ROCS microscopy with distinct zero-order blocking.

Research in modern light microscopy continuously seeks to improve spatial and temporal resolution in combination with user-friendly, cost-effective imaging systems. Among different label-free imaging approaches, Rotating Coherent Scattering (ROCS) microscopy in darkfield mode achieves superior resolution and contrast without image reconstructions, which is especially helpful in life cell experiments. Here we demonstrate how to achieve 145 nm resolution with an amplitude transmission mask for spatial filtering. This mask blocks the reflected 0-th order focus at 12 distinct positions, thereby increasing the effective aperture for the light back-scattered from the object. We further show how angular correlation analysis between coherent raw images helps to estimate the information content from different illumination directions.

Magnetic sensor for arterial distension and blood pressure monitoring.

A novel sensor for measuring arterial distension, pulse and pressure waveform is developed and evaluated. The system consists of a magnetic sensor which is applied and fixed to arterial vessels without any blood vessel constriction, hence avoiding stenosis. The measurement principle could be validated by in vitro experiments on silicone tubes, and by in vivo experiments in an animal model, thereby indicating the non-linear viscoelastic characteristics of real blood vessels. The sensor is capable to provide absolute measurements of the dynamically varying arterial diameter. By calibrating the sensor, a long-term monitoring system for continuously measuring blood pressure and other cardiovascular parameters could be developed based on the method described. This will improve diagnostics for high risk patients and enable a better, specific treatment.

Implantable impedance plethysmography.

We demonstrate by theory, as well as by ex vivo and in vivo measurements that impedance plethysmography, applied extravascularly directly on large arteries, is a viable method for monitoring various cardiovascular parameters, such as blood pressure, with high accuracy. The sensor is designed as an implant to monitor cardiac events and arteriosclerotic progression over the long term.

An implantable optical blood pressure sensor based on pulse transit time.

An implantable sensor system for long-term monitoring of blood pressure is realized by taking advantage of the correlation between pulse transit time and blood pressure. The highly integrated implantable sensor module, fabricated using MEMS technologies, uses 8 light emitting diodes (LEDs) and a photodetector on chip level. The sensor is applied to large blood vessels, such as the carotid or femoral arteries, and allows extravascular measurement of highly-resolved photoplethysmograms. In addition, spectrophotometric approaches allow measurement of hemoglobin derivatives. For the calibration of blood pressure measurements, the sensor system has been successfully implemented in animal models.

Subcutaneous blood pressure monitoring with an implantable optical sensor.

We introduce a minimally invasive, implantable system that uses pulse transit time to determine blood pressure. In contrast to previous approaches, the pulse wave is detected by a photoplethysmographic (PPG) signal, acquired with high quality directly on subcutaneous muscle tissue. Electrocardiograms (ECG) were measured with flexible, implantable electrodes on the same tissue. PPG detection is realized by a flat 20 mm x 6 mm optoelectronic pulse oximeter working in reflection mode. The optical sensor as well as the ECG electrodes can be implanted using minimally invasive techniques, with only a small incision into the skin, making long-term monitoring of blood pressure in day-to-day life for high-risk patients possible. The in vivo measurements presented here show that the deviation to intra-arterial reference measurements of the systolic blood pressure in a physiologically relevant range is only 5.5 mmHg, demonstrated for more than 12 000 pulses. This makes the presented sensor a grade B blood pressure monitor.

100 Hz ROCS microscopy correlated with fluorescence reveals cellular dynamics on different spatiotemporal scales.

Fluorescence techniques dominate the field of live-cell microscopy, but bleaching and motion blur from too long integration times limit dynamic investigations of small objects. High contrast, label-free life-cell imaging of thousands of acquisitions at 160 nm resolution and 100 Hz is possible by Rotating Coherent Scattering (ROCS) microscopy, where intensity speckle patterns from all azimuthal illumination directions are added up within 10 ms. In combination with fluorescence, we demonstrate the performance of improved Total Internal Reflection (TIR)-ROCS with variable illumination including timescale decomposition and activity mapping at five different examples: millisecond reorganization of macrophage actin cortex structures, fast degranulation and pore opening in mast cells, nanotube dynamics between cardiomyocytes and fibroblasts, thermal noise driven binding behavior of virus-sized particles at cells, and, bacterial lectin dynamics at the cortex of lung cells. Using analysis methods we present here, we decipher how motion blur hides cellular structures and how slow structure motions cover decisive fast motions.

Fast parallel interferometric 3D tracking of numerous optically trapped particles and their hydrodynamic interaction.

Multi-dimensional, correlated particle tracking is a key technology to reveal dynamic processes in living and synthetic soft matter systems. In this paper we present a new method for tracking micron-sized beads in parallel and in all three dimensions - faster and more precise than existing techniques. Using an acousto-optic deflector and two quadrant-photo-diodes, we can track numerous optically trapped beads at up to tens of kHz with a precision of a few nanometers by back-focal plane interferometry. By time-multiplexing the laser focus, we can calibrate individually all traps and all tracking signals in a few seconds and in 3D. We show 3D histograms and calibration constants for nine beads in a quadratic arrangement, although trapping and tracking is easily possible for more beads also in arbitrary 2D arrangements. As an application, we investigate the hydrodynamic coupling and diffusion anomalies of spheres trapped in a 3 × 3 arrangement.

Photonic sensing of arterial distension.

Most cardiovascular diseases, such as arteriosclerosis and hypertension, are directly linked to pathological changes in hemodynamics, i.e. the complex coupling of blood pressure, blood flow and arterial distension. To improve the current understanding of cardiovascular diseases and pave the way for novel cardiovascular diagnostics, innovative tools are required that measure pressure, flow, and distension waveforms with yet unattained spatiotemporal resolution. In this context, miniaturized implantable solutions for continuously measuring these parameters over the long-term are of particular interest. We present here an implantable photonic sensor system capable of sensing arterial wall movements of a few hundred microns in vivo with sub-micron resolution, a precision in the micrometer range and a temporal resolution of 10 kHz. The photonic measurement principle is based on transmission photoplethysmography with stretchable optoelectronic sensors applied directly to large systemic arteries. The presented photonic sensor system expands the toolbox of cardiovascular measurement techniques and makes these key vital parameters continuously accessible over the long-term. In the near term, this new approach offers a tool for clinical research, and as a perspective, a continuous long-term monitoring system that enables novel diagnostic methods in arteriosclerosis and hypertension research that follow the trend in quantifying cardiovascular diseases by measuring arterial stiffness and more generally analyzing pulse contours.

Stretchable optoelectronic circuits embedded in a polymer network.

Stretchable optoelectronic circuits, incorporating chip-level LEDs and photodiodes in a silicone membrane, are demonstrated. Due to its highly miniaturized design and tissue-like mechanical properties, such an optical circuit can be conformally applied to the epidermis and be used for measurement of photoplethysmograms. This level of optical functionality in a stretchable substrate is potentially of great interest for personal health monitoring.

Implantable pulse oximetry on subcutaneous tissue.

Blood oxygen saturation is one of the most prominent measurement parameters in daily clinical routine. However up to now, it is not possible to continuously monitor this parameter reliably in mobile patients. High-risk patients suffering from cardiovascular diseases could benefit from long-term monitoring of blood oxygen saturation. In this paper, we present a minimally invasive, implantable patient monitor which is capable of monitoring vital signs. The capability of this multimodal sensor to subcutaneously determine blood pressure, pulse and ECG has been demonstrated earlier. This paper focuses on monitoring of blood oxygen saturation. Even though the signal amplitudes are much weaker than for standard extracorporeal measurements, photoplethysmographic signals were recorded with high quality in vivo directly on subcutaneous muscle tissue. For the first time, it has been shown that blood oxygen saturation can be measured with an implantable, but extravascular sensor. The sensor was implanted for two weeks in a sheep and did not cause any complications. This opens new perspectives for home monitoring of patients with cardiovascular diseases.

Lock-in amplification for implantable multiwavelength pulse oximeters.

Standard as well as multiwavelength pulse oximetry as established methods for measuring blood oxygen saturation or fractions of dyshemoglobins suffer from different kinds of interference and noise. Employing lock-in technique as a read-out approach for multiwavelength pulse oximetry is proposed here and strongly decreases such signal disturbance. An analog lock-in amplifier was designed to modulate multiple LEDs simultaneously and to separate the signals detected by a single photodiode. In vivo measurements show an improved signal-to-noise ratio of photoplethysmographic signals and a suppression of interference by means of the lock-in approach. This allows the detection of higher order overtones and, therefore, more detailed data for pulse wave analysis, especially for implantable sensors directly applied at arteries.

Radiative transport in large arteries.

A refined model for the photon energy distribution in a living artery is established by solving the radiative transfer equation in a cylindrical geometry, using the Monte Carlo method. Combining this model with the most recent experimental values for the optical properties of flowing blood and the biomechanics of a blood-filled artery subject to a pulsatile pressure, we find that the optical intensity transmitted through large arteries decreases linearly with increasing arterial distension. This finding provides a solid theoretical foundation for measuring photoplethysmograms.

Implantable acceleration plethysmography for blood pressure determination.

This paper presents an implantable accelerometer which detects plethysmograms directly at an artery. The sensor provides a new method for continuous blood pressure monitoring. In vivo measurements indicate that the accelerometer is well suited for determining the Pulse Transit Time (PTT) and the Reflected Wave Transit Time (RWTT). Both parameters show a high correlation with the systolic blood pressure. By varying the blood pressure, it was seen that RWTT more closely agrees with theory than PTT. Through several blood pressure sweeps the RWTT, as detected by the accelerometer, coincided very well with the systolic blood pressure, with a correlation coefficient of 0.96 and mean deviation of 4.3% for 1800 pulses.

Arterial strain measurement by implantable capacitive sensor without vessel constriction.

Cardiovascular disease caused 32.8% of deaths in the United States in 2008 [1]. The most important medical parameter is the arterial blood pressure. The origin of high or low blood pressure can mostly be found in the vessel compliance. With the presented implantable sensor, we are able to directly measure strain of arteries, as an indicator of arteriosclerosis. The sensor is designed as a cuff with integrated capacitive structures and is wrapped around arteries. With a new and innovative locking method, we could show that the system does not affect the arteries. This is demonstrated by theory as well as experimental in vivo investigations. Biocompatibility tests, confirmed by histological cuts and MRI measurements, showed that no stenosis, allergic reactions or inflammation occurs. The sensor shows excellent linear behavior with respect to stress and strain.

Determination of vessel wall dynamics by optical microsensors.

Spectralphotometric measurement methods as, for example, pulse oximetry are established approaches for extracorporeal determination of blood constituents. We measure the dynamics of the arterial distension intracorporeally thus extending the scope of the method substantially. A miniaturized opto-electronic sensor is attached directly to larger arteries without harming the vessel. The transmitted light through the arteries shows a linear correlation with the pulsatile expansion in theory as well as in experiments. Intra-arterial blood pressure also shows a linear interrelationship with the optical signal. Measurements of blood vessel wall dynamics has great potential to quantify arteriosclerosis by this new and innovative approach.

Wavelet based data analysis for implantable pulse oximetric sensors.

Cardiovascular data recording by implantable sensor modules exhibits a number of advantages over extra-corporeal standard approaches. Implantable sensors feature their benefits in particular for high risk patients suffering from chronic heart diseases, because diagnosis can be combined with therapy in a closed loop system. Nevertheless, the measured photoplethysmographic signals reveal different kinds of noise and artifacts. There are several parametric and non-parametric mathematical techniques that try to achieve optimality and generality in estimating the actual signal out of its noisy representation. The determination of blood oxygen saturation and pulse transit time requires one of these mathematical techniques for gaining the exact position and magnitude of maxima and minima in the photoplethysmograph. A robust wavelet algorithm resolves the difficulties arising from physiological data.