatory markers is crucial for stabilizing the graft site and minimizing inflammatory responses that could compromise graft survival. For instance, Wolde et al. highlighted that HBOT inhibits the activation of nuclear factor kappa B (NF-κB), a key transcription factor involved in the expression of pro-inflammatory genes, thereby contributing to its anti-inflammatory effects [24]. Moreover, Bosco et al. demonstrated that HBOT can alter the expression of multiple inflammatory markers, including IL-6 and IL-10, suggesting that the therapy not only reduces pro-inflammatory cytokines but also enhances the production of anti-inflammatory mediators [25]. This dual action is critical for maintaining a balanced inflammatory response, which is essential for the healing process following skin grafting.

2.3.2. Enhanced Cellular Recovery

The anti-inflammatory properties of HBOT also promote rapid cellular recovery and decrease the extent of tissue damage, which is particularly critical in the early postoperative phase. By reducing inflammation, HBOT facilitates a more favorable environment for cellular repair and regeneration. Resanović et al. suggested that the anti-inflammatory effects of HBOT may be linked to the reduction in nuclear factor kappa B (NF-κB) and the consequent reduction in activity and expression of inducible nitric oxide synthase, which is often associated with inflammatory responses [26]. This reduction can help mitigate tissue damage and promote healing, thereby enhancing graft integration. Furthermore, Novak et al. found that HBOT treatment significantly reduced the expression of pro-inflammatory cytokines in models of induced colitis, further supporting the notion that HBOT can effectively modulate inflammatory responses [27]. The study indicated that HBOT not only alleviates inflammation but also promotes the expression of antioxidative enzymes, which can further protect tissues from oxidative damage during the healing process. In summary, the anti-inflammatory effects of HBOT are mediated through the reduction in inflammatory markers and the enhancement of cellular recovery. By downregulating pro-inflammatory cytokines and promoting a favorable healing environment, HBOT significantly contributes to the success of skin grafts, minimizing complications and improving overall patient outcomes.

2.4. Anti-Infective Properties

Hyperbaric Oxygen Therapy (HBOT) is recognized for its bactericidal and bacteriostatic effects, which are particularly beneficial in the context of skin grafting and the management of infections. The mechanisms through which HBOT achieves these effects include the creation of a hyperoxic environment that is detrimental to anaerobic bacteria and the enhancement of the efficacy of certain antibiotics.

2.4.1. Bactericidal and Bacteriostatic Effects

HBOT creates a hyperoxic environment that significantly reduces the viability of anaerobic bacteria, which are often responsible for infections in compromised tissues. The increased oxygen levels not only inhibit the growth of these bacteria but also enhance the bactericidal activity of leukocytes, which is crucial in grafted tissues that may be prone to bacterial colonization. Fournier’s Gangrene, a severe soft tissue infection, has been effectively treated with HBOT due to its ability to destroy anaerobic organisms and stimulate neovascularization, thereby preventing the extension of the infection [28]. This bactericidal effect is further supported by Mandour et al., who noted that HBOT enhances the leukocyte bacteria-killing capacity, which is typically impaired in hypoxic conditions [29]. The role of HBOT in acute severe infections is also highlighted by Frawley and Fock, who reported its effectiveness in conditions such as clostridial myonecrosis and necrotizing fasciitis. They emphasized that HBOT restores normoxia or achieves hyperoxia in previously hypoxic tissues, which is crucial for enhancing neutrophil function and inhibiting exotoxin production [30]. This is particularly important in the context of skin grafts, where the risk of infection can lead to graft failure.

2.4.2. Synergistic Role with Antibiotics

In addition to its direct bactericidal effects, HBOT has been shown to enhance the efficacy of certain antibiotics, particularly those that require oxygen for optimal function. For example, studies have indicated that HBOT can synergistically enhance the antimicrobial activity of antibiotics such as nitrofurantoin and trimethoprim, making them more effective against resistant bacterial strains [31]. This synergistic effect is critical in managing infections that pose a risk to graft survival, as highlighted by Singam et al., who noted the benefits of combining HBOT with broad-spectrum antibiotics in treating necrotizing fasciitis [32]. Moreover, the work of Kryeziu emphasizes that HBOT not only increases oxygen concentration in hemoglobin and plasma but also halts bacterial toxin production, thereby improving patient outcomes when combined with surgical debridement and antibiotics [33]. This combined approach is essential in reducing the risk of graft failure due to infectious complications, as it addresses both the bacterial load and the underlying tissue hypoxia. In conclusion, HBOT’s bactericidal and bacteriostatic effects are vital in the context of skin grafting, as they help to reduce the risk of infection and enhance the efficacy of antibiotics. By creating a hyperoxic environment and improving leukocyte function, HBOT significantly contributes to the success of grafts and the overall management of infections. As shown in Figure 1, Hyperbaric Oxygen Therapy (HBOT) supports skin graft success through enhanced oxygenation, stimulation of angiogenesis, reduction in inflammation, and antibacterial effects, each addressing key challenges in graft integration and healing.

3. Clinical Evidence of HBOT in Skin Grafting

3.1. Review of Clinical Studies

Clinical studies have provided substantial evidence supporting the use of Hyperbaric Oxygen Therapy (HBOT) to enhance outcomes in skin grafting, particularly through its vasoconstrictive properties, which can reduce edema and improve tissue viability in cases where standard healing is compromised. As shown in Figure 2, HBOT contributes to improved graft survival, faster healing times, and reduced complication rates, supporting its use as an adjunctive treatment in skin grafting procedures.
Multiple clinical studies have demonstrated that HBOT possesses vasoconstrictive properties, which can reduce edema and improve tissue viability in cases where standard healing is compromised, such as certain skin grafts [34]. For example, a clinical trial compared HBOT with conventional treatment for patients undergoing full-thickness skin grafts. The survival rate of grafts was 92.25% in the conventional group and 97.69% in the HBOT group, indicating a clear benefit for graft viability with HBOT [35]. Another study on chronic diabetic foot ulcers included a placebo group and an HBOT-treated group. At a one-year follow-up, 52% of patients in the HBOT group achieved complete healing, compared to 29% in the placebo group, supporting HBOT’s role as an adjunctive treatment for skin grafts in high-risk patients [36].

3.2. Comparative Studies with Other Interventions

Comparative studies provide further support for HBOT’s efficacy in enhancing skin graft outcomes, especially when compared to conventional wound care treatments. A study conducted from 2012 to 2016 on patients requiring full-thickness skin grafts demonstrated a graft survival rate of 97.69% in the HBOT group versus 92.25% in the conventional treatment group, showing a clear advantage for HBOT over standard care [9]. Similarly, in a large study involving 774 patients receiving HBOT as an adjunct to standard wound care, 39.7% of patients achieved wound closure, while 21.3% achieved more than 80% surface area reduction. In contrast, patients receiving standard wound care alone had significantly lower rates of wound closure and surface area reduction [37,38]. In diabetic patients at high risk for lower-extremity amputations, HBOT was shown to reduce the need for major amputations. Meta-analysis revealed that only 10.7% of those treated with HBOT required amputations, compared to 26.0% among those receiving standard care [39]. These findings underscore HBOT’s potential as a valuable adjunctive therapy for improving graft survival and overall wound healing outcomes in patients undergoing complex skin graft procedures.

3.3. Evidence on the Use of HBOT for Skin Grafting from Case Studies and Reports

Several case studies have highlighted the effectiveness of HBOT in improving skin graft outcomes, particularly in challenging cases where standard treatments have failed. For example, a case study reported the use of HBOT to successfully treat postfiller skin complications. A patient received HBOT at 2.4 atm and 100% oxygen for 90 min over six days, resulting in complete recovery by the fifth day, with no postprocedural scarring [34,40,41,42]. This case underscores HBOT’s ability to accelerate healing and prevent complications in situations where skin integrity is compromised. Another case involved a four-year-old child who sustained a traumatic near-total ear amputation. The patient was treated with HBOT for 90 min twice daily over six days. Significant improvement was observed midway through treatment, leading to complete healing without tissue necrosis by postoperative day 53 [43,44,45,46]. These cases demonstrate HBOT’s efficacy in preventing tissue necrosis and supporting skin graft healing, even in severe traumatic injuries.

3.4. Long-Term Outcomes and Follow Up Studies

Long-term follow-up studies provide further evidence of HBOT’s effectiveness in enhancing skin graft outcomes. In a retrospective study of patients with lower-extremity trauma requiring grafting, the use of HBOT resulted in minimal graft loss in 9% of patients, compared to 14% in the control group. Moreover, healing times were reduced in the HBOT group, averaging 33.1 days, compared to 39.9 days in the control group [47]. In a study on HBOT after nipple-sparing mastectomy, 10 patients received HBOT within an optimal 48-h postsurgery window, with 9 of these patients achieving successful flap healing. Successful healing of mastectomy flaps reduces complications, such as infections and flap loss, and decreases the likelihood of additional surgical interventions. These results emphasize the potential of HBOT to mitigate graft necrosis and other complications in skin graft-like procedures, particularly in high-risk reconstructive surgeries [48,49,50]. These findings suggest that HBOT may decrease graft loss and expedite recovery in patients undergoing skin graft procedures. Another study reported on the outcomes of 11 patients who underwent HBOT following skin grafts for flap ischemia. Seven patients with grade 3 and 4 grafts achieved significant wound healing, while four patients with grade 1 and 2 grafts required additional surgical interventions, highlighting HBOT’s ability to alleviate ischemia and improve graft viability [42]. In a study on HBOT following nipple-sparing mastectomy, 10 patients received HBOT within 48 h of surgery, with 9 achieving successful flap healing. This contrasts with previous outcomes in standard care groups, where rates of flap complications, such as necrosis and infection, were higher. These results demonstrate that early intervention with HBOT can reduce the risk of complications and improve long-term outcomes compared to standard care alone [51,52].

3.5. HBOT for Other Types of Wound Healing and Procedures

In addition to its application in skin grafting, Hyperbaric Oxygen Therapy (HBOT) has shown promise in improving outcomes for other types of wound healing and various medical procedures.

3.5.1. Traumatic Injuries and Soft Tissue Repair

HBOT has been utilized in treating scrotal soft tissue injuries, including traumatic injuries and necrotizing fasciitis. Patients with traumatic injuries who received HBOT postreconstruction experienced significant wound healing. In cases of necrotizing fasciitis, HBOT was administered both pre- and postsurgery, with the greatest benefits observed when HBOT was used both before and after debridement [21]. This highlights the therapy’s potential in enhancing healing and reducing complications in severe soft tissue injuries.

3.5.2. Sensorineural Hearing Loss

HBOT has also been applied in cases of sensorineural hearing loss, often in combination with medical therapy. Clinical studies have shown that HBOT can improve hearing recovery, particularly in patients with severe hearing loss. Benefits are typically observed after a minimum treatment duration of 1200 min [37].

3.5.3. Chronic Wounds and Diabetic Foot Ulcers

A larger study involving 774 patients receiving HBOT as an adjunct to standard wound care demonstrated its efficacy in improving wound healing outcomes. On average, patients received 39 sessions, with 39.7% achieving wound closure and significant surface area reduction [38]. In patients with diabetic foot ulcers, HBOT was shown to reduce the rate of major amputations. A systematic review revealed that 10.7% of patients treated with HBOT required amputations, compared to 26.0% among those who did not receive HBOT, underscoring its potential to lower amputation rates in this high-risk population [39].

3.5.4. Crohn’s Disease

HBOT has also demonstrated efficacy in treating fistulizing Crohn’s disease. A systematic review of 164 patients found that 87% of those treated with HBOT showed a clinical response, with 59% achieving clinical remission [40]. These findings suggest that HBOT may serve as a safe and effective treatment option for this challenging condition.

3.5.5. Crush Injuries and Wound Healing in Severe Trauma

In a French study of 36 patients with crush injuries, HBOT facilitated complete wound healing in 94% of patients, compared to 56% in those receiving sham-HBOT, demonstrating the therapy’s ability to enhance healing in severe traumatic injuries [8]. Similarly, a study from 2006 to 2014 found that HBOT improved survival rates of compromised flaps in patients with crush injuries, preserving hand function and reducing the need for additional surgeries to correct stiffness, contracture scars, and tendon adhesions [47].

3.5.6. Burns and Complex Wounds

In burn patients, HBOT has been shown to significantly reduce healing times. A study involving 63 burn patients treated with HBOT reported healing times averaging 19.7 days, compared to 43.8 days in the conventional treatment group [8]. This demonstrates the potential of HBOT in accelerating recovery in patients with severe burns.
HBOT has also proven effective in treating complex cases of wound healing, such as in a 40-year-old man with penile calciphylaxis. After three weeks of HBOT, the patient experienced significant pain reduction and lesion healing, indicating that HBOT can serve as a last-resort treatment for particularly challenging wounds [45].

3.5.7. Animal Models and Cross-Species Applications

HBOT has shown potential applications across species, as demonstrated by a case study in Brazil involving a mixed-breed dog suffering from extensive necrotic wounds following a snake bite. The dog received 12 HBOT sessions, leading to wound re-epithelialization and complete healing. This case suggests that HBOT protocols used in human medicine may have cross-species applicability for severe wound healing cases [46].

3.5.8. Radiation-Induced Tissue Injury

HBOT has also been applied in treating radiation-induced tissue injuries in cancer patients. In one study, 64% of participants experienced complete resolution or significant improvement of symptoms following HBOT, highlighting its potential for managing late-stage complications in radiation therapy [52].

4. Discussion

4.1. Mechanism Comparison

The mechanisms underlying the efficacy of Hyperbaric Oxygen Therapy (HBOT) in enhancing skin graft viability and promoting wound healing are multifaceted. HBOT facilitates improved oxygenation and angiogenesis, which are critical for graft integration and cellular resilience against hypoxia-induced stress. This is particularly important in the early postoperative phase, where tissues are at heightened risk of ischemia and necrosis. Studies have shown that HBOT enhances the oxygenation of hypoxic tissues, thereby improving the killing ability of neutrophils and stimulating angiogenesis, fibroblast activity, and collagen synthesis, which are essential for effective wound healing [53,54,55]. Furthermore, HBOT has been demonstrated to reduce oxidative stress and inflammation, leading to an increase in growth factors that favor the healing process [24,54]. The anti-inflammatory properties of HBOT also contribute to creating a conducive environment for healing by mitigating local inflammatory responses that could otherwise lead to tissue rejection [53,56].

4.2. Clinical Evidence and Comparative Efficacy

Clinical evidence supports the efficacy of HBOT in treating ischemic and high-risk wounds, although variability in treatment outcomes suggests that factors such as session duration, frequency, and patient-specific variables significantly influence its effectiveness. For instance, some studies indicate that shorter, more frequent HBOT sessions may yield better healing outcomes compared to longer, less frequent sessions [8,57]. Additionally, HBOT has been shown to be cost-effective by reducing the need for additional surgeries and prolonged hospital stays due to complications arising from non-healing wounds [57,58]. However, to establish HBOT as a standard intervention, future studies should focus on stratified analyses that consider factors like age, pre-existing conditions, and wound etiology, ideally through multicenter randomized controlled trials that can provide more generalized results [59,60].

4.3. Future Directions

Looking ahead, the integration of HBOT with other advancements in regenerative medicine, such as bioengineered graft materials or tissue scaffolds, holds significant potential for solving clinical problems associated with graft failure in complex reconstructive procedures. Research should focus not only on enhancing outcomes but also on how HBOT can address specific issues, such as insufficient angiogenesis, ischemia, or graft necrosis. Investigating the molecular impacts of HBOT on cytokine expression and stem cell mobilization can provide crucial insights into how these processes contribute to solving the core problem of graft take failure and improving patient outcomes [16,61]. Moreover, applying machine learning tools could help refine patient selection and predict responses to HBOT, allowing clinicians to tailor treatments more effectively. This personalized approach would not merely optimize treatment but ensure that HBOT is used where it can have the greatest problem-solving impact, improving both graft viability and overall recovery [16,61]. Additionally, future studies should explore not just the physiological effects of HBOT but also the psychological and quality-of-life benefits for patients undergoing skin grafts. By improving graft success and reducing complications, HBOT may significantly alleviate postoperative stress and improve long-term patient satisfaction, thus solving the psychological burdens often associated with complex reconstructive surgeries [16,61]. In summary, future research should focus on how HBOT can be used to solve clinical challenges at various levels, from bioprocesses like oxygenation and angiogenesis to clinical outcomes such as graft survival and patient well-being. This problem-solving approach could ultimately expand HBOT’s utility across multiple clinical applications, solidifying its role as a core strategy for addressing challenges in personalized wound care and reconstructive surgery.

5. Conclusions

Hyperbaric Oxygen Therapy (HBOT) offers a promising adjunctive approach for solving clinical challenges in skin grafting by enhancing oxygenation, promoting angiogenesis, mitigating ischemia and necrosis, reducing inflammation, and providing anti-infective effects. Clinical and comparative studies substantiate HBOT’s ability to improve graft viability and reduce complications, particularly in high-risk patient populations, such as those with diabetes or compromised immune systems. However, limitations in study design, patient selection, and treatment protocols highlight the need for further randomized clinical trials to establish standard guidelines for HBOT’s use in grafting procedures. Future research should focus not only on optimizing treatment protocols, but also on how HBOT can be used to address specific clinical problems, such as graft failure due to ischemia or necrosis. Identifying optimal dosing schedules and patient selection criteria and exploring HBOT’s efficacy in combination with advanced wound healing techniques, are essential next steps. By addressing these critical areas, HBOT has the potential to become a cornerstone in problem-solving strategies for reconstructive surgery and wound management, ultimately improving patient outcomes and quality of life. This review provides a foundation for further investigation into HBOT’s integration into standard wound care protocols, particularly in reconstructive and high-risk grafting contexts, where clinical challenges like graft necrosis and infection remain significant obstacles.

Author Contributions

Conceptualization, O.A.I.; methodology, O.A.I.; software, O.A.I., A.L.U. and S.H.; validation, K.V.S.II; formal analysis, O.A.I.; investigation, O.A.I.; resources, O.A.I.; writing—original draft preparation, O.A.I. and A.L.U.; writing—review and editing, O.A.I., A.L.U., S.H. and K.V.S.II; visualization, O.A.I., A.L.U. and S.H.; supervision, K.V.S.II; project administration, O.A.I. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

Author Omer A. Idris was employed by the company Malate Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Figure 1. Mechanisms of Action of HBOT in Skin Grafting. This figure illustrates the five primary mechanisms by which Hyperbaric Oxygen Therapy (HBOT) enhances skin graft outcomes: (1) Enhanced oxygenation—increases oxygen delivery to hypoxic tissues, supporting cellular metabolism and promoting collagen synthesis. (2) Angiogenesis promotion—stimulates endothelial cell proliferation and vascular endothelial growth factor (VEGF) expression, facilitating blood vessel formation within grafts. VEGF is produced by multiple cell types, including endothelial cells, fibroblasts, keratinocytes, and immune cells, all of which contribute to angiogenesis and enhanced graft success. (3) Ischemia and necrosis mitigation—enhances oxygen content in plasma, improving viability in ischemic tissues. (4) Anti-inflammatory effects—reduces pro-inflammatory cytokines (e.g., TNF-alpha, IL-1) and promotes anti-inflammatory mediators, stabilizing the graft environment. (5) Anti-infective properties—creates a hyperoxic environment detrimental to anaerobic bacteria, enhancing leukocyte function and potentially increasing antibiotic efficacy. Each mechanism targets specific challenges associated with graft integration and viability. This figure was created in BioRender. Hollins, S. (2024) https://BioRender.com/y13l274 (accessed on 23 October 2024).
Figure 1. Mechanisms of Action of HBOT in Skin Grafting. This figure illustrates the five primary mechanisms by which Hyperbaric Oxygen Therapy (HBOT) enhances skin graft outcomes: (1) Enhanced oxygenation—increases oxygen delivery to hypoxic tissues, supporting cellular metabolism and promoting collagen synthesis. (2) Angiogenesis promotion—stimulates endothelial cell proliferation and vascular endothelial growth factor (VEGF) expression, facilitating blood vessel formation within grafts. VEGF is produced by multiple cell types, including endothelial cells, fibroblasts, keratinocytes, and immune cells, all of which contribute to angiogenesis and enhanced graft success. (3) Ischemia and necrosis mitigation—enhances oxygen content in plasma, improving viability in ischemic tissues. (4) Anti-inflammatory effects—reduces pro-inflammatory cytokines (e.g., TNF-alpha, IL-1) and promotes anti-inflammatory mediators, stabilizing the graft environment. (5) Anti-infective properties—creates a hyperoxic environment detrimental to anaerobic bacteria, enhancing leukocyte function and potentially increasing antibiotic efficacy. Each mechanism targets specific challenges associated with graft integration and viability. This figure was created in BioRender. Hollins, S. (2024) https://BioRender.com/y13l274 (accessed on 23 October 2024).
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Figure 2. Clinical Benefits of HBOT in Skin Grafting. This figure highlights clinical outcomes associated with HBOT in skin graft procedures, including improved graft survival rates (e.g., 97.69% in HBOT-treated groups vs. 92.25% in controls), reduced healing times (e.g., 19.7 days in HBOT-treated burn patients vs. 43.8 days in controls), and decreased complication rates such as ischemia, necrosis, and infection. This figure was created in BioRender. Hollins, S. (2024) https://BioRender.com/a28l453 (accessed on 23 October 2024).
Figure 2. Clinical Benefits of HBOT in Skin Grafting. This figure highlights clinical outcomes associated with HBOT in skin graft procedures, including improved graft survival rates (e.g., 97.69% in HBOT-treated groups vs. 92.25% in controls), reduced healing times (e.g., 19.7 days in HBOT-treated burn patients vs. 43.8 days in controls), and decreased complication rates such as ischemia, necrosis, and infection. This figure was created in BioRender. Hollins, S. (2024) https://BioRender.com/a28l453 (accessed on 23 October 2024).
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MDPI and ACS Style

Idris, O.A.; Uridge, A.L.; Hollins, S.; Steeg, K.V., II. Evaluating the Role of Hyperbaric Oxygen Therapy in Enhancing Skin Graft Outcomes: Mechanisms, Clinical Evidence, and Comparative Efficacy. Oxygen 2024, 4, 377-388. https://doi.org/10.3390/oxygen4040023

AMA Style

Idris OA, Uridge AL, Hollins S, Steeg KV II. Evaluating the Role of Hyperbaric Oxygen Therapy in Enhancing Skin Graft Outcomes: Mechanisms, Clinical Evidence, and Comparative Efficacy. Oxygen. 2024; 4(4):377-388. https://doi.org/10.3390/oxygen4040023

Chicago/Turabian Style

Idris, Omer A., Alexandra L. Uridge, Syann Hollins, and Kyle Ver Steeg, II. 2024. "Evaluating the Role of Hyperbaric Oxygen Therapy in Enhancing Skin Graft Outcomes: Mechanisms, Clinical Evidence, and Comparative Efficacy" Oxygen 4, no. 4: 377-388. https://doi.org/10.3390/oxygen4040023

APA Style

Idris, O. A., Uridge, A. L., Hollins, S., & Steeg, K. V., II. (2024). Evaluating the Role of Hyperbaric Oxygen Therapy in Enhancing Skin Graft Outcomes: Mechanisms, Clinical Evidence, and Comparative Efficacy. Oxygen, 4(4), 377-388. https://doi.org/10.3390/oxygen4040023

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