Neuromonitoring of Pediatric and Adult Extracorporeal Membrane Oxygenation Patients: The Importance of Continuous Bedside Tools in Driving Neuroprotective Clinical Care.

Extracorporeal membrane oxygenation (ECMO) is a form of temporary cardiopulmonary bypass for patients with acute respiratory or cardiac failure refractory to conventional therapy. Its usage has become increasingly widespread and while reported survival after ECMO has increased in the past 25 years, the incidence of neurological injury has not declined, leading to the pressing question of how to improve time-to-detection and diagnosis of neurological injury. The neurological status of patients on ECMO is clinically difficult to evaluate due to multiple factors including illness, sedation, and pharmacological paralysis. Thus, increasing attention has been focused on developing tools and techniques to measure and monitor the brain of ECMO patients to identify dynamic risk factors and monitor patients' neurophysiological state as a function in time. Such tools may guide neuroprotective interventions and thus prevent or mitigate brain injury. Current means to continuously monitor and prevent neurological injury in ECMO patients are rather limited; most techniques provide indirect or postinsult recognition of irreversible brain injury. This review will explore the indications, advantages, and disadvantages of standard-of-care, emerging, and investigational technologies for neurological monitoring on ECMO, focusing on bedside techniques that provide continuous assessment of neurological health.

Correlations Between Quantitative EEG Parameters and Cortical Blood Flow in Patients Undergoing Extracorporeal Membrane Oxygenation With and Without Encephalopathy.

PURPOSE: The neurologic examination of patients undergoing extracorporeal membrane oxygenation (ECMO) is crucial for evaluating irreversible encephalopathy but is often obscured by sedation or neuromuscular blockade. Noninvasive neuromonitoring modalities including diffuse correlation spectroscopy and EEG measure cerebral perfusion and neuronal function, respectively. We hypothesized that encephalopathic ECMO patients with greater degree of irreversible cerebral injury demonstrate less correlation between electrographic activity and cerebral perfusion than those whose encephalopathy is attributable to medications. METHODS: We performed a prospective observational study of adults undergoing ECMO who underwent simultaneous continuous EEG and diffuse correlation spectroscopy monitoring. (Alpha + beta)/delta ratio and alpha/delta Rartio derived from quantitative EEG analysis were correlated with frontal cortical blood flow index. Patients who awakened and followed commands during sedation pauses were included in group 1, whereas patients who could not follow commands for most neuromonitoring were placed in group 2. (Alpha + beta)/delta ratio-blood flow index and ADR-BFI correlations were compared between the groups. RESULTS: Ten patients (five in each group) underwent 39 concomitant continuous EEG and diffuse correlation spectroscopy monitoring sessions. Four patients (80%) in each group received some form of analgosedation during neuromonitoring. (Alpha + beta)/delta ratio-blood flow index correlation was significantly lower in group 2 than group 1 (left: 0.05 vs. 0.52, P = 0.03; right: -0.12 vs. 0.39, P = 0.04). Group 2 ADR-BFI correlation was lower only over the right hemisphere (-0.06 vs. 0.47, P = 0.04). CONCLUSIONS: Correlation between (alpha + beta)/delta ratio and blood flow index were decreased in encephalopathic ECMO patients compared with awake ones, regardless of the analgosedation use. The combined use of EEG and diffuse correlation spectroscopy may have utility in monitoring cerebral function in ECMO patients.

Design for a low-cost heterodyne frequency domain-diffuse optical spectroscopy system.

A design for a low-cost, heterodyne, frequency domain-diffuse optical spectroscopy system is presented and validated. The system uses a single wavelength of 785 nm and a single detector to illustrate the capability, but is built in a modular fashion to make it easily expandable to additional wavelengths and detectors. The design incorporates methods to allow software-based control over the system operating frequency, laser diode output amplitude, and detector gain. Validation methods include characterization of electrical designs as well as determination of the system stability and accuracy using tissue-mimicking optical phantoms. The system requires only basic equipment for its construction and can be built for under $600.

Introduction to the Biophotonics Congress 2022 feature issue.

A feature issue is being presented by a team of guest editors containing papers based on studies presented at the Optica Biophotonics Congress: Biomedical Optics held on April 24-27, 2022 in Fort Lauderdale, Florida, USA.

Co-registered speckle contrast optical tomography and frequency domain-diffuse optical tomography for imaging of the fifth metatarsal.

A co-registered speckle contrast optical tomography and frequency domain-diffuse optical tomography system has been designed for imaging total hemoglobin concentration, blood oxygenation, and blood flow with the future aim of monitoring Jones fractures of the fifth metatarsal. Experimental validation was performed using both in vitro tissue-mimicking phantoms and in vivo cuff occlusion experiments. Results of these tissue phantom experiments ensure accurate recovery of three-dimensional distributions of optical properties and flow. Finally, cuff occlusion experiments performed on one healthy human subject demonstrate the system's ability to recover both decreasing tissue oxygenation and blood flow as caused by an arterial occlusion.

Cerebral Blood Flow Hemispheric Asymmetry in Comatose Adults Receiving Extracorporeal Membrane Oxygenation.

Peripheral veno-arterial extracorporeal membrane oxygenation (ECMO) artificially oxygenates and circulates blood retrograde from the femoral artery, potentially exposing the brain to asymmetric perfusion. Though ECMO patients frequently experience brain injury, neurologic exams and imaging are difficult to obtain. Diffuse correlation spectroscopy (DCS) non-invasively measures relative cerebral blood flow (rBF) at the bedside using an optical probe on each side of the forehead. In this study we observed interhemispheric rBF differences in response to mean arterial pressure (MAP) changes in adult ECMO recipients. We recruited 13 subjects aged 21-78 years (7 with cardiac arrest, 4 with acute heart failure, and 2 with acute respiratory distress syndrome). They were dichotomized via Glasgow Coma Scale Motor score (GCS-M) into comatose (GCS-M ≤ 4; n = 4) and non-comatose (GCS-M > 4; n = 9) groups. Comatose patients had greater interhemispheric rBF asymmetry (ASYMrBF) vs. non-comatose patients over a range of MAP values (29 vs. 11%, p = 0.009). ASYMrBF in comatose patients resolved near a MAP range of 70-80 mmHg, while rBF remained symmetric through a wider MAP range in non-comatose patients. Correlations between post-oxygenator pCO2 or pH vs. ASYMrBF were significantly different between comatose and non-comatose groups. Our findings indicate that comatose patients are more likely to have asymmetric cerebral perfusion.

Semiparametric mixed-effects model for analysis of non-invasive longitudinal hemodynamic responses during bone graft healing.

When dealing with longitudinal data, linear mixed-effects models (LMMs) are often used by researchers. However, LMMs are not always the most adequate models, especially if we expect a nonlinear relationship between the outcome and a continuous covariate. To allow for more flexibility, we propose the use of a semiparametric mixed-effects model to evaluate the overall treatment effect on the hemodynamic responses during bone graft healing and build a prediction model for the healing process. The model relies on a closed-form expectation-maximization algorithm, where the unknown nonlinear function is estimated using a Lasso-type procedure. Using this model, we were able to estimate the effect of time for individual mice in each group in a nonparametric fashion and the effect of the treatment while accounting for correlation between observations due to the repeated measurements. The treatment effect was found to be statistically significant, with the autograft group having higher total hemoglobin concentration than the allograft group.

Biomaterials for Orthopaedic Diagnostics and Theranostics.

Despite widespread use of conventional diagnostic methods in orthopaedic applications, limitations still exist in detection and diagnosing many pathologies especially at early stages when intervention is most critical. The use of biomaterials to develop diagnostics and theranostics, including nanoparticles and scaffolds for systemic or local applications, has significant promise to address these shortcomings and enable successful clinical translation. These developments in both modular and holistic design of diagnostic and theranostic biomaterials may improve patient treatments for myriad orthopaedic applications ranging from cancer to fractures to infection.

Introduction to the Biophotonics Congress 2020 feature issue.

The guest editors introduce a feature issue containing papers based on research presented at the OSA Biophotonics Congress (the former BIOMED) 20-23 April 2020, in the first all virtual, web conference format undertaken by OSA.

Towards detection of brain injury using multimodal non-invasive neuromonitoring in adults undergoing extracorporeal membrane oxygenation.

Extracorporeal membrane oxygenation (ECMO) is a form of cardiopulmonary bypass that provides life-saving support to critically ill patients whose illness is progressing despite maximal conventional support. Use in adults is expanding, however neurological injuries are common. Currently, the existing brain imaging tools are a snapshot in time and require high-risk patient transport. Here we assess the feasibility of measuring diffuse correlation spectroscopy, transcranial Doppler ultrasound, electroencephalography, and auditory brainstem responses at the bedside, and developing a cerebral autoregulation metric. We report preliminary results from two patients, demonstrating feasibility and laying the foundation for future studies monitoring neurological health during ECMO.

Spatial frequency domain imaging for the longitudinal monitoring of vascularization during mouse femoral graft healing.

Allograft is the current gold standard for treating critical-sized bone defects. However, allograft healing is usually compromised partially due to poor host-mediated vascularization. In the efforts towards developing new methods to enhance allograft healing, a non-terminal technique for monitoring the vascularization is needed in pre-clinical mouse models. In this study, we developed a non-invasive instrument based on spatial frequency domain imaging (SFDI) for longitudinal monitoring of the mouse femoral graft healing. SFDI technique provided total hemoglobin concentration (THC) and oxygen saturation (StO2) of the graft and the surrounding soft tissues. SFDI measurements were performed from 1 day before to 44 days after graft transplantation. Autograft, another type of bone graft with higher vascularization potential was also measured as a comparison to allograft. For both grafts, the overall temporal changes of the measured THC agreed with the physiological expectations of vascularization timeline during bone healing. A significantly greater increase in THC was observed in the autograft group compared to the allograft group, which agreed with the expectation that allografts have more compromised vascularization.

Investigating the effect of fatigue on muscle microvasculature blood flow during intermittent isometric contraction.

Localized muscle fatigue (LMF) decreases muscular strength, while affects the performance and potentially increases the risk of musculoskeletal disorders (MSD). An important mechanism in recovering from muscle fatigue is blood flow (BF). The BF response to muscle contraction and fatigue is highly dynamic and difficult to predict, as it depends on both metabolic demand and intramuscular pressure. The aim of this study was to measure both fatigue and BF during intermittent exertion of the first dorsal interosseous (FDI) muscle, in order to better characterize the relationship between BF and LMF during muscle contraction and rest. This study utilized Diffuse Correlation Spectroscopy (DCS) for BF measurement within the microvasculature of the FDI muscle. Exertion levels (EL) for intermittent fatiguing contraction were set to 20%, 30%, and 40% of an individual's maximum voluntary contraction (MVC). Our results showed that as an individual fatigued, relative BF rates increased, on average, by ~66% during exertion periods and ~330% during rest periods. Differences between exerting and resting BF increased over time for every EL (p<0.04), increasing by up to 11 times the baseline BF. At the same levels of muscle capacity (%MVC), resting BF was also found to increase with EL consistently. Our findings highlight BF dependence on both EL and history of muscle contraction. These results imply a variable recovery rate based on both the current state of contraction, (i.e., exertion vs. rest), and the muscle contraction history. The outcome of our study may facilitate the estimation of BF, thus, the muscle recovery rate, which can be implemented in the fatigue models to improve the prediction of muscle capacity to generate force/power.

Longitudinal 3D Blood Flow Distribution Provided by Diffuse Correlation Tomography during Bone Healing in a Murine Fracture Model.

Noninvasive monitoring of vascularization can potentially diagnose impaired bone healing earlier than current radiographic methods. In this study, a noncontact diffuse correlation tomography (DCT) technique was employed to measure longitudinal blood flow changes during bone healing in a murine femoral fracture model. The three-dimensional distribution of the relative blood flow was quantified from one day pre-fracture to 48 days post-fracture. For three mice, frequent DCT measurements were performed every other day for one week after fracture, and then weekly thereafter. A decrease in blood flow was observed in the bone fracture region at one day post-fracture, followed by a monotonic increase in blood flow beyond the pre-injury baseline until five to seven days post-fracture. For the remaining 12 mice, only weekly DCT measurements were performed. Data collected on a weekly basis show the blood flow for most mice was elevated above baseline during the first two post-fracture weeks, followed by a subsequent decrease. Torsional strength of the excised femurs was measured for all 15 mice after 7 weeks of healing. A metric based on the early blood flow changes shows a statistically significant difference between the high strength group and the low strength group.

Special Section Guest Editorial: Translational Biophotonics.

This guest editorial introduces the special section on Translational Biophotonics.

Non-invasive acoustic fabrication methods to enhance collagen hydrogel bioactivity.

Much attention has focused recently on utilizing components of the extracellular matrix (ECM) as natural building blocks for a variety of tissue engineering applications and regenerative medicine therapies. Consequently, new fabrication methods are being sought to enable molecular control over the structural characteristics of ECM molecules in order to improve their biological function. Exposing soluble collagen to acoustic forces associated with ultrasound propagation produces localized variations in collagen microfiber organization that in turn, promote cell behaviors essential for tissue regeneration, including cell migration and matrix remodeling. In the present study, mechanisms by which ultrasound interacts with polymerizing collagen to produce functional changes in collagen microstructure were investigated. The rate of collagen polymerization was manipulated by adjusting the pH of collagen solutions and the temperature at which gels were polymerized. Results demonstrate that the phase transition of type I collagen from fluid to gel triggered a simultaneous increase in acoustic absorption. This phase transition of collagen involves the lateral growth of early-stage collagen microfibrils and importantly, corresponded to a defined period of time during which exposure to ultrasound introduced both structural and functional changes to the resultant collagen hydrogels. Together, these experiments isolated a critical window in the collagen fiber assembly process during which mechanical forces associated with ultrasound propagation are effective in producing structural changes that underlie the ability of acoustically-modified collagen hydrogels to stimulate cell migration. These results demonstrate that changes in material properties associated with collagen polymerization are a fundamental component of the mechanism by which acoustic forces modify collagen biomaterials to enhance biological function.

Temporal blood flow changes measured by diffuse correlation tomography predict murine femoral graft healing.

Blood flow changes during bone graft healing have the potential to provide important information about graft success, as the nutrients, oxygen, circulating cells and growth factors essential for integration are delivered by blood. However, longitudinal monitoring of blood flow changes during graft healing has been a challenge due to limitations in current techniques. To this end, non-invasive diffuse correlation tomography (DCT) was investigated to enable longitudinal monitoring of three-dimensional blood flow changes in deep tissue. Specific to this study, longitudinal blood flow changes were utilized to predict healing outcomes of common interventions for massive bone defects using a common mouse femoral defect model. Weekly blood flow changes were non-invasively measured using a diffuse correlation tomography system for 9 weeks in three types of grafts: autografts (N = 7), allografts (N = 6) and tissue-engineered allografts (N = 6). Healing outcomes were quantified using an established torsion testing method 9 weeks after transplantation. Analysis of the spatial and temporal blood flow reveals that major differences among the three groups were captured in weeks 1-5 after graft transplantation. A multivariate model to predict maximum torque by relative blood flow changes over 5 weeks after graft transplantation was built using partial least squares regression. The results reveal lower bone strength correlates with greater cumulative blood flow over an extended period of time (i.e., 1-5 weeks). The current research demonstrates that DCT-measured blood flow changes after graft transplantation can be utilized to predict long-term healing outcomes in a mouse femoral graft model.

Validation of diffuse correlation spectroscopy sensitivity to nicotinamide-induced blood flow elevation in the murine hindlimb using the fluorescent microsphere technique.

Nicotinamide has been shown to affect blood flow in both tumor and normal tissues, including skeletal muscle. Intraperitoneal injection of nicotinamide was used as a simple intervention to test the sensitivity of noninvasive diffuse correlation spectroscopy (DCS) to changes in blood flow in the murine left quadriceps femoris skeletal muscle. DCS was then compared with the gold-standard fluorescent microsphere (FM) technique for validation. The nicotinamide dose-response experiment showed that relative blood flow measured by DCS increased following treatment with 500- and 1000-mg / kg nicotinamide. The DCS and FM technique comparison showed that blood flow index measured by DCS was correlated with FM counts quantified by image analysis. The results of this study show that DCS is sensitive to nicotinamide-induced blood flow elevation in the murine left quadriceps femoris. Additionally, the results of the comparison were consistent with similar studies in higher-order animal models, suggesting that mouse models can be effectively employed to investigate the utility of DCS for various blood flow measurement applications.

Pre-clinical longitudinal monitoring of hemodynamic response to anti-vascular chemotherapy by hybrid diffuse optics.

The longitudinal effect of an anti-vascular endothelial growth factor receptor 2 (VEGFR-2) antibody (DC 101) therapy on a xenografted renal cell carcinoma (RCC) mouse model was monitored using hybrid diffuse optics. Two groups of immunosuppressed male nude mice (seven treated, seven controls) were measured. Tumor microvascular blood flow, total hemoglobin concentration and blood oxygenation were investigated as potential biomarkers for the monitoring of the therapy effect twice a week and were related to the final treatment outcome. These hemodynamic biomarkers have shown a clear differentiation between two groups by day four. Moreover, we have observed that pre-treatment values and early changes in hemodynamics are highly correlated with the therapeutic outcome demonstrating the potential of diffuse optics to predict the therapy response at an early time point.

Non-invasive diffuse correlation tomography reveals spatial and temporal blood flow differences in murine bone grafting approaches.

Longitudinal blood flow during murine bone graft healing was monitored non-invasively using diffuse correlation tomography. The system utilized spatially dense data from a scanning set-up, non-linear reconstruction, and micro-CT anatomical information. Weekly in vivo measurements were performed. Blood flow changes in autografts, which heal successfully, were localized to graft regions and consistent across mice. Poor healing allografts showed heterogeneous blood flow elevation and high inter-subject variabilities. Allografts with tissue-engineered periosteum showed responses intermediate to both autografts and allografts, consistent with healing observed. These findings suggest that spatiotemporal blood flow changes can be utilized to differentiate the degree of bone graft healing.

Chemotherapeutic drug-specific alteration of microvascular blood flow in murine breast cancer as measured by diffuse correlation spectroscopy.

The non-invasive, in vivo measurement of microvascular blood flow has the potential to enhance breast cancer therapy monitoring. Here, longitudinal blood flow of 4T1 murine breast cancer (N=125) under chemotherapy was quantified with diffuse correlation spectroscopy based on layer models. Six different treatment regimens involving doxorubicin, cyclophosphamide, and paclitaxel at clinically relevant doses were investigated. Treatments with cyclophosphamide increased blood flow as early as 3 days after administration, whereas paclitaxel induced a transient blood flow decrease at 1 day after administration. Early blood flow changes correlated strongly with the treatment outcome and distinguished treated from untreated mice individually for effective treatments.