Microfluidics for 3D Cell and Tissue Cultures: History
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Traditional cell cultures are performed in two-dimensional (2D) systems such as Petri dishes, multiwell plates or flasks. However, they cannot realistically mimic the morphophysiological complexity of the original three-dimensional (3D) in vivo environment from which the cells of specific lines originate. Without opposing animal experimentation but promoting its responsible application, the development of alternative cell culture systems tries to ensure compliance with the 3R principles. Reduction (reduction in the animals used for in vivo tests), Refinement (experimental design optimization to limit stress and affliction to laboratory animals) and Replacement (total or partial replacement of animal testing with alternative valid methods) are increasingly desired and strongly recommended as fundamental ethical aspects in the use of animals in scientific experiments.

  • 3D cell cultures
  • microfluidics
  • lab on chip

1. Introduction

Traditional cell cultures are performed in two-dimensional (2D) systems such as Petri dishes, multiwell plates or flasks. However, they cannot realistically mimic the morphophysiological complexity of the original three-dimensional (3D) in vivo environment from which the cells of specific lines originate [1]. Without opposing animal experimentation but promoting its responsible application, the development of alternative cell culture systems tries to ensure compliance with the 3R principles. Reduction (reduction in the animals used for in vivo tests), Refinement (experimental design optimization to limit stress and affliction to laboratory animals) and Replacement (total or partial replacement of animal testing with alternative valid methods) are increasingly desired and strongly recommended as fundamental ethical aspects in the use of animals in scientific experiments [2].
Three-dimensional cell cultures can better mimic in vivo conditions than two-dimensional monolayer cell cultures, since, after isolation, cells generally lose their original morphology, changing the way they perform most of their physiological functions. Growth on an adhesion substrate results in cellular loss of polarity and it understandably influences intracellular trafficking, the functionality of subcellular compartments and some functions such as cell signaling and secretion, limiting the access to the culture media’s nutrients, the gaseous exchanges and the removal of waste substances [3]. In 2D cell cultures the complex network of regulatory interactions in the extracellular matrix (ECM), cells and tissue are altered, therefore the use of properly designed 3D culture systems assists researchers in obtaining more reliable results, deepening our understanding of what really happens in vivo [4,5]. Many studies report data concerning the significant differences in the morphology, protein expression, differentiation, viability, and functionality of cells grown in 2D or 3D systems [1,3,6,7,8,9,10,11].
Three-dimensional cell cultures can be successfully used for many different applications, including cell or drug screenings [12,13,14,15] and tissue generation (engineering) purposes [16,17,18]; however, the reproduction of a biomimetic environment is challenging [19,20,21]. It is very important to replicate as close as possible the original in vivo physiological cell microenvironment. When dealing with 3D cell cultures, one of the big issues is to provide a physiological exchange of substances (gas and molecules) between cells and their related microenvironment, inward for the cell nutrients and outward for the waste products. It is known that unfortunately 2D cell culture usually results in low nutrients and/or hypoxic regions related to cellular aggregation phenomena, biological media and gas consumption rates [22].
The use of optimized ECM-analog biomaterials with physico-chemical and structural properties, able to guarantee optimized degradation or residence rate and micro/nanoporosity, improves in vitro cell proliferation, differentiation, and interactions [23,24].
Decellularized engineered ECM and bioreactor-based solutions constitute valid alternatives to 2D cell cultures. The application of decellularization protocols in tissue engineering and regenerative medicine limits the possible immune response in the transplanted host by removing all the potential immunogenic biomaterials. The non-immunogenic ECM can be re-cellularized with autologous or stem cells, carrying out a fully personalized medicine approach [25,26]. In addition, micro-bioreactors can be regarded as a major step toward more complex organ-on-a-chip (OoC) systems [27], providing manageable 3D cell culture settings usually including suitable fluid flow supply and low amounts of chemicals and cells [28,29,30,31].

This entry is adapted from the peer-reviewed paper 10.3390/cells11101699

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