Development of a perfusable, hierarchical microvasculature-on-a-chip model.

Several methods have been developed for generating 3D, in vitro, organ-on-chip models of human vasculature to study vascular function, transport, and tissue engineering. However, many of these existing models lack the hierarchical nature of the arterial-to-capillary-to-venous architecture that is key to capturing a more comprehensive view of the human microvasculature. Here, we present a perfusable, multi-compartmental model that recapitulates the three microvascular compartments to assess various physiological properties such as vessel permeability, vasoconstriction dynamics, and circulating cell arrest and extravasation. Viscous finger patterning and passive pumping create the larger arterial and venular lumens, while the smaller diameter capillary bed vessels are generated through self-assembly. These compartments anastomose and form a perfusable, hierarchical system that portrays the directionality of blood flow through the microvasculature. The addition of collagen channels reduces the apparent permeability of the central capillary region, likely by reducing leakage from the side channels, enabling more accurate measurements of vascular permeability-an important motivation for this study. Furthermore, the model permits modulation of fluid flow and shear stress conditions throughout the system by using hydrostatic pressure heads to apply pressure differentials across either the arteriole or the capillary. This is a pertinent system for modeling circulating tumor or T cell dissemination and extravasation. Circulating cells were found to arrest in areas conducive to physical trapping or areas with the least amount of shear stress, consistent with hemodynamic or mechanical theories of metastasis. Overall, this model captures more features of human microvascular beds and is capable of testing a broad variety of hypotheses.

Microphysiological endothelial models to characterize subcutaneous drug absorption.

The high variability in subcutaneous bioavailability of protein therapeutics is poorly understood, contributing to critical delays in patient access to new therapies. Preclinical animal and in vitro models fail to provide a physiologically relevant testbed to parse potential contributors to human bioavailability, therefore new strategies are necessary. Here, we present a microphysiological model of the human hypodermal vasculature at the injection site to study the interactions of administered protein therapeutics within the microenvironment that influence subcutaneous bioavailability. Our model combines human dermal endothelial cells, fibroblasts, and adipocytes, self-assembled into three-dimensional, perfusable microvessels that express relevant extracellular matrix. We demonstrate the utility of the model for measurement of biophysical parameters within the hypodermal microenvironment that putatively impact protein kinetics and distribution at the injection site. We propose that microphysiological models of the subcutaneous space have applications in preclinical development of protein therapeutics intended for subcutaneous administration with optimal bioavailability.

Microheart: A microfluidic pump for functional vascular culture in microphysiological systems.

Advances in microphysiological systems have prompted the need for long-term cell culture under physiological flow conditions. Conventional laboratory pumps typically lack the ability to deliver cell culture media at the low flow rates required to meet the physiological ranges of fluid flow, and are often pulsatile or require flow reversal. Here, a microfluidic-based pump is presented, which allows for the controlled delivery of media for vascular microphysiological applications. The performance of the pump was characterized in a range of microfluidic systems, including straight channels of varying dimensions and self-assembled microvascular networks. A theoretical framework was developed based on lumped element analysis to predict the performance of the pump for different fluidic configurations and a finite element model of the included check-valves. The use of the pump for microvascular physiological studies demonstrated the utility of this system to recapitulate vascular fluid transport phenomena in microphysiological systems, which may find applications in disease models and drug screening.

Here and Gone: Rapid Transfer From the General Care Floor to the PICU.

BACKGROUND: Children admitted to the general care floor sometimes require acute escalation of care and rapid transfer (RT) to the PICU shortly after admission. In this study, we aim to investigate the characteristics of RTs and the impact RTs have on patient outcomes, including PICU length of stay (LOS), mortality, and emergency transfer defined as critical care interventions occurring within 1 hour on either side of transfer to the PICU. METHODS: We conducted a 2-year, single-center, retrospective analysis including all patients admitted to the general care floor of a tertiary children's hospital that were subsequently transferred to the PICU, with attention to those transferred within 4 hours of admission, meeting criteria as RTs. Patient-level data and outcomes were tracked. Statistical summaries were stratified by RT or non-RT strata and between-strata comparisons were performed. Significant univariate factors were entered into a multivariate logistic regression model and reduced with statistical significance required for final model inclusion. RESULTS: Of 450 patients with an unplanned PICU transfer, 105 (23.3%) experienced RTs. Significant factors in the reduced multivariate logistic regression model associated with decreased risk for RT were increased baseline Pediatric Overall Performance Category (P = .046) and PICU origin of admission (P = .012). RT patients had shorter PICU LOSs (2.8 vs 5.5 days, P < .001) compared with non-RT patients despite a higher rate of emergency transfer (15.2% vs 7.5%, P = .018) and no difference in mortality (P = .741). CONCLUSIONS: In this study, we demonstrate RTs have an increase in emergency transfer rate but no apparent risk of increased PICU LOS or mortality.