Alexander M. Gorbach

Ultrathin conformal devices for precise and continuous thermal characterization of human skin

Precision thermometry of the skin can, together with other measurements, provide clinically relevant information about cardiovascular health, cognitive state, malignancy and many other important aspects of human physiology. Here, we introduce an ultrathin, compliant skin-like sensor/actuator technology that can pliably laminate onto the epidermis to provide continuous, accurate thermal characterizations that are unavailable with other methods. Examples include non-invasive spatial mapping of skin temperature with millikelvin precision, and simultaneous quantitative assessment of tissue thermal conductivity. Such devices can also be implemented in ways that reveal the time-dynamic influence of blood flow and perfusion on these properties. Experimental and theoretical studies establish the underlying principles of operation, and define engineering guidelines for device design. Evaluation of subtle variations in skin temperature associated with mental activity, physical stimulation and vasoconstriction/dilation along with accurate determination of skin hydration through measurements of thermal conductivity represent some important operational examples.

Physiological Parameter Monitoring from Optical Recordings With a Mobile Phone

We show that a mobile phone can serve as an accurate monitor for several physiological variables, based on its ability to record and analyze the varying color signals of a fingertip placed in contact with its optical sensor. We confirm the accuracy of measurements of breathing rate, cardiac R-R intervals, and blood oxygen saturation, by comparisons to standard methods for making such measurements (respiration belts, ECGs, and pulse-oximeters, respectively). Measurement of respiratory rate uses a previously reported algorithm developed for use with a pulse-oximeter, based on amplitude and frequency modulation sequences within the light signal. We note that this technology can also be used with recently developed algorithms for detection of atrial fibrillation or blood loss.

How well does a three-sphere model predict positions of dipoles in a realistically shaped head?

The electrical potential produced by a dipole in the temporal or frontal lobe was calculated for a realistically shaped scalp, skull, and brain. This potential distribution was then used with a 3-sphere model to predict the position, orientation, and strength of the dipole source. The original and predicted dipole positions differed by an average of 1.97 cm, with a difference of more than 4 cm in some cases. Control calculations demonstrated that this difference was not caused by numerical artifacts in the computation, but instead was due to a true difference between the 3-sphere and realistically shaped head models.

Adiposity and human regional body temperature

BACKGROUND Human obesity is associated with increased heat production; however, subcutaneous adipose tissue provides an insulating layer that impedes heat loss. To maintain normothermia, therefore, obese individuals must increase their heat dissipation. OBJECTIVE The objective was to test the hypothesis that temperature in a heat-dissipating region of the hand is elevated in obese adults. DESIGN Obese [body mass index (in kg/m(2)) > or = 30] and normal-weight (NW; body mass index = 18-25) adults were studied under thermoneutral conditions at rest. Core body temperature was measured by using ingested telemetric capsules. The temperatures of the third fingernail bed of the right hand and of abdominal skin from an area 1.5 cm inferior to the umbilicus were determined by using infrared thermography. Abdominal skin temperatures were also measured via adhesive thermistors that were placed over a prominent skin-surface blood vessel and over an adjacent nonvessel location. The groups were compared by analysis of covariance with age, sex, race, and room temperature as covariates. RESULTS Core temperature did not differ significantly between the 23 obese and 13 NW participants (P = 0.74). However, infrared thermography-measured fingernail-bed temperature was significantly higher in obese subjects than in NW subjects (33.9 +/- 0.7 degrees C compared with 28.6 +/- 0.9 degrees C; P < 0.001). Conversely, infrared thermography-measured abdominal skin temperature was significantly lower in obese subjects than in NW subjects (31.8 +/- 0.2 degrees C compared with 32.8 +/- 0.3 degrees C; P = 0.02). Nonvessel abdominal skin temperatures measured by thermistors were also lower in obese subjects (P = 0.04). CONCLUSIONS Greater subcutaneous abdominal adipose tissue in obese adults may provide a significant insulating layer that blunts abdominal heat transfer. Augmented heat release from the hands may offset heat retention in areas of the body with greater adiposity, thereby helping to maintain normothermia in obesity. This trial was registered at clinicaltrials.gov as NCT00266500.

Epidermal devices for noninvasive, precise, and continuous mapping of macrovascular and microvascular blood flow

Advances in ultrathin, skin-like electronics lead to wearable devices for continuous, noninvasive blood flow monitoring. Continuous monitoring of variations in blood flow is vital in assessing the status of microvascular and macrovascular beds for a wide range of clinical and research scenarios. Although a variety of techniques exist, most require complete immobilization of the subject, thereby limiting their utility to hospital or clinical settings. Those that can be rendered in wearable formats suffer from limited accuracy, motion artifacts, and other shortcomings that follow from an inability to achieve intimate, noninvasive mechanical linkage of sensors with the surface of the skin. We introduce an ultrathin, soft, skin-conforming sensor technology that offers advanced capabilities in continuous and precise blood flow mapping. Systematic work establishes a set of experimental procedures and theoretical models for quantitative measurements and guidelines in design and operation. Experimental studies on human subjects, including validation with measurements performed using state-of-the-art clinical techniques, demonstrate sensitive and accurate assessment of both macrovascular and microvascular flow under a range of physiological conditions. Refined operational modes eliminate long-term drifts and reduce power consumption, thereby providing steps toward the use of this technology for continuous monitoring during daily activities.

Core body temperature in obesity

BACKGROUND A lower core body temperature set point has been suggested to be a factor that could potentially predispose humans to develop obesity. OBJECTIVE We tested the hypothesis that obese individuals have lower core temperatures than those in normal-weight individuals. DESIGN In study 1, nonobese [body mass index (BMI; in kg/m(2)) <30] and obese (BMI ≥30) adults swallowed wireless core temperature-sensing capsules, and we measured core temperatures continuously for 24 h. In study 2, normal-weight (BMI of 18-25) and obese subjects swallowed temperature-sensing capsules to measure core temperatures continuously for ≥48 h and kept activity logs. We constructed daily, 24-h core temperature profiles for analysis. RESULTS Mean (±SE) daily core body temperature did not differ significantly between the 35 nonobese and 46 obese subjects (36.92 ± 0.03°C compared with 36.89 ± 0.03°C; P = 0.44). Core temperature 24-h profiles did not differ significantly between 11 normal-weight and 19 obese subjects (P = 0.274). Women had a mean core body temperature ≈0.23°C greater than that of men (36.99 ± 0.03°C compared with 36.76 ± 0.03°C; P < 0.0001). CONCLUSIONS Obesity is not generally associated with a reduced core body temperature. It may be necessary to study individuals with function-altering mutations in core temperature-regulating genes to determine whether differences in the core body temperature set point affect the regulation of human body weight. These trials were registered at clinicaltrials.gov as NCT00428987 and NCT00266500.

Vasculopathy, inflammation, and blood flow in leg ulcers of patients with sickle cell anemia

Chronic leg ulcers are frequent and debilitating complications of sickle cell anemia. Inadequate blood supply has been postulated to be an important factor in their occurrence and delayed healing. Little is known about their microcirculatory and histopathological changes. We evaluated the microcirculation of lower extremity ulcers with laser speckle contrast imaging and infrared thermography and obtained clinical and laboratory characteristics in 18 adults with sickle cell anemia and chronic leg ulcers. Skin biopsies were obtained in four subjects. Subjects had markers of severe disease, anemia, high degree of hemolysis, inflammation, and thrombophilia. The highest blood flow was present in the ulcer bed, progressively less in the immediate periwound area, and an unaffected control skin area in the same extremity. Microscopic examination showed evidence of venostasis, inflammation, and vasculopathy. Blood vessels were increased in number, had activated endothelium and evidence of thrombosis/recanalization. High blood flow may be due to chronic inflammation, cutaneous vasodilatation, venostasis, and in situ thrombosis. These changes in skin microcirculation are similar to chronic venous ulcers in the non‐sickle cell disease (SCD) population, thus suggesting that leg ulcers may be another end‐organ complication with endothelial dysfunction that appears in patients with SCD at a younger age and with higher frequency than in the general population. Am. J. Heamtol. 89:1–6, 2014.

Skin surface temperature rhythms as potential circadian biomarkers for personalized chronotherapeutics in cancer patients

Chronotherapeutics involve the administration of treatments according to circadian rhythms. Circadian timing of anti-cancer medications has been shown to improve treatment tolerability up to fivefold and double efficacy in experimental and clinical studies. However, the physiological and the molecular components of the circadian timing system (CTS), as well as gender, critically affect the success of a standardized chronotherapeutic schedule. In addition, a wrongly timed therapy or an excessive drug dose disrupts the CTS. Therefore, a non-invasive approach to accurately detect and monitor circadian rhythms is needed for a dynamic assessment of the CTS in order to personalize chronomodulated drug delivery schedule in cancer patients. Since core body temperature is a robust circadian biomarker, we recorded temperature at multiple locations on the skin of the upper chest and back of controls and cancer patients continuously. Variability in the circadian phase existed among patch locations in individual subjects over the course of 2–6 days, demonstrating the need to monitor multiple skin temperature locations to determine the precise circadian phase. Additionally, we observed that locations identified by infrared imaging as relatively cool had the largest 24 h temperature variations. Disruptions in skin temperature rhythms during treatment were found, pointing to the need to continually assess circadian timing and personalize chronotherapeutic schedules.

Objective, Real‐Time, Intraoperative Assessment of Renal Perfusion Using Infrared Imaging

Allograft ischemia induces delayed graft function and is correlated with increasing rates of rejection. There is not currently a way to objectively measure the effects of ischemia in real‐time, nor to relate therapies combating reperfusion injury with their intended effects.

Topical sodium nitrite for chronic leg ulcers in patients with sickle cell anaemia: a phase 1 dose-finding safety and tolerability trial

BACKGROUND Well-tolerated and effective treatments are needed for chronic leg ulcers in sickle cell anaemia. Topical sodium nitrite, a known nitric oxide donor, enhances blood flow in ulcers and has known bacteriostatic effects. We aimed to assess the safety, tolerability, and pharmacokinetics of topical sodium nitrite in patients with sickle cell disease and chronic leg ulcers. METHODS We enrolled adult patients from an ambulatory clinic at the National Institutes of Health (Bethesda, MD, USA) with sickle cell anaemia with leg ulcers (with a surface area of 2.5-100 cm2) persisting for at least 4 weeks into a safety and tolerability phase 1 dose-escalation trial of topical sodium nitrite. Increasing concentrations of sodium nitrite cream were applied twice weekly for 4 weeks to one ulcer per patient at five dose levels (0.5%, 1%, 1.5%, 1.8%, and 2%). The primary endpoints were safety and tolerability, with secondary endpoints of pharmacokinetics, blood flow, and wound healing. Pain relief was analysed post hoc. Endpoints were analysed over time for the whole study population and according to dose level. This study is registered with ClinicalTrials.gov, number NCT01316796. FINDINGS Between April 4, 2011, and March 19, 2013, we enrolled 18 adult patients with sickle cell anaemia and leg ulcers into our trial. We assigned three patients into each cohort, and each cohort was treated with a different concentration of sodium nitrite cream (cohort 1: 0.5%, cohort 2: 1.0%, cohort 3: 1.5%, and cohort 4: 2.0%). Patients were not enrolled into the next cohort dose until we were able to establish that no dose-limiting toxicities were observed. An additional six patients were enrolled to cohort 3a: 1.8%, after two patients in cohort 4 had asymptomatic drops in diastolic blood pressure. No grade 3-4 adverse events were observed, and there were no serious adverse events or dose-limiting side-effects. Pharmacokinetic analysis showed that systemic absorption of sodium nitrite was very low. Application of topical sodium nitrite was associated with a significant increase in peri-wound cutaneous blood flow measured by laser speckle contrast imaging (p=0.0002), corroborated by increased peri-wound skin temperature by infrared thermography (p=0.0119). We recorded a dose-dependent decrease in leg ulcer size (p=0.0012) and pain (p<0.0001). Ulcers healed completely in three patients who received the highest concentrations of topical sodium nitrite (the 1.8% and 2% cream). In our post-hoc analysis of pain, brief pain inventory scores improved in pain severity (p=0.0048) and pain interference (p=0.0013). INTERPRETATION Our results indicate that topical sodium nitrite 2% cream is suitable for additional clinical trials in adults with sickle cell anaemia to promote healing of leg ulcers. FUNDING National Heart, Lung and Blood Institute Division of Intramural Research (National Institutes of Health).