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Industry-Leading Noninvasive Transdermal Microcirculatory Technology For Rapid Closure of Complex Wounds With Significant Pain Relief
Industry-Leading Noninvasive Transdermal Microcirculatory Technology For Rapid Closure of Complex Wounds With Significant Pain Relief
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, O 2 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 skins 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 devices water
chamber, which creates a Supersaturated CO2 + H2O Vapor. By achieving the correct pH balance of CO2 and water,
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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`OXYVAs 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.]
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.
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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.
Sliding Door
D`OXYVA Device
Cartridge Cup
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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, shins 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
3 Months Post-D`OXYVA
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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.
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. FDAcleared 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
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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 NovDec; 17(6): 763771.
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 CO 2 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).
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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. Circularitys 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.
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