Reconfigurable Microphysiological Systems for Modeling Innervation and Multitissue Interactions

Abstract

Tissue‐engineered models continue to experience challenges in delivering structural specificity, nutrient delivery, and heterogenous cellular components, especially for organ‐systems that require functional inputs/outputs and have high metabolic requirements, such as the heart. While soft lithography has provided a means to recapitulate complex architectures in the dish, it is plagued with a number of prohibitive shortcomings. Here, concepts from microfluidics, tissue engineering, and layer‐by‐layer fabrication are applied to develop reconfigurable, inexpensive microphysiological systems that facilitate discrete, 3D cell compartmentalization, and improved nutrient transport. This fabrication technique includes the use of the meniscus pinning effect, photocrosslinkable hydrogels, and a commercially available laser engraver to cut flow paths. The approach is low cost and robust in capabilities to design complex, multilayered systems with the inclusion of instrumentation for real‐time manipulation or measures of cell function. In a demonstration of the technology, the hierarchal 3D microenvironment of the cardiac sympathetic nervous system is replicated. Beat rate and neurite ingrowth are assessed on‐chip and quantification demonstrates that sympathetic‐cardiac coculture increases spontaneous beat rate, while drug‐induced increases in beating lead to greater sympathetic innervation. Importantly, these methods may be applied to other organ‐systems and have promise for future applications in drug screening, discovery, and personal medicine.

In Situ Formation of Microgel Array Via Patterned Electrospun Nanofibers Promotes 3D Cell Culture and Drug Testing in a Microphysiological System

“…As is well known, cell viability in dynamic culture is highly dependent on the fluid shear stress . Herein, we also calculated the fluid shear stress applied on the microgel and encapsulated cells during perfusion of cell culture media according to eq where τ w is the fluid shear stress, μ is the fluidic viscosity (9.4 × 10 –4 N s m –2 ), Q is the volume flowing through the rectangular microchannel per unit time (1.35 × 10 –11 m 3 s –1 ), and w and h are the width (4 × 10 –4 m) and the height (1 × 10 –4 m) of the rectangular microchannel, respectively. At a flow rate of 50 μL h –1 , the fluid shear stress around the microgel is calculated as ∼0.02 N m –2 , which is not only far less than 2 N m –2 (a typical threshold value of the physiological fluid shear stress), but also far less than the stress that can cause displacement of the microgel and nanofibers.…”

Experimental models to study osteoarthritis pain and develop therapeutics

“…All of these systems take advantage of the ability to assess the influence of cell-cell interactions under “naïve” and pathological conditions [ [92] , [93] , [94] ]. Other examples of microfluidic-based nerve-tissue MPSs include teeth, where nerve-tooth interactions were studied [ 96 ], as well as the heart, where it is possible to study the impact of autonomic nerve dysfunction on heart problems, such as those associated with myocardial infarction and arrhythmia [ 90 , 91 ].…”

Perspectives for Future Use of Cardiac Microtissues from Human Pluripotent Stem Cells

“…The ICNS is composed of sensory, motor, and interconnecting neurons that contribute to the heart rate, contractility, conduction, and blood flow . ICNS involvement in cardiac pathophysiology has been recognized previously; in some cases, a therapeutic option has been to sever these nerves, but the effects of nerve cells in 3D cardiac models in vitro are largely unexplored. , This may help in understanding the dialogue between the nervous system in the heart and the cardiomyocytes.…”