Hyperbaric oxygen therapy is an innovative treatment modality that involves the breathing of pure oxygen or oxygen at elevated concentrations under atmospheric pressure greater than that of the surrounding environment. The mechanism of action primarily involves creating a high-pressure, high-oxygen environment for the damaged tissue, directly enhancing the hypoxic condition, promoting angiogenesis and collateral circulation, and improving the blood oxygen supply to ischemic tissue (Damineni et al., 2025). It can augment the bactericidal capacity of leukocytes by elevating reactive oxygen species generation (Damineni et al., 2025), and modulate the equilibrium of inflammatory mediators and oxidase activities to exert anti-inflammatory and antioxidant effects (Cannellotto et al., 2024). Moreover, hyperbaric oxygen therapy can stimulate cellular metabolism and regenerative capacity, facilitating tissue remodeling (Mackay et al., 2025). Hyperbaric oxygen therapy, recognized for its high safety, ease of operation, low cost, and non-invasive nature, has been endorsed by the International Society of Underwater and Hyperbaric Medicine for the treatment of 14 clinical conditions, including refractory wounds, thermal burns, gas gangrene, and other tissue damage disorders, establishing it as a significant adjunctive therapy for tissue repair (Ortega et al., 2021).

Hyperbaric oxygen therapy facilitates tissue repair via multiple processes, primarily by enhancing cellular function and expediting the healing process through elevated partial pressure of oxygen in the tissue. Hyperbaric oxygen markedly elevates the dissolved oxygen levels in the blood by creating high-pressure and hyperoxic conditions within an enclosed environment. The elevation of dissolved oxygen under high-pressure conditions can enhance the oxygen levels in local wound tissue, including areas not reachable by red blood cells, thereby satisfying cellular oxygen requirements and accelerating tissue metabolic activity, thus facilitating wound healing (Cannellotto et al., 2024). Secondly, hyperbaric oxygen facilitates the healing and regeneration of injured tissues by stimulating angiogenesis and collagen production. Research indicates that hyperbaric oxygen facilitates angiogenesis in wound healing and enhances local oxygen levels, consequently stimulating fibroblast proliferation and collagen synthesis (Gupta and Rathored, 2024). Oxygen serves as a metabolic substrate and a signaling molecule that modulates cellular activity, participating in glycoprotein manufacturing during cell growth (Zoneff et al., 2024). During cell maturation or remodeling, oxygen participates in the synthesis of fibrous collagen as a cofactor for hydroxyproline, followed by the hydroxylation of prolyl, which acts as a cosubstrate under the catalysis of prolyl hydroxylase. Consequently, it facilitates the cross-linking of collagen molecules and improves tissue stability (Salo and Myllyharju, 2021).

Moreover, hyperbaric oxygen can diminish tissue damage by decreasing the adhesion of inflammatory cells, preventing lipid peroxidation, and exhibiting antibacterial capabilities. Research indicates that hyperbaric oxygen can enhance the expression of antioxidant enzymes (such as catalase, superoxide dismutase), anti-apoptotic proteins (such as B-cell lymphoma-2, silent information regulator related enzyme 1), and intercellular junction proteins (such as β-catenin, tight junction protein 1, occludin). Down-regulating inflammatory mediators (such as tumor necrosis factor-alpha (TNF-α) and IL-1β) and apoptosis-related proteins (such as caspase-3) to mitigate the inflammatory response, augment antioxidant capacity, and diminish cell apoptosis has demonstrated beneficial effects in expediting tissue repair (Capó et al., 2023; Ortega et al., 2021; Tejada et al., 2019). Simultaneously, hyperbaric oxygen therapy exhibits enhanced antibacterial activities, particularly against anaerobic bacteria and illnesses associated with biofilms. The body generates reactive oxygen species that are detrimental to bacteria, capable of infiltrating the bacterial cell wall, resulting in cellular damage and bacterial mortality (Cannellotto et al., 2024). The interplay of these systems renders hyperbaric oxygen therapy an excellent complement for enhancing complex wound healing and augmenting the reparative ability of injured tissues.

Exosomes are extracellular vesicles released by cells, measuring approximately 40–200 nm in diameter, and containing diverse substances, including complex RNAs and proteins. They exhibit significant potential in intercellular communication, disease diagnosis, and treatment, emerging as a frontier in recent research on non-cellular therapies for regenerative medicine (Krylova and Feng, 2023). In addition to the remarkable regenerative and immunomodulatory capabilities of stem cells, exosomes generated from stem cells have simpler structure, higher stability, larger yield, easier storage and transportation, and lower immunogenicity, which are key carriers to replace stem cell therapy (Tan et al., 2024). Numerous research indicate that exosomes have effective reparative properties on injured tissues in dermatological conditions (including diabetic wounds, psoriasis, and certain dermatitis) and neurological disorders (such as neurodegenerative diseases or spinal cord injuries) (Wang and Yang, 2023; Yu et al., 2024). The latest report indicates that exosomes derived from mesenchymal stem cells can diminish the expression of inflammatory genes in pulmonary oxygen toxicity induced by hyperbaric oxygen, potentially aiding in the development of novel strategies to decelerate or even reverse the progression of hyperbaric oxygen injury in patients (Shi et al., 2025). Exosomes, with their exceptional properties and benefits, exhibit significant potential in tissue repair and regeneration, paving a novel pathway for the treatment of many tissue damage disorders.

The mechanism of exosomes in tissue repair mainly includes the following aspects. Exosomes can modulate the polarization of immune cells, thereby diminishing the inflammatory response and creating a favorable milieu for the healing of injured tissues (Wang et al., 2025). Studies demonstrate that exosomes produced from adipose-derived mesenchymal stem cells (ADSCs-Exos) promote tissue repair by altering macrophage polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype (Wang et al., 2025). Secondly, exosomes are abundant in several growth factors that might facilitate angiogenesis and tissue regeneration in injured tissues (Hade et al., 2021). Exosomes generated from bone marrow mesenchymal stem cells (BMSC-Exos) have demonstrated the ability to regulate angiogenesis and facilitate bone tissue regeneration through the release and transfer of miR-29a. BMSC-derived exosomes enhanced tendon-bone healing by facilitating angiogenesis in rotator cuff repair (Chen et al., 2025). Third, exosomes can expedite tissue repair by transporting particular miRNAs or proteins that enhance fibroblast proliferation and collagen formation (Xiong et al., 2023). Research demonstrates that BMSC-Exosomes significantly enhanced the expression of collagen I and III in skin fibroblasts and promoted skin wound healing via the upregulation of miR-542-3p (Xiong et al., 2023). In addition, non-coding RNAs in exosomes play an equally important role in regulating cell proliferation and tissue remodeling (Gowtham and Kaundal, 2025). Fourth, exosomes can also reduce fibrosis and scarring by regulating extracellular matrix synthesis and remodeling (Baral et al., 2021). Research indicates that exosomes produced from mesenchymal stem cells (MSC-Exos) can impede skin fibrosis and diminish tissue scarring in mice through the delivery of miR-196b-5p (Baral et al., 2021). The research revealed that ultrasound-pretreated BMSC-Exosomes modulated chondrogenic and anti-adipogenic pathways, enhanced cartilage matrix regeneration, and facilitated fibrocartilage maturation via the targeted delivery of miR-140 in rotator cuff repair (Wu et al., 2024). Exosomes from human foreskin cells modulate collagen synthesis and fibrocyte differentiation in skin wound healing by stimulating the ERK/MAPK pathway, hence diminishing scar formation (Sağraç et al., 2024). Furthermore, ADSCs-Exosomes facilitated the swift restoration of corneal architecture by diminishing oxidative stress, consequently improving cell viability, decreasing cell apoptosis, and boosting the migration of corneal epithelial cells (Ma et al., 2025).

Exosomes can transport medications across the blood-brain barrier for central nervous system disorders. It has demonstrated significant potential in treating central nervous system disorders by facilitating the regeneration and repair of nerve tissue, positioning it as a promising target for such treatments (Wang and Yang, 2023). In summary, exosomes exhibit significant tissue repair capabilities through multiple pathways, including the modulation of inflammatory responses, facilitation of angiogenesis, regulation of cell proliferation and collagen synthesis, inhibition of fibrosis and scar formation, and targeted medication delivery.

The secretion of exosomes is a multifaceted biological process necessitating several membrane fusions (Krylova and Feng, 2023). A hypoxic environment can enhance the secretion of exosomes from cells. Muñiz-García et al. (2022) demonstrated that the exosomal release from human embryonic kidney cells was markedly elevated following hypoxia induction, correlating with the heightened expression of HIF-1α under hypoxic circumstances. Wang et al. (2014) indicated that HIF-1α enhanced Rab22a expression following hypoxic treatment of breast cancer cells, resulting in an almost twofold increase in released exosomes. A separate study by Dorayappan et al. (2018) indicated that HIF-1α facilitated the upregulation of Rab27a and the downregulation of Rab7, lysosomal membrane-associated proteins 1 and 2, and neuraminidase-1 in ovarian cancer cells subjected to hypoxia. Despite the hyperbaric oxygen environment offering elevated oxygen concentration and partial pressure, which theoretically should suppress HIF-1α activity through prolyl hydroxylase activation resulting in degradation (Fiorini and Schofield, 2024), it frequently elicits a response akin to hypoxic circumstances in practice. As shown in Figure 1, on the one hand, the excessive accumulation of reactive oxygen species produced by hyperbaric oxygen can not only oxidize key cysteine residues in the catalytic domain of prolyl hydroxylase (such as the formation of disulfide bond between Cys201 and Cys208), causing conformational change of the enzyme and inactivation (Bae et al., 2024), but also oxidize Fe²⁺ to Fe³⁺ in the active center of prolyl hydroxylase (Chandel et al., 2000). The enzyme loses the reduced cofactor required for catalysis (Chandel et al., 2000), thereby stabilizing HIF-1α. On the other hand, cellular oxygen sensing is based on fluctuations in oxygen concentration rather than absolute values. When hyperbaric oxygen therapy restores cells to normoxia by occasional hyperoxia, the cells will display a condition of relative hypoxia, hence activating regeneration pathways often induced by actual hypoxia. This occurrence is referred to as the “hyperoxia-hypoxia paradox” (Hadanny and Efrati, 2020). Repeated exposure to hyperbaric oxygen enhances the generation of reactive oxygen species and stimulates the synthesis of antioxidant enzymes, including glutathione. The half-life of antioxidant enzymes much exceeds that of reactive oxygen species, leading to a marked decrease in the ratio of reactive oxygen species to antioxidant enzymes upon reestablishment of normoxia following hyperbaric oxygen exposure. The inhibition of prolyl hydroxylase activity prevents the hydroxylation and degradation of HIF-1α, resulting in its buildup. The stability and expression level of HIF-1α facilitate the release of exosomes (Muñiz-García et al., 2022). The “hyperoxia-hypoxia paradox” exemplifies the paradoxical mechanism of exosomes release generated by hyperbaric oxygen. In a hyperoxia exposure model of neonatal lung damage, the transition to normoxia following hyperoxia treatment initiated the creation of multivesicular bodies in mast cells and stimulated exosomes release (Veerappan et al., 2016). Simultaneously, clinical evidence from Siewiera et al. (2024) shown that serum exosomes levels in patients with idiopathic acute sensorineural hearing loss dramatically increased following hyperbaric oxygen treatment (p < 0.05). This study’s results underscore the therapeutic importance of the “hyperoxia-hypoxia paradox” and offer a novel perspective on the mechanism of hyperbaric oxygen, suggesting that it may function via modulating exosomes levels. Consequently, exosomes are implicated in hyperbaric oxygen’s facilitation of illness recovery, and variations in exosomes levels may serve as a possible biomarker for the treatment’s success.

Prior research has demonstrated that hypoxic treatment of mesenchymal stem cells alters the mix of microRNAs and proteins in exosomes generated by these cells, hence augmenting the therapeutic potential of the exosomes (Zhuo et al., 2024). Shyu et al. (2019) observed alterations in the expression of RNA fragments and angiogenic factors in exosomes from human coronary artery endothelial cells (HCAECs) subjected to hyperbaric oxygen therapy, attributed to the relative hypoxic effects of the “hyperoxa-hypoxia paradox”. Research indicates that hyperbaric oxygen markedly enhances the expression of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in exosomes produced from HCAECs. MALAT1, a long non-coding RNA, directly targets vascular endothelial growth factor receptor 2, regulates endothelial cell activity, promotes angiogenesis (Liu et al., 2022), and inhibits miR-92a, which is partially complementary to MALAT1 and influences angiogenesis. Consequently enhancing the expression of the angiogenic factor Kruppel-like factor 2 (KLF2) (Kattih et al., 2024). Following exposure of HCAECs to varying levels of absolute atmospheric (ATA) pressure in a hyperbaric oxygen environment, it was shown that at 2.5 ATA, the expression of MALAT1 in both HCAECs and HCAECs-derived exosomes was maximized. The peak effect was observed after 2 days of exposure and returned to baseline levels by day six. The diminished expression of MALAT1 in HCAECs and exosomes produced from HCAECs may result from elevated oxygen partial pressure or a hyperbaric oxygen environment below 2.5 ATA, which fails to sufficiently induce relative hypoxia in the cells.

Moreover, another research has demonstrated that hyperbaric oxygen can influence the expression of inflammation-associated genes in exosomes (refer to Table 1). Yin et al. (2024) utilized PCR to demonstrate that hyperbaric oxygen treatment resulted in the downregulation of several inflammation-related genes in exosomes, including TLR5, FAAH2, SLC11A1, EGR3, and SRPK3 (all P < 0.01) and EGR1 (P < 0.001). Whole genome sequencing was conducted on exosomes obtained from human umbilical vein endothelial cells, both without and with hyperbaric oxygen treatment. Following comparison, functions and pathways of many biological components were identified as enriched in exosomes subsequent to hyperbaric oxygen treatment (refer to Table 1). Engaged in the MHCII biosynthetic process, transport of basic amino acids, development of primary sexual characteristics, synaptic assembly, intrinsic membrane components, DNA alkylation, DNA methylation, and pathways related to the development of primary male sexual characteristics and the reproductive system, the reproductive system development pathway exhibited the highest level of enrichment. Hyperbaric oxygen regulates gene expression and signaling pathways in exosomes, significantly enhancing fibroblast proliferation and expediting the healing of diabetic wounds (Yin et al., 2024).

Excessive oxygen concentration and partial pressure of breathed oxygen, or prolonged exposure, can result in oxygen toxicity, which may be life-threatening in severe instances (Alva et al., 2023). Despite the extensive application of hyperbaric oxygen in medicine for many ailments, vigilance regarding the potential for medical errors remains essential. Certain investigation by Braun et al. (2018) have demonstrated that intraperitoneal administration of exosomes produced from mesenchymal stromal cells can safeguard the lung from hyperoxia-induced bronchopulmonary dysplasia, with the mechanism manifesting in two facets. As shown in Figure 2, (refer to Table 1) exosomes exert a notable anti-inflammatory effect by suppressing the M1/M2 polarization of macrophages and down-regulating the inflammatory cascade. Conversely, exosomes can stimulate the creation of tubular networks in pulmonary vascular endothelial cells by delivering and targeting vascular endothelial growth factor, thus facilitating neovascularization and enhancing tissue healing and homeostasis restoration. Likewise, as shown in Figure 2, additional study by Yin et al. (2024) indicated that MSC-Exos could diminish the percentage of inflammation-associated lymphocytes (NK cells, B cells, CD8⁺T cells, and CD4⁺T cells) and the concentrations of pro-inflammatory cytokines (IL-6 and TNF-α) in lung tissue, thereby effectively suppressing the inflammatory response in a hyperoxic environment. It also facilitates the proliferation of alveolar epithelial cells (AT1/AT2 cells), underscoring its pivotal function in lung tissue regeneration. Together, these mechanisms demonstrate the numerous protective benefits of exosomes in lung function repair through the dual effects of tissue regeneration and immune regulation, and they offer a strong scientific foundation for the potential benefits of exosomes in combination with hyperbaric oxygen.

Chronic hyperglycemia in diabetic individuals can cause peripheral nerve and microvascular damage, leading to diminished angiogenesis, heightened oxidative stress, infections, and other risk factors, ultimately resulting in the development of diabetic refractory wounds (Lin et al., 2023). Hyperbaric oxygen is an efficacious treatment for diabetic wounds (OuYang et al., 2024), primarily functioning by enhancing the hypoxic environment, stimulating cell proliferation and angiogenesis, and diminishing oxidative stress and inflammatory responses (Capó et al., 2023). Recent evidence has proved that exosomes are one of the key secreted products that mediate intercellular communication and accelerate wound healing (Hade et al., 2022). A study by Yin et al. (2024) demonstrated that exosomes released from human umbilical vein endothelial cells subjected to hyperbaric oxygen were co-cultured with white adipose tissue in culture medium, resulting in the Browning of white adipose tissue, which transformed into beige adipocytes after phagocytosis of the endothelial cell-derived exosomes. Beige adipocytes can induce M2 polarization in macrophages via elevated release of neuregulin 4, suppress inflammatory responses, and enhance fibroblast proliferation and angiogenesis, thereby facilitating tissue regeneration and enhancing diabetic wound healing (Cai et al., 2024). The in vitro findings of this study indicated that hyperbaric oxygen-induced exosomes from vascular endothelial cells may enhance diabetic wound healing by promoting the browning of adipocytes.

Moreover, exosomes produced from stem cells might expedite the healing of diabetic wounds by transporting therapeutic growth factors and microRNAs (Qiao et al., 2023), however, the hypoxic conditions following injury may impair the transportation effectiveness of exosomes within cells (Tong et al., 2023). Consequently, the concurrent delivery of exosomes and oxygen is notably significant. Numerous research have addressed the constraint of hypoxia by developing a novel method including exosomes-coated oxygen nanoparticles, which have demonstrated significant therapeutic efficacy in improving diabetic wound healing (Han et al., 2024; Zhang, et al., 2023a). This therapy technique necessitates advanced technologies and substantial costs, hindering its widespread clinical implementation. Hyperbaric oxygen, as an economical and straightforward oxygen supply method, has been extensively utilized in clinical settings. Its integration with exosomes presents significant potential for the treatment of diabetic wounds, representing a novel avenue for future research.

Vascular disease is a significant contributor to morbidity and death globally; thus, identifying effective non-invasive treatment methods is crucial to mitigate adverse outcomes (Balta, 2021). Shyu et al. (2019) initially discovered that hyperbaric oxygen induces exosomes containing MALAT1, which can enhance angiogenesis. In this investigation, HCAECs were subjected to a minor hyperbaric oxygen chamber (2.5 ATA, 60 min, twice) for 2 days, after which exosomes were extracted from the cell culture medium utilizing a whole exosomes isolation reagent. Subsequently, 70 μg of exosomes were transfected into a rat model of right femoral artery ligation wound via a low-pressure accelerated gene gun (n = 6). Post-treatment, laser Doppler perfusion imaging revealed that exosomes induced by hyperbaric oxygen markedly enhanced blood flow in the ischemic hind limb of rats, with the blood flow ratio (ischemic hind limb/normal hind limb) significantly exceeding that of the control group (p < 0.001). Additionally, a unique mechanism was hypothesized, as shown in Figure 3, whereby hyperbaric oxygen stimulates HCAEC-derived exosomes to suppress miR-92a expression by upregulating MALAT1, thereby counteracting the inhibitory effect of miR-92a on KLF2 expression and promoting angiogenesis.

This study’s findings indicate that another investigation by the same research team identified the therapeutic potential of hyperbaric oxygen-induced exosomes containing MALAT1 for myocardial infarction and further elucidated the mechanism of their combined application to enhance angiogenesis (Shyu et al., 2020). In this study, 70 μg of isolated cardiomyocyte-derived exosomes were administered into the peri-infarct region of a rat myocardial infarction model (n = 5) by a low-pressure accelerated gene gun in three separate instances, in conjunction with hyperbaric oxygen therapy (2.5 ATA, 60 min, a total of 14 sessions). As shown in Figure 3, the co-administration of hyperbaric oxygen and exosomes facilitated the interaction between MALAT1 and miR-92a in rat cardiomyocytes, enhancing the release of KLF2 and the endothelial cell adhesion molecule CD31, which resulted in a substantial decrease in myocardial infarct size (p < 0.01). Moreover, the cardiac ejection fraction was increased by 14% on average compared with non-hyperbaric oxygen-induced exosomes. The function of MALAT1 in myocardial infarction, as shown by prior research, is contentious. Certain investigation by Guo et al. (2019) have indicated the advantageous role of MALAT1 following myocardial infarction; nevertheless, another study by Gong et al. (2019) reported that elevated MALAT1 levels induced myocardial cell death in mice with myocardial infarction, and the rationale for this discrepancy remains inadequately elucidated. These findings offer substantial evidence for clarifying the beneficial effects of MALAT1 during myocardial infarction, and the integration of MALAT1-enriched exosomes with hyperbaric oxygen therapy may represent a promising therapeutic approach for enhancing angiogenesis.

The evaluation of the safety of hyperbaric oxygen in conjunction with exosomes to enhance tissue repair is fundamental to clinical application. This combined therapy technique demonstrates evident synergistic effects in anti-inflammatory, anti-oxidative, pro-angiogenic, and neuroprotective domains, alongside minimal toxicity in animal trials; however, potential human hazards must not be overlooked. A systematic review and meta-analysis of the adverse effects of hyperbaric oxygen therapy included 24 randomized controlled trials with 1,497 subjects, revealing an overall adverse effect rate of 30.11%, with ear discomfort being the most prevalent side effect (113 cases). Nonetheless, when the hyperbaric oxygen treatment regimen (≤10 sessions) or chamber pressure (<2.5 ATA) was adequately regulated, the occurrence of adverse effects was markedly diminished (Zhang, et al., 2023b). Therefore, the hyperbaric oxygen dose is particularly important. As nanoscale vesicles, the immunogenicity of exosomes is the key factor. Exosomes derived from autologous cells are generally well tolerated, but allogeneic or xenogeneic sources may trigger immune rejection or allergic reactions. A review of exosomes immunogenicity points to the potential risk that exosomes surface proteins, such as MHC complexes, may activate T cell responses, leading to autoimmune diseases (Théry et al., 2018). In addition, contamination during exosomes extraction and purification, such as viral or bacterial endotoxins, may also introduce infection risk (Théry et al., 2018). Furthermore, in a hyperbaric oxygen environment, the stability of exosomal membranes may be compromised, resulting in the release of contents and the activation of unforeseen cellular signaling pathways, hence exacerbating toxicity. Consequently, while the approach of utilizing hyperbaric oxygen in conjunction with exosomes to enhance tissue healing is interesting, its safety requires additional investigation.

The effective delivery of exosomes is the major bottleneck in clinical translation. According to pharmacokinetic data, exogenous exosomes have a short residence time in the human circulation and are susceptible to clearance by macrophages associated with organs of the mononuclear phagocytic system (liver, spleen, and lung) (Parada et al., 2021). In the hyperoxic environment created by hyperbaric oxygen, the lipid membrane of exosomes may undergo oxidation and degradation, hence diminishing their bioavailability (Lis et al., 2011). Furthermore, existing delivery methods (including intravenous or topical administration) exhibit inefficiency, with about 10%–20% of exosomes attaining the target regions (Lener et al., 2015). The exosomes delivery protocol for the aforementioned investigation in the myocardial infarction model involves injection into the infarct border zone, which poses challenges for practical translation. To improve stability in tissue repair, it is essential to produce tailored exosomes, including surface-modified targeting ligands, or biomaterial carriers, such as hydrogels (Tran et al., 2020). The pressure gradient of hyperbaric oxygen may disrupt these delivery routes, resulting in non-specific distribution and possible toxicity. Consequently, imaging techniques like fluorescent tagging should be a crucial instrument for evaluating delivery efficacy in clinical trials.

The effective dose of exosomes in animal research (about 10⁹–10¹⁰ exosomes per kilogram of body weight) presents challenges for direct scaling to humans (Gupta et al., 2021). Variations in human body size and metabolism may necessitate a 10- to 100-fold augmentation in dosage; nevertheless, excessive dosing poses a danger of immunotoxicity or thrombosis, while insufficient dosing may prove ineffectual. The interplay between hyperbaric oxygen therapy and variations in oxygen partial pressure can influence the kinetics of exosomes release, hence complicating dose optimization. Consequently, clinical translation necessitates pharmacokinetic and pharmacodynamic modeling to replicate human dosages, accompanied by dose-escalation trials to mitigate risk. In addition, there are physiological differences between animal models and humans, including the immune system, oxygen metabolism, and tissue repair mechanisms (Dietz and Schwab, 2017; Nardone et al., 2017). For example, the high metabolic rate in mice may exaggerate the oxygenation benefits of hyperbaric oxygen (Mortola, 2023). Furthermore, the majority of prior studies administered hyperbaric oxygen or exosomes interventions shortly after model building to achieve optimal outcomes. In clinical practice, treatment is typically commenced during the subacute or chronic phase of injury, and this timely approach is constrained by certain objective characteristics that are challenging to mimic in a clinical environment. These discrepancies may result in diminished efficacy or unforeseen adverse outcomes in clinical trials. Consequently, it is imperative to assess the effectiveness of delayed intervention in large animal models (such as non-human primates) prior to translation, optimize the timing of intervention to confirm its efficacy, and incorporate omics data (such as transcriptome analysis) to bridge the interspecies gap.

In conclusion, while hyperbaric oxygen combined with exosomes demonstrates enhanced efficacy in facilitating tissue repair in animal models, the application of this combination in human clinical trials encounters several constraints, including exosomes delivery methods, dosage scaling, interspecies variations, and timing of intervention. These problems must be resolved by meticulous preclinical optimization and phase I/II trials to guarantee a balance between efficacy and safety.