Chronic non-healing wounds remain a major clinical challenge that would benefit from the development of advanced, regenerative dressings that promote wound closure within a clinically relevant time frame. The use of copper ions has shown promise in wound healing applications possibly by promoting angiogenesis. However, reported treatments that use copper ions require multiple applications of copper salts or oxides to the wound bed, exposing the patient to potentially toxic levels of copper ions and resulting in variable outcomes. Herein we set out to assess whether copper metal organic framework nanoparticles (HKUST-1 NPs) embedded within an antioxidant thermoresponsive citrate-based hydrogel would decrease copper ion toxicity and accelerate wound healing in diabetic mice. HKUST-1 and poly-(polyethyleneglycol citrate-co-N-isopropylacrylamide) (PPCN) were synthesized and characterized. HKUST-1 NP stability in a protein solution with and without embedding them in PPCN hydrogel was determined. Copper ion release, cytotoxicity, apoptosis, and in vitro migration processes were measured. Wound closure rates and wound blood perfusion were assessed in vivo using the splinted excisional dermal wound diabetic mouse model. HKUST-1 NP disintegrated in protein solution while HKUST-1 NPs embedded in PPCN (H-HKUST-1) were protected from degradation and copper ions were slowly released. Cytotoxicity and apoptosis due to copper ion release were significantly reduced while dermal cell migration in vitro and wound closure rates in vivo were significantly enhanced. In vivo, H-HKUST-1 induced angiogenesis, collagen deposition, and re-epithelialization during wound healing in diabetic mice. These results suggest that a cooperatively stabilized, copper ion-releasing H-HKUST-1 hydrogel is a promising innovative dressing for the treatment of chronic wounds.

The lack of capability to quantify oxygen metabolism noninvasively impedes both fundamental investigation and clinical diagnosis of a wide spectrum of diseases including all the major blinding diseases such as age-related macular degeneration, diabetic retinopathy, and glaucoma. Using visible light optical coherence tomography (vis-OCT), we demonstrated accurate and robust measurement of retinal oxygen metabolic rate (rMRO2) noninvasively in rat eyes. We continuously monitored the regulatory response of oxygen consumption to a progressive hypoxic challenge. We found that both oxygen delivery, and rMRO2 increased from the highly regulated retinal circulation (RC) under hypoxia, by 0.28 ± 0.08 μL min−1 (p < 0.001), and 0.20 ± 0.04 μL min−1 (p < 0.001) per 100 mmHg systemic pO2 reduction, respectively. The increased oxygen extraction compensated for the deficient oxygen supply from the poorly regulated choroidal circulation. Results from an oxygen diffusion model based on previous oxygen electrode measurements corroborated our in vivo observations. We believe that vis-OCT has the potential to reveal the fundamental role of oxygen metabolism in various retinal diseases.

Visible light optical coherence tomography (vis-OCT) has demonstrated its capability of measuring vascular oxygen saturation (sO2) in vivo. Enhanced by OCT angiography, the signal from microvasculature can be further isolated and directly used for sO2 extraction. In this work, we extended the theoretical formulation for OCT angiography-based oximetry by incorporating the contribution from motion contrast enhancement. We presented a new method to eliminate the associated confounding variables due to blood flow. First, we performed in vitro experiments to verify our theory, showing a stable spectral derivative within the selected wavelength bands for sO2 extraction. Then, we tested our method in vivo to measure retinal sO2 in rats inhaling different gas mixtures: normal air, 5% CO2, pure O2, and 10% O2. Absolute sO2 values in major arterioles and venules in the retinal circulation can be accurately measured. In addition, we demonstrated the relative changes of sO2 can be measured non-invasively from choriocapillaris immediately underneath the retinal pigmented epithelium (RPE) in rodents.

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Abstract:We achieved human retinal imaging using visible-light optical coherence tomography (vis-OCT) guided by an integrated scanning laser ophthalmoscopy (SLO). We adapted a spectral domain OCT configuration and used a supercontinuum laser as the illumating source. The center wavelength was 564 nm and the bandwidth was 115 nm, which provided a 0.97 µm axial resolution measured in air. We characterized the sensitivity to be 86 dB with 226 µW incidence power on the pupil. We also integrated an SLO that shared the same optical path of the vis-OCT sample arm for alignment purposes. We demonstrated the retinal imaging from both systems centered at the fovea and optic nerve head with 20° × 20° and 10° × 10° field of view. We observed similar anatomical structures in vis-OCT and NIR-OCT. The contrast appeared different from vis-OCT to NIR-OCT, including slightly weaker signal from intra-retinal layers, and increased visibility and contrast of anatomical layers in the outer retina.

Abstract:We measured hemoglobin oxygen saturation (sO 2 ) in the retinal circulation in healthy humans using visible-light optical coherence tomography (vis-OCT). The measurements showed clear oxygenation differences between central retinal arteries and veins close to the optic nerve head. Spatial variations at different vascular branching levels were also revealed. In addition, we presented theoretical and experimental results to establish that noises in OCT intensity followed Rice distribution. We used this knowledge to retrieve unbiased estimation of true OCT intensity to improve the accuracy of vis-OCT oximetry, which had inherently lower signal-to-nose ratio from human eyes due to safety and comfort limitations. We demonstrated that the new statistical-fitting sampling strategy could reduce the estimation error in sO 2 by three percentage points (pp). The presented work aims to provide a foundation for using vis-OCT to achieve accurate retinal oximetry in clinical settings. G. Garhöfer, and L. Schmetterer, "Retinal oxygen metabolism during normoxia and hyperoxia in healthy subjects," Invest.

Although hemoglobin oxygen saturation (sO2) in the microvasculature is an essential physiological parameter of local tissue functions, non-invasive measurement of microvascular sO2 is still challenging. Here, we demonstrated that visible-light optical coherence tomography (vis-OCT) can simultaneously provide three-dimensional anatomical tissue morphology, visualize microvasculature at the capillary level, and measure sO2 from the microvasculature in vivo. We utilized speckle contrast caused by the moving blood cells to enhance microvascular imaging. We applied a series of short-time inverse Fourier transforms to obtain the spectroscopic profile of blood optical attenuation, from which we quantified sO2. We validated the sO2 measurement in mouse ears in vivo through hypoxia and hyperoxia challenges. We further demonstrated that vis-OCT can continuously monitor dynamic changes of microvascular sO2.

Milk production and time effects are considered related to heat stress but they have not yet been combined in predictive models. In two parts, this study aimed to develop new models to predict heat stress (rectal temperature and respiration rate) of lactating dairy cows by inputting predictors, including ambient temperature (T a ), relative humidity (RH), wind speed (WS), milk yield (MY), and time blocks. In the first part of the study, we built the quantitative foundation for the second part, including the regression relation between respiration rate and rectal temperature (to convert predicted respiration rate to predicted body temperature), as well as between rectal temperature and respiration rate when heat stress was triggered (to recognize whether herds were under stress). In the second part, we built models that combined the abovementioned predictors to predict respiration rate. In part I, data were obtained from 45 high-producing Holstein cows within a T a range of 9.5 to 30.8°C. We found a very strong correlation between mean respiration rate (MRR) and mean rectal temperature (MRT), where MRT = 0.021 × MRR + 37.6 (R 2 = 0.925), suggesting that for each 4.8 breaths per minute (bpm) increase of MRR, MRT would be expected to increase by 0.1°C. Rectal temperature was determined to be 38.6°C when heat stress was triggered, which corresponded to a respiration rate of 48 bpm. In part II, data were obtained in 3 stalls within a T a range of 6.9 to 33.3°C over 3 time blocks, all of which were the 90 min preceding milking (0630-0800, 1230-1400, and 1830-2000 h). We found a nonlinear response of MRR to T a , which could be linearized by the quadratic term of T a . The response of MRR was the highest in the 0630-0800 h block, followed by 1230-1400 h, and finally 1830-2000 h. We proposed a model combining 3 time blocks (R 2 = 0.836): MRR in 0630-0800 h was determined to 56.28 + (−3.40 + 0.11 × T a + 0.02 × RH) × T a − 0.21 × RH − 2.82 × WS + 0.62 × MY; MRR in 1230-1400 h and 1830-2000 h were 4.6 and 10.3 bpm lower than that in 0630-0800 h, respectively (reducing the intercept of the expression in 0630-0800 h). Compared with temperature-humidity index equations, the proposed model performed better at suppressing prediction error, and had better sensitivity and accuracy in recognizing whether heat stress was triggered.