Modeling sensitivity and uncertainties in platelet activation models applied on centrifugal pumps for extracorporeal life support.

Two platelet activation models were studied with respect to uncertainties of model parameters and variables. The sensitivity was assessed using two direct/deterministic approaches as well as the statistical Monte Carlo method. The first two, are linear in character whereas the latter is non-linear. The platelet activation models were applied on platelets moving within an extracorporeal centrifugal blood pump. The phenomenological, Lagrangian stress- and time-based power law-based models under consideration, have experimentally calibrated parameters and the stress expressed in a scalar form. The sensitivity of the model with respect to model parameters and the expression of the scalar stress was examined focusing on a smaller group of platelets associated with an elevated risk of activation. The results showed a high disparity between the models in terms of platelet activation state, found to depend on the platelets' trajectory in the pump and the expression used for the scalar stress. Monte Carlo statistics was applied to the platelets at risk for activation and not to the entire platelet population. The method reveals the non-linear sensitivity of the activation models. The results imply that power-law based models have a restricted range of validity. The conclusions of this study apply to both platelet activation and hemolysis models.

Flow-induced platelet activation in components of the extracorporeal membrane oxygenation circuit.

Extracorporeal membrane oxygenation (ECMO) is used for rescue in severe respiratory and/or circulatory failure. The patient's blood is pumped over artificial surfaces in the ECMO circuit. A platelet activation model was applied to study the potential thrombogenicity of ECMO circuit components: the centrifugal blood pump, cannulae, and tubing connectors. Based on the accumulated effect of the scalar form of the stress acting on the platelet over time, the activation model enables assessment of platelet activation and pinpoints regions of elevated activation risk in a component. Numerical simulations of the flow in different components of the ECMO circuit was carried out where the activation level is a function of the impact of local stress and its history along the path that the platelets follow. The results showed that the pump carried the largest risk for platelet activation followed by the reinfusion cannula and lastly the connectors. Pump thrombogenicity was mainly due to long residence time and high shear-rate while the connector showed a high level of non-stationary shear-rate that in turn may contribute to the formation of aggregates through direct platelet activation or through high shear-rate modulation of the vWF multimers.

Detection of Thrombosis in the Extracorporeal Membrane Oxygenation Circuit by Infrasound: Proof of Concept.

As of today, there exist no reliable, objective methods for early detection of thrombi in the extracorporeal membrane oxygenators (ECMO) system. Within the ECMO system, thrombi are not always fixed to a certain component or location in the circuit. Thus, clot fragments of different shapes and consistencies may circulate and give rise to vibrations and sound generation. By bedside sound measurements and additional laboratory experiments (although not detailed herein), we found that the presence of particles (clots or aggregates and fragments of clots) can be detected by analyzing the strength of infra-sound (< 20 Hz) modes of the spectrum near the inlet and outlet of the centrifugal pump in the ECMO circuit. For the few patients that were considered in this study, no clear false positive or negative examples were found when comparing the spectral approach with clinical observations. A laboratory setup provided insight to the flow in and out of the pump, confirming that in the presence of particles a low-amplitude low-frequency signal is strongly amplified, enabling the identification of a clot.

Tropism of the in situ growth from biopsies of childhood neuroectodermal tumors following transplantation into experimental teratoma.

Experimental teratoma induced from human pluripotent stem cells with normal karyotype can be described as a failed embryonic process and includes besides advanced organoid development also large elements of tissue with a prolonged occurrence of immature neural components. Such immature components, although benign, exhibit strong morphological resemblance with tumors of embryonic neuroectodermal origin. Here, we demonstrate that biopsy material from childhood tumors of neural embryonic origin transplanted to mature experimental teratoma can show an exclusive preference for matching tissue. Tumor specimens from five children with; Supratentorial primitive neuroectodermal tumor (sPNET); Pilocytic astrocytoma of the brainstem; Classic medulloblastoma; peripheral primitive neuroectodermal tumor (pPNET) or neuroblastoma (NB), respectively, were transplanted. Analysis of up to 120 sections of each tumor revealed an engraftment for three of the transplanted tumors: pPNET, sPNET, and NB, with a protruding growth from the latter two that were selected for detailed examination. The histology revealed a strict tropism with a non-random integration into what morphologically appeared as matched embryonic microenvironment recuperating the patient tumor histology. The findings suggest specific advantages over xenotransplantation and lead us to propose that transplantation to the human embryonic microenvironment in experimental teratoma can be a well-needed complement for preclinical in vivo studies of childhood neuroectodermal tumors.