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1 of 8 | P a g e Podiatry-WoundCare-Overview_v4_21216
www.DOXYVA.com
Industry-Leading Noninvasive Transdermal Microcircula...
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www.DOXYVA.com
D`OXYVA is able to produce a stable solution that is ...
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www.DOXYVA.com
experimental support is the “capillary steal syndrome...
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Effects in Humans
The effects of transdermal CO2 have...
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www.DOXYVA.com
2. In an another case study, a male patient with seve...
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Skin Perfusion Pressure
Skin perfusion pressure (SPP)...
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Marketing Materials & D`OXYVA Centers of Excellence
T...
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Irie H et al CO2-bathing induces VEGF expression and ...
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Industry-Leading Noninvasive Transdermal Microcirculatory Technology for Rapid Closure of Complex Wounds with Significant Pain Relief

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Circularity Healthcare significantly updated Wound Care White Paper discussing mechanisms of action and diagnosis.

D`OXYVA® is able to produce a stable solution that is 50 times more highly concentrated than competing products. The vapor exits the water chamber and is almost imperceptibly misted onto the skin. Independent clinical research suggests that without the high CO2 content in the supersaturated vapor, it is not possible to generate such elevated blood flow and oxygenation levels and efficient transdermal delivery of molecules in the skin tissue. The increased presence of CO2 in the bloodstream auto-regulates the blood supply while inducing the Bohr Effect, attaching to red blood cells and ultimately leading to increased blood flow and oxygen delivery within the tissues. In a past IRB-approved human clinical study, the increased CO2 concentration significantly improved tissue perfusion (microcirculation) and blood flow locally and throughout the body in every subject often by over 100% without any adverse event, and D`OXYVA® has been recognized as a Non-Significant Risk (NSR) device. Therefore, the D`OXYVA® product is considered an "investigational device" when used for medical purposes and has an "investigational device exemption" ("IDE") status.

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Industry-Leading Noninvasive Transdermal Microcirculatory Technology for Rapid Closure of Complex Wounds with Significant Pain Relief

  1. 1. 1 of 8 | P a g e Podiatry-WoundCare-Overview_v4_21216 www.DOXYVA.com Industry-Leading Noninvasive Transdermal Microcirculatory Technology for Rapid Closure of Complex Wounds with Significant Pain Relief (Seeking Investigators) Introduction The term chronic wound is used to refer to wounds that both medical and surgical treatments fail to heal according to the normal repair times and mechanisms. Such wounds typically present in patients with compromised local and systemic conditions, which contribute to inhibition of tissue repair. The non-healing aspects are due in large part to insufficient microcirculatory blood flow. Chronic wounds represent a significant burden to patients, health care professionals, and the U.S. health care system, affecting 5.7 million patients and costing an estimated $20 billion annually (Branski LK, Gauglitz GG, Herndon DN, et al., Frykberg RG, Banks J.). The global wound care market is expected to reach $18.3 billion by 2019 from $15.6 billion in 2014, growing at a CAGR of 3.2% from 2014 to 2019, according to MarketsandMarkets. The burden is growing rapidly due to increasing health care costs, an aging population and a sharp rise in the incidence of diabetes and obesity worldwide. In developed countries, it has been estimated that 1% to 2% of the population experiences a chronic wound during their lifetime. Chronic wounds are rarely seen in individuals who are otherwise healthy. In fact, chronic wound patients frequently suffer from “highly branded” diseases such as diabetes and obesity (Chandan Sen et al 2009). The treatment of wounds, especially non-healing requires treatment of co-morbidities and proper wound care treatment. The medical treatment of wound includes proper and adequate oxygenation, adequate nutrition, treatment of infections and dressing of the wound (removal of foreign bodies, irrigation of wound, compression therapy) and management of pain. The wound healing treatment has advanced rapidly, particularly as a result of new therapeutic approaches such as growth factors, platelet rich plasma gel, skin substitutes, and gene and stem cell therapy, O2 milsy machine, Laser therapy, Ozone therapy, hyperbaric O2 (HBO) therapy and CO2 therapy (Ashok Damir2011). Medical gases have historically been administered via the inhalation route of administration. However, in light of the physiology of human skin, it may be possible to deliver medical gases transdermally. It is known that CO2 elicits vasodilation of arterioles in various vascular beds. D`OXYVA® (deoxyhemoglobin vasodilator) from Circularity Healthcare, LLC is a groundbreaking noninvasive transdermal delivery (NTD) system for microcirculatory health for the wound care industry. It delivers a Supersaturated CO2 + H2O Vapor™ to the skin’s sweat pores and glands, overcomes the issues found with most transdermal delivery technologies as it allows for large molecule delivery up to antibody size without breaking the skin barrier while it is not channeling molecules via skin layers but utilizes a fast and effective skin absorption process widely studied in balneotherapy. A recent study by Rogers et al. (unpublished) demonstrates increases in skin perfusion pressure at the toe following a 5-minute treatment with D`OXYVA at the thumb in normal, healthy subjects and diabetic patients. Additionally, systolic and diastolic arterial blood pressures are also reduced following treatment. CO2 application to the skin raises the oxygen partial pressure not only of the skin but of the muscles as well (Komoto et al., 1986). CO2 stimulates the warmth receptors in the skin and inhibits the cold receptors, as result, carbon dioxide enriched water feels about 2 degrees Celsius warmer than fresh water. In addition, CO2 has an anti-inflammatory effect and the change in CO2 concentration affects the intermediate metabolism. Increase in the CO2 concentration brings about a rise in serum phosphorus and in the lactic dehydrogenize. This is based on the inhibition of glycolysis or the promotion of glycogen formation (B. Hartmann et al. unpublished). The rise in CO2 concentration within the tissue and peripheral blood vessels causes pre-capillary arterioles to dilate, thereby opening the capillary that were functionally closed (Irie H et al., 2005). The same is true when CO2 is applied to the skin, peripheral resistance decreases and blood pressure decreases. With the combination of genetics and modern lifestyle choices contributing to this growing epidemic of poor microcirculation and non-healing wounds, the stage is set for the D`OXYVA technology to create a new standard in wound care. The D`OXYVA technology has a method of controlling the rate of mixing CO2 and water inside the device’s water chamber, which creates a Supersaturated CO2 + H2O Vapor™. By achieving the correct pH balance of CO2 and water,
  2. 2. 2 of 8 | P a g e Podiatry-WoundCare-Overview_v4_21216 www.DOXYVA.com D`OXYVA is able to produce a stable solution that is 50 times more highly concentrated than competing products. The vapor exits the water chamber and is almost imperceptibly misted onto the skin. Independent clinical research suggests that without the high CO2 content in the supersaturated vapor, it is not possible to generate such elevated blood flow and oxygenation levels and efficient transdermal delivery of molecules in the skin tissue. The increased presence of CO2 in the bloodstream auto-regulates the blood supply while inducing the Bohr Effect, attaching to red blood cells and ultimately leading to increased blood flow and oxygen delivery within the tissues. In a past IRB-approved human clinical study, the increased CO2 concentration significantly improved tissue perfusion (microcirculation) and blood flow locally and throughout the body in every subject often by over 100% without any adverse event, and D`OXYVA has been recognized as a Non-Significant Risk (NSR) device. Therefore, the D`OXYVA product is considered an “investigational device” when used for medical purposes and has an “investigational device exemption” (“IDE”) status. Thus, D`OXYVA works by effectively and quickly delivering CO2 transdermally, where it can enter the bloodstream directly. D`OXYVA is the ideal value proposition for podiatry and wound healing practices seeking ways to simultaneously improve patient outcomes and boost revenue. Its low-cost, high-value non-toxic treatments with zero adverse event reports after years on the market offer practices freedom from capital-intensive commitments to competing products that occupy large blocks of office space, require specialized training to operate, and produce inferior results. D`OXYVA delivers simple, fast, affordable, painless, noninvasive, and effective total wound care and closure solutions coupled with exceptional quality of life benefits such as significant reduction of pain and improvement of sleep, appetite, energy and mood. It significantly improves tissue perfusion, oxygen-rich blood flow, nutrient delivery and waste removal via activating the microcirculatory system. D`OXYVA’s success in pharma-grade CO2 delivery via the skin and in drastic tissue perfusion improvement has been demonstrated in numerus quality human clinical studies. Various studies were completed by Dr. Chester Ray, PhD, Penn State University; Dr. Lee C. Rogers, Valley Presbyterian Hospital; Dr. Harikrishna K. R. Nair; Hospital Kuala Lumpur, Prof. Ito Puruhito, Arlingga University, and many others. [In advance of the results being published, they can be made available for review to interested parties under nondisclosure agreement.] Microcirculation & Wound Healing The challenge with non-healing wounds is that they require better oxygen-rich microcirculatory blood flow in order to heal…but they are non-healing in the first place due to insufficient microcirculatory blood flow1. This chicken-and-egg conundrum is leading to serious health problems and a rapidly growing number of amputations. The pathogenesis of macrocirculatory disease has been discussed in depth elsewhere. Microcirculation includes the capillaries, arterioles, and venules. These microvessels are arranged in two horizontal network patterns with a superficial subpapillary plexus and a deeper cutaneous plexus with capillary blood flow providing nutrition and arteriovenous shunts that serve a thermoregulatory function (Chao & Cheing, 2009). The nutritional capillaries are organized into functional units within the papillary layer of the dermis. A precapillary sphincter is situated just upstream of the capillary which controls vasodilation and constriction (LaFontaine, et al., 2006). Arteriovenous anastomoses exist between the arterioles and venules to allow normal shunting of blood under physiologic conditions. The internal vessel lumen is lined with a single-layer-thick endothelium. This endothelium lies on a basement membrane which is normally thicker in the foot than other body locations due to the increased hydrostatic pressure associated with stance (LaFontaine, et al., 2006). Blood flow to the skin runs through this arteriovenous system supplying nutrition, oxygen, and regulating temperature through an increase or decrease of blood flow to the dermal papilla. Blood flow to the skin is controlled by the peripheral sympathetic nervous system via vasodilatory cholinergic and vasoconstrictor adrenergic nerve fibers (Chao & Cheing, 2009) as well as vasoactive substances such as nitric oxide. Additionally, the endothelial basement membrane regulates blood flow and the local inflammatory response via vasoactive substances (Guerci, et al. 2001). The pathogenesis of microvascular disease in diabetics is complex and multifactorial. Hyperglycemia is considered the most important risk factor (LaFontaine, et al., 2006) and is noted to occur in two stages, a reversible functional stage and a structural adaptation and remodeling stage leading to a thickened basement membrane and capillary failure (LaFontaine, et al., 2006). The hemodynamic hypothesis of microangiopathic disease was first described by Parving, et al (Parving, et al. 1983). Blood flow dysregulation, caused by neuropathic changes to the sympathetic nerve fibers, is mediated by hyperglycemia. The resulting stimulation of the polyol pathway decreases nitric oxide production, increasing blood flow and capillary pressure. This increased pressure leads to thickening of the basement membrane which resists vasodilation and increases capillary permeability with ensuing chronic edema. A second mechanism that has gained 1 Spronk, Peter E., Zandstra, Durk F., and Ince, Can (2004), Bench-to-Bedside Review: Sepsis is a Disease of the Microcirculation. Critical Care, 8:462-468.
  3. 3. 3 of 8 | P a g e Podiatry-WoundCare-Overview_v4_21216 www.DOXYVA.com experimental support is the “capillary steal syndrome” (Uccioli, et al. 1992). This is thought to result from sympathetic denervation with chronic vasodilation, resulting in an increased blood flow through the arteriovenous shunt away from the arterioles in the papillary dermis. As blood moves more rapidly toward the postcapillary venule, nutrition, metabolite, and oxygen exchange are significantly reduced (Boulton, et al, 1982). It is unknown which pathway is dominant or if another mechanism is responsible, though there is most likely a combination of both pathogenic pathways that end with functionalischemia, reduced nutritional capacity, and increased metabolic end products that function together to limit healing capacity in the face of skin ulceration. The D`OXYVA Technology & Product D`OXYVA is a transdermal delivery device of CO2, developed and manufactured by Circularity Healthcare for the management of burns, non-healing ulcers, and wounds due to diabetes and cardiovascular complications. The D`OXYVA device is manufactured in compliance with internal procedures that are consistent with the requirements of ISO 13485:2012, Medical devices – Quality management systems – Requirements for regulatory purposes and ISO 14971:2009 and medical devices – Application of risk management to medical devices. The D`OXYVA device consists of a patent-pending ergonomic polymer shell that is propelled by a patented, GMP-compliant, single-use, disposable, recyclable, mini, steel, pressurized cartridge (45 psi) filled with liquid, purified, pharma-grade (99.95%) CO2, a patented, mechanical dual-stage gas flow regulator controlled by a manual trigger mechanism, and an essentially plastic, refillable, removable, and sealed Water Capsule. The far end of the device is an outlet that directs the supersaturated CO2 + H2O vapor to the skin locality. The D`OXYVA device is comprised of the following components: 1) Water Capsule with Cap 2) Cartridge Cup 3) Sliding Door The entire device weighs nearly a pound and is about 1½ inch in diameter and 11 inches in length (15 inches together with the Cartridge Cup attached). The non-reactive materials used in the construction of the device are glass filled Nylon 6, clear Polycarbonate, Nylon Tubing, and brass and stainless steel. The device should be stored in a cool dry location. Sliding Door D`OXYVA® Device Cartridge Cup Water Capsule with Cap Mini Premium Easytwist Cartridge™ (16g CO2)
  4. 4. 4 of 8 | P a g e Podiatry-WoundCare-Overview_v4_21216 www.DOXYVA.com Effects in Humans The effects of transdermal CO2 have been widely noted in wound care as demonstrated in clinical studies. Healing, closure and recovery of an ulcer (non-healing) due to diabetes and cardiovascular complications is much quicker and often successful when other modalities have failed. Carbon dioxide is one of the mediators of local autoregulation of blood supply. If its levels are high, the capillaries expand to allow a greater blood flow to that tissue. Hemoglobin, the main oxygen-carrying molecule in red blood cells, carries both oxygen and carbon dioxide. However, the CO2 bound to hemoglobin does not bind to the same site as oxygen. Instead, it combines with the N-terminal groups on the four globin chains. However, because of allosteric effects on the hemoglobin molecule, the binding of CO2 decreases the amount of oxygen that is bound for a given partial pressure of oxygen. The decreased binding to carbon dioxide in the blood due to increased oxygen levels is known as the Haldane Effect. It is important in the transport of carbon dioxide from the tissues to the lungs. Conversely, a rise in the partial pressure of CO2 or a lower pH will cause offloading of oxygen from hemoglobin, which is known as the Bohr Effect. Two case studies with D`OXYVA, which have shown improvement in non-healing ulcer: 1. A case study of a 68-year-old insulin-dependent septic diabetic male patient with unbalanced glycemic status showed improvement and healing of diabetic wound. This patient had a forklift truck accident with trimalleolar fracture, massive soft tissue contusion, crural decollement, and had mixed bacterial infection. The skin had necrotized on heel, medial malleoli, shin’s anterior surface. A non-healing wound developed and amputation was recommended. Prior to amputation, use of transdermal CO2 (D`OXYVA) sprayed directly on the wound 2 times daily showed improvement and healing. Pre-D`OXYVA 25 Days 2x Daily D`OXYVA 3 Months Post-D`OXYVA
  5. 5. 5 of 8 | P a g e Podiatry-WoundCare-Overview_v4_21216 www.DOXYVA.com 2. In an another case study, a male patient with severe diabetic and cardiovascular complications with extreme neuropathy pain and high blood pressure had wounds in lower extremities, which were spreading to upper body and arms. Use of D`OXYVA application 2 times daily demonstrated healing of wounds, lowering blood pressure, and pain. Pre-D`OXYVA (various therapies for 2 years) 6 Weeks 2x Daily D`OXYVA In a pilot study, a total of 14 subjects (6 with diabetes, 8 without diabetes) were enrolled. Transdermal CO2 was delivered by D`OXYVA for 5 minutes on the thumb. Skin perfusion pressure (SPP) was measured with Sensilase® (Vasamed®) in the hallux pre-treatment, and 5, 30, 60, 120, and 240 minutes post-treatment. Blood pressure and heart rate was measured at the same intervals. Comparisons between subjects with and without diabetes of the absolute change from pre-treatment for SPP were performed using the Mann-Whitney test. Each post-treatment study through 4 hours showed a significant increase in the SPP. Systolic and diastolic blood pressures were also significantly reduced. The findings share some similarity with hemodynamic changes occurring following acute bout of exercise, in which both neural, vascular components contribute to sustained decrease in vascular resistance and blood pressure persisting after cessation of exercise. Rogers et.al., recorded a period of sustained vasodilation in response to transdermal CO2 was heightened in diabetics. Interestingly, in hypertensive individuals, post-exercise hypotension period magnitude and duration was greater as compared to normotensive individuals. Paradoxically, the findings of this pilot study in diabetics and previous findings in hypertensive patients post-exercise imply sensitivity to signals mediating cardiovascular responses increases in patients with pre-existing cardiovascular dysfunction. Sustained systolic blood pressure decrease occurs post-exercise after CO2 delivery, suggesting neural mechanisms contribute to observed reduction in systemic vascular resistance. Roles of efferent sympathetic nerve activity, afferent nerve activity from muscle, baroreceptor reflex in mediating post-exercise hypotension remain controversial. Neural mechanism(s) could contribute to changes in skin SPP, systolic blood pressure, induced by exposure to transdermal CO2 with D`OXYVA. The following graphs show a sample SPP result conducted by U.S. FDA- cleared Vasamed® SensiLase® 3000, measured on a healthy 30-year old female with a single 5-minute D`OXYVA. SPP Reading Pre-D`OXYVA: 64 mmHg SPP Reading 10 Minutes Post-D`OXYVA (single cartridge): 105% Capillary Blood Flow Increase from 64 to 131 mmHg*
  6. 6. 6 of 8 | P a g e Podiatry-WoundCare-Overview_v4_21216 www.DOXYVA.com Skin Perfusion Pressure Skin perfusion pressure (SPP) utilizes a laser Doppler and pressure cuff to evaluate reactive hyperemia. SPP measures the pressure at which blood flow first returns to the capillary during the controlled release of occlusive pressure. A laser sensor is placed on the desired location while a pressure cuff is placed at the ankle. The cuff is inflated until occlusion of the arterial flow to the extremity occurs and is then released. As arteriolar flow is restored and the subsequent reactive hyperemia occurs, the laser sensor reads the resulting arteriolar pressures. Skin perfusion pressures greater than 40mmHg are considered non-ischemic while marginal ischemia is noted between 30 and 40mmHg. The wound is unlikely to heal below a pressure of 30mmHg (Castronuovo, et al., 1997). The advantages of SPP are the following: it can be used in the presence of edema and in the plantar foot, no calibration is needed, no maintenance is required, no skin warming is necessary, and it is faster than TcPO2 measurement (2-3 minutes per site). The limitations of SPP are that it provides data regarding the limited area of skin under the sensor. Multiple separate readings are necessary to obtain a global understanding of pedal microvasculature. SPP predicts a 90% healing ability above 30mmHg (Castronuovo, et al., 1997) and has a 100% negative predictive value (Adera, et al. 1995). In patients with critical limb ischemia SPP was 80% accurate in diagnosing this condition (Castronuovo, et al., 1997). Similarly, Faris and colleagues found SPP was useful in predicting healing of ulcers or gangrene of the feet in 35 of 40 diabetic patients with levels above 40mmHg. Conversely healing was unlikely if the SPP was less than 40mmHg (Faris, et al. 1985). Yamada, et al. studied a larger cohort of 211 patients with ischemic limbs. However, this cohort was not restricted to diabetic patients alone. As with the above mentioned studies, this group also found a threshold of 40mmHg as predictive of healing ulceration or gangrene but with a slightly lower sensitivity and specificity (72% and 88%, respectively) (Yamada, et al. 2008). In 85 limbs of 71 patients referred to a vascular laboratory, skin perfusion pressure measurement was found to correlate closely with toe pressure measurements (Tsai, et al. 2000), allowing substitution of SPP for toe pressures. This is a significant benefit in certain circumstances since it may be impractical to determine toe pressures due to the commonality of wounds on the toes. D`OXYVA for the Wound Healing Practice D`OXYVA is both patient-friendly and doctor-friendly, making it a perfect fit for the wound healing practice. Users have reported quick and complete wound healing that could potentially save limbs from amputation when used as a regimen. For the doctor running a wound healing practice, D`OXYVA represents a valuable addition. It is low-cost to acquire, and because it can be administered by a non-specialist with minimal training, it is simple and inexpensive to use in practice. D`OXYVA is a portable device that can be held in the palm of the hand, requiring no storage space, and because each application takes only 5 minutes, a practice can increase revenue by sustaining a very high throughput of patients, day-in and day-out, all while producing better patient outcomes. D`OXYVA makes great medical and financial sense to the wound healing practice. D`OXYVA is the ideal addition to the forward-thinking wound healing practice seeking to remain on the cutting edge of patient care while simultaneously boosting its bottom line. There are several primary methods by which offering D`OXYVA can increase a practice’s revenue: 1. Sell as service an industry-leading, non-invasive, non-significant risk, non-toxic, fast, and effective solution targeting the underlying cause of the condition with unmatched clinical results that can be detected at the point of care via diagnostics (e.g., Moor Instruments, Vasamed, Masimo, Perimed) 2. Retail and/or prescribe D`OXYVA to patients who want to self-administer it at home (website discount code) 3. Increase sales of tests with various microcirculatory, SpO2 and other diagnostics or begin to offer them if they are not currently available (before/after, progress assessment, long-term record keeping offline and online) 4. Increase the sale of other therapies as ancillary services to D`OXYVA patients
  7. 7. 7 of 8 | P a g e Podiatry-WoundCare-Overview_v4_21216 www.DOXYVA.com Marketing Materials & D`OXYVA Centers of Excellence To introduce D`OXYVA to your patients and test it effectively, call or chat with us or talk to your local Circularity-certified representative and ask for information about our Centers of Excellence programs and for the following items: Patient Brochures Waiting Room Posters, Banners, DVDs Wound Care Brochure Clinical Study Papers, Protocols, Investigator’s Brochure, Informed Consent Independent CO2 Studies Study Effect of Carbon Dioxide Water Bath Therapy (Carbothera) in Treatment of 100 Patients with Diabetic Foot http://www.iasj.net/iasj?func=fulltext&aId=48581 The Role of Carbon Dioxide Therapy in the Treatment of Chronic Wounds http://iv.iiarjournals.org/content/24/2/223.abstract Transdermal CO2 Application in Chronic Wounds http://ijl.sagepub.com/cgi/content/abstract/3/2/103 Two Cases of Arteriosclerosis Obliterans (Fontaine Stage IV) with Total Occlusion of Below-the-Knee Vessels, for Which Artificial CO2 Foot Bath Therapy Was Found to Be Effective http://www.co2bath.com/toriyama.pdf The Effect of Artificial CO2 Water Immersion on Physiological Functions http://www.co2bath.com/academic-a-1.htm The Effect of Artificial Carbon Dioxide Foot Bathing on the Skin of Ischemic Feet, as Measured by a Laser Doppler Flowmeter http://www.co2bath.com/matsuo.pdf Carbon Dioxide Therapy in the Treatment of Localized Adiposities: Clinical Study and Histopathological Correlations http://www.nutecint.com/Docs/APS%20Article.pdf REFERENCES Branski LK, Gauglitz GG, Herndon DN, et al. A review of gene and stem cell therapy in cutaneous wound healing. Burns. 2008 Jul 4. Frykberg RG, Banks J. Challenges in the Treatment of Chronic Wounds. Adv Wound Care (New Rochelle). 2015 Sep 1. 4 (9):560-582. Rogers et al; Transdermal CO2 Delivery with D`OXYVA Increases Skin Perfusion Pressure in Subjects with and without Diabetes. Diabetic Foot Global Conference, Los Angeles, CA, March 21 -23, 2013. Chandan K Sen, Gayle M, Robert Kirsner, Lynn Lambert, CHT, Thomas K. Hunt, Finn Gottrup, Geoffrey C Gurtner, and Michael T. Longaker; Human Skin Wounds: A Major and Snowballing Threat to Public Health and the Economy, Wound Repair Regen. 2009 Nov–Dec; 17(6): 763–771. Ashok Damir; Recent Advances in Management of Chronic Non healing Diabetic Foot Ulcers, JIMSA October - December 2011 Vol. 24 No. 4. Komoto. Y. Komoto.T. Sunakawa, M. et al; Dermal and subcutaneous tissue perfusion with CO2 bathing. Z. p hysiode. 38; 103-112. 1986. B. Hartmann, M, Pittler and B. Drews, CO2 Balneotherapy for Arterial Occlusion Diseases*: Physiology and Clinical Practice, unpublished (Institute of Applied Physiology and Balneology, University of Freiburg).
  8. 8. 8 of 8 | P a g e Podiatry-WoundCare-Overview_v4_21216 www.DOXYVA.com Irie H et al CO2-bathing induces VEGF expression and NO-dependent neocapillary formation. Circulation 2005. U Wollina et al., Transdermal CO2 application in chronic wounds, J Low Extrem Wounds, Int J Low Extrem Wounds 2004 Jun;3(2):103-6. Chao C and Cheing G. Microvascular dysfunction in diabetic foot disease and ulceration. Diabetes Metabolism Research and Reviews, 2009; 25: 604-614. La Fontaine J, et al. Current concepts in diabetic microvascular dysfunction. Journal of the American Podiatric Medical Association, May 2006; 96(3): 245-252. Guerci B, et al. Endothelial dysfunction and type 2 diabetes. Diabetes Metabolism, 2001; 27(4): 4360447. Parving H, et al. Hemodynamic factors in the genesis of diabetic microangiopathy. Metabolism, Sept 1983; 32(9): 943-949. Adera H, et al. Prediction of amputation wound healing with skin perfusion pressure. Journal of Vascular Surgery, May 1995; 21(5): 823-828. Faris I, et al. Skin perfusion pressure in the prediction of healing in diabetic patients with ulcers or gangrene of the foot. Journal of Vascular Surgery, July 1985; 2(4): 536-540. Yamada T, et al. Clinical reliability and utility of skin perfusion pressure measurement in ischemic limbs – comparison with other noninvasive diagnostic methods. Journal of Vascular Surgery, Feb 2008; 47(2): 318-323. Tsai F, et al. Skin perfusion pressure of the foot is a good substitute for toe pressure in the assessment of limb ischemia. Journal of Vascular Surgery, July 2000; 32(1): 32-36. Uccioli L, et al. Lower limb arterio-venous shunts, autonomic neuropathy and diabetic foot. Diabetes Research and Clinical Practice, May 1992; 16(2): 123-130. Castronuovo J. J., Carter S. A. (2000) Skin perfusion pressure of the foot is a good substitute for toe pressure in the assessment of limb ischemia. Journal of Vascular Surgery, 32(1), pp 32-36. Legal Disclaimer Copyright © 2016 Circularity Healthcare, LLC. All rights reserved. D`OXYVA and Circularity are trademarks and/or registered trademarks of Circularity Healthcare in the U.S. and other countries. All other trademarks mentioned herein belong to their owners. Third party brands, product names, trade names, corporate names and company names mentioned herein may be trademarks of their respective owners or registered trademarks of other companies and are used for purposes of explanation and to the owner's benefit, without implying a violation of copyright law. Information herein is intended only for U.S. residents. Circularity’s D`OXYVA has not been evaluated yet by the U.S. Food and Drug Administration (FDA) and is not intended to diagnose, treat, cure, or prevent any disease. The information provided herein is for educational purposes and is not intended to replace medical advice. Ask your physician or therapist about using D`OXYVA. Results may vary by individual. www.circularityhealthcare.com www.DOXYVA.com info@circularityhealthcare.com info@doxyva.com Worldwide Headquarters Circularity Healthcare, LLC 790 E. Colorado Blvd., 9th Floor Pasadena, CA 91101 U.S.A. Phone: +1 (626) 240-0956

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