Search

LifeTec Group has developed a Cardiac Biosimulator where a dead porcine heart is used to mimic a beating heart in a simulated environment. This is useful for assessment of medical devices or as a training platform for medical professionals. The research presented aims at extending this simulator by designing feedback controllers for the time-averaged relevant pressures and flow, which reduces the startup time and potentially increases stability of the simulator. To achieve this, both the continuous and time-averaged models of the simulator are presented together with their state-space representations. The proposed controller consists of three independent PI controllers, which are presented along with simulation and measurement results and show promising system performance. Lastly, the controller implementation was tested on the Biosimulator with a pathological heart (Mitral prolapse), which showed no significant decrease in performance compared to the physiological heart.

Isolated hearts offer the opportunity to evaluate heart function, treatments, and diagnostic tools without in vivo factor interference. However, the early loss of cardiac function and edema occur over time and do limit the duration of the experiment. This research focuses on delaying these limitations using optimal blood control. This study examines whether blood conditioning by means of the combination of blood predilution and hemodialysis can significantly reduce cardiac function degradation. Slaughterhouse porcine hearts were revived in the PhysioHeart™ platform to restore physiological cardiac performance. Twelve hearts were divided into a control group and a dialysis group; in the latter group, hemodialysis was attached to the blood reservoir. Cardiac hemodynamics and blood parameters were recorded and evaluated. Blood conditioning significantly reduced the loss of cardiac pump function (control group vs dialysis group, −14.9 ± 6.3%/h vs −9.7 ± 2.7%/h) and loss of cardiac output (control group vs dialysis group, −11.8 ± 3.4%/h vs −5.9 ± 2.0%/h). Hemodialysis resulted in physiological and stable blood parameters, whereas in the control group ions reached pathological values, while interstitial edema still occurred. The combination of blood predilution and hemodialysis significantly attenuated ex vivo cardiac function degradation and delayed the loss of cardiac hemodynamics. We hypothesized that besides electrolyte and metabolic control, the hemodialysis-accompanied increase in hematocrit resulted in improved oxygen transport. This could have temporarily compensated the deleterious effect of an increased oxygen-diffusion distance due to edema in the dialysis group and resulted in less progression of cell decay. Clinically validated measures delaying edema might improve the effectiveness of the PhysioHeart™ platform.

Objectives The success of the ex vivomachine perfusion of pig livers used for preclinical research depends on organ quality and availability. In this study, we investigated whether livers obtained from slaughterhouses are suitable and equivalent to livers obtained from laboratory pigs.Methods Livers were obtained from slaughterhouse pigs stunned by electrocution or CO2inhalation and from laboratory pigs. For the latter group, 45 minutes of warm ischemia was mimicked for a subgroup, ensuring a valid comparison with slaughterhouse-derived livers.Results Livers from CO2-stunned pigs showed lower indocyanine green clearance and bile production, higher blood lactate and potassium concentrations, and higher alanine aminotransferase activities than electrically stunned pigs. Furthermore, livers from electrically stunned pigs, and livers from laboratory pigs, subjected or not to warm ischemia, showed similar performance in terms of perfusion and metabolism.Conclusion For an ex vivoliver model generated using slaughterhouse pigs, electrical stunning is preferable to CO2stunning. Livers from electrically stunned slaughterhouse pigs performed similarly to laboratory pig livers. These findings support the use of livers from electrically stunned slaughterhouse pigs, which may therefore provide an alternative to livers obtained from laboratory pigs, consistent with the principle of the 3Rs.

Introduction:The cardiovascular disease that causes most of the deaths is atherosclerosis. The current research to assess efficacy of treatments is based on animal models, but these present several limitations related to time and costs associated. Ex-vivo systems represent useful models to study vascular biology and to test medical devices. The main goal of this research was to culture coronary arteries in an ex-vivo vascular bioreactor in order to maintain them alive and functional by mimicking physiological conditions.Methods:Culture experiments were performed on porcine right coronary arteries (RCA). Duration was set to 2 (n=3), 4 (n=3), and 9 days (n=3). The RCAs were dissected from hearts harvested from a local slaughterhouse. The bioreactor containing the dissected RCA was placed in a 38°C incubator. The RCA was cultured in a blood-mimicking culture medium. To assess RCA morphology and diameter, ultrasound imaging was performed. Pressure and flow rate were monitored daily. The flow rate was set to ensure a physiological peak endothelial shear stress of around 0.8-1.8 Pa. After 2, 4 or 9 days of culture, the RCA was embedded in paraffin and cut into 4 μm sections. Histological stainings (H&E and RF) were performed on the sections.Results:During RCA cultures, the mean pressure was 60-100 mmHg, and the peak flow rate was around 60 ml/min. Ultrasound imaging showed that the morphology and structure of cultured arteries was maintained during the culture. Histological analyses showed preserved endothelium and extracellular matrix. After 2 days of culture, endothelial coverage was not complete while after 4 days it was completely restored. After 9 days of culture, a layer of newly formed neointima was visible.Conclusions:The cultured RCAs maintained their physiological morphology up to 9 days of culture. The investigated model represents a useful tool for testing vascular therapies and devices, supporting the translational phase between in-vitro and in-vivo studies.

Pulse oximeters measure a patient's heart rate and blood oxygenation by illuminating the skin and measuring the intensity of the light that has propagated through it. The measured intensities, called photoplethysmograms (PPGs), are highly susceptible to motion, which can distort the PPG derived data. Part of the motion artifacts are considered to result from sensor deformation, leading to a change in emitter-detector distance. It is hypothesized that these motion artifacts correlate to movement of the emitter with respect to the skin. This has been investigated in a laboratory setup in which motion artifacts can be reproducibly generated by translating the emitter with respect to a flowcell that models skin perfusion. The top of the flowcell is a diffuse scattering Delrin skin phantom under which a cardiac induced blood pulse is modeled by a changing milk volume. By illuminating the flowcell, a PPG can be measured. The emitter's translation has been accurately measured using self-mixing interferometry (SMI). The motion artifacts in the PPG as a result of emitter motion are shown to correlate with the emitter's displacement. Moreover, it is shown that these artifacts are significantly reduced by a least-mean-square algorithm that uses the emitter's displacement measured via SMI as artifact reference.

Ex vivo systems represent important models to study vascular biology and to test medical devices, combining the advantages of in vitro and in vivo models such as controllability of parameters and the presence of biological response, respectively. The aim of this study was to develop a comprehensive ex vivo vascular bioreactor to long-term culture and study the behavior of native blood vessels under physiologically relevant conditions. The system was designed to allow for physiological mechanical loading in terms of pulsatile hemodynamics, shear stress, and longitudinal prestretch and ultrasound imaging for vessel diameter and morphology evaluation. In this first experience, porcine carotid arteries (n = 4) from slaughterhouse animals were cultured in the platform for 10 days at physiological temperature, CO2 and humidity using medium with blood-mimicking viscosity, components, and stability of composition. As expected, a significant increase in vessel diameter was observed during culture. Flow rate was adjusted according to diameter values to reproduce and maintain physiological shear stress, while pressure was kept physiological. Ultrasound imaging showed that the morphology and structure of cultured arteries were comparable to in vivo. Histological analyses showed preserved endothelium and extracellular matrix and neointimal tissue growth over 10 days of culture. In conclusion, we have developed a comprehensive pulsatile system in which a native blood vessel can be cultured under physiological conditions. The present model represents a significant step toward ex vivo testing of vascular therapies, devices, drug interaction, and as basis for further model developments.

The use of slaughterhouse-based hearts has advantages over hearts obtained from laboratory animals for preclinical testing. However, slaughterhouse hearts have greater variability in cardiac function; this has resulted in a dispute over their actual reproducibility. This study explores the feasibility of examining the cardioplegic effluent during hypothermic cardiac arrest for the presence of biomarkers to predict poststorage heart function of slaughterhouse hearts. This may enable proactive measures to optimize preservation strategies and improve the initial cardiac performance of slaughterhouse heart experiments. Slaughterhouse pig hearts (n = 9; 420 ± 30 g) were arrested and flushed with an additional liter cardioplegia after 1 h. Effluent samples were examined for ammonia, lactate, troponin, and inorganic phosphate. After 2 h, hearts were hemoreperfused in the ex vivo heart platform PhysioHeart™ to restore physiological cardiac functions and to identify correlations between biomarkers and cardiac output. There was a negative correlation between cardiac output of revived hearts and levels of ammonia (r = −0.865; p = 0.002) and lactate (r = −0.763; p = 0.01). No correlation was found between cardiac output and levels of phosphate (r = −0.553; p = 0.12) and troponin (r = −0.367; p = 0.331). The analysis approach to assess cardioplegic biomarkers was feasible and enabled the estimation of the effectiveness of organ protection and cardiac function before reperfusion. Ammonia is a predictor for cardiac dysfunction. Effluent analysis prior to heart revival can uncover poststorage cardiac dysfunction in isolated hearts and may prevent failed experiments while improving reproducibility and standardization.

The inability to discern between pathology and physiological variability is a key issue in cardiac electrophysiology since this prevents the use of minimally invasive acquisitions to predict early pathological behavior. The goal of this work is to demonstrate how experimentally calibrated populations of models (ePoM) may be employed to inform which cellular-level pathologies are responsible for abnormalities observed in organ-level acquisitions while accounting for intersubject variability; this will be done through an exemplary computational and experimental approach. Unipolar epicardial electrograms (EGM) were acquired during an ex vivo porcine heart experiment. A population of the Ten Tusscher 2006 model was calibrated to activation–recovery intervals (ARI), measured from the electrograms, at three representative times. The distributions of the parameters from the resulting calibrated populations were compared to reveal statistically significant pathological variations. Activation–recovery interval reduction was observed in the experiments, and the comparison of the calibrated populations of models suggested a reduced L-type calcium conductance and a high extra-cellular potassium concentration as the most probable causes for the abnormal electrograms. This behavior was consistent with a reduction in the cardiac output (CO) and was confirmed by other experimental measurements. A proof of concept method to infer cellular pathologies by means of organ-level acquisitions is presented, allowing for an earlier detection of pathology than would be possible with current methods. This novel method that uses mathematical models as a tool for formulating hypotheses regarding the cellular causes of observed organ-level behaviors, while accounting for physiological variability has been unexplored.