Wearable laser Doppler flowmetry for non-invasive assessment of diabetic foot microcirculation: methodological considerations and clinical implications.

Significance: Type 2 diabetes mellitus (T2DM) is a global health concern with significant implications for vascular health. The current evaluation methods cannot achieve effective, portable, and quantitative evaluation of foot microcirculation. Aim: We aim to use a wearable device laser Doppler flowmetry (LDF) to evaluate the foot microcirculation of T2DM patients at rest. Approach: Eleven T2DM patients and twelve healthy subjects participated in this study. The wearable LDF was used to measure the blood flows (BFs) for regions of the first metatarsal head (M1), fifth metatarsal head (M5), heel, and dorsal foot. Typical wavelet analysis was used to decompose the five individual control mechanisms: endothelial, neurogenic, myogenic, respiratory, and heart components. The mean BF and sample entropy (SE) were calculated, and the differences between diabetic patients and healthy adults and among the four regions were compared. Results: Diabetic patients showed significantly reduced mean BF in the neurogenic (p=0.044) and heart (p=0.001) components at the M1 and M5 regions (p=0.025) compared with healthy adults. Diabetic patients had significantly lower SE in the neurogenic (p=0.049) and myogenic (p=0.032) components at the M1 region, as well as in the endothelial (p<0.001) component at the M5 region and in the myogenic component at the dorsal foot (p=0.007), compared with healthy adults. The SE in the myogenic component at the dorsal foot was lower than at the M5 region (p=0.050) and heel area (p=0.041). Similarly, the SE in the heart component at the dorsal foot was lower than at the M5 region (p=0.017) and heel area (p=0.028) in diabetic patients. Conclusions: This study indicated the potential of using the novel wearable LDF device for tracking vascular complications and implementing targeted interventions in T2DM patients.

Analysis of the Chaotic Component of Photoplethysmography and Its Association with Hemodynamic Parameters.

Wearable technologies face challenges due to signal instability, hindering their usage. Thus, it is crucial to comprehend the connection between dynamic patterns in photoplethysmography (PPG) signals and cardiovascular health. In our study, we collected 401 multimodal recordings from two public databases, evaluating hemodynamic conditions like blood pressure (BP), cardiac output (CO), vascular compliance (C), and peripheral resistance (R). Using irregular-resampling auto-spectral analysis (IRASA), we quantified chaotic components in PPG signals and employed different methods to measure the fractal dimension (FD) and entropy. Our findings revealed that in surgery patients, the power of chaotic components increased with vascular stiffness. As the intensity of CO fluctuations increased, there was a notable strengthening in the correlation between most complexity measures of PPG and these parameters. Interestingly, some conventional morphological features displayed a significant decrease in correlation, indicating a shift from a static to dynamic scenario. Healthy subjects exhibited a higher percentage of chaotic components, and the correlation between complexity measures and hemodynamics in this group tended to be more pronounced. Causal analysis showed that hemodynamic fluctuations are main influencers for FD changes, with observed feedback in most cases. In conclusion, understanding chaotic patterns in PPG signals is vital for assessing cardiovascular health, especially in individuals with unstable hemodynamics or during ambulatory testing. These insights can help overcome the challenges faced by wearable technologies and enhance their usage in real-world scenarios.

Temporal complexity in photoplethysmography and its influence on blood pressure.

Objective: The temporal complexity of photoplethysmography (PPG) provides valuable information about blood pressure (BP). In this study, we aim to interpret the stochastic PPG patterns with a model-based simulation, which may help optimize the BP estimation algorithms. Methods: The classic four-element Windkessel model is adapted in this study to incorporate BP-dependent compliance profiles. Simulations are performed to generate PPG responses to pulse and continuous stimuli at various timescales, aiming to mimic sudden or gradual hemodynamic changes observed in real-life scenarios. To quantify the temporal complexity of PPG, we utilize the Higuchi fractal dimension (HFD) and autocorrelation function (ACF). These measures provide insights into the intricate temporal patterns exhibited by PPG. To validate the simulation results, continuous recordings of BP, PPG, and stroke volume from 40 healthy subjects were used. Results: Pulse simulations showed that central vascular compliance variation during a cardiac cycle, peripheral resistance, and cardiac output (CO) collectively contributed to the time delay, amplitude overshoot, and phase shift of PPG responses. Continuous simulations showed that the PPG complexity could be generated by random stimuli, which were subsequently influenced by the autocorrelation patterns of the stimuli. Importantly, the relationship between complexity and hemodynamics as predicted by our model aligned well with the experimental analysis. HFD and ACF had significant contributions to BP, displaying stability even in the presence of high CO fluctuations. In contrast, morphological features exhibited reduced contribution in unstable hemodynamic conditions. Conclusion: Temporal complexity patterns are essential to single-site PPG-based BP estimation. Understanding the physiological implications of these patterns can aid in the development of algorithms with clear interpretability and optimal structures.

Blood pressure assessment with in-ear photoplethysmography.

Objective. In this study, we aimed to estimate blood pressure (BP) from in-ear photoplethysmography (PPG). This novel implementation provided an unobtrusive and steady way of recording PPG, whereas previous PPG measurements were mostly performed at the wrist, finger, or earlobe.Methods. The time between forward and reflected PPG waves was very short at the ear site. To minimize errors introduced by feature extraction, a multi-Gaussian decomposition of in-ear PPG was performed. Both hand-crafted and whole-based features were extracted and the best combination of features was selected using a backward-search wrapper method and evaluated by the Akaike information criteria. Hemodynamic parameters such as compliance and inertance were estimated from a four-element Windkessel (WK4) model, which was used to pre-classify PPG signals and generate different BP estimation algorithms. Calibration was done by using previous measurements from the same class. To validate this novel approach, 53 subjects were recruited for a one-month follow-up study, and 17 subjects were recruited for a two-month follow-up study. Calibrated systolic BP estimation accuracy was significantly improved with inertance-based pre-classification, while diastolic BP showed less improvement.Results. With proper feature selection, pre-classification and calibration, we have achieved a mean absolute error of 5.35 mmHg for SBP estimation, compared to 6.16 mmHg if no pre-classification was carried out. The performance did not deteriorate in two months, showing a decent BP trend-tracking ability.Conclusion. The study demonstrated the feasibility of in-ear PPG to reliably measure BP, which represents an important technological advancement in terms of unobtrusiveness and steadiness.

Robust blood pressure estimation from finger photoplethysmography using age-dependent linear models.

OBJECTIVE: This work aims to develop an efficient and robust age-dependent multiple linear regression (MLR) model to estimate blood pressure (BP) from a single-source photoplethysmography (PPG) and biometrics, which could be embedded in the microcontroller of pulse oximeters. APPROACH: Hemodynamic features were extracted from the PPG signal using its waveform, derivatives, and biometrics. Whole-based, feature-based, and fusion models were evaluated and compared for different age groups. Their performance was tested using 1086 subjects with a leave-one-subject-out cross-validation. The improvement by adding biometrics and the long-term calibration effect were investigated in detail. The relative importance of each feature was compared between different age groups and the implication was discussed. MAIN RESULTS: The fusion model achieved the best performance in subjects with well-defined PPG features, whereas the feature-based method was better suited for subjects with damped signals. Adding age significantly improved both systolic BP (SBP) and diastolic BP (DBP) estimation accuracy for older subjects (> 50 years old) with well-defined features, while it only improved diastolic BP accuracy for older subjects with damped signals. For younger subjects (≤ 50 years old), the contribution of age was very small. A simple subtraction of subject-specific calibration factors significantly reduced biometric-related errors, which also improved the linearity of BP estimation. The relative importance analysis of input features suggests that separate models are indeed necessary for different age groups with different signal qualities, especially for DBP estimation in older subjects. SIGNIFICANCE: This study shows a reasonable BP estimation accuracy with age-dependent MLR models, which may help to equip current pulse oximeters with additional functionalities.

An Unobtrusive and Calibration-free Blood Pressure Estimation Method using Photoplethysmography and Biometrics.

We introduce a novel paradigm to unobtrusively and optically measure blood pressure (BP) without calibration. The algorithm combines photoplethysmography (PPG) waveform analysis and biometrics to estimate BP, and was evaluated in subjects with various age, height, weight and BP levels (n = 1249). In the young population (<50 years old) with low, medium and high systolic blood pressures (SBP, <120 mmHg; 120-139 mmHg; ≥140 mmHg), the fitting errors are 6.3 ± 7.2, -3.9 ± 7.2 and -20.2 ± 14.2 mmHg for SBP respectively; In the older population (>50 years old) with the same categories, the fitting errors are 12.8 ± 9.0, 0.5 ± 8.2 and -14.6 ± 11.5 mmHg for SBP respectively. A simple personalized calibration reduces fitting errors significantly (n = 147), and good peripheral perfusion helps to improve the fitting accuracy. In conclusion, PPG may be used to calculate BP without calibration in certain populations. When calibrated, it shows great potential to serially monitor BP fluctuation, which can bring tremendous economic and health benefits.

Optical blood pressure estimation with photoplethysmography and FFT-based neural networks.

We introduce and validate a beat-to-beat optical blood pressure (BP) estimation paradigm using only photoplethysmogram (PPG) signal from finger tips. The scheme determines subject-specific contribution to PPG signal and removes most of its influence by proper normalization. Key features such as amplitudes and phases of cardiac components were extracted by a fast Fourier transform and were used to train an artificial neural network, which was then used to estimate BP from PPG. Validation was done on 69 patients from the MIMIC II database plus 23 volunteers. All estimations showed a good correlation with the reference values. This method is fast and robust, and can potentially be used to perform pulse wave analysis in addition to BP estimation.

Diffuse optical characterization of an exercising patient group with peripheral artery disease.

Peripheral artery disease (PAD) is a common condition with high morbidity. While measurement of tissue oxygen saturation (S(t)O(2)) has been demonstrated, this is the first study to assess both S(t)O(2) and relative blood flow (rBF) in the extremities of PAD patients. Diffuse optics is employed to measure hemodynamic response to treadmill and pedal exercises in 31 healthy controls and 26 patients. For S(t)O(2), mild and moderate/severe PAD groups show pronounced differences compared with controls. Pre-exercise mean S(t)O(2) is lower in PAD groups by 9.3% to 10.6% compared with means of 63.5% to 66.2% in controls. For pedal, relative rate of return of S(t)O(2) to baseline is more rapid in controls (p < 0.05). Patterns of rBF also differ among groups. After both exercises, rBF tend to occur at depressed levels among severe PAD patients compared with healthy (p < 0.05); post-treadmill, rBF tend to occur at elevated levels among healthy compared with severe PAD patients (p < 0.05). Additionally, relative rate of return to baseline S(t)O(2) is more rapid among subjects with reduced levels of depression in rBF (p = 0.041), even after adjustment for ankle brachial index. This suggests a physiologic connection between rBF and oxygenation that can be measured using diffuse optics, and potentially employed as an evaluative tool in further studies.

Fluence rate-dependent intratumor heterogeneity in physiologic and cytotoxic responses to Photofrin photodynamic therapy.

Photodynamic therapy (PDT) can lead to the creation of heterogeneous, response-limiting hypoxia during illumination, which may be controlled in part through illumination fluence rate. In the present report we consider (1) regional differences in hypoxia, vascular response, and cell kill as a function of tumor depth and (2) the role of fluence rate as a mediator of depth-dependent regional intratumor heterogeneity. Intradermal RIF murine tumors were treated with Photofrin PDT using surface illumination at an irradiance of 75 or 38 mW cm(-2). Regional heterogeneity in tumor response was examined through comparison of effects in the surface vs. base of tumors, i.e. along a plane parallel to the skin surface and perpendicular to the incident illumination. 75 mW cm(-2) PDT created significantly greater hypoxia in tumor bases relative to their surfaces. Increased hypoxia in the tumor base could not be attributed to regional differences in Photofrin concentration nor effects of fluence rate distribution on photochemical oxygen consumption, but significant depth-dependent heterogeneity in vascular responses and cytotoxic response were detected. At a lower fluence rate of 38 mW cm(-2), no detectable regional differences in hypoxia or cytotoxic responses were apparent, and heterogeneity in vascular response was significantly less than that during 75 mW cm(-2) PDT. This research suggests that the benefits of low-fluence-rate PDT are mediated in part by a reduction in intratumor heterogeneity in hypoxic, vascular and cytotoxic responses.

Epidermal growth factor receptor inhibition modulates the microenvironment by vascular normalization to improve chemotherapy and radiotherapy efficacy.

BACKGROUND: Epidermal growth factor receptor (EGFR) inhibitors have shown only modest clinical activity when used as single agents to treat cancers. They decrease tumor cell expression of hypoxia-inducible factor 1-alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF). Hypothesizing that this might normalize tumor vasculature, we examined the effects of the EGFR inhibitor erlotinib on tumor vascular function, tumor microenvironment (TME) and chemotherapy and radiotherapy sensitivity. METHODOLOGY/PRINCIPAL FINDINGS: Erlotinib treatment of human tumor cells in vitro and mice bearing xenografts in vivo led to decreased HIF-1alpha and VEGF expression. Treatment altered xenograft vessel morphology assessed by confocal microscopy (following tomato lectin injection) and decreased vessel permeability (measured by Evan's blue extravasation), suggesting vascular normalization. Erlotinib increased tumor blood flow measured by Power Doppler ultrasound and decreased hypoxia measured by EF5 immunohistochemistry and tumor O(2) saturation measured by optical spectroscopy. Predicting that these changes would improve drug delivery and increase response to chemotherapy and radiation, we performed tumor regrowth studies in nude mice with xenografts treated with erlotinib and either radiotherapy or the chemotherapeutic agent cisplatin. Erlotinib therapy followed by cisplatin led to synergistic inhibition of tumor growth compared with either treatment by itself (p<0.001). Treatment with erlotinib before cisplatin led to greater tumor growth inhibition than did treatment with cisplatin before erlotinib (p = 0.006). Erlotinib followed by radiation inhibited tumor regrowth to a greater degree than did radiation alone, although the interaction between erlotinib and radiation was not synergistic. CONCLUSIONS/SIGNIFICANCE: EGFR inhibitors have shown clinical benefit when used in combination with conventional cytotoxic therapy. Our studies show that targeting tumor cells with EGFR inhibitors may modulate the TME via vascular normalization to increase response to chemotherapy and radiotherapy. These studies suggest ways to assess the response of tumors to EGFR inhibition using non-invasive imaging of the TME.