Hydrogen sulfide (H 2 S) generated in the endothelium of small arteries has been shown to contribute to vasodilation, angiogenesis, and antioxidant properties. We have developed a non-invasive way to measure H 2 S emitted by the skin (TAGS™) and have shown that the ratio of leg:arm emitted levels correlate with severity of microvascular impairment in subjects with diabetes. This study evaluated the correlation of transdermal H 2 S ratios with the current gold standard method of evaluating leg skin blood flow, transcutaneous oxygen pressures (tcpO 2 ). TAGS™ measurements were made on the forearm and lower limbs in subjects to calculate the leg:arm ratio while tcpO 2 was recorded only from legs. Other measurements included ankle brachial index (ABI), fasting blood glucose, HbA1c, plasma lipids, blood pressure, and BMI. We observed that TAGS™ ratios correlated strongly with HbA1c (p = 0.0002) and with tcpO 2 (p = 0.0009). In addition, TAGS ratios were significantly lower in subjects with diabetes (0.69 +/- 0.18) compared to healthy controls (1.13 +/- 0.40) (p = <0.0001). These results suggest lower leg:arm ratios of transdermal H 2 S measurements are indicative of impaired microvascular function and that the TAGS™ measurements may be a simpler way than tcpO 2 to detect and monitor diminished skin blood flow that leads to PAD complications.

Ischemic wounds are frequently encountered in clinical practice and may be related to ischemia secondary to diabetes, peripheral artery disease and other chronic conditions. Angiogenesis is critical to the resolution of ischemia. Hydrogen sulfide (H2S) is now recognized as an important factor in this process. H2S donors NaHS and GYY4137 were incorporated into the photosensitive polymer hydrogel gelatin methacrylate and evaluated. Human umbilical vein endothelial cell (HUVEC) culture was used to quantify toxicity and angiogenesis. Sprague Dawley rats were subjected to ischemic myocutaneous flap wound creation with and without application of H2S-eluting hydrogels. Tissue perfusion during wound healing was quantified using laser speckle contrast imaging, and gene and protein expression for VEGF were evaluated. Vascular density was assessed by CD31 immunohistochemistry. Successful incorporation of sulfide compounds was confirmed by scanning electron microscopy with energy-dispersive X-ray analysis, and under physiologic conditions, detectable H2S was present for up to 14 days by high-performance liquid chromatography. HUVECs exposed to hydrogels did not demonstrate excess cytotoxicity or apoptosis. A two-fold increase in angiogenic tube formation was observed in HUVECs exposed to H2S-eluting hydrogels. Rat ischemic flap wounds demonstrated greater perfusion at 14 days, and there was greater vascularity of healed wounds compared to untreated animals. A nearly two-fold increase in VEGF mRNA and a four-fold increase in VEGF protein expression were present in wounds from treated animals. Local-regional administration of H2S represents a novel potential therapeutic strategy to promote angiogenesis and improve wound healing after tissue injury or as a result of ischemic disease.

Objective: A novel transdermal arterial gasotransmitter sensor (TAGS) has been tested as a diagnostic tool for lower limb microvascular disease in individuals with and without diabetes mellitus (DM). Methods: The TAGS system noninvasively measures hydrogen sulfide (H2S) emitted from the skin. Measurements were made on the forearm and lower limbs of individuals from three cohorts, including subjects with DM and chronic limb -threatening ischemia, to evaluate skin microvascular integrity. These measurements were compared with diagnosis of peripheral artery disease (PAD) using the standard approach of the toe brachial index. Other measures of vascular health were made in some subjects including fasting blood glucose, hemoglobin A1c, plasma lipids, blood pressure, estimated glomerular filtration, and body mass index. Results: The leg:arm ratio of H2S emissions correlated with risk factors for microvascular disease (ie, high-density lipo-protein levels, estimated glomerular filtration rate, systolic blood pressure, and hemoglobin A1c). The ratios were signif-icantly lower in symptomatic DM subjects being treated for chronic limb-threatening ischemia (n = 8, 0.48 & PLUSMN; 0.21) compared with healthy controls (n = 5, 1.08 & PLUSMN; 0.30; P = .0001) and with asymptomatic DM subjects (n = 4, 0.79 & PLUSMN; 0.08; P = .0086). The asymptomatic DM group ratios were also significantly lower than the healthy controls (P = .0194). Using ratios of leg:arm transdermal H2S measurement (17 subjects, 34 ratios), the overall accuracy to identify limbs with severe PAD had an area under the curve of the receiver operating curve of 0.93. Conclusions: Ratios of transdermal H2S measurements are lower in legs with impaired microvascular function, and the decrease in ratio precedes clinically apparent severe microvascular disease and diabetic ulcers. The TAGS instrument is a novel, sensitive tool that may aid in the early detection and monitoring of PAD complications and efforts for limb salvage. (J Vasc Surg Cases Innov Tech 2023;9:101101.)

Hypoxia is the reduction of alveolar partial pressure of oxygen ([Formula: see text]). Military members and people who practice recreational activities from moderate to high altitudes are at risk for hypoxic exposure. Hypoxemia’s signs and symptoms vary from asymptomatic to severe responses, such as excessive hypoxic ventilatory responses and residual neurobehavioral impairment. Therefore, it is essential to identify hypoxia-induced biomarkers to indicate people with exposure to hypoxia. Advances have been made in understanding physiological responses to hypoxia, including elevations in circulating levels of endothelin 1 (ET-1) and microRNA 21 (miR-21) and reduction in circulating levels of hydrogen sulfide (H 2 S). Although the levels of these factors change upon exposure to hypoxia, it is unclear if these changes are sustained on return to normoxia. We hypothesize that hypoxia-induced ET-1 and miR-21 remain elevated, whereas hypoxia-reduction in H 2 S sustains after returning to normoxic conditions. To test this hypothesis, we exposed male rats to 6 h of 12% O 2 and measured circulating levels of ET-1 and miR-21, pre, during, and posthypoxia. We found that ET-1 plasma levels increased in response to hypoxia but returned to normal levels within 30 min after the restoration of normoxia. miR-21 plasma levels and transdermal H 2 S emissions decreased in response to hypoxia, remaining decreased on return to normoxia, thus following the biomarker criteria. Therefore, this study supports a unique role for plasma miR21 and transdermal H 2 S as hypoxia biomarkers that could be used to identify individuals after exposure to hypoxia.

Introduction: Hydrogen sulfide (H 2 S) has been recognized as an important signaling molecule in cellular O 2 sensing, wound healing and angiogenesis. Studies have shown abnormal H 2 S levels in diabetic patients with cardiovascular disease. Diminished H 2 S signaling may play a causative role in diabetic foot wounds. The Transdermal Arterial Gasotransmitter Sensor (TAGS) device measures real-time H 2 S emissions through the skin. In this work, we utilize the novel TAGS device to characterize transdermal H 2 S emissions during diabetic and non-diabetic wound healing for the first time. Methods: Dorsal peninsular-shaped myocutaneous ischemic flap wounds were created under anesthesia. Sprague Dawley (SD) and Zucker Diabetic Fatty (ZDF) rats (n=10 each) were compared. Transdermal H 2 S emissions, laser speckle contrast images (LSCI) and planimetric photos were serially taken from the wound flap area over 14 days. After animal sacrifice, healed flap tissue was collected for histologic (H&E) analysis of panniculus carnosus (skin muscle) viability as a proxy for degree of ischemic insult. Results: ZDF rats were significantly hyperglycemic (mean 516 mg/dL vs. 201 mg/dL for SD, P=0.002). Similar mean baseline (preoperative) H 2 S emissions were observed in SD (16 ppb) and ZDF (12 ppb) rats (P=0.25). During revascularization and healing, ZDF wounds emitted significantly less H 2 S (10 ppb at day 14) as compared to SD (28 ppb at day 14, P<0.01). ZDF wounds demonstrated impaired flap engraftment and revascularization by LSCI (mean 65.6 Perfusion Units (PU) for ZDF vs. 188.0 PU for SD at day 14, p<0.01) and planimetric analysis (mean 16.6% necrosis for ZDF vs. 5.3% necrosis for SD at day 14, p=0.01). Panniculus carnosus mean myofibril count, myofibril diameter, and layer thickness were significantly decreased (p<0.01) in the ZDF cohort, suggesting greater tissue ischemic insult and muscle loss. Conclusion: Diabetic rats have impaired wound H 2 S production and poor revascularization. These physiologic alterations are accompanied by greater wound necrosis and histologic ischemic insult. This suggests H 2 S abnormalities in diabetes may play a role in the pathogenesis of impaired wound healing and could represent a potential future therapeutic target for these difficult wounds.

Rapid in-situ chemical analysis of flowing gas streams is of interest in a wide range of applications but requires deconvolution of the time-scales associated with the analyte source concentration, its accumulation within a sampling chamber, and its detection by a sensor. A mathematical analysis is presented on the use of a flow-through sample chamber for rapid, in-situ breath analysis utilizing analyte diffusion through a Nafion membrane optode. We show that this approach yields apparently non-Fickian (anomalous or Case II) transport that varies from t1/2 to t as t → 0 with constant inlet concentration. Such behavior arises due to the transition from membrane-limited to sample chamber-limited transport dynamics depending on test conditions. The model is validated utilizing experimental data obtained from the color response associated with the Friedel-Craft acylation of acetone vapor with resorcinol reagent immobilized in Nafion membrane solid-state catalyst. Reduction of optode membrane thickness and increase in membrane humidification yield an optical response limited only by sample chamber material accumulation. At this limit, the exhaled breath signal for acetone obtained from a healthy individual is found to vary as t2 (apparently Super Case II transport). Utilizing a simplified material balance on the human lung, this observation is ascribed to a constant acetone exhalation rate as opposed to a constant exhaled acetone concentration. This conclusion is shown to have broad implications on the use of exhaled breath biomarkers for medical diagnosis, in particular, lung physiology and permeability.

We report here a novel approach to measure circulating hydrogen sulfide (H 2 S) non-invasively as a potential way to diagnose and monitor endothelial dysfunction and peripheral artery disease (PAD). PAD is a life-threatening condition caused by arterial constriction and obstruction of blood flow leading to limb ischemia. Current methods to diagnose and monitor PAD lack sensitivity, are expensive, and technically difficult. Recent studies indicate that decreased H 2 S production is an underlying cause of PAD. Also, reduced plasma H 2 S correlates with endothelial dysfunction in individuals with untreated hypertension, diabetes, sleep apnea and other cardiovascular diseases. The TAGS device was designed to measure transdermal H 2 S to test the hypothesis that the diffusion rate (and therefore gas phase concentration) of H 2 S is directly proportional to dermal blood flow. Healthy volunteers between the ages of 21-65 were recruited. Exclusion criteria included subjects currently treated for hypertension, hyperlipidemia, and diabetes. Smokers and pregnant women were also excluded. We demonstrate that H 2 S can be detected in healthy volunteers (n=11) at 10.8 part per billion (ppb). Interestingly, there is a positive correlation between age and TAGS readings in male volunteers (r=0.614; n= 6) and a negative correlation in female volunteers (r=0.482, n=5). The TAGS device has the potential, therefore, to serve as a more sensitive, economical, and easy to use diagnostic tool to detect H 2 S and predict dermal blood flow.

We report here a novel approach to measure circulating hydrogen sulfide (H 2 S) non‐invasively as a potential way to diagnose and monitor endothelial dysfunction and peripheral artery disease (PAD). PAD is a life‐threatening condition caused by arterial constriction and obstruction of blood flow leading to limb ischemia. Current methods to diagnose and monitor PAD lack sensitivity, result in frequent false‐negatives, and require specialized technicians. Recent studies indicate that decreased H 2 S production is an underlying cause of PAD. In addition, reduced plasma H 2 S correlates with endothelial dysfunction in untreated hypertension, diabetes, sleep apnea and other cardiovascular diseases. Conversely, excess H 2 S is cytotoxic causing irreversible damage to mitochondrial function. Therefore, careful monitoring of plasma H 2 S levels is essential to diagnose and treat vascular disease and to prevent H 2 S toxicity. This device was designed to measure H 2 S at the surface of the skin to test the hypothesis that the diffusion rate (and therefore gas phase concentration) of H 2 S is directly proportional to the concentration of H 2 S in the blood. Our results demonstrate that the device is sensitive enough to detect H 2 S at 10 part per billion (ppb) or lower in gas standards and in the headspace of a 3 nM solution of Na 2 S (H 2 S donor). In vitro studies used excised rat skin superfused on the subcutaneous surface with a H 2 S solution. H 2 S was detected in a stream of N 2 gas flowing through a sealed chamber on the epidermal side both by GC/MS measurement and with the sensor only when the superfusing solution contained an H 2 S donor demonstrating that H 2 S diffuses through the skin. The diffusion rate of H 2 S through excised abdominal skin from a male Sprague‐Dawley rat is approximately 1.42×10 −9 μmol/s/cm 2 /μM. The device also detected increases in H 2 S on the skin surface in anesthetized rats within seconds of intra‐venous injection of Na 2 S at doses that caused a fall in arterial pressure, with an estimated average diffusion rate of 4×10 −8 μmol/s/cm 2 /μM. Therefore, this noninvasive, highly‐sensitive and portable device has the potential to transform diagnosis and monitoring of early stage PAD and to monitor H 2 S biosynthesis or exposure in vivo .

Are we fooling ourselves? As dutiful engineers and scientists, it’s our job to find solutions to “impossible” problems. But there are some indications that we are approaching a dead end in thermal management. We’ve all heard the story dozens of times before: as the miniaturization of semiconductor electronics continues with no slowdown in sight, the number of transistors and devices per unit area of the substrate is increasing ferociously, as is the associated power consumed and dissipated in these devices. More transistors are being packed into a single chip, more dice into multi-chip modules, and more devices into small confined spaces in systems. In addition, the heat generated by each device is increasing, due to higher operating frequencies, Moore’s Law, etc. This has become such a familiar, repetitive mantra for thermal engineers that we’re in danger of forgetting its true meaning. The truth is that, like it or not, physical systems have practical limits. Someday, maybe soon, we’re going to smack hard into the thermal ceiling. The heat densities in electronic devices are spiraling exponentially upward, but our cooling technologies are not keeping pace. Already, designers are limiting clock speeds and throttling performance for lack of adequate cooling.