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Peripheral Artery Disease

TAGS™ for Early Detection of PAD

TAGS™ is intended to be used as an inexpensive screening method for early detection of Peripheral Artery Disease (PAD). It can be used to routinely screen those at risk for PAD including smokers, diabetics and patients with elevated plasma cholesterol. With early detection and as a prognostics tool, lifestyle modification could help prevent disease progression to much more severe symptoms such as Critical Limb Threatening Ischemia (CLTI) and more effective treatment options such as angioplasty and revascularization.

The TAGS™ system consists of a H2S sensor and one or more DermalPuck™ that are placed on the skin of a patient. The DermalPuck™ is a sealed microfluidics chamber that collects gases emitted from the skin over several minutes. The collected gas is then analyzed by the sensor to determine H2S levels to calculate the permeation rate for each individual patient as an indicator of microvascular health.

There are significant shortcomings in the existing diagnostic techniques to screen for PAD that preclude widespread early detection needed to prevent the excessive morbidity attributed to this condition [1-5]. Because H2S molecules are critical to a healthy microvasculature and Exhalix’s unique capability to detect H2S at trace levels, the Exhalix product line is being developed as an alternative non-intrusive and inexpensive approach for early diagnosis of PAD.

To date, Exhalix TAGS™ measurements on limited number of human samples have been verified to be indicative of the levels of H2S transdermally emitted from the forearm skin of healthy and diabetic patients (lower left graph). These results indicate the potential for correlation between TAGS™ readings and blood biomarkers such as triglycerides (middle graph) as well as general risk of Cardiovascular events quantified by the cardiovascular risk factor (lower right graph). Exhalix and its research partners are continuing these measurements on a larger, more diverse diabetic population to further correlate against other cardiovascular health indicators. Some of these results are currently in review for publication.

The H2S permeation rate is an indicator of endothelial health (or damage) and microvascular blood flow. Low transdermal H2S levels are an indicator of low production from damaged endothelial layer or low delivery of H2S due to poor blood flow. Transcutaneous oximetry (TCPO2 or TCOM) is a noninvasive test for blood flow that directly measures the oxygen level of tissue beneath the skin. TCOM provides a measure of blood perfusion, whereas TAGS™ provides an indication of the availability of H2S through both blood flow and local production rate, both working together to provide an indication of the local endothelial health, thus making it superior to both TCOM and ankle brachial index (ABI).

Endothelial dysfunction is the leading cause of blood flow issues in diabetic patients, namely peripheral artery disease or PAD (large vessels) and microvascular disorder (small vessels). It is often missed until the symptoms become advanced enough to cause critical limb threatening ischemia (CLTI), ischemic and neuro-ischemic foot ulcers, wounds, and amputations.

As a low-cost screening device for early detection of PAD, TAGS™ has the potential to significantly reduce the suffering and costs associated with the advanced symptoms of PAD.

The H2S permeation rate is an indicator of endothelial health (or damage) and microvascular blood flow. Low transdermal H2S levels are an indicator of low production from damaged endothelial layer or low delivery of H2S due to poor blood flow. Transcutaneous oximetry (TCPO2 or TCOM) is a noninvasive test for blood flow that directly measures the oxygen level of tissue beneath the skin. TCOM provides a measure of blood perfusion, whereas TAGS™ provides an indication of the availability of H2S through both blood flow and local production rate, both working together to provide an indication of the local endothelial health, thus making it superior to both TCOM and ankle brachial index (ABI).

Endothelial dysfunction is the leading cause of blood flow issues in diabetic patients, namely peripheral artery disease or PAD (large vessels) and microvascular disorder (small vessels). It is often missed until the symptoms become advanced enough to cause critical limb threatening ischemia (CLTI), ischemic and neuro-ischemic foot ulcers, wounds, and amputations.

As a low-cost screening device for early detection of PAD, TAGS™ has the potential to significantly reduce the suffering and costs associated with the advanced symptoms of PAD.

Wound Therapy

ReLIS™ for Treatment of Disadvantaged Wounds

Repair by Local Infusion of Sulfides (ReLIS™) is an active wound dressing that protects the wound and locally maintains therapeutic levels of sulfides in the affected area, high enough to be effective but well below the cytotoxic levels. ReLIS™ is designed to control inflammation while stimulating the angiogenic pathway and accelerated healing by controlling the rate of Sulfide delivery, uniformly maintaining it during the treatment period.

ReLIS™ has applications in hard to heal surgical wounds, such as CLTI revascularization surgeries, and ischemic wounds like Diabetic Foot Ulcers (DFUs). For Surgical wounds, a proprietary biocompatible implantable scaffold matrix, formed to fit the incision, to ensure spatially uniform release of therapeutic solution for efficient angiogenesis. For DFUs the therapeutic H2S compound is subcutaneously released by microneedles into the wound area.

The proprietary dressing not only covers and protects but also monitors the environment above the surgical incision or diabetic wound: Extended beyond the functionality of a typical dressing, it allows for capturing skin emitted H2S gas for measurement and control. A clinician may replace the dressing by detaching the fluidic connections and reconnecting to a new dressing before sealing against the skin.

The most common treatment paths to limb salvage in CLTI patients are open surgical bypass (revascularization) and percutaneous transluminal angioplasty with or without stenting (PTA/S). However, these techniques are plagued by recurrence due to underlying issues and post-operative surgical healing complications due to microvascular and skin perfusion insufficiency. A novel technology to to help heal ischemic wounds and to solve the surgical incision healing problems characteristic of CLTI patients is needed.

Dose of drug needed
Precision of targeted therapy
Ability to adjust therapy in real time (i.e., controlled therapy)
Precision H2S Wound Therapy

The important role of H2S and its deficiency that lead to endothelial dysfunction has only been revealed during the past decade. H2S has been shown to promote angiogenesis-related behavior in endothelial cells including enhanced cell growth, migration, and tube formation through activation of pathways that include nitric oxide signaling and the canonical HIF-1a and VEGF-A-mediated angiogenesis cascade. In vivo, sulfide donors successfully improved new vessel formation and limb perfusion after femoral artery ligation in a manner dependent on NO and monocyte recruitment. The translational importance of H2S is highlighted by studies revealing decreased sulfide levels in the plasma of both humans and rodents afflicted with diabetes.

However, the backbone of many sulfide-related studies to-date is systemic delivery of agents that directly augment H2S levels including NaHS and Na2S but which are plagued by a narrow therapeutic window and known severe systemic toxicity.

Exhalix is developing an ideal sulfide delivery system would target active drug only to areas where a therapeutic effect is desired and would supply a predictable and adjustable dose over the required period of time.

Mechanisms of Hydrogen Sulfide Angiogenesis and Arteriogenesis

The most common treatment paths to limb salvage in CLTI patients are open surgical bypass (revascularization) and percutaneous transluminal angioplasty with or without stenting (PTA/S). However, these techniques are plagued by recurrence due to underlying issues and post-operative surgical healing complications due to microvascular and skin perfusion insufficiency. A novel technology to to help heal ischemic wounds and to solve the surgical incision healing problems characteristic of CLTI patients is needed.

The important role of H2S and its deficiency that lead to endothelial dysfunction has only been revealed during the past decade. H2S has been shown to promote angiogenesis-related behavior in endothelial cells including enhanced cell growth, migration, and tube formation through activation of pathways that include nitric oxide signaling and the canonical HIF-1a and VEGF-A-mediated angiogenesis cascade. In vivo, sulfide donors successfully improved new vessel formation and limb perfusion after femoral artery ligation in a manner dependent on NO and monocyte recruitment. The translational importance of H2S is highlighted by studies revealing decreased sulfide levels in the plasma of both humans and rodents afflicted with diabetes.

However, the backbone of many sulfide-related studies to-date is systemic delivery of agents that directly augment H2S levels including NaHS and Na2S but which are plagued by a narrow therapeutic window and known severe systemic toxicity.

Exhalix is developing an ideal sulfide delivery system would target active drug only to areas where a therapeutic effect is desired and would supply a predictable and adjustable dose over the required period of time.

Mechanisms of Hydrogen Sulfide Angiogenesis and Arteriogenesis

Pulmonary Edema

Small Molecule Biomarkers to Detect Pulmonary Edema and other Chronic Disease

There are more than 1849 endogenous volatile organic compounds (VOC) identified in healthy human individuals, majority of which is detected through the breath. Molecules such as hydrogen sulfide, acetone, isoprene, nitric oxide, hydrogen cyanide and formaldehyde, have unique properties and have been proven as biomarkers of specific diseases.

An electronic nose capable of sensing the small molecules offer the opportunity to improve quality of life for at risk individuals and lower healthcare costs by early detection of some of the more prevalent Chronic Diseases.

Dynamic Breath Gas Sensor (DBGS™) for Detecting Pulmonary Edema

Exhalix is in the early stages of developing a beath gas analyzer for detection of Pulmonary Edema. Pulmonary edema (PE), characterized by excessive accumulation of extravascular lung water (EVLW), is the underlying cause of acute respiratory distress syndrome and acute heart failure. DBGS utilizes the concentrations of H2S and C3H6O in breath to detect presence of excess alveolar fluid in lungs. The technology has the potential to extend to other biomarkers and detection of other chronic diseases.

Small Molecule Biomarkers to Detect Pulmonary Edema and other Chronic Disease

There are more than 1849 endogenous volatile organic compounds (VOC) identified in healthy human individuals, majority of which is detected through the breath. Molecules such as hydrogen sulfide, acetone, isoprene, nitric oxide, hydrogen cyanide and formaldehyde, have unique properties and have been proven as biomarkers of specific diseases.

An electronic nose capable of sensing the small molecules offer the opportunity to improve quality of life for at risk individuals and lower healthcare costs by early detection of some of the more prevalent Chronic Diseases.

Dynamic Breath Gas Sensor (DBGS™) for Detecting Pulmonary Edema

Exhalix is in the early stages of developing a beath gas analyzer for detection of Pulmonary Edema. Pulmonary edema (PE), characterized by excessive accumulation of extravascular lung water (EVLW), is the underlying cause of acute respiratory distress syndrome and acute heart failure. DBGS utilizes the concentrations of H2S and C3H6O in breath to detect presence of excess alveolar fluid in lungs. The technology has the potential to extend to other biomarkers and detection of other chronic diseases.