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Scalable Fabrication of Stretchable, Dual Channel, Microfluidic Organ Chips

A significant number of lead compounds fail in the pharmaceutical pipeline because animal studies often fail to predict clinical responses in human ...

Harvard University

An  model of the human kidney glomerulus - the major site of blood filtration - could facilitate drug discovery and illuminate kidney-disease mechanisms. Microfluidic organ-on-a-chip technology has been used to model the human proximal tubule, yet a kidney-glomerulus-on-a-chip has not been possible because of the lack of functional human podocytes - the cells that regulate selective permeability in the glomerulus. Here, we demonstrate an efficient (> 90%) and chemically defined method for directing the differentiation of human induced pluripotent stem (hiPS) cells into podocytes that express markers of the mature phenotype (nephrin+, WT1+, podocin+, Pax2-) and that exhibit primary and secondary foot processes. We also show that the hiPS-cell-derived podocytes produce glomerular basement-membrane collagen and recapitulate the natural tissue/tissue interface of the glomerulus, as well as the differential clearance of albumin and inulin, when co-cultured with human glomerular endothelial cells in an organ-on-a-chip microfluidic device. The glomerulus-on-a-chip also mimics adriamycin-induced albuminuria and podocyte injury. This  model of human glomerular function with mature human podocytes may facilitate drug development and personalized-medicine applications.

Mature induced-pluripotent-stem-cell-derived human podocytes reconstitute kidney glomerular-capillary-wall function on a chip.

Physiologically based pharmacokinetic (PBPK) modeling and simulation approaches are beginning to be integrated into drug development and approval processes because they enable key pharmacokinetic (PK) parameters to be predicted from in vitro data. However, these approaches are hampered by many limitations, including an inability to incorporate organ-specific differentials in drug clearance, distribution, and absorption that result from differences in cell uptake, transport, and metabolism. Moreover, such approaches are generally unable to provide insight into pharmacodynamic (PD) parameters. Recent development of microfluidic Organ-on-a-Chip (Organ Chip) cell culture devices that recapitulate tissue-tissue interfaces, vascular perfusion, and organ-level functionality offer the ability to overcome these limitations when multiple Organ Chips are linked via their endothelium-lined vascular channels. Here, we discuss successes and challenges in the use of existing culture models and vascularized Organ Chips for PBPK and PD modeling of human drug responses, as well as in vitro to in vivo extrapolation (IVIVE) of these results, and how these approaches might advance drug development and regulatory review processes in the future.

Physiologically Based Pharmacokinetic and Pharmacodynamic Analysis Enabled by Microfluidically Linked Organs-on-Chips.

Microfluidic systems can be applied to develop unique tools for cell culture, low-cost diagnostics, and precision experimentation by leveraging microscale fluid flow. As the field has expanded and matured, there is a need for rapid prototyping that is both accessible to most research groups and can readily translate toward scalable commercial manufacturing. Here, we describe a protocol that incorporates rapid computer numerical control (CNC) milling of positive molds, casting of a negative high-durometer silicone mold, and hot embossing to produce microfluidic devices composed of virtually any thermoplastic material. The method bypasses the need for high-precision machining of the bonding surfaces by using a cast acrylic stock and only milling channels, thus expanding this protocol to any CNC platform This technique represents a versatile, high-fidelity prototyping method that enables fast turnaround of prototype devices in a standard laboratory setting, while offering scalability for commercial manufacturing.

Richard Novak

Wyss Institute for Biologically Inspired Engineering

Harvard University

Scalable Fabrication of Stretchable, Dual Channel, Microfluidic Organ Chips

Richard Novak

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Harvard University

Scalable Fabrication of Stretchable, Dual Channel, Microfluidic Organ Chips

Wyss Institute for Biologically Inspired Engineering