Non-invasive Transdermal Delivery ofMedical Carbon Dioxide with D`OXYVA®

Boosts Microcirculation, Balances Parasympathetic/Sympathetic Nerve Activity

"There are a lot of possibilities here and we are really excited about conducting future studies to determine what D`OXYVA

may be able to provide to people with microvascular disease.“

- Prof. Judy M. Delp, Ph.D., Florida State University, U.S.A.

Delivers Wide Ranging

Industry-Leading OutcomesDate: August 8, 2016

Think Beyond Different, Way Beyond Different™

Transdermal Delivery Breakthrough

• Concept: administration of active molecules to the body by DIRECT TRANSMISSION THROUGH THE SKIN

– Common: patches, microneedle, nanoparticles, high velocity fluid streams

• Issues: DEVELOPMENT/USAGE IS 3X IN RECENT YEARS, but all try penetrating skin’s MULTIPLE BARRIERS WITH SMALL MOLECULES

• Benefits: GREAT ALTERNATIVE TO ORAL AND NEEDLE DELIVERY, greater effectiveness, absorption with less invasiveness, patient discomfort

• Solution: D`OXYVA® OVERCOMES ALL ISSUES, ENHANCES DELIVERYwith proprietary, rapid, safe absorption process via skin pores; not breaking skin barrier; enhancing absorption for small to large molecules

D`OXYVA®

Marketed exclusively by Circularity Healthcare

Oxygen Delivery Depends on:

1. Heart2. Arteries3. Arterioles4. Capillaries

Arteriole

Smooth muscle cells

Decreased

resistance

Smooth

muscle

relaxation

Normal

resting

tone

Smooth

muscle

contraction

Increased

resistance

Smooth

muscle

cell

Interior

of arteriole

Source: Prof. Judy M. Delp, PhD

Importance of Microcirculation • Recognition of importance of proper microcirculatory

function is growing rapidly, improved microcirculatory health can support better outcomes in a wide variety of conditions, both localized and systemic

• Optimal microvascular function is critical in regulating blood flow, tissue perfusion, blood pressure, oxygen delivery, waste removal

• Proper functioning has beneficial effects on prevention, treatment of disease states; sepsis8, non-healing wounds, diabetes9, hypertension10, 11, obesity12, metabolic syndrome13, respiratory disorders, sexual dysfunction, and age-related syndromes

A Few Well-Known Benefits of Improved Microvascular Function

Better, Faster Healing

Pain Relief

Increased Metabolism

Fatigue Reduction

Better Sleep Appetite

D`OXYVA® DELIVERS ALL AND MUCH MORE AT LEVELS NEVER DETECTED BEFORE

Targeting of Microcirculation

• Studies suggest diabetics suffer most from macrovascular, microvascular impairment, though there seems to be no limit

• Traditional methods of revascularization surgery or angioplasty can repair the macrovascular impairment, but no convincing studies showing microvascular function improvements

• Microvascular disease is implicated in foot ulcers and delayed healing

• Expensive, inefficient therapies; HBOT (inconclusive studies), NPWT

• D`OXYVA® 5-yr zero adverse events, administer in home or facilities, comparatively inexpensive to most modalities and incomes (controlled, randomized, double-bind, positive industry-leading study results)

Published Microcirculation Research• Assessment of microcirculation

and the prediction of healing in diabetic foot ulcers

• Microcirculation in chronic venous insufficiency

• Role of renal microcirculation in experimental renovasculardisease

• The microcirculation in venous hypertension

• The microcirculation as a therapeutic target in the treatment of sepsis

• Coronary microcirculation - the new frontier in coronary artery disease

• Impaired tissue perfusion

• Microcirculation in hypertension -A New Target for Treatment

• Microcirculation in obesity - an unexplored domain

• Microcirculation in skeletal muscle

• Microvascular dysfunction in obesity

Published CO2 Research• Promising previous results using carbon dioxide to trigger peripheral vasodilation

• Duling14 found an increase in perivascular PO2 and arteriolar diameter in hamster cheek pouch after bathing the tissue in CO2

• Hartmann et al. bathed lower extremities in CO2-enriched water and measured an increase in PO2 by 10%, while vasomotion by laser Doppler increased 300%. Some subjects had mild peripheral artery disease. They concluded the Bohr effect resulted in better oxygen utility 15

• In a subsequent investigation by the same authors using the same methods, they found an improvement in dorsal foot TcPO2 and pain-free walking distance in claudicants

• Savin et al.12 used administration methods similar to that described in a study with D'OXYVA in 10 subjects with peripheral artery disease and claudication. Femoral blood flow, tibial pressure, and TcPO2 in the foot were significantly increased after skin exposure of CO2 gas

• Fabry et al.16 randomized 62 patients to transdermal CO2 or room air for 18 consecutive days. In the experimental group, there was an increase in great toe arterial pressure, a 20% increase in baseline PO2, and improvements in vasomotion. These effects continued at 3- and 12-month follow-ups.

• Toriyama et al.17 studied the effect of CO2 bathing in 83 limbs with critical ischemia and achieved limb salvage in 83% without surgery. They concluded that peripheral vasodilation from CO2 bathing resulted from an increased parasympathetic and decreased sympathetic activity.

Signaling Gas Molecules

• 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.

Published Study - Diabetic Foot Global ConferenceLos Angeles, CA - March 21-23, 2013

D`OXYVA® Study Design

Subjects:6 subjects with diabetes 8 subjects without diabetes

Treatment:The subject’s thumb was inserted into the D`OXYVA® device and “bathed” in CO2 water/gas vapor for 5 minutes.

Measurements:Brachial blood pressure

A graph displays pressure andperfusion during cuff deflation andindicates the pressure at whichskin perfusion is found to return.

Vasamed SensiLase®Skin Perfusion Pressure

Skin perfusion pressure in the toe

5 minutes pre-treatment 5 min post-treatment 30 minutes post-treatment 60 minutes post-treatment120 minutes post-treatment240 minutes post-treatment

Microvascular Treatment Breakthrough • Transdermal delivery of gaseous CO2 offers distinct advantage of increasing SPP, a

reliable predictor of wound healing7, 44

• 5-min CO2 immersion of thumb demonstrated significant increase in measures of remote skin microvascular function/perfusion in toe, suggesting improving peripheral wound healing

• Effects evident at all periods up to and including last test period at 240-min post-exposure

• Clear SPP, SPP/SBP ratio increase, SBP, DBP decrease continued 4 hours post-treatment

• Differences in skin perfusion, blood pressure responses detected between diabetic, non-diabetic subjects requires further examination in larger studies

Transdermal delivery of CO2 to the thumb promotes sustained huge blood flow at the foot

Time (minutes)

-5 5 30 60 120 240

Ch

an

ge

in

SP

P (

mm

Hg

)

0

10

20

30

40

50 Diabetic (n =6)

Non-Diabetic (n=8)

*

** *

*

B

How Transdermal CO2 Delivered at the Thumb Causes Blood Flow Increase to the Foot?

1. Neural Signals Metaboreflex

2. Hormonal Signals Epinephrine Angiotensin

3. Tissue Signals Adenosine Potassium }

Source: Prof. Judy M. Delp, PhD

Discussion

• Rogers et.al., found transdermal CO2 with D`OXYVA® in a localized area produced a sustained, remote vasodilation, and a lowering of systemic blood pressure

• 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, blood pressure persisting after cessation of exercise18

• Rogers et.al., recorded that period of sustained vasodilation in response to transdermal CO2 was heightened in diabetics

• Interestingly, in hypertensive individuals, post-exercise hypotension periodmagnitude and duration is greater as compared to normotensive individuals18, 19

Discussion (cont.)• Paradoxically, Rogers et.al. findings in diabetics and previous findings in

hypertensive patients post-exercise imply, sensitivity to signals mediating cardiovascular responses increases in patients with pre-existing cardiovascular dysfunction19

• Sustained systolic blood pressure decrease occurs post-exercise and after CO2

delivery, suggesting neural mechanisms contribute to observed reduction in systemic vascular resistance

• Roles of efferent sympathetic nerve activity18-20, afferent nerve activity from muscle21-24, baroreceptor reflex20, 23 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®

Studying Autonomic Nerve Activity

• Studies to monitor heart rate, heart rate variability, sympathetic nerve activity during/after D`OXYVA® transdermal CO2

• Fully assessing autonomic nervous system role(s)in mediating sustained SPP, systolic blood pressureincreases reported in initial study

THE AUTONOMIC NERVOUS SYSTEM CONTROLS INTERNAL BODY PROCESSES:

Blood pressure Heart and breathing rates Body temperature Digestion Metabolism (thus affecting body weight) The balance of water and electrolytes

(such as sodium and calcium) The production of body fluids (saliva,

sweat, and tears) Urination Defecation Sexual response

THE AUTONOMIC NERVOUS SYSTEM HAS TWO MAIN DIVISIONS:

Sympathetic Parasympathetic

Randomized TrialPenn State University, PA

• The Effect of Transdermal CO2 Diffusion on Sympathetic Nerve Activity and Vascular Responses in Humans– Phase I, randomized, placebo-controlled, double-blind human clinical trial on 13

subjects

• Goal: Determining the effects of transdermal CO2 diffusion on the SYMPATHETIC NERVOUS SYSTEM, VASCULAR BEDS is important in determining its efficacy for use as treatment in chronic conditions, disease states

• Method: Examine MUSCLE, SKIN SYMPATHETIC NERVE ACTIVITY, RENAL, CORONARY, SKIN, LEG BLOOD FLOW, before, during, after transdermal CO2diffusion in healthy subjects

• Principal Investigator: CHESTER A. RAY, PhD, Department of Medicine, The Heart & Vascular Institute, College of Medicine, Pennsylvania State University, U.S.A.

Randomized TrialPenn State University, PA

• Subjects: Normal Humans – Both genders, age 18+, no history of respiratory or vascular disease

– Recruit from companies and schools

• Data Collection: – General information

– Effects:• Vital sign

• Heart Rate Variability (HRV)

• ETCO2

• TcPO2

D`OXYVA®

5-min treatment

0 min

Baseline

5 min 30 min 60 min

Studying Autonomic Nerve ActivityDr. Yen - Taipei Medical University, Taiwan

Male Female Total

10 3 13

Average Min Max

Age 32.5±12.7 23 60

height 169±7.3 155 179

weight 65.9±10.1 47 80

General Information

Studying Autonomic Nerve ActivityResults

• Increase oxygen concentration and lower carbon dioxide concentration in blood at 30 mins. after treatment, and may persist over 60 mins.

• Tend to decrease RRIV, stabilize overly-high heart rate variation, reduce the risk of cardiac arrhythmia

• Balance the sympathetic and parasympathetic tone, this effect may due to parasympathetic extend

97

97.2

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98

baseline 5 min 30 min 60 min

(SpO2)

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baseline 5 min 30 min 60 min

(ETCO2)

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Heart Function

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baseline 5 min 30 min 60 min

交感神經功能(SYM)

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副交感神經功能(VAG)

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baseline 5 min 30 min 60 min

自律神經偏向(Balance)

Autonomic Nervous System Function

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baseline 5 min 30 min 60 min

自律神經年齡(ANS Age)

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自律神經整體功能(ANS)

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交感調控(SYM Modulation)

Autonomic Nervous System Function

Diagnostics Used in D`OXYVA® Studies

Moor Instruments Vasamed Masimo

WeGeneHitachiSenTec

Case Study – Military HospitalTaipei, Taiwan

Pre-D`OXYVA®

Lower extremity arterial embolism. 1st catheter poor results, 2nd

cannot pass to knee. 6-mo on painkillers, morphine, hormones; enlarging wound.

Post-D`OXYVA® (2x daily)

Case Study – Dr. Benjamin SinappanKuala Lumpur, Malaysia

Week 1 Week 2 Week 3

Post-D`OXYVA® (3-wk 2x daily)

Case Study – Dr. Benjamin SinappanKuala Lumpur, Malaysia

Pre-D`OXYVA®: Lower extremity chronic venous insufficiency (CVI). 6-mo on painkillers, morphine, hormones; enlarging varicose vein. Hypoxia-inducible factor pathways are thought to play a key role.

Post-D`OXYVA® (1x on affected area)Pre-D`OXYVA®

Case Study - University of Szeged, Hungary

Pre-D`OXYVA (2 Mo. Hospital) Post-D`OXYVA (25 days 2x daily)

68-year-old male suffered forklift truck accident, trimalleolar fracture with massive soft tissue contusion and crural decollement, extensive decollement was not realized and treated adequately, septic, glycaemic status unbalanced, skin necrotized around anterior surface leg, medial malleoli and around heel.

16th Congress of the European Society for Trauma and Emergency Surgery (ESTE)May 10-12, 2015 – Amsterdam, Netherlands

Presented by Prof. Endre Varga, MD(habil), PhD (med)

Very drastic surgical debridement, necrotised skin removed, microbiological analysis of swab wound samples, mixed infection (Enterobacter cloacae and ludwigii, Acinetobacter sp., Proteus mirabilis and Escherichia coli.), antibiotic treatment. Every two days surgical debridement, jet lavage, no further necrotisedtissue 10 days after, 2-wk VAC, Integra®. Compliance dropped off, psychological support as he removed dressings, surprisingly after 2 wks fly larvae (Diptera: Sarcophagidae) in skin graft area.Post-D`OXYVA®: Walks with crutches after 3-mo, discharged.

Pilot Study – Dr. Harikrishna R. K. NairHospital Kuala Lumpur, KL, Malaysia

• Successful Late Stage Gangrenous Diabetic Wound Pilot Studies were Recently Completed at HKL with D`OXYVA® that Launched Randomized Diabetic Foot Ulcer Trials

• The results of the study clearly demonstrated SIGNIFICANT QUALITY OF LIFE BENEFITS AND SPEEDING UP WOUND HEALING using Circularity's D`OXYVA® proprietary, noninvasive, handheld transdermal delivery system as an adjunct therapy.

• Results: All four (4) volunteers enrolled in the pilot study experienced SIGNIFICANT REDUCTION OF PAIN, TYPICALLY FROM AN 8 ON THE VISUALANALOG SCALE FOR PAIN (VAS SCALE) DOWN TO 1 in a week or two.

• Results: All volunteers saw an INCREASE IN APPETITE, MOOD AND MARKEDLY BETTER SLEEP. Patients suffering from stage IV gangrene experienced improvements in wound healing within a few weeks. No adverse events of any kind were reported by the subjects.

Randomized Clinical TrialDr. Harikrishna R. K. Nair, HKL - Malaysia

• Randomized clinical trial; 60 volunteers with stage II diabetic ulcer wounds

• Goal: Design proper dosing and length of treatment with D`OXYVA® to maximize benefits and better determine time of healing

• Method: Measure various parameters for wound healing using FDA-cleared noninvasive diagnostics, including:– continuous and noninvasive capillary blood flow volume change,

continuous and noninvasive real-time monitoring of transcutaneous CO2 partial pressure (PCO2), functional oxygen saturation (SpO2), pulse rate (PR), pulsation index (PI), heart rate (HR), and perfusion index (PI).

The Effect of Deoxyhaemoglobin Vasodilator in Heart Failure Patient:A Case Report - Zurairie, M1, Afandi, M2, Filza, IA3

• 1Wound Care and 2Cardiothoracic Surgical Unit, Hospital Raja Perempuan Zainab II, Malaysia 3Department of Community Medicine, School of Medical Sciences, Universiti Sains Malaysia, Malaysia

• Background: WHO projects the largest increases in cardiovascular disease worldwide are occurring in Asia. In the heart failure patients, the risk of death increasing particularly with left ventricular ejection fraction (LVEF) less than 40%. There is resistance in practicing the implantation of defibrillator to reduce sudden cardiac death among the Asian populations and there is less option could be taken to increase the LVEF.

• We are reporting a case of a 62 year-old gentleman, with history of four times angioplasty done for vessels disease with poor LVEF (37%) and the first experience in Malaysia with deoxyhaemoglobinvasodilator therapy in increasing the LVEF. After a month of therapy, our experience with dosage and frequency of the transdermal carbon dioxide (CO2) delivery as well as patient’s LVEF before and after the treatment were documented.

• Results: After 4 weeks, the patient clinically improved from heart failure symptoms. Objectively, his LVEF was increased from 37.17% to 46.99% and the PaO2 increased from 84.5mmHg to 104.7mmHg

Case Study - Bangkok, Thailand

Pre-D`OXYVA® (2-yr therapy) Post-D`OXYVA® (6-wk 2x daily)

Pilot Study – Moor Blood FlowChulalongkorn University, Bangkok, Thailand

Equine Study – Moor Cont. Blood FlowEsler Arabians, San Francisco, CA

~100-300% capillary flux

increase60-90 min

Post-D`OXYVA®

(1x) in 5 horses

No change in control group of

5 horses

Case Study - Moor / Masimo iSpO2

Taipei, Taiwan400% peak increase in Perfusion Index (PI)30 min Post-D`OXYVA® (1x) same time both hands, both Moor & Masimo diagnostics

The moorFLPI-2 blood flow imager uses the laser speckle contrast technique to deliver real-time, high-resolution blood flow images, providing outstanding performance in a wide range of pre-clinical and clinical research applications.Source: Moor Instruments

The iSpO2

MasimoPersonal Health app coupled with your iSpO2 pulse oximeter allows you to track and trend your blood saturation (SpO2), pulse rate (PR), and Perfusion Index (PI).Source: Masimo

Highlighted User Feedback

• My heartfelt thank you to InvisiDerm management for their support before and after my heart attack.– I firmly believe the collateral capillaries that have formed

on my heart, bypassing the damage, is a direct result of my using the (D`OXYVA®) system. I'm very happy to report an increase from 15% to an estimated 30% in the injection fraction number (I believe that is the correct name) that has occurred since I left the hospital. The generous gift of treatment cartridges has allowed me to increase my daily usage to 2-3 times per day and the cardiologist now says I may be a candidate for bypass surgery. I will keep the company informed of my progress. Again THANK YOU INVISIDERM for making it possible for me to write this letter.

Highlighted User Feedback

• Scar tissues are healingAs an Esthetician, I noticed certain scar tissues are healing and the cut that I have is healing really fast. I am very happy with it.

• Better vision, breathing and sleeping"My vision seems to be a little clearer. I have been experiencing chemically induced asthma from noxious fumes from a Nail Salon next door. I noticed that when I am struggling to breath, I will do an application and my ability to breath is noticeably better. Also, I am sleeping better now."

• Better metabolism, weight loss, sex driveI have found that after only two weeks of using the D'OXYVA system daily that my metabolism has increased and is helping me to lose weight. My sex drive has increased and I am sleeping better throughout the night.

In-facility Patient Needs

• PRE-HEALING

• Average Use (e.g., Stage 1-3)– 1 device per 10 patients

– 2 boxes (25 cartridges) per patient per month

• Severe cases (e.g., late Stage 4)– 1 device per 5 patients

– 3-4 boxes per patient per month

• POST-HEALING (e.g., wound closure, post-operative)– 1 device per 20 patients

– 1 box per patient per month

Benefits to Health Facilities

• Faster, more complete healing, recovery; better patient outcomes

• Faster patient discharge ~ half the time as usual

• Significantly less readmissions

• Significantly lower cost of care

• Significant savings on other therapies

Market Drivers for D`OXYVA®

• Diabetes, cardiovascular, arthritis, COPD complications creating an epidemic globally with uncontrollable costs, Asia is hardest hit

• Several major long term trends are reshaping the healthcare industry worldwide, DRIVING THE DEMAND FOR D`OXYVA®:

– Movement to outpatient setting; care for wounds, disorders facing increasing demands for EXPEDIENCY, NON-INVASIVENESS, LOW COST

– Increasing demand for post hospitalization care; driving need for HOME BASED WOUND CARE AND INEXPENSIVE HOME HEALTH options

– Increasing role of TELEMEDICINE & TELEDIAGNOSTICS tracking patient progress & satisfaction, making patient comfort & quick recovery top priority

– SHRINKING HEALTHCARE BUDGETS and reimbursement for hospital stays

Circularity Healthcare at a Glance

• By expert opinion, Circularity Healthcare is bringing about a change in the standard of care, drug delivery, circulatory, and neurological fields

• Attracted top scientific and medical experts in a dozen countries

• Obtained critical clinical evidence and user feedback with an outsized safety and efficacy record

– Zero adverse events (4 years), hundreds of thousands apps

Circularity Healthcare at a Glance

• ISO13485:2012 certified manufacturer since 2015

• CE-marked drug delivery device since 2016

• FDA-cleared pharmaceutical CO2 (Medical CO2)

• Upcoming approvals for chronic disease treatment

• Entry in dozens of countries worldwide

• 4 years five star customer satisfaction rating

• Oncology, endocrinology, cardiovascular, respiratory, dermatology, etc.

Circularity Healthcare at a Glance

• Active in 50 countries, in North America, Europe, and Asia with joint ventures, distribution channels

• Established business model in the U.S. and internationally, validated by and marketed with leading FDA-cleared diagnostics

• Affordable applications for the vast majority of the population with one of the lowest risk profiles on the market

• Obtained uniquely strong, sizeable patent portfolio in over 70 countries coupled with several technological, legal, and regulatory safeguards

• Strong clinical research, product, technology, research and development program with years of advances in store

Thank You for Your Attention

Ecommerce website:

DOXYVA.com

Corporate website:

CircularityHealthcare.com

Social Media:

Facebook.com/DOXYVA

Video:

Youtube.com/CircularityDOXYVAS.com

Toll Free Phone:

+1-855-5DOXYVA

Email:

info@doxyva.com

info@circularityhealthcare.com

Legal Disclaimer

• Notice! Medical Carbon Dioxide is manufactured and delivered under applicable standards per each country's regulatory requirements. In the United States, the Food and Drug Administration has cleared the use of Medical Carbon Dioxide for the route of inhalation for humans but not yet for transdermal delivery with D`OXYVA. Transportation of Medical Carbon Dioxide via any postal or courier service requires certification for handling Dangerous Goods (HAZMAT) by the U.S. Department of Transportation (DOT). Use of unapproved substances and products may be illegal, cause serious injury, and even death!

• Warning! Ask your physician before using D`OXYVA FOR MEDICAL AND CLINICAL RESEARCH PURPOSES, prescription only. The D`OXYVA transdermal delivery device holds a growing number of Class I (low risk) licenses around the world. Use for non-medical purposes is available over-the-counter (OTC) and in various retail stores online and offline. Circularity's novel D`OXYVA patented transdermal drug delivery pathway with FDA-cleared Medical Carbon Dioxide (UN1013) 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 and research purposes and is not intended to replace medical advice.