HYPERBARIC OXYGEN & STEM CELL MOBILIZATION

American Hyperbaric Awareness Association

 

The first documented use of hyperbaric therapy was in the 1600’s prior to the “discovery” of oxygen.  

In the early 1800’s, the medical community started to experiment with pressurized therapy for pulmonary afflictions.  

By the late 1800’s, hyperbaric chambers were widely in use throughout Europe for a variety of afflictions.  

It was not until the second half of the 20th century that hyperbaric oxygen therapy (HBOT) started to enter the mainstream of medical thought.  The first International Congress on Hyperbaric Medicine was held in Amsterdam in 1963.  The American College of Hyperbaric Medicine was formed in 1983.  The International Society of Hyperbaric Medicine was formed in 1988.  The use and effects of HBOT continues to evolve with many FDA-approved as well as emerging off-label treatments being discovered around the world.

The hippocampus – named after its resemblance in size and shape to a seahorse – is a small area just below the cerebral cortex which appears to have many important interactions with key areas of brain function.

 

  •  The hippocampus is one of the first areas to show deterioration in Alzheimer’s disease

  •  Spatial memory and navigation ability are thought to be key areas supported

  •  Long term potentiation (a form of neural plasticity) occurs in the hippocampus

  •  The hippocampus has a definite, but yet little understood, role in memory

  •  The hippocampus is particularly susceptible to damage from long term stress

  •  Damage to the hippocampus is often seen in epilepsy and schizophrenia

  •  In cases of severe depression the hippocampus has been found to shrink

  •  The hippocampus is easily damaged by oxygen deprivation

  •  Military and others suffering from PTSD frequently show damage to the hippocampus

Med Gas Res. 2014 Dec 4;4:18. doi: 10.1186/2045-9912-4-18. eCollection 2014.

Hyperbaric oxygen therapy applied research in traumatic brain injury: from mechanisms to clinical investigation.

Wang Y1, Chen D1, Chen G1.

Traumatic brain injury (TBI) is the leading cause of mortality and morbidity for millions of young people and military personnel around the world every year. Regardless of severity, neurological dysfunction is a sequela of TBI. Although many preclinical and clinical trials have been carried out to explore its underlying pathophysiology, few effective treatment options have been used to ameliorate the prognosis of TBI, particularly with regard to the recovery of neurological deficits. Translational medicine has increasingly emphasized secondary brain injury, as distinguished from the mechanical damage occurring at the moment of traumatic impact; this includes cerebral ischemia, vasospasm, metabolic dysfunction, oxygenation absence and edema.

 * Hyperbaric oxygen therapy (HBOT) is defined as the inhalation of pure oxygen in a hyperbaric chamber that is pressurized to greater than 1 atm. High concentrations of oxygen in the blood could affect brain tissue hypoxia readily thereby avoiding neuronal cell death through increased cerebral oxygen metabolism.

Therefore, HBOT has been suggested as a scientific and effective treatment for TBI. The effectiveness and feasibility of HBOT has been confirmed by several studies. Following the widespread application of HBOT in cerebrovascular diseases and TBI, non-standard therapies frequently occur in primary care institutions, causing great controversy. The systematic analysis of the progress of both animal and clinical studies in this article provides the basis for further study of HBOT.

Biomed Res Int. 2019 Feb 25;2019:3290894. doi: 10.1155/2019/3290894. eCollection 2019.

Review of the Current Knowledge on the Role of Stem Cell Transplantation in Neurorehabilitation.

Kamelska-Sadowska AM1, Wojtkiewicz J2, Kowalski IM1,3.

Author information

Abstract

The management involving stem cell (SC) therapy along with physiotherapy offers tremendous chance for patients after spinal cord injury (SCI), traumatic brain injury (TBI), stroke, etc. However, there are still only a limited number of reports assessing the impact of stem cells(SCs) on the rehabilitation process and/or the results of the simultaneous use of SC and rehabilitation. Additionally, since there is still not enough convincing evidence about the effect of SCT on humans, e.g., in stroke, there have been no studies conducted concerning rehabilitation program formation and expected outcomes.

 * It has been shown that bone marrow-derived mesenchymal stem cell (BMSCs) transplantation in rats combined with hyperbaric oxygen therapy (HBO) can promote the functional recovery of hind limbs after SCI.

 ** An anti-inflammatory effect has been shown.

One case study showed that, after the simultaneous use of SCT and rehabilitation, an SCI patient progressed from ASIA Grade A to ASIA Grade C. Such promising data in the case of complete tetraplegia could be a breakthrough in the treatment of neurologic disorders in humans. Although SCT appears as a promising method for the treatment of neurological conditions, e.g., complete tetraplegia, much work should be done towards the development of rehabilitation protocols.

 J Nanobiotechnology. 2019 Apr 1;17(1):47. doi: 10.1186/s12951-019-0483-1.

Mild thermotherapy and hyperbaric oxygen enhance sensitivity of TMZ/PSi nanoparticles via decreasing the stemness in glioma.

Zeng X1, Wang Q1, Tan X1, Jia L1, Li Y1, Hu M1, Zhang Z1, Bai X1, Zhu Y2, Yang X3.

Author information

Abstract

BACKGROUND:

Glioma is a common brain tumor with a high mortality rate. A small population of cells expressing stem-like cell markers in glioma contributes to drug resistance and tumor recurrence.

METHODS:

Porous silicon nanoparticles (PSi NPs) as photothermal therapy (PTT) agents loaded with TMZ (TMZ/PSi NPs), was combined with hyperbaric oxygen (HBO) therapy in vitro and in vivo. To further investigate underlying mechanism, we detected the expression of stem-like cell markers and hypoxia related molecules in vitro and in vivo after treatment of TMZ/PSi NPs in combination with PTT and HBO.

RESULTS:

NCH-421K and C6 cells were more sensitive to the combination treatment. Moreover, the expression of stem-like cell markers and hypoxia related molecules were decreased after combination treatment. The in vivo results were in line with in vitro.

 * The combination treatment presents significant antitumor effects in mice bearing C6 tumor compared with the treatment of TMZ, PTT or TMZ/PSi NPs only.

CONCLUSION:

 ** These results suggested the TMZ/PSi NPs combined with HBO and PTT could be a potential therapeutic strategy for glioma.

Biol Blood Marrow Transplant. 2019 Jun 3. pii: S1083-8791(19)30353-2. doi: 10.1016/j.bbmt.2019.05.028. [Epub ahead of print]

Results of the First Clinical Study in Humans That Combines Hyperbaric Oxygen Pretreatment with Autologous Peripheral Blood Stem Cell Transplantation.

Abdelhakim H1, Shune L2, Bhatti S3, Cantilena AR4, Baran A5, Lin TL2, Ganguly S2, Singh AK2, Abhyankar S2, Divine C2, Lipe B6, McGuirk J2, Allin D7, Aljitawi OS8.

Author information

Abstract

Patients undergoing high-dose chemotherapy and autologous hematopoietic cell transplantation (auto-HCT) are at risk for multiple morbidities, including mucosal inflammation and neutropenic fever, both related to neutropenia.

 * Evidence from our preclinical work in an umbilical cord blood (UCB) transplantation murine model suggests that treatment with hyperbaric oxygen (HBO) before UCB infusion improves UCB CD34+ cell engraftment by reducing erythropoietin levels.

 * A pilot clinical trial using HBO in patients undergoing UCB transplantation showed improvement in kinetics of blood count recovery.

 

In this study, we evaluated HBO in combination with auto-HCT. Our primary aim was to determine the safety of HBO in this setting and secondarily to determine its efficacy in reducing time to neutrophil and platelet engraftment compared with matched historic controls.

Patients with multiple myeloma, non-Hodgkin lymphoma, and Hodgkin disease eligible for auto-HCT were included. On day 0, patients received HBO treatment consisting of exposure to 2.5 atmosphere absolutes for a total of 90 minutes, in a monoplace hyperbaric chamber, breathing 100% oxygen.

Six hours after the start of HBO, peripherally mobilized stem/progenitor cells were infused and patients were followed daily for toxicity and blood count recovery.

 ** All patients received daily granulocyte colony-stimulating factor starting on day +5 and until absolute neutrophil count (ANC) of ≥1500 or ANC of 500 for 3 consecutive days.

A matched historic cohort of 225 patients who received auto-HCT between January 2008 and December 2012 was chosen for comparison and matched on sex, age, conditioning regimen, and disease type. We screened 26 patients for this study; 20 were treated and included in the primary analysis, and 19 completed the HBO therapy and were included in the secondary analysis. Although the median time to neutrophil count recovery was 11 days in both the HBO and control cohorts, the Kaplan-Meier estimates of the full distributions indicate that the time to neutrophil recovery was generally about 1 day sooner for HBO versus historical controls (log-rank P = .005; range, 9 to 13 for HBO patients and 7 to 18 for controls). The median time to platelet count recovery was 16 days (range, 14 to 21) for HBO versus 18 days (range, 11 to 86) for controls (log-rank P < .0001). In the secondary analysis comparing the HBO cohort who completed HBO therapy (n = 19) with our historical cohort, we evaluated neutropenic fever, growth factor use, mucositis, day +100 disease responses, and blood product use. HBO was associated with less growth factor use (median 6 days in HBO cohort versus median 8 days in controls, P < .0001). Packed RBC and platelet transfusion requirements were not statistically different between the 2 cohorts. Mucositis incidence was significantly lower in the HBO cohort (26.3% in HBO cohort versus 64.2% in controls, P = .002).

 * HBO therapy appears to be well tolerated in the setting of high-dose therapy and auto-HCT. Prospective studies are needed to confirm potential benefits of HBO with respect to earlier blood count recovery, reduced mucositis, and growth factor use, and a cost-benefit analysis is warranted.

 

Med Gas Res. 2018 Apr 18;8(1):24-28. doi: 10.4103/2045-9912.229600. eCollection 2018 Jan-Mar.

Hyperbaric oxygen therapy as adjunctive strategy in treatment of glioblastoma multiforme.

Huang L1,2, Boling W1, Zhang JH1,2,3.

Author information

Abstract

Glioblastoma multiforme (GBM) is the most common type of malignant intracranial tumor in adults. Tumor tissue hypoxia, high mitotic rate, and rapid tumor spread account for its poor prognosis

 * Hyperbaric oxygen therapy (HBOT) may improve the sensitivity of radio-chemotherapy by increasing oxygen tension within the hypoxic regions of the neoplastic tissue.

This review summarizes the research of HBOT applications within the context of experimental and clinical GBM. Limited clinical trials and preclinical studies suggest that radiotherapy immediately after HBOT enhances the effects of radiotherapy in some aspects.

 ** HBOT also is able to strengthen the anti-tumor effect of chemotherapy when applied together. Overall, HBOT is well tolerated in the GBM patients and does not significantly increase toxicity. However, HBOT applied by itself as curative strategy against GBM is controversial in preclinical studies and has not been evaluated rigorously in GBM patients. In addition to HBOT favorably managing the therapeutic resistance of GBM, future research needs to focus on the multimodal or cocktail approaches to treatment, as well as molecular strategies targeting GBM stem cells.

Cond Med. 2018 Jun;1(4):151-166.

A Dual Role for Hyperbaric Oxygen in Stroke Neuroprotection: Preconditioning of the Brain and Stem Cells.

Liska GM1, Lippert T1, Russo E1, Nieves N1, Borlongan CV1.

Author information

Abstract

Stroke continues to be an extremely prevalent disease and poses a great challenge in developing safe and effective therapeutic options. Hyperbaric oxygen therapy (HBOT) has demonstrated significant pre-clinical effectiveness for the treatment of acute ischemic stroke, and limited potential in treating chronic neurological deficits.

 * Reported benefits include reductions in oxidative stress, inflammation, neural apoptosis, and improved physiological metrics such as edema and oxygen perfusion, all of which contribute to improved functional recovery.

This pre-clinical evidence has failed to translate into an effective evidence-based therapy, however, due in large part to significant inconsistencies in treatment protocols and design of clinical studies. While the medical community works to standardize clinical protocols in an effort to advance HBOT for acute stroke, pre-clinical investigations continue to probe novel applications of HBOT in an effort to optimize stroke neuroprotection. One such promising strategy is HBOT preconditioning. Based upon the premise of mild oxidative stress priming the brain for tolerating the full-blown oxidative stress inherent in stroke, HBOT preconditioning has displayed extensive efficacy. Here, we first review the pre-clinical and clinical evidence supporting HBOT delivery following ischemic stroke and then discuss the scientific basis for HBOT preconditioning as a neuroprotective strategy.

 ** Finally, we propose the innovative concept of stem cell preconditioning, in tandem with brain preconditioning, as a promising regenerative pathway for maximizing the application of HBOT for ischemic stroke treatment.

Sci Rep. 2018 Jan 22;8(1):1288. doi: 10.1038/s41598-018-19670-x.

Hyperbaric oxygen reduces inflammation, oxygenates injured muscle, and regenerates skeletal muscle via macrophage and satellite cell activation.

Oyaizu T1,2, Enomoto M3,4, Yamamoto N1,2, Tsuji K5, Horie M2, Muneta T6, Sekiya I7, Okawa A1, Yagishita K2,8.

Author information

Abstract

Hyperbaric oxygen treatment (HBO) promotes rapid recovery from soft tissue injuries. However, the healing mechanism is unclear. Here we assessed the effects of HBO on contused calf muscles in a rat skeletal muscle injury model. An experimental HBO chamber was developed and rats were treated with 100% oxygen, 2.5 atmospheres absolute for 2 h/day after injury.

 * HBO reduced early lower limb volume and muscle wet weight in contused muscles, and promoted muscle isometric strength 7 days after injury.

 ** HBO suppressed the elevation of circulating macrophages in the acute phase and then accelerated macrophage invasion into the contused muscle. This environment also increased the number of proliferating and differentiating satellite cells and the amount of regenerated muscle fibers. In the early phase after injury, HBO stimulated the IL-6/STAT3 pathway in contused muscles.

 *** Our results demonstrate that HBO has a dual role in decreasing inflammation and accelerating myogenesis in muscle contusion injuries.

Front Physiol. 2018 Jul 30;9:995. doi: 10.3389/fphys.2018.00995. eCollection 2018.

Hyperbaric Oxygen Increases Stem Cell Proliferation, Angiogenesis and Wound-Healing Ability of WJ-MSCs in Diabetic Mice.

Peña-Villalobos I1,2, Casanova-Maldonado I2, Lois P2, Prieto C2, Pizarro C2, Lattus J3, Osorio G4, Palma V2.

Author information

Abstract

Hyperbaric oxygen therapy (HBOT) is effective for the medical treatment of diverse diseases, infections, and tissue injury. In fact, in recent years there is growing evidence on the beneficial effect of HBOT on non-healing ischemic wounds. However, there is still yet discussion on how this treatment could benefit from combination with regenerative medicine strategies.

Here we analyzed the effects of HBOT on three specific aspects of tissue growth, maintenance, and regeneration: (i) modulation of adult rodent (Mus musculus) intestinal stem cell turnover rates; (ii) angiogenesis dynamics during the development of the chorio-allantoic membrane (CAM) in Gallus gallus embryos; (iii) and wound-healing in a spontaneous type II diabetic mouse model with a low capacity to regenerate skin.

To analyze these aspects of tissue growth, maintenance, and regeneration, we used HBOT alone or in combination with cellular therapy. Specifically, Wharton Jelly Mesenchymal Stem cells (WJ-MSC) were embedded in a commercial collagen-scaffold. HBOT did not affect the metabolic rate of adult mice nor of chicken embryos.

  *  HBOT modified the proliferation rate of stem cells in the mice small intestinal crypts, increased angiogenesis in the CAM, and improved wound-healing and tissue repair in diabetic mice.

 ** Moreover, our study demonstrates that combining stem cell therapyand HBOT has a collaborative effect on wound-healing. In summary, our data underscore the importance of oxygen tension as a regulator of stem cell biology and support the potential use of oxygenation in clinical treatments.

Gastrointest Endosc Clin N Am. 2019 Jul;29(3):515-530. doi: 10.1016/j.giec.2019.02.011.

Advances in Perianal Disease Associated with Crohn's Disease-Evolving Approaches.

Wang X1, Shen B2.

Author information

Abstract

Perianal diseases, common complications of Crohn's disease, are difficult to diagnose/manage. Patients with perianal Crohn's disease suffer from persistent pain and drainage, recurrent perianal sepsis, impaired quality of life, and financial burden. Conventional medical and surgical therapies carry risk of infection, myelosuppression, incontinence, disease recurrence. Although the phenotype of Crohn's disease has been extensively studied, reported outcomes are inconsistent. Endoanal ultrasonography is also becoming popular because of low cost and ability to acquire images in real time.

 * Emerging management strategies for treatment including laser therapy, local injection of agents, use of hyperbaric oxygen, and stem cell therapy, have demonstrated efficacy.

PLoS One. 2017 May 23;12(5):e0178182. doi: 10.1371/journal.pone.0178182. eCollection 2017.

Effect of hyperbaric oxygen on BDNF-release and neuroprotection: Investigations with human mesenchymal stem cells and genetically modified NIH3T3 fibroblasts as putative cell therapeutics.

Schulze J1,2, Kaiser O1,2, Paasche G1,2, Lamm H1, Pich A3, Hoffmann A4, Lenarz T1,2, Warnecke A1,2.

Author information

Abstract

Hyperbaric oxygen therapy (HBOT) is a noninvasive widely applied treatment that increases the oxygen pressure in tissues. In cochlear implant (CI) research, intracochlear application of neurotrophic factors (NTFs) is able to improve survival of spiral ganglion neurons (SGN) after deafness. Cell-based delivery of NTFs such as brain-derived neurotrophic factor (BDNF) may be realized by cell-coating of the surface of the CI electrode. Human mesenchymal stem cells (MSC) secrete a variety of different neurotrophic factors and may be used for the development of a biohybrid electrode in order to release endogenously-derived neuroprotective factors for the protection of residual SGN and for a guided outgrowth of dendrites in the direction of the CI electrode. HBOT could be used to influence cell behaviour after transplantation to the inner ear.

The aim of this study was to investigate the effect of HBOT on the proliferation, BDNF-release and secretion of neuroprotective factors. Thus, model cells (an immortalized fibroblast cell line (NIH3T3)-native and genetically modified) and MSCs were repeatedly (3 x - 10 x) exposed to 100% oxygen at different pressures. The effects of HBO on cell proliferation were investigated in relation to normoxic and normobaric conditions (NOR). Moreover, the neuroprotective and neuroregenerative effects of HBO-treated cells were analysed by cultivation of SGN in conditioned medium. Both, the genetically modified NIH3T3/BDNF and native NIH3T3 fibroblasts, showed a highly significant increased proliferation after five days of HBOT in comparison to normoxic controls. By contrast, the number of MSCs was decreased in MSCs treated with 2.0 bar of HBO. Treating SGN cultures with supernatants of fibroblasts and MSCs significantly increased the survival rate of SGN. HBO treatment did not influence (increase / reduce) this effect. Secretome analysis showed that HBO treatment altered the protein expression pattern in MSCs.

Undersea Hyperb Med. 2017 May-June;44(3):257-269.

Increased circulating stem cells and better cognitive performance in traumatic brain injury subjects following hyperbaric oxygen therapy.

Shandley S1, Wolf EG2, Schubert-Kappan CM3, Baugh LM4, Richards MF2, Prye J1, Arizpe HM1, Kalns J1.

Author information

Abstract

Traumatic brain injury (TBI) may cause persistent cognitive dysfunction. A pilot clinical study was performed to determine if hyperbaric oxygen (HBO₂) treatment improves cognitive performance.

 * It was hypothesized that stem cells, mobilized by HBO₂ treatment, are recruited to repair damaged neuronal tissue.

 

This hypothesis was tested by measuring the relative abundance of stem cells in peripheral blood and cognitive performance during this clinical trial. The subject population consisted of 28 subjects with persistent cognitive impairment caused by mild to moderate TBI suffered during military deployment to Iraq or Afghanistan. Fluorescence-activated cell sorting (FACS) analysis was performed for stem cell markers in peripheral blood and correlated with variables resulting from standard tests of cognitive performance and post-traumatic stress disorder: ImPACT, BrainCheckers and PCL-M test results.

 ** HBO₂ treatment correlated with stem cell mobilization as well as increased cognitive performance. Together these results support the hypothesis that stem cell mobilization may be required for cognitive improvement in this population.

Hyperbaric Oxygen Therapy for Adults with Mental Illness: A Review of the Clinical Effectiveness

Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2014 Aug. 
CADTH Rapid Response Reports.

Excerpt

Mental illness, including major depressive episode, bipolar disorder, generalized anxiety disorder, alcohol abuse, and other drug abuse or dependence, affects approximately 1 in 3 Canadians at some point in their lives. Depression is the most common mood disorder, with a lifetime incidence of 11.3%, while the lifetime incidence of generalized anxiety disorder is 8.7%. 

Hyperbaric oxygen therapy (HBOT) is administered inside a treatment chamber and provides the patient with 100% oxygen at high atmospheric pressures. There have been a number of medical conditions in which treatment with hyperbaric oxygen has been investigated, including, but not limited to, treatment of carbon monoxide poisoning, improved wound healing, and decompression sickness and air embolism due to ascending too quickly in aviation or deep water diving.

It has been hypothesized that hyperbaric oxygen therapy may be beneficial in the treatment of certain mental health disorders such as post-traumatic stress disorder occurring in the setting of a traumatic brain injury. In an uncontrolled pre-post study, a group of patients with blast-induced post-concussion syndrome with or without post-traumatic stress disorder demonstrated improvement in a number of physical, psychological, and cognitive measured when tested within a week of completing 30 days of HBOT.

 * The proposed mechanism of action of hyperbaric oxygen in traumatic brain injury is that increasing oxygenation of blood and tissues to supraphysiological levels results in the improvement of neuronal functioning by the reactivation of metabolic or electrical pathways. Stem cell mobilization to sites of injury, immune modulation and impact on neurotransmitters have also been hypothesized as possible mechanisms. Currently, the value of using hyperbaric oxygen therapy in the treatment of mental illness has not been well-established. The purpose of this report was to review existing studies on the use of hyperbaric oxygen therapy for adults with post-traumatic stress disorder, generalized anxiety disorder, or depression.

Stem Cell Res Ther. 2017 Feb 7;8(1):29. doi: 10.1186/s13287-017-0470-0.

Endothelial differentiation of bone marrow mesenchyme stem cells applicable to hypoxia and increased migration through Akt and NFκB signals.

Liu C1,2,3, Tsai AL2,4, Li PC5,6, Huang CW4,7, Wu CC8,9,10.

Author information

Abstract

BACKGROUND:

Bone marrow mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs) are used to repair hypoxic or ischemic tissue. However, the underlining mechanism of resistance in the hypoxic microenvironment and the efficacy of migration to the injured tissue are still unknown. The current study aims to understand the hypoxia resistance and migration ability of MSCs during differentiation toward endothelial lineages by biochemical and mechanical stimuli.

METHOD:

MSCs were harvested from the bone marrow of 6-8-week-old Sprague-Dawley rats. The endothelial growth medium (EGM) was added to MSCs for 3 days to initiate endothelial differentiation. Laminar shear stress was used as the fluid mechanical stimulation.

RESULTS:

Application of EGM facilitated the early endothelial lineage cells (eELCs) to express EPC markers. When treating the hypoxic mimetic desferrioxamine, both MSCs and eELCs showed resistance to hypoxia as compared with the occurrence of apoptosis in rat fibroblasts. The eELCs under hypoxia increased the wound closure and C-X-C chemokine receptor type 4 (CXCR4) gene expression. Although the shear stress promoted eELC maturation and aligned cells parallel to the flow direction, their migration ability was not superior to that of eELCs either under normoxia or hypoxia. The eELCs showed higher protein expressions of CXCR4, phosphorylated Akt (pAkt), and endogenous NFκB and IκBα than MSCs under both normoxia and hypoxia conditions. The potential migratory signals were discovered by inhibiting either Akt or NFκB using specific inhibitors and revealed decreases of wound closure and transmigration ability in eELCs.

CONCLUSION:

The Akt and NFκB pathways are important to regulate the early endothelial differentiation and its migratory ability under a hypoxic microenvironment.

Antioxid Redox Signal. 2014 Oct 10;21(11):1634-47. doi: 10.1089/ars.2014.5940. Epub 2014 May 19.

Hyperbaric oxygen, vasculogenic stem cells, and wound healing.

Fosen KM1, Thom SR.

Author information

Oxidative stress is recognized as playing a role in stem cell mobilization from peripheral sites and also cell function.

This review focuses on the impact of hyperoxia on vasculogenic stem cells and elements of wound healing.

CRITICAL ISSUES:

Components of the wound-healing process in which oxidative stress has a positive impact on the various cells involved in wound healing are highlighted. A slightly different view of wound-healing physiology is adopted by departing from the often used notion of sequential stages: hemostatic, inflammatory, proliferative, and remodeling and instead organizes the cascade of wound healing as overlapping events or waves pertaining to reactive oxygen species, lactate, and nitric oxide. This was done because hyperoxia has effects of a number of cell signaling events that converge to influence cell recruitment/chemotaxis and gene regulation/protein synthesis responses which mediate wound healing.

Our alternative perspective of the stages of wound healing eases recognition of the multiple sites where oxidative stress has an impact on wound healing. This aids the focus on mechanistic events and the interplay among various cell types and biochemical processes. It also highlights the areas where additional research is needed.

Stem Cell Res. 2014 May;12(3):638-45. doi: 10.1016/j.scr.2014.02.005. Epub 2014 Feb 28.

CD34+/CD45-dim stem cell mobilization by hyperbaric oxygen - changes with oxygen dosage.

Heyboer M 3rd1, Milovanova TN2, Wojcik S1, Grant W1, Chin M2, Hardy KR2, Lambert DS2, Logue C2, Thom SR3.

Author information

Abstract

Because hyperbaric oxygen treatment mobilizes bone marrow derived-stem/progenitor cells by a free radical mediated mechanism, we hypothesized that there may be differences in mobilization efficiency based on exposure to different oxygen partial pressures. Blood from twenty consecutive patients was obtained before and after the 1st, 10th and 20th treatment at two clinical centers using protocols involving exposures to oxygen at either 2.0 or 2.5 atmospheres absolute (ATA).

Post-treatment values of CD34+, CD45-dim leukocytes were always 2-fold greater than the pre-treatment values for both protocols.

Values for those treated at 2.5 ATA were significantly greater than those treated at 2.0 ATA by factors of 1.9 to 3-fold after the 10th and before and after the 20th treatments. Intracellular content of hypoxia inducible factors -1, -2, and -3, thioredoxin-1 and poly-ADP-ribose polymerase assessed in permeabilized CD34+ cells with fluorophore-conjugated antibodies were twice as high in all post- versus pre-treatment samples with no significant differences between 2.0 and 2.5 ATA protocols.

We conclude that putative progenitor cell mobilization is higher with 2.5 versus 2.0 ATA treatments, and all newly mobilized cells exhibit higher concentrations of an array of regulatory proteins.

Cancer Med. 2016 Nov;5(11):3147-3155. doi: 10.1002/cam4.851. Epub 2016 Oct 13.

Hyperbaric oxygen therapy sensitizes nimustine treatment for glioma in mice.

Lu Z1, Ma J1, Liu B1, Dai C1, Xie T1, Ma X1, Li M2, Dong J1, Lan Q1, Huang Q1.

Author information

Abstract

Nimustine (ACNU) has antitumor activities in patients with malignant glioma

Hyperbaric oxygen (HBO) may enhance the efficacy of certain therapies that are hampered by the hypoxic microenvironment. We examined the combined effects of ACNU and HBO in a GFP transgenic nude mice bearing human glioma model. Mice inoculated with human glioma cells SU3 were randomly divided into the four groups: (A) the control group, (B) the HBOT (HBO therapy) group, (C) the ACNU group, and (D) the HBOT+ACNU group. Tumor size was measured at the indicated time intervals with a caliper; mice were sacrificed 28 days after treatment, and immunohistochemistry staining and western blot analysis were carried out. By the end of the trial, the tumor weights of groups A, B, C, and D were (P < 0.05), 6.03 ± 1.47, 4.13 ± 1.82 (P < 0.05), 2.39 ± 0.25 (P < 0.05), and 1.43 ± 0.38 (P < 0.01), respectively. The expressions of TNF-α, MMP9, HIF-α, VEGF, NF-κB, and IL-1β were associated with the infiltration of inflammatory cells and the inhibition rate of tumor cells. 

 * Hyperbaric oxygen therapy (HBOT) could inhibit glioma cell proliferation and inflammatory cell infiltration, and exert a sensitizing effect on ACNU therapy partially through enhancing oxygen pressure (PO2 ) in tumor tissues and lower expression levels of HIF-1α, TNF-α, IL-1β, VEGF, MMP9, and NF-κB.

BMJ Open Gastroenterol. 2016 Apr 28;3(1):e000082. doi: 10.1136/bmjgast-2016-000082. eCollection 2016.

Hyperbaric oxygen therapy stimulates colonic stem cells and induces mucosal healing in patients with refractory ulcerative colitis: a prospective case series.

Bekheit M1, Baddour N2, Katri K3, Taher Y4, El Tobgy K5, Mousa E3.

Author information

Abstract

BACKGROUND:

Hyperbaric oxygen (HBO) is used as part of treatment in a variety of clinical conditions. Its use in the treatment of ulcerative colitis has been reported in few clinical reports.

OBJECTIVE:

We report the effect of HBO on refractory ulcerative colitis exploring one potential mechanism of action.

DESIGN:

A review of records of patients with refractory ulcerative colitis who received HBO was conducted. Clinical and histopathological scoring was utilised to evaluate the response to HBO therapy (HBOT).

RESULTS:

All patients manifested clinical improvement by the 40th cycle of HBOT. The median number of stool frequency dropped from seven motions/day (range=3-20) to 1/day (range=0.5-3), which was significant (z=-4.6, p<0.001). None of the patients manifested persistent blood passage after HBOT (z=-3.2, p=0.002). The severity index significantly improved after HBOT (z=-4.97, p<0.001). Histologically, a significant reduction of the scores of activity was recorded accompanied by a significant increase in the proliferating cell nuclear antigen labelling index of the CD44 cells of the colonic mucosa (p=0.001).

CONCLUSIONS:

 * HBOT is effective in the setting of refractory ulcerative colitis. The described protocol is necessary for successful treatment. HBOT stimulates colonic stem cells to promote healing.

Undersea Hyperb Med. 2015 Jul-Aug;42(4):333-51.

Clinical results in brain injury trials using HBO2 therapy: Another perspective.

Figueroa XAWright JK.

Abstract

The current debate surrounding the use of hyperbaric oxygen (HBO2) for neurological indications, specifically mild to moderate chronic traumatic brain injury (mTBI) and post-concussion syndrome (PCS), is mired in confusion due to the use of non-validated controls and an unfamiliarity by many practitioners of HBO2 therapy with the experimental literature. In the past 40 years, the use of an air sham (21% oxygen, 1.14-1.5 atmospheres absolute/atm abs) in clinical and animal studies, instead of observational or crossover controls, has led to false acceptance of the null hypothesis (declaring no effect when one is present), due to the biological activity of these "sham" controls. The recent Department of Defense/Veterans Administration (DoD/VA) sponsored trials, previous published reports on the use of HBO2 therapy on stroke and mTBI and preliminary reports from the HOPPS Army trial, have helped to highlight the biological activity of pressurized air, validate the development of a convincing control for future studies and demonstrate the effectiveness of a hyperbaric intervention for mTBI/ PCS.

 * Approval of HBO2 for neurological indications, especially for mTBI/PCS, should be granted at the federal, state and certifying body levels as a safe and viable treatment for recovery in the post-acute phase.

Wound Repair Regen. 2011 Mar-Apr;19(2):149-61. doi: 10.1111/j.1524-475X.2010.00660.x.

Vasculogenic stem cell mobilization and wound recruitment in diabetic patients: increased cell number and intracellular regulatory protein content associated with hyperbaric oxygen therapy.

Thom SR1, Milovanova TNYang MBhopale VMSorokina EMUzun GMalay DSTroiano MAHardy KRLambert DSLogue CJMargolis DJ.

Author information

Abstract

 * Diabetic patients undergoing hyperbaric oxygen therapies (HBO(2)T) for refractory lower extremity neuropathic ulcers exhibit more than a twofold elevation (p=0.004) in circulating stem cells after treatments and the post-HBO(2)T CD34(+) cell population contains two- to threefold higher levels of hypoxia inducible factors-1, -2, and -3, as well as thioredoxin-1 (p<0.003), than cells present in blood before HBO(2)T.

Skin margins obtained from 2-day-old abdominal wounds exhibit higher expression of CD133, CD34, hypoxia inducible factor-1, and Trx-1 vs. margins from refractory lower extremity wounds and expression of these proteins in all wounds is increased due to HBO(2)T (p<0.003).
 ** HBO(2)T is known to mobilize bone marrow stem cells by stimulating nitric oxide synthase.

We found that nitric oxide synthase activity is acutely increased in patients' platelets following HBO(2)T and remains elevated for at least 20 hours.

 *** We conclude that HBO(2) T stimulates vasculogenic stem cell mobilization from bone marrow of diabetics and more cells are recruited to skin wounds.

Am J Physiol Heart Circ Physiol. 2006 Apr;290(4):H1378-86. Epub 2005 Nov 18.

Stem cell mobilization by hyperbaric oxygen.

Thom SR1, Bhopale VMVelazquez O

CGoldstein LJThom LHBuerk DG.

Author information

Abstract

We hypothesized that exposure to hyperbaric oxygen (HBO(2)) would mobilize stem/progenitor cells from the bone marrow by a nitric oxide (*NO) -dependent mechanism. The population of CD34(+) cells in the peripheral circulation of humans doubled in response to a single exposure to 2.0 atmospheres absolute (ATA) O(2) for 2 h.

 * Over a course of 20 treatments, circulating CD34(+) cells increased eightfold, although the overall circulating white cell count was not significantly increased. The number of colony-forming cells (CFCs) increased from 16 +/- 2 to 26 +/- 3 CFCs/100,000 monocytes plated. Elevations in CFCs were entirely due to the CD34(+) subpopulation, but increased cell growth only occurred in samples obtained immediately post treatment. A high proportion of progeny cells express receptors for vascular endothelial growth factor-2 and for stromal-derived growth factor.

 ** In mice, HBO(2) increased circulating stem cell factor by 50%, increased the number of circulating cells expressing stem cell antigen-1 and CD34 by 3.4-fold, and doubled the number of CFCs. Bone marrow *NO concentration increased by 1,008 +/- 255 nM in association with HBO(2). 

Stem cell mobilization did not occur in knockout mice lacking genes for endothelial *NO synthase. Moreover, pretreatment of wild-type mice with a *NO synthase inhibitor prevented the HBO(2)-induced elevation in stem cell factor and circulating stem cells.

 *** We conclude that HBO(2) mobilizes stem/progenitor cells by stimulating *NO synthesis.

 

Stem Cells Transl Med. 2014 Mar;3(3):277-89. doi: 10.5966/sctm.2013-0160. Epub 2013 Dec 27.

Influence of in vitro and in vivo oxygen modulation on β cell differentiation from human embryonic stem cells.

Cechin S1, Alvarez-Cubela SGiraldo JAMolano RDVillate SRicordi CPileggi AInverardi LFraker CADomínguez-Bendala J.

Author information

Abstract

The possibility of using human embryonic stem (hES) cell-derived β cells as an alternative to cadaveric islets for the treatment of type 1 diabetes is now widely acknowledged. However, current differentiation methods consistently fail to generate meaningful numbers of mature, functional β cells.

In order to address this issue, we set out to explore the role of oxygen modulation in the maturation of pancreatic progenitor (PP) cells differentiated from hES cells. We have previously determined that oxygenation is a powerful driver of murine PP differentiation along the endocrine lineage of the pancreas.

We hypothesized that targeting physiological oxygen partial pressure (pO2) levels seen in mature islets would help the differentiation of PP cells along the β-cell lineage. This hypothesis was tested both in vivo (by exposing PP-transplanted immunodeficient mice to a daily hyperbaric oxygen regimen) and in vitro (by allowing PP cells to mature in a perfluorocarbon-based culture device designed to carefully adjust pO2 to a desired range).

 * Our results show that oxygen modulation does indeed contribute to enhanced maturation of PP cells, as evidenced by improved engraftment, segregation of α and β cells, body weight maintenance, and rate of diabetes reversal in vivo, and by elevated expression of pancreatic endocrine makers, β-cell differentiation yield, and insulin production in vitro. Our studies confirm the importance of oxygen modulation as a key variable to consider in the design of β-cell differentiation protocols and open the door to future strategies for the transplantation of fully mature β cells.

Neurochem Res. 2009 Jul;34(7):1304-16. doi: 10.1007/s11064-008-9910-7. Epub 2009 Jan 17.

Human amniotic fluid mesenchymal stem cells in combination with hyperbaric oxygen augment peripheral nerve regeneration.

Pan HC1, Chin CSYang DYHo SPChen CJHwang SMChang MHCheng FC.

Author information

Abstract

PURPOSE:

Attenuation of pro-inflammatory cytokines and associated inflammatory cell deposits rescues human amniotic fluid mesenchymal stem cells (AFS) from apoptosis. Hyperbaric oxygen (HBO) suppressed stimulus-induced pro-inflammatory cytokine production in blood-derived monocyte-macrophages. Herein, we evaluate the beneficial effect of hyperbaric oxygen on transplanted AFS in a sciatic nerve injury model.

METHODS:

Peripheral nerve injury was produced in Sprague-Dawley rats by crushing the left sciatic nerve using a vessel clamp. The AFS were embedded in fibrin glue and delivered to the injured site. Hyperbaric oxygen (100% oxygen, 2 ATA, 60 min/day) was administered 12 h after operation for seven consecutive days. Transplanted cell apoptosis, oxidative stress, inflammatory cell deposits and associated chemokines, pro-inflammatory cytokines, motor function, and nerve regeneration were evaluated 7 and 28 days after injury.

RESULTS:

Crush injury induced an inflammatory response, disrupted nerve integrity, and impaired nerve function in the sciatic nerve. However, crush injury-provoked inflammatory cytokines, deposits of inflammatory cytokines, and associated macrophage migration chemokines were attenuated in groups receiving hyperbaric oxygen but not in the AFS-only group. No significant increase in oxidative stress was observed after administration of HBO. In transplanted AFS, marked apoptosis was detected and this event was reduced by HBO treatment. Increased nerve myelination and improved motor function were observed in AFS-transplant, HBO-administrated, and AFS/HBO-combined treatment groups. Significantly, the AFS/HBO combined treatment showed the most beneficial effect.

CONCLUSION:

 * AFS in combination with HBO augment peripheral nerve regeneration, which may involve the suppression of apoptotic death in implanted AFS and the attenuation of an inflammatory response detrimental to peripheral nerve regeneration.

Undersea Hyperb Med. 2008 Mar-Apr;35(2):113-29.

Hyperbaric oxygen induces endogenous neural stem cells to proliferate and differentiate in hypoxic-ischemic brain damage in neonatal rats.

Yang YJ1, Wang XLYu XHWang XXie MLiu CT.

Author information

Abstract

BACKGROUND AND PURPOSE:

Studies suggest that after brain injury, hyperbaric oxygen (HBO2) is neuroprotective by stimulating cell proliferation. We examine whether HBO2 promotes neural stem cells (NSC) to proliferate and differentiate in neonatal hypoxic-ischemic (HI) rats.

METHODS:

Seven-day-old rat pups were subjected to unilateral carotid artery ligation followed by 2 hours of hypoxia (8% O2). HBO2 was administered (2 ATA (atmospheres absolutes), once daily for 7 days) within 3 hours after HI. The proliferating neural stem cells in the subventricular zone (SVZ) and dentate gyrus (DG) were dynamically examined by 5-bromo-2-deoxyuridine (BrdU)/nestin immunofluorescence. Nestin protein was detected by western blot analysis at various time points (from 6 hours to 14 days) after HI. The migrating NSC were examined by BrdU/doublecortin (DCX) immunofluorescence 7 and 14 days after HI. The phenotype of the newborn cellswas identified by BrdU/beta-tubulin, BrdU/ glial fibrillary acidic protein (GFAP) and BrdU/O4 (oligodendrocyte marker) immunofluorescence. Myelin basic protein (MBP) was examined by immunohistochemistry and pathological changes of the brain tissue were detected 28 days after HI.

RESULTS:

In neonatal HI rats treated with HBO2, the proliferation of endogenous NSC was observed in the SVZ and DG. Cell numbers peaked 7 days after HI and proliferating NSC migrated to the cerebral cortex at 14 d after HI. Twenty-eight days after HI, an increase in newly generated neurons, oligodendrocytes and MBP was observed in the HBO2 group compared to the untreated and HI-treated rats.

CONCLUSIONS:

This study suggests that HBO2 treatment may promote neurogenesis of the endogenous NSC in neonatal HI rats, contributing to repair of the injured brain.