Integrating in vitro organ-specific function with the microcirculation

Highlights

• The structure/function of the microcirculation is unique for each organ system.

• Microphysiological systems can enhance our understanding of physiology and drug discovery.

• Induced pluripotent stem cell technology offers a new paradigm to mimic organ physiology in vitro.

There is significant interest within the tissue engineering and pharmaceutical industries to create 3D microphysiological systems of human organ function. The interest stems from a growing concern that animal models and simple 2D culture systems cannot replicate essential features of human physiology that are crucial to predict drug response, or simply to develop new therapeutic strategies to repair or replace damaged organs. Central to human organ function is a microcirculation that not only enhances the rate of nutrient and waste transport by convection, but also provides essential additional physiological functions that can be specific to each organ. This review highlights progress in the creation of in vitro functional microvessel networks, and emphasizes organ-specific functional and structural characteristics that should be considered in the future mimicry of four organ systems that are of primary interest: lung, brain, liver, and muscle (skeletal and cardiac).

Introduction

Recent advancements in both biology and microfluidic technologies have generated unprecedented opportunities to create sophisticated microphysiological systems that mimic human organ function. Within the last decade, 3D systems that recapitulate the human organ microenvironment under highly controlled conditions have emerged and been met with much excitement [1•, 2•, 3•]. Such systems provide new tools for basic research of both pathological and physiological states, but are also predictive of human physiology and hence attractive for drug efficacy and toxicity screening.

Global challenges to develop in vitro organ systems include cell sources, selection of matrix, and the development of a vascular supply. Advances in human induced pluripotent (iPS) stem cell technology offer a promising solution to the cell source issue while continued innovation in synthetic and native biomaterials can potentially address the hurdle of creating realistic cell–matrix interactions; however an often simplified challenge in organ microphysiological system development is the creation of a vascular network. Essentially all human tissue contains a vascular supply, and thus new microphysiological systems must include a vascular supply if they want to truly replicate normal human physiology. Initial work in constructing in vitro vessel networks was in the form of either printing or coating rigid channels with cells [4, 5, 6, 7]. Although such methods provide precise control of vessel architecture, the channels are not dynamic and thus cannot remodel or respond to changes in the microenvironment. More recently, cylindrical networks in natural extracellular matrices have been endothelialized and have shown the ability to invade into the surrounding matrix [8, 9, 10]. Within the past two years several groups have emerged with microfluidic models that allow for vessels to either sprout or self assemble in a hydrogel compartment resulting in perfused human capillaries [11••, 12, 13, 14, 15]. To date, only our work has shown physiological flow and shear rate [11^••]. The ability of endothelial cells to self-assemble into 3D perfusable networks requires cues in the microenvironment. For example, fibrin is often used as a matrix because of it is naturally pro-angiogenic and promotes production of basement membrane such as collagen [16, 17]. Another key feature is the presence of stromal cells which can generate freely diffusible growth factors and matrix proteins such as collagen, vascular endothelial growth factor, transforming growth factor β-induced protein, hepatocyte growth factor and fibronectin [18, 19].

The next iteration or natural progression of these designs is establishing tissue or organ specificity. Although the most basic role of microvessel networks is to provide the exchange of nutrients, oxygen and waste, the microcirculation is often coupled and integrated into many of the organ system's function in addition to carrying out regulatory functions in response to environmental cues. As a result, there is significant heterogeneity in the structure and function of the microcirculation between different organs. This review will focus on the unique features of the microcirculations of four organs (lung, brain, liver and heart) to emphasize the need to create organ-specific functional and structural characteristics of microvessel networks in the development of realistic 3D microphysiologic systems.