Changes In Tissue Oxygenation Research Articles

In vivo measurements of change in tissue oxygen level during irradiation reveal novel dose rate dependence

Background and purposeThis study aimed to investigate the radiochemical oxygen depletion (ROD) in vivo by directly measuring oxygen levels in various mouse tissues during ultra-high dose rate (UHDR) irradiation at clinically relevant doses and dose rates. Materials and methodsMice bearing subcutaneous human glioblastoma (U-87 MG) tumors were used for tumor and normal tissue (skin, muscle, brain) measurements. An oxygen-sensitive phosphorescent probe (Oxyphor PtG4) was injected into the tissues, and oxygen levels were monitored using a fiberoptic phosphorometer during UHDR irradiation with a 6 MeV electron linear accelerator (LINAC). Dose escalation experiments (10–40 Gy) were performed at a dose rate of 1300 Gy/s, and dose rate escalation experiments were conducted at a fixed dose of 40 Gy with dose rates ranging from 2 to 101 Gy/s. ResultsRadiation-induced change in tissue oxygenation (ΔpO2) increased linearly with dose and correlated with baseline tissue oxygenation levels in the range of 0 – 30 mmHg. At higher baseline tissue oxygenation levels, such as those observed in muscle and brain, there was no corresponding increase in ΔpO2. When we modulated dose rate, ΔpO2 increased steeply up to ∼ 20 Gy/s and plateaued thereafter. The relationship between ΔpO2 and dose rate showcases the interplay between ROD and reoxygenation. ConclusionWhile UHDR irradiation induces measurable oxygen depletion in tissues, the observed changes in oxygenation levels do not support the hypothesis that ROD-induced radioresistance is responsible for the FLASH tissue-sparing effect at clinically relevant doses and dose rates. These findings highlight the need for further investigation into alternative mechanisms underlying the FLASH effect.

In vivo optical assessment of cerebral and skeletal muscle microvascular response to phenylephrine.

This study aimed to investigate the simultaneous response of the cerebral and skeletal muscle microvasculature to the same phenylephrine (PE) boluses. A hybrid optical system that combines hyperspectral near-infrared spectroscopy (hs-NIRS) and diffuse correlation spectroscopy (DCS) was used to monitor changes in tissue oxygenation and perfusion. Data were collected from the head and hind limb of seven male Sprague-Dawley rats while administering intravenous (IV) injections of PE or saline to all animals. The response to saline was used as a control. Skeletal muscle oxygenation decreased significantly after PE injection, while a statistically underpowered decrease in perfusion was observed, followed by an increase beyond baseline. Vascular conductance also decreased in the muscle reflecting the drug's vasoconstrictive effects. Tissue oxygenation and perfusion increased in the brain in response to PE. Initially, there was a sharp increase in cerebral perfusion but no changes in cerebral vascular conductance. Subsequently, cerebral flow and vascular conductance decreased significantly below baseline, likely reflecting autoregulatory mechanisms to manage the excess flow. Further, fitting an exponential function to the secondary decrease in cerebral perfusion and increase in muscular blood flow revealed a quicker kinetic response in the brain to adjust blood flow. In the skeletal muscle, PE caused a transient decrease in blood volume due to vasoconstriction, which resulted in an overall decrease in hemoglobin content and tissue oxygen saturation. Since PE does not directly affect cerebral vessels, this peripheral vasoconstriction shunted blood into the brain, resulting in an initial increase in oxygenated hemoglobin and oxygen saturation.

Effects of the feeding protocol during blood transfusion on splanchnic tissue oxygenation and complications in very premature infants.

The effects of blood transfusions on splanchnic oxygenation and complications related to blood transfusions, including red blood cell (RBC) transfusions, in premature infants undergoing enteral feeding, to provide clinical evidence for a management protocol for premature infants during the peri-transfusion period. This single-blind, randomized, controlled trial enrolled sixty eligible preterm infants who were randomly divided into the withholding feeding group (n = 30) or feeding group (n = 30). Enteral feeding was withheld for 8 h, beginning from the start of transfusion infants in the feeding group were fed according to the pre-transfusion feeding approach during and after RBC transfusion. Baseline characteristics of those in the withholding and feeding groups were as follows: gestational age (weeks) 27.52 (24.86-30.14) and 27.13 (25.43-30.14); birth weight (g), 1,027 (620-1,450) and 1,027 (620-1,270); blood transfusion day, 48 (14-79) and 39 (10-78); and hemoglobin before blood transfusion (g/L), 81.67 (±10.56) and 85.93 (±14.77). No significant differences were observed between groups at baseline. No significant differences were observed in the average splanchnic tissue oxygenation changes or clinical results at any time. One patient in the withholding feeding group experienced transfusion-associated necrotizing enterocolitis. No differences in splanchnic oxygenation observed these feeding protocols. This study suggests the feasibility of a sizable trial to evaluate clinical outcomes. The risks of mesenteric ischemia and transfusion-related necrotizing enterocolitis for premature infants were not increased by enteral feeding during RBC transfusion. ChiCTR2200055726 (https://www.chictr.org.cn/).

Transient Changes in Cerebral Tissue Oxygen, Glucose, and Temperature by Microstrokes: A Computational Study.

This study focuses on evaluating the disruptions in key physiological parameters during microstroke events to assess their severity. A mathematical model was developed to simulate the changes in cerebral tissue pO2, glucose concentration, and temperature due to blood flow interruptions. The model considers variations in baseline cerebral blood flow (CBF), capillary density, and blood oxygen/glucose levels, as well as ambient temperature changes. Simulations indicate that complete blood flow obstruction still allows for limited glucose availability, supporting nonoxidative metabolism and potentially exacerbating lactate buildup and acidosis. Partial obstructions decrease tissue pO2, with minimal impact on glucose level, which can remain almost unchanged or even slightly increase. Reduced CBF, capillary density, or blood oxygen due to aging or disease enhances hypoxia risk at lower obstruction levels, with capillary density having a significant effect on stroke severity by influencing both pO2 and glucose levels. Conditions could lead to co-occurrence of hypoxia/hypoglycemia or hypoxia/hyperglycemia, each worsening outcomes. Temperature effects were minimal in deep brain regions but varied near the skull by 0.2-0.8°C depending on ambient temperature. The model provides insights into the conditions driving severe stroke outcomes based on estimated levels of hypoxia, hypoglycemia, hyperglycemia, and temperature changes.

Photoacoustic imaging for non-invasive assessment of biomarkers of intestinal injury in experimental necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) is an often-lethal disease of the premature infant intestinal tract, exacerbated by significant diagnostic difficulties. In NEC, the intestine exhibits hypoperfusion and dysmotility, contributing to disease pathogenesis. However, these features cannot be accurately and quantitively assessed with current imaging modalities. We have previously demonstrated the ability of photoacoustic imaging (PAI) to non-invasively assess intestinal tissue oxygenation and motility in a healthy neonatal rat model. In this first-in-disease application, we evaluated NEC using PAI to assess intestinal health biomarkers in an experimental model of NEC. NEC was induced in neonatal rats from birth to 4-days. Healthy breastfed (BF) and NEC rat pups were imaged at 2- and 4-days. Intestinal tissue oxygen saturation was measured with PAI, and NEC pups showed significant decreases at 2- and 4-days. Ultrasound and PAI cine recordings were used to capture intestinal peristalsis and contrast agent transit within the intestine. Intestinal motility, assessed using computational intestinal deformation analysis, demonstrated significant reductions in both early and established NEC. NEC damage was confirmed with histology and dysmotility was confirmed by small intestinal transit assay. This preclinical study presents PAI as an emerging diagnostic imaging modality for intestinal disease assessment in premature infants. Necrotizing enterocolitis (NEC) is a devastating intestinal disease affecting premature infants with significant mortality. NEC presents significant clinical diagnostic difficulties, with limited diagnostic confidence complicating timely and effective interventional efforts. This study is an important foundational first-in-disease preclinical study that establishes the utility for PAI to detect changes in intestinal tissue oxygenation and intestinal motility with NEC disease induction and progression. This study demonstrates the feasibility and exceptional promise for the use of PAI to non-invasively assess oxygenation and motility in the healthy and diseased infant intestine.

Development and Characterization of Hemoglobin Microbubbles for Acoustic Blood Oxygen Level Dependent Imaging.

Oxygen levels in tissues and organs are crucial for their normal functioning, and approaches to monitor them non-invasively have wide biological and clinical applications. In this study, we developed a method of acoustically detecting oxygenation using contrast-enhanced ultrasound (CEUS) imaging. Our approach involved the use of specially designed hemoglobin-based microbubbles (HbMBs) that reversibly bind to oxygen and alter the state-dependent acoustic response. We confirmed that the bioactivity of hemoglobin remained intact after the microbubble shell was formed, and we did not observe any significant loss of heme. We conducted passive cavitation detection (PCD) experiments to confirm whether the acoustic properties of HbMBs vary based on the level of oxygen present. The experiments involved driving the HbMBs with a 1.1 MHz focused ultrasound transducer. Through the PCD data collected, we observed significant differences in the subharmonic and harmonic responses of the HbMBs when exposed to an oxygen-rich environment versus an oxygen-depleted one. We used a programmable ultrasound system to capture high-frame rate B mode videos of HbMBs in both oxy and deoxy conditions at the same time in a two-chambered flow phantom and observed that the mean pixel intensity of deoxygenated HbMB was greater than in the oxygenated state using B-mode imaging. Finally, we demonstrated that HbMBs can circulate in vivo and are detectable by a clinical ultrasound scanner. To summarize, our results indicate that CEUS imaging with HbMB has the potential to detect changes in tissue oxygenation and could be a valuable tool for clinical purposes in monitoring regional blood oxygen levels.

Effects of furosemide, acetazolamide and amiloride on renal cortical and medullary tissue oxygenation in non-anaesthetised healthy sheep.

It has been proposed that diuretics can improve renal tissue oxygenation through inhibition of tubular sodium reabsorption and reduced metabolic demand. However, the impact of clinically used diuretic drugs on the renal cortical and medullary microcirculation is unclear. Therefore, we examined the effects of three commonly used diuretics, at clinically relevant doses, on renal cortical and medullary perfusion and oxygenation in non-anaesthetised healthy sheep. Merino ewes received acetazolamide (250mg; n=9), furosemide (20mg; n=10) or amiloride (10mg; n=7) intravenously. Systemic and renal haemodynamics, renal cortical and medullary tissue perfusion and , and renal function were then monitored for up to 8h post-treatment. The peak diuretic response occurred 2h (99.4±14.8mL/h) after acetazolamide, at which stage cortical and medullary tissue perfusion and were not significantly different from their baseline levels. The peak diuretic response to furosemide occurred at 1h (196.5±12.3mL/h) post-treatment but there were no significant changes in cortical and medullary tissue oxygenation during this period. However, cortical tissue fell from 40.1±3.8mmHg at baseline to 17.2±4.4mmHg at 3h and to 20.5±5.3mmHg at 6h after furosemide administration. Amiloride did not produce a diuretic response and was not associated with significant changes in cortical or medullary tissue oxygenation. In conclusion, clinically relevant doses of diuretic agents did not improve regional renal tissue oxygenation in healthy animals during the 8h experimentation period. On the contrary, rebound renal cortical hypoxia may develop after dissipation of furosemide-induced diuresis.

Skeletal muscle mitochondrial capacity in patients with statin-associated muscle symptoms (SAMS)

ObjectiveThe objective of this article is to evaluate near-infrared spectroscopy (NIRS), a non-invasive technique to assess tissue oxygenation and mitochondrial function, as a diagnostic tool for statin-associated muscle symptoms (SAMS).MethodsWe...

Monitoring the Effect of Continuous Topical Oxygen Therapy With Near-Infrared Spectroscopy: A Pilot Case Series in Wound Healing

Background. Sufficient oxygen is critical for multiple processes in wound healing. Nonhealing wounds have low tissue oxygen levels due to damaged microvasculature and comorbidities limiting tissue perfusion. Hypoxia may be reversed using continuous topical oxygen therapy (cTOT). Objective measures to identify and track hypoxic wounds and their response to adjunctive oxygen are key. Objective. To understand the effect of cTOT on recalcitrant wounds by tracking wound area and changes in tissue oxygenation using a near-infrared spectroscopy (NIRS) device. Materials and Methods. Five patients with nonhealing wounds received treatment with cTOT over 5 weeks. Routine wound measures and tissue oxygenation were recorded over that period. Results. Reductions in wound area and improvements in tissue oxygenation were seen in all 5 patients, with 3 patients healing within 5 weeks despite the previous long duration of their wounds. Trends in tissue oxygenation and relative wound surface area over the treatment period demonstrated a reduction in wound area as tissue oxygenation improved. Conclusion. This case series reinforces previous studies that cTOT is an effective, noninvasive treatment as a key adjunct to standard care in nonhealing wounds. Moreover, point-of-care tools such as the NIRS imaging device provided objective information concerning tissue oxygenation improvements, thus giving useful insights to the clinician.

Is near-infrared spectroscopy a promising predictor for early intracranial hemorrhage diagnosis in the Emergency Department?

Intracranial hemorrhage (ICH) is a serious medical condition that can lead to significant morbidity and mortality if not diagnosed and treated promptly. Early detection and treatment are essential for improving the outcome in patients with ICH. Near-infrared spectroscopy (NIRS) is a non-invasive imaging technique that has been used to detect changes in brain tissue oxygenation and blood flow in various conditions. The aim of this study was to investigate the predictive potential of NIRS for early diagnosis of ICH in patients presenting to the Emergency Department (ED) triage with headache. A total of 378 patients were included in the study. According to the final diagnosis of the patients, 4 groups were formed: migraine, tension-cluster headache, intracranial hemorrhage and intracranial mass, and control group. Cerebral NIRS values "rSO2" were measured at the first professional medical contact with the patient. The right and left rSO2 (RrSO2, LrSO2) were significantly lower and the rSO2 difference was significantly higher in the intracranial hemorrhage group compared to all other patient groups (P<0.001). The cut-off values determined in the receiver operating characteristics (ROC) analysis were RrSO2 ≤67, LrSO2 ≤67, and ΔrSO2 ≥9. This study found that a difference of more than 9 in cerebral right-left NIRS values can be a non-invasive, easy-to-administer, rapid, and reliable diagnostic test for early detection of intracranial bleeding. NIRS holds promise as an objective method in ED triage for patients with intracranial hemorrhage. However, further research is needed to fully understand the potential benefits and limitations of this method.

Functional MRI evaluation of blood oxygen dependent (BOLD) in renal allograft dysfunction: a prospective study.

Blood oxygen level dependent-magnetic resonance imaging (BOLD-MRI) is a non-invasive functional imaging technique that can be used to assess renal allograft dysfunction. To evaluate the diagnostic performance of BOLD-MRI using a 3-T scanner in discriminating causes of renal allograft dysfunction in the post-transplant period. This prospective study was conducted on 112 live donor-renal allograft recipients: 53 with normal graft function, as controls; 18 with biopsy-proven acute rejection (AR); and 41 with biopsy-proven acute tubular necrosis (ATN). Multiple fast-field echo sequences were performed to obtain T2*-weighted images. Cortical R2* (CR2*) level, medullary R2* (MR2*) level, and medullary over cortical R2* ratio (MCR) were measured in all participants. The mean MR2* level was significantly lower in the AR group (20.8 ± 2.8/s) compared to the normal group (24 ± 2.4/s, P <0.001) and ATN group (27.4 ± 1.7/s, P <0.001). The MCR was higher in ATN group (1.47 ± 0.18) compared to the AR group (1.18 ± 0.17) and normal functioning group (1.34 ± 0.2). Both MR2* (area under the curve [AUC] = 0.837, P <0.001) and MCR (AUC = 0.727, P = 0.003) can accurately discriminate ATN from AR, however CR2* (AUC = 0.590, P = 0.237) showed no significant difference between both groups. In early post-transplant renal dysfunction, BOLD-MRI is a valuable non-invasive diagnostic technique that can differentiate between AR and ATN by measuring changes in intra-renal tissue oxygenation.

Quadriceps fatigue during hypoxic and ischemic knee-extension exercise is similar in males and females.

Hypoxia is known to increase muscle fatigue via both central and peripheral mechanisms. Females are typically less fatigable than males during isometric fatiguing contractions due to greater peripheral blood flow. However, sex differences in fatigue are blunted during dynamic fatiguing tasks. Thus, this study determined the interactions of sex and hypoxia on knee extensor muscle contractile function during a dynamic, ischemic fatiguing contraction. Electrical stimulation was used to determine contractile properties of the knee extensor muscles in eight males and eight females before and after an ischemic, dynamic fatiguing task while inspiring room air or a hypoxic gas mixture (10% O2:90% N2). Fatigue (assessed as time-to-task failure) was ∼10% greater during the hypoxic condition (94.3 ± 33.4 s) compared with normoxic condition (107.0 ± 42.8 s, P = 0.041) and ∼40% greater for females than males (77.1 ± 18.8 vs. 124.2 ± 38.7, P < 0.001). Immediately after the dynamic fatiguing task, there were reductions in maximal voluntary contraction force (P = 0.034) and electrically evoked twitch force (P < 0.001), and these reductions did not differ based on sex or inspirate. Cerebral tissue oxygenation showed a significant interaction of time and inspirate (P = 0.003) whereby it increased during normoxia and remained unchanged in hypoxia. No sex-related differences in the changes of cerebral tissue oxygenation were observed (P = 0.528). These data suggest that acute hypoxia increases central fatigue during ischemic single-leg exercise resulting in earlier exercise termination, but the effect does not differ based on sex.NEW & NOTEWORTHY Hypoxia exacerbates fatigue via central mechanisms after ischemic single-leg exercise. The greater fatigue observed during ischemic dynamic fatiguing exercise with hypoxia inspirate did not differ between the sexes. Hypoxia-induced central limitations are present in acute ischemic exercise and do not appear different in males and females.

Hemodynamic changes in the temporalis and masseter muscles during acute stress in healthy humans.

Autonomic control of orofacial areas is an integral part of the stress response, controlling functions such as pupil dilatation, salivation, and skin blood flow. However, the specific control of blood flow in head muscles during stress is unknown. This study aims to investigate the hemodynamic response of temporalis and masseter muscles in response to five different stressors. Sixteen healthy individuals were subjected to a randomized series of stressors, including cold pressor test, mental arithmetic test, apnea, isometric handgrip, and post-handgrip muscle ischemia, while in the sitting posture. Finger-pulse photoplethysmography was used to measure arterial blood pressure, heart rate, and cardiac output. Near-infrared spectroscopy was used to measure changes in tissue oxygenation and hemoglobin indices from the temporalis and masseter muscles. All stressors effectively and significantly increased arterial blood pressure. Tissue oxygenation index significantly increased in both investigated head muscles during mental arithmetic test (temporalis: 4.22 ± 3.52%; masseter: 3.43 ± 3.63%) and isometric handgrip (temporalis: 3.45 ± 3.09%; masseter: 3.26 ± 3.07%), suggesting increased muscle blood flow. Neither the masseter nor the temporalis muscles evidenced a vasoconstrictive response to any of the stressors tested. In the different conditions, temporalis and masseter muscles exhibited similar hemodynamic patterns of response, which do not include the marked vasoconstriction generally observed in limb muscles. The peculiar sympathetic control of head muscles is possibly related to the involvement of these muscles in aggressive/defensive reactions and/or to their unfavorable position with regard to hydrostatic blood levels.

Tissue Oxygenation Changes After Transfusion and Outcomes in Preterm Infants

Preterm infants with varying degrees of anemia have different tissue oxygen saturation responses to red blood cell (RBC) transfusion, and low cerebral saturation may be associated with adverse outcomes. To determine whether RBC transfusion in preterm infants is associated with increases in cerebral and mesenteric tissue saturation (Csat and Msat, respectively) or decreases in cerebral and mesenteric fractional tissue oxygen extraction (cFTOE and mFTOE, respectively) and whether associations vary based on degree of anemia, and to investigate the association of Csat with death or neurodevelopmental impairment (NDI) at 22 to 26 months corrected age. This was a prospective observational secondary study conducted among a subset of infants between August 2015 and April 2017 in the Transfusion of Prematures (TOP) multicenter randomized clinical trial at 16 neonatal intensive care units of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Preterm neonates with gestational age 22 to 28 weeks and birth weight 1000 g or less were randomized to higher or lower hemoglobin thresholds for transfusion. Data were analyzed between October 2020 and May 2022. Near-infrared spectroscopy monitoring of Csat and Msat. Primary outcomes were changes in Csat, Msat, cFTOE, and mFTOE after transfusion between hemoglobin threshold groups, adjusting for age at transfusion, gestational age, birth weight stratum, and center. Secondary outcome at 22 to 26 months was death or NDI defined as cognitive delay (Bayley Scales of Infant and Toddler Development-III score <85), cerebral palsy with Gross Motor Function Classification System level II or greater, or severe vision or hearing impairment. A total of 179 infants (45 [44.6%] male) with mean (SD) gestational age 25.9 (1.5) weeks were enrolled, and valid data were captured from 101 infants during 237 transfusion events. Transfusion was associated with a significant increase in mean Csat of 4.8% (95% CI, 2.7%-6.9%) in the lower-hemoglobin threshold group compared to 2.7% (95% CI, 1.2%-4.2%) in the higher-hemoglobin threshold group, while mean Msat increased 6.7% (95% CI, 2.4%-11.0%) vs 5.6% (95% CI, 2.7%-8.5%). Mean cFTOE and mFTOE decreased in both groups to a similar extent. There was no significant change in peripheral oxygen saturation (SpO2) in either group (0.2% vs -0.2%). NDI or death occurred in 36 infants (37%). Number of transfusions with mean pretransfusion Csat less than 50% was associated with NDI or death (odds ratio, 2.41; 95% CI, 1.08-5.41; P = .03). In this secondary study of the TOP randomized clinical trial, Csat and Msat were increased after transfusion despite no change in SpO2. Lower pretransfusion Csat may be associated with adverse outcomes, supporting further investigation of targeted tissue saturation monitoring in preterm infants with anemia. ClinicalTrials.gov Identifier: NCT01702805.

Diabetic Foot Ulcer Imaging: An Overview and Future Directions.

Diabetic foot ulcers (DFUs) affect one in every three people with diabetes. Imaging plays a vital role in objectively complementing the gold-standard visual yet subjective clinical assessments of DFUs during the wound treatment process. Herein, an overview of the various imaging techniques used to image DFUs is summarized. Conventional imaging modalities (e.g., computed tomography, magnetic resonance imaging, positron emission tomography, single-photon emitted computed tomography, and ultrasound) are used to diagnose infections, impact on the bones, foot deformities, and blood flow in patients with DFUs. Transcutaneous oximetry is a gold standard to assess perfusion in DFU cases with vascular issues. For a wound to heal, an adequate oxygen supply is needed to facilitate reparative processes. Several optical imaging modalities can assess tissue oxygenation changes in and around the wounds apart from perfusion measurements. These include hyperspectral imaging, multispectral imaging, diffuse reflectance spectroscopy, near-infrared (NIR) spectroscopy, laser Doppler flowmetry or imaging, and spatial frequency domain imaging. While perfusion measurements are dynamically monitored at point locations, tissue oxygenation measurements are static two-dimensional spatial maps. Recently, we developed a spatio-temporal NIR-based tissue oxygenation imaging approach to map for the extent of asynchrony in the oxygenation flow patterns in and around DFUs. Researchers also measure other parameters such as thermal maps, bacterial infections (from fluorescence maps), pH, collagen, and trans-epidermal water loss to assess DFUs. A future direction for DFU imaging would ideally be a low-cost, portable, multi-modal imaging platform that can provide a visual and physiological assessment of wounds for comprehensive wound care intervention and management.

From functional neuroimaging to neurostimulation: fNIRS devices as cognitive enhancers.

Functional near-infrared spectroscopy (fNIRS) relies on near-infrared (NIR) light for changes in tissue oxygenation. For decades, this technique has been used in neuroscience to measure cortical activity. However, recent research suggests that NIR light directed to neural populations can modulate their activity through "photobiomodulation" (PBM). Yet, fNIRS is being used exclusively as a measurement tool. By adopting cognitive tests sensitive to prefrontal functioning, we show that a 'classical' fNIRS device, placed in correspondence of the prefrontal cortices of healthy participants, induces faster RTs and better accuracy in some of the indexes considered. A well-matched control group, wearing the same but inactive device, did not show any improvement. Hence, our findings indicate that the 'standard' use of fNIRS devices generates PBM impacting cognition. The neuromodulatory power intrinsic in that technique has been so far completely overlooked, and future studies will need to take this into account.

Radiosensitizing oxygenation changes in murine tumors treated with VEGF-ablation therapy are measurable using oxygen enhanced-MRI (OE-MRI)

PurposeThere is a significant need for a widely available, translatable, sensitive and non-invasive imaging biomarker for tumor hypoxia in radiation oncology. Treatment-induced changes in tumor tissue oxygenation can alter the sensitivity of cancer tissues to radiation, but the relative difficulty in monitoring the tumor microenvironment results in scarce clinical and research data. Oxygen-Enhanced MRI (OE-MRI) uses inhaled oxygen as a contrast agent to measure tissue oxygenation. Here we investigate the utility of dOE-MRI, a previously validated imaging approach employing a cycling gas challenge and independent component analysis (ICA), to detect VEGF-ablation treatment-induced changes in tumor oxygenation that result in radiosensitization. MethodsMurine squamous cell carcinoma (SCCVII) tumor-bearing mice were treated with 5 mg/kg anti-VEGF murine antibody B20 (B20-4.1.1, Genentech) 2–7 days prior to radiation treatment, tissue collection or MR imaging using a 7 T scanner. dOE-MRI scans were acquired for a total of three repeated cycles of air (2 min) and 100% oxygen (2 min) with responding voxels indicating tissue oxygenation. DCE-MRI scans were acquired using a high molecular weight (MW) contrast agent (Gd-DOTA based hyperbranched polygylcerol; HPG-GdF, 500 kDa) to obtain fractional plasma volume (fPV) and apparent permeability-surface area product (aPS) parameters derived from the MR concentration–time curves. Changes to the tumor microenvironment were evaluated histologically, with cryosections stained and imaged for hypoxia, DNA damage, vasculature and perfusion. Radiosensitizing effects of B20-mediated increases in oxygenation were evaluated by clonogenic survival assays and by staining for DNA damage marker γH2AX. ResultsTumors from mice treated with B20 exhibit changes to their vasculature that are consistent with a vascular normalization response, and result in a temporary period of reduced hypoxia. DCE-MRI using injectable contrast agent HPG-GDF measured decreased vessel permeability in treated tumors, while dOE-MRI using inhaled oxygen as a contrast agent showed greater tissue oxygenation. These treatment-induced changes to the tumor microenvironment result in significantly increased radiation sensitivity, illustrating the utility of dOE-MRI as a non-invasive biomarker of treatment response and tumor sensitivity during cancer interventions. ConclusionsVEGF-ablation therapy-mediated changes to tumor vascular function measurable using DCE-MRI techniques may be monitored using the less invasive approach of dOE-MRI, an effective biomarker of tissue oxygenation that can monitor treatment response and predict radiation sensitivity.

Altered tissue oxygenation in patients with post COVID-19 syndrome.

Post COVID-19 syndrome (PCS) is a complex condition with partly substantial impact on patients' social and professional life and overall life quality. Currently, the underlying cause(s) of PCS are unknown. Since PCS-specific symptoms could be associated with systemic alterations in tissue oxygen supply, we aimed to investigate changes in tissue oxygenation in patients with PCS. A case-control study including 30 PCS patients (66.6 % males, 48.6 ± 11.2 years, mean time after (first) acute infection: 324 days), 16 cardiologic patients (CVD) (65.5 % males, 56.7 ± 6.3 years) and 11 young healthy controls (55 % males, 28.5 ± 7.4 years) was conducted. Near infrared spectroscopy (NIRS) was used to assess changes in tissue oxygenation during an arterial occlusion protocol on the non-dominant forearm (brachioradialis, 760/850 nm, 5 Hz). The protocol included 10-min rest, a 2-min baseline measurement followed by a 3-min ischemic period (upper-arm cuff, 50 mmHg above resting systolic blood pressure) and a 3-min reoxygenation period. PCS patients were grouped by presence of arterial hypertension and elevated BMI to assess the impact of risk factors. No differences in mean tissue oxygenation in the pre-occlusion phase existed between groups (p ≥ 0.566). During ischemia, comparisons of linear regressions slopes revealed slower oxygen desaturation for PCS patients (-0.064 %/s) compared to CVD patients (-0.08 %/s) and healthy subjects (-0.145 %/s) (p < 0.001). After cuff release, slowest speed for reoxygenation was detected in PCS patients at 0.84 %/s compared to CVD patients (1.04 %/s) and healthy controls (CG: 2.07 %/s) (p < 0.001). The differences between PCS patients and CVD patients during ischemia remained significant also after correction for risk factors. Analyses of complications during acute infection, persistence of PCS symptoms (time after acute infection), or PCS severity (number of lead symptoms) as confounding factors did not reveal a significant effect. This study provides evidence that the rate of tissue oxygen consumption is persistently altered in PCS and that PCS patients show an even slower decline in tissue oxygenation during occlusion than CVD patients. Our observations may at least partly explain PCS-specific symptoms such as physical impairment and fatigue.

Concurrent Optical- and Magnetic-Stimulation-Induced Changes on Wound Healing Parameters, Analyzed by Hyperspectral Imaging: An Exploratory Case Series.

The effects of concurrent optical and magnetic stimulation (COMS) therapy on wound-healing-related parameters, such as tissue oxygenation and water index, were analyzed by hyperspectral imaging: an exploratory case series. Background: Oedema and inadequate perfusion have been identified as key factors in delayed wound healing and have been linked to reduced mitochondrial respiration. Targeting mitochondrial dysfunction is a promising approach in the treatment of therapy refractory wounds. This sub-study aimed to investigate the effects of concurrent optical and magnetic stimulation (COMS) on oedema and perfusion through measuring tissue oxygenation and water index, using hyperspectral imaging. Patients and methods: In a multi-center, prospective, comparative clinical trial, eleven patients with chronic leg and foot ulcers were treated with COMS additively to Standard of Care (SOC). Hyperspectral images were collected during patient visits before and after treatment to assess short- and long-term hemodynamic and immunomodulatory effects through changes in tissue oxygenation and water index. Results: The average time for wound onset in the eleven patients analyzed was 183 days, with 64% of them being considered unresponsive to SOC. At week 12, the rate of near-complete and complete wound closure was 64% and 45%, respectively. COMS therapy with SOC resulted in an increased short-term tissue oxygenation over the 8-week treatment phase, with oxygen levels decreasing in-between patient visits. The study further found a decrease in tissue water content after the therapy, with a general accumulation of water levels in-between patient visits. This study's long-term analysis was hindered by the lack of absolute values in hyperspectral imaging and the dynamic nature of patient parameters during visits, resulting in high interpatient and intervisit variability. Conclusions: This study showed that COMS therapy as an adjunct to SOC had a positive short-term effect on inflammation and tissue oxygenation in chronic wounds of various etiologies. These results further supported the body of evidence for safety and effectiveness of COMS therapy as a treatment option, especially for stagnant wounds that tended to stay in the inflammatory phase and required efficient phase transition towards healing.

Hemodynamic monitoring in the human temporalis muscle using near-infrared spectroscopy

Objective. Altered temporal muscle perfusion is implicated in several painful disorders afflicting orofacial and head regions, including temporomandibular joint dysfunctions, bruxism, and headache. Knowledge about the regulation of blood supply to the temporalis muscle is limited, due to methodological difficulties. The study aimed to test the feasibility of near-infrared spectroscopy (NIRS) monitoring of the human temporal muscle. Approach. Twenty-four healthy subjects were monitored with a 2-channel NIRS: a muscle probe placed over the temporal muscle and a brain probe placed on the forehead. A series of teeth clenching at 25, 50, and 75% of maximum voluntary contraction for 20 s and hyperventilation for 90 s at 20 mmHg of end-tidal CO2 were performed, to elicit hemodynamic changes in muscle and brain, respectively. Main results. In twenty responsive subjects, NIRS signals from both probes were consistently different during both tasks. The absolute change in tissue oxygenation index (ΔTOI) as detected by muscle and brain probes was −9.40 ± 12.28 and 0.29 ± 1.54% during teeth clenching (p < 0.01) at 50% maximum voluntary contraction, while −1.03 ± 2.70 and −5.11 ± 3.81% during hyperventilation (p < 0.01), respectively. Significance. Distinct response patterns were observed from the temporal muscle and prefrontal cortex which proves that this technique is adequate to monitor tissue oxygenation and hemodynamic changes in human temporal muscle. Noninvasive and reliable monitoring of hemodynamics in this muscle will help to extend basic and clinical investigations about the peculiar control of blood flow in head muscles.