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Open microfluidics can be employed in the multidimensional culturing of cell types for various applications including organ-on-a-chip studies, oxygen-driven reactions, neurodegeneration, cell migration, and other cellular pathways. [1] [2]
The use of conventional microfluidic devices for cell studies has already improved upon the cost effectiveness and sample volume requirement, however using open microfluidic channels adds the benefit of removing syringe pumps to drive flow, now governed by surface tensions that drive spontaneous capillary flow (SCF), and exposes cells to the surrounding environment. [3] [4] [5] The miniaturization of this process allows for improved sensitivity, high throughput, and ease of manipulation and integration, as well as dimensions that can be more physiologically relevant. [4] [5] [6] [7] [1] The benefits of both open and closed microfluidic platforms have allowed the option for the combination of the two, where the device is open for the introduction and culturing of cells, and can be sealed prior to analysis. [3]
Cells and proteins can be patterned in microfluidic devices with one of the channel walls exposed in different geometries and designs depending on the behaviors and interactions to be studied, such as quorum sensing or co-culturing of several types of cells. [6] [8] A majority of cell culturing has been carried out by introducing the cells in a perfused conditioned medium to simulate the desired cell populations in traditional close-channel microfluidic devices. The challenge to support the cell growth and simultaneously study multiple cell types in a single device with an exposed channel is that the interactions between cells in this medium needs to be controlled since the timing and location of the interactions is critical. [9] This issue can be addressed in several ways including the modification of the device design, using droplet microfluidics, and cell sorting. [9] [10] Not only does this allow for the ease of manipulating the environment of the cells, but having an open channel wall allows for a better understanding of biological interactions at this interface. [9] Creating designs of microfluidic platforms with different compartments that are isolated and have different dimensions allows for co-culturing of several types of cells. [6] These devices often incorporate droplet formation to encapsulate cells and act as transport and reaction vehicles in two or more immiscible phases, making it possible to carry out numerous parallel analyses using different conditions. [5] [11] Open microfluidics has also been coupled with fluorescence-activated cell sorting (FACS) to allow for cells to be contained in individually sorted compartments in an open microfluidic network for culturing in an exposed environment. [10] The exposure of one of the channel walls introduces the issue of evaporation and therefore cell loss, however this issue can be minimized by using droplet microfluidics where the cell-containing droplets are submerged in a fluorinated oil. [12] Although evaporation is a major disadvantage of using an open microfluidic system for cell culturing, the advantages over a closed system include ease of manipulation and access to the cells. For certain applications, such as the study of drug transport and lung function using alveolar epithelium cells, air exposure to is essential for developing the lungs. [7]
Polydimethylsiloxane (PDMS) is a common material for open microfluidic devices that introduces additional advantages and disadvantages. The adsorption of small biological molecules from cell culturing samples as well as the release of oligomers into the culture medium have both been posed as issues of using PDMS for biological studies, however these can be reduced by adopting pretreatment procedures to create optimal environments. [13] Advantages of using PDMS include the ease of surface modification, low cost, biocompatibility, and optical transparency. [14] In addition, PDMS is an attractive material to use for generating oxygen gradients for cell culturing in studies that involve monitoring ROS governed cellular pathways due to its oxygen permeability. [15] Plastics such as polystyrene can be used to create microfluidic devices by embossing and bonding methods, CNC milling, injection molding, or stereolithography. [16] [17] Devices created with polystyrene by these methods include microfluidic platforms that integrate several microfluidic systems, creating arrays to study several cell cultures simultaneously. [16] Another type of material that is used for open-microfluidic cell culturing is paper-based microfluidics. Cell culturing on paper-based microfluidic devices is accomplished either by encapsulating cells in a hydrogel or directly seeding them in stacked cellulose filter papers and the cell culture medium is passively transported to the culture areas. [18] A major advantage of this type of open-microfluidics includes the low cost, the variety of dimensions of porous papers that are commercially available, improved cell viability, adhesion, and migration over tissue culture plates. [18] [19] In addition, it is an attractive substrate for 3D cell culture devices due to its ability to incorporate essential characteristics such as oxygen and nutrient gradients, fluid flow that can control cell migration, and stacking filter papers with different cells suspended in hydrogel to monitor cellular interactions or complex populations. [19] [20] [21]
Microfluidics refers to a system that manipulates a small amount of fluids ( using small channels with sizes ten to hundreds micrometres. It is a multidisciplinary field that involves molecular analysis, biodefence, molecular biology, and microelectronics. It has practical applications in the design of systems that process low volumes of fluids to achieve multiplexing, automation, and high-throughput screening. Microfluidics emerged in the beginning of the 1980s and is used in the development of inkjet printheads, DNA chips, lab-on-a-chip technology, micro-propulsion, and micro-thermal technologies.
Digital microfluidics (DMF) is a platform for lab-on-a-chip systems that is based upon the manipulation of microdroplets. Droplets are dispensed, moved, stored, mixed, reacted, or analyzed on a platform with a set of insulated electrodes. Digital microfluidics can be used together with analytical analysis procedures such as mass spectrometry, colorimetry, electrochemical, and electrochemiluminescense.
A surface acoustic wave (SAW) is an acoustic wave traveling along the surface of a material exhibiting elasticity, with an amplitude that typically decays exponentially with depth into the material, such that they are confined to a depth of about one wavelength.
A lab-on-a-chip (LOC) is a device that integrates one or several laboratory functions on a single integrated circuit of only millimeters to a few square centimeters to achieve automation and high-throughput screening. LOCs can handle extremely small fluid volumes down to less than pico-liters. Lab-on-a-chip devices are a subset of microelectromechanical systems (MEMS) devices and sometimes called "micro total analysis systems" (µTAS). LOCs may use microfluidics, the physics, manipulation and study of minute amounts of fluids. However, strictly regarded "lab-on-a-chip" indicates generally the scaling of single or multiple lab processes down to chip-format, whereas "µTAS" is dedicated to the integration of the total sequence of lab processes to perform chemical analysis.
Polydimethylsiloxane (PDMS), also known as dimethylpolysiloxane or dimethicone, is a silicone polymer with a wide variety of uses, from cosmetics to industrial lubrication.
Plasma cleaning is the removal of impurities and contaminants from surfaces through the use of an energetic plasma or dielectric barrier discharge (DBD) plasma created from gaseous species. Gases such as argon and oxygen, as well as mixtures such as air and hydrogen/nitrogen are used. The plasma is created by using high frequency voltages to ionise the low pressure gas, although atmospheric pressure plasmas are now also common.
Bio-MEMS is an abbreviation for biomedical microelectromechanical systems. Bio-MEMS have considerable overlap, and is sometimes considered synonymous, with lab-on-a-chip (LOC) and micro total analysis systems (μTAS). Bio-MEMS is typically more focused on mechanical parts and microfabrication technologies made suitable for biological applications. On the other hand, lab-on-a-chip is concerned with miniaturization and integration of laboratory processes and experiments into single chips. In this definition, lab-on-a-chip devices do not strictly have biological applications, although most do or are amenable to be adapted for biological purposes. Similarly, micro total analysis systems may not have biological applications in mind, and are usually dedicated to chemical analysis. A broad definition for bio-MEMS can be used to refer to the science and technology of operating at the microscale for biological and biomedical applications, which may or may not include any electronic or mechanical functions. The interdisciplinary nature of bio-MEMS combines material sciences, clinical sciences, medicine, surgery, electrical engineering, mechanical engineering, optical engineering, chemical engineering, and biomedical engineering. Some of its major applications include genomics, proteomics, molecular diagnostics, point-of-care diagnostics, tissue engineering, single cell analysis and implantable microdevices.
Ambient ionization is a form of ionization in which ions are formed in an ion source outside the mass spectrometer without sample preparation or separation. Ions can be formed by extraction into charged electrospray droplets, thermally desorbed and ionized by chemical ionization, or laser desorbed or ablated and post-ionized before they enter the mass spectrometer.
Cell sorting is the process through which a particular cell type is separated from others contained in a sample on the basis of its physical or biological properties, such as size, morphological parameters, viability and both extracellular and intracellular protein expression. The homogeneous cell population obtained after sorting can be used for a variety of applications including research, diagnosis, and therapy.
Laser ablation electrospray ionization (LAESI) is an ambient ionization method for mass spectrometry that combines laser ablation from a mid-infrared (mid-IR) laser with a secondary electrospray ionization (ESI) process. The mid-IR laser is used to generate gas phase particles which are then ionized through interactions with charged droplets from the ESI source. LAESI was developed in Professor Akos Vertes lab by Dr. Peter Nemes in 2007 and it was marketed commercially by Protea Biosciences, Inc until 2017. Fiber-LAESI for single-cell analysis approach was developed by Dr. Bindesh Shrestha in Professor Vertes lab in 2009. LAESI is a novel ionization source for mass spectrometry (MS) that has been used to perform MS imaging of plants, tissues, cell pellets, and even single cells. In addition, LAESI has been used to analyze historic documents and untreated biofluids such as urine and blood. The technique of LAESI is performed at atmospheric pressure and therefore overcomes many of the obstacles of traditional MS techniques, including extensive and invasive sample preparation steps and the use of high vacuum. Because molecules and aerosols are ionized by interacting with an electrospray plume, LAESI's ionization mechanism is similar to SESI and EESI techniques.
An organ-on-a-chip (OOC) is a multi-channel 3-D microfluidic cell culture, integrated circuit (chip) that simulates the activities, mechanics and physiological response of an entire organ or an organ system. It constitutes the subject matter of significant biomedical engineering research, more precisely in bio-MEMS. The convergence of labs-on-chips (LOCs) and cell biology has permitted the study of human physiology in an organ-specific context. By acting as a more sophisticated in vitro approximation of complex tissues than standard cell culture, they provide the potential as an alternative to animal models for drug development and toxin testing.
Microfluidics in chemical biology is the application of microfluidics in the study of chemical biology.
In the field of cellular biology, single-cell analysis is the study of genomics, transcriptomics, proteomics, metabolomics and cell–cell interactions at the single cell level. The concept of single-cell analysis originated in the 1970s. Before the discovery of heterogeneity, single-cell analysis mainly referred to the analysis or manipulation of an individual cell in a bulk population of cells at a particular condition using optical or electronic microscope. To date, due to the heterogeneity seen in both eukaryotic and prokaryotic cell populations, analyzing a single cell makes it possible to discover mechanisms not seen when studying a bulk population of cells. Technologies such as fluorescence-activated cell sorting (FACS) allow the precise isolation of selected single cells from complex samples, while high throughput single cell partitioning technologies, enable the simultaneous molecular analysis of hundreds or thousands of single unsorted cells; this is particularly useful for the analysis of transcriptome variation in genotypically identical cells, allowing the definition of otherwise undetectable cell subtypes. The development of new technologies is increasing our ability to analyze the genome and transcriptome of single cells, as well as to quantify their proteome and metabolome. Mass spectrometry techniques have become important analytical tools for proteomic and metabolomic analysis of single cells. Recent advances have enabled quantifying thousands of protein across hundreds of single cells, and thus make possible new types of analysis. In situ sequencing and fluorescence in situ hybridization (FISH) do not require that cells be isolated and are increasingly being used for analysis of tissues.
Microfluidic cell culture integrates knowledge from biology, biochemistry, engineering, and physics to develop devices and techniques for culturing, maintaining, analyzing, and experimenting with cells at the microscale. It merges microfluidics, a set of technologies used for the manipulation of small fluid volumes within artificially fabricated microsystems, and cell culture, which involves the maintenance and growth of cells in a controlled laboratory environment. Microfluidics has been used for cell biology studies as the dimensions of the microfluidic channels are well suited for the physical scale of cells. For example, eukaryotic cells have linear dimensions between 10 and 100 μm which falls within the range of microfluidic dimensions. A key component of microfluidic cell culture is being able to mimic the cell microenvironment which includes soluble factors that regulate cell structure, function, behavior, and growth. Another important component for the devices is the ability to produce stable gradients that are present in vivo as these gradients play a significant role in understanding chemotactic, durotactic, and haptotactic effects on cells.
Droplet-based microfluidics manipulate discrete volumes of fluids in immiscible phases with low Reynolds number and laminar flow regimes. Interest in droplet-based microfluidics systems has been growing substantially in past decades. Microdroplets offer the feasibility of handling miniature volumes of fluids conveniently, provide better mixing, encapsulation, sorting, sensing and are suitable for high throughput experiments. Two immiscible phases used for the droplet based systems are referred to as the continuous phase and dispersed phase.
Andrew James deMello is a British chemist and Professor of Biochemical Engineering at ETH Zürich.
Paper-based microfluidics are microfluidic devices that consist of a series of hydrophilic cellulose or nitrocellulose fibers that transport fluid from an inlet through the porous medium to a desired outlet or region of the device, by means of capillary action. This technology builds on the conventional lateral flow test which is capable of detecting many infectious agents and chemical contaminants. The main advantage of this is that it is largely a passively controlled device unlike more complex microfluidic devices. Development of paper-based microfluidic devices began in the early 21st century to meet a need for inexpensive and portable medical diagnostic systems.
Microfluidics refers to the flow of fluid in channels or networks with at least one dimension on the micron scale. In open microfluidics, also referred to as open surface microfluidics or open-space microfluidics, at least one boundary confining the fluid flow of a system is removed, exposing the fluid to air or another interface such as a second fluid.
Secondary electro-spray ionization (SESI) is an ambient ionization technique for the analysis of trace concentrations of vapors, where a nano-electrospray produces charging agents that collide with the analyte molecules directly in gas-phase. In the subsequent reaction, the charge is transferred and vapors get ionized, most molecules get protonated and deprotonated. SESI works in combination with mass spectrometry or ion-mobility spectrometry.
Alexandra Ros is a German analytical chemist who is a professor in both the School of Molecular Sciences and Center for Applied Structural Discovery at The Biodesign Institute, Arizona State University. Her research considers microfluidic platforms and their use in analysis. She was awarded the 2020 Advancing Electrokinetic Science AES Electrophoresis Society Mid-Career Achievement Award.
