Microfluidics and Lab-on-a-Chip Devices: History and Challenges

Abstract

The rapid advances in microfabrication and nanofabrication in combination with the synthesis and discovery of new materials have propelled the drive to develop new technological devices such as smartphones, personal and tablet computers. These devices have changed the way humankind interacts and communicates and this change occurred very quickly due in part to decreased production and commercialization costs. As a result, not only nations with powerful economies but also emerging economies and poor countries can get access to these technologies and experience new ways to interact and instantly communicate what is happening around us. Following the advances of all these communication devices as well as those in microfabrication and nanofabrication and the emergence of new materials, technologies such as lab-on-a-chip (LOC) and micro total analysis systems (microTAS) were also boosted, albeit at a slower pace. LOC and microTAS applications have principally been utilized in the biomedical, food and environmental fields. But lately they have also found their place in the synthesis of new chemical compounds and the fabrication of nanostructures. It has become obvious that the LOC and microTAS technologies need to join forces with those behind the new communication devices which provide sources of power, detection and data transmission complementing the features that lab-on-a-chip and microTAS platforms can offer. An increasing number of microfluidic-based devices, developed both in small start-ups and large pharmaceutical and biomedical companies, is being released and entering the market. This chapter offers an overview of the first events in the history of LOC and microTAS devices, the biggest achievements and the challenges that still need to be overcome in order to accelerate the use of this technology.

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1.1 History

The origin of microfluidics devices fabricated using the technology of micromechanics is usually associated with the late 1960s and the works on gas chromatography at Stanford University and the ink jet printer nozzles developed at IBM. But hundreds of years earlier, researchers were already curious about the information they could extract from body fluids and were trying to understand the behavior of liquids confined in small diameters. Hippocrates (400 BC), Galen (200 AD), and Theophilus (700 AD) among others were interested in analyzing urine samples as a means of interpreting the functions of the human body (Gazzaniga 1999; Kouba et al. 2007; Wallis 2000). They performed these analyses bedside and tried to match the color and appearance of urine with symptoms, mainly fever and psychiatric disturbances. They did not have the possibility to use microfluidic chips; instead, they investigated the urine samples in examination flasks known as “matulas” verifying the color and appearance of the sample (Wittern-Sterzel 2000). They even tried to standardize this analysis method by drawing diagrams and pictures of “matulas” of colored urine to be used as a diagnostic tool (Kouba et al. 2007).

Hundreds of years later, James Jurin, a British physician and natural philosopher (1684–1749), Jean Léonard Marie Poiseuille, a French physicist and physiologist, and Gotthilf Heinrich Ludwing Hagen (1791–1884), a German physicist and hydraulic engineer, worked on describing the behavior of fluids that were confined in glass containers of small diameters. They published their studies on capillarity, in the case of Jurin, and formulated the famous Hagen–Poiseuille equation that describes the pressure drop in a fluid flowing through a cylindrical pipe establishing the basis of the theory explaining the behavior of fluids at reduced scales.

Today, thanks to the advances in microfabrication and nanofabrication and the synthesis of new materials, researchers can confine fluids into microchannels or nanochannels instead of “matulas” and have theoretical tools and simulation software that help them predict and understand the behavior of fluids contained in microfluidic devices. Currently, not only body fluids but also cells, tissues and even a whole organ can be investigated inside microfluidic chips.

As mentioned above, thanks to the new fabrication methods and available tools, the end of the 1960s saw the development of a first prototype of a quadrupole GC/MS by Finnigan Instrument Corporation who delivered it to Stanford and Purdue University. This first instrument cost 100,000 USD and it was controlled by a minicomputer (Brock 2011). A couple of years later, following the idea of William Thomson (later knows as Lord Kelvin), who in 1867 patented the use of electrostatic forces to control the release of ink drops onto paper, in 1951, Siemens produced the first continuous inkjet printer used in medical strip chart recorders. Then, in 1976, researchers at IBM produced the first commercially available continuous forms of laser printers (Bassous et al. 1977).

In 1993, Andreas Manz published a fundamental article describing the fabrication of a miniaturized capillary electrophoresis-based chemical analysis system on a chip (Harrison et al. 1993). In this work, a microchip of 1 cm by 2 cm was micromachined in glass and electroosmotic pumping was employed to drive the fluid flow and perform electrophoretic separation on-chip.

Just 1 year after the publication of Manz’s work, the first International Conference on Micro-Total Analysis Systems took place in Enschede, The Netherlands, and has since then strengthened its position as the premier forum for reporting the latest research results in microfluidics, Lab-on-a-Chip, microfabrication, nanotechnology, integration and detection technologies for life science and chemistry (www.cbmsociety.org).

In 1998, Professor George Whitesides, one of the leaders and more active members of the microfluidics and Lab-on-a-Chip community, published an article on the rapid prototyping of microfluidic systems in polydimethylsiloxane (PDMS). This publication described the design and fabrication of microfluidic chips in a transparent elastomeric material in less than a day using a photolithography technique. It had a large impact on the microfluidics community and pushed the field forward providing researchers with an easy and fast fabrication method that has been widely used in various studies (Duffy et al. 1998; Xia and Whitesides 1998).

Two years later, the group of Dr. Richard D. Fair at Duke University (USA), published an article on the rapid actuation of discrete liquid droplets accomplished by direct electrical control of the surface tension (Pollack et al. 2000). This is one of the first publications describing a liquid handling technology known as digital microfluidics. This handling technique allows a controlled manipulation of picoliter- to microliter-sized droplets independently addressed on an open array of electrodes. This new method had a huge impact on chemical and enzymatic reactions, DNA-based applications, immunoassays, clinical diagnostics, cell-based applications, and proteomics due to its flexible device geometry, simple instrumentation, and easy integration with other technologies (Choi et al. 2012).

Seven years later, a new fabrication method was published by Prof. Whiteside’s group describing the use of paper as a new, portable, low-cost alternative for the development of bioassay microfluidic devices (Martinez et al. 2007). By patterning paper, Whitesides and coworkers created well-defined millimeter-sized channels and hydrophilic and hydrophobic zones enabling the transport of fluid to desired locations without the need for pumps due to the capillarity effect. This new fabrication method offered a cheap alternative for the development of biosensing platforms at a very low cost that could be applied in countries with limited resources (Yetisen et al. 2013). More details regarding the use of paper-based microfluidic devices can be found in Chap. 7.

A couple of years ago, a technology called 3D imprinting, developed in the early 1980s at Ultra Violet Products in California by Charles Hull, probed the possibility of fabricating miniaturized fluidic reactors for the chemical syntheses of secondary amines, gold nanoparticles, and large polyoxometalate clusters (Kitson et al. 2012). One of the more attractive features of this new technology is the possibility to fabricate devices with three-dimensional features in a quite simple way which is expected to help the manufacture of large-scale integrated multilayer devices and their standardization between laboratories. This could possibly start the third decade of microfluidic revolution (Gross et al. 2014; Lee 2013).

A clear example of the impact of the 3D imprinting technology can already be found in studies involving cells and organs-on-chips (Kim et al. 2008; Tasoglu et al. 2013; Young 2013). By using 3D printing, microfluidic environments mimicking the in vivo situation can be fabricated providing a “closer to reality” environment that is being used in pharmaceutical labs to evaluate new drug candidates. Recently, the idea of building a body-on-chip device has been presented (Moraes et al. 2013; van der Meer and van den Berg 2012). The idea involved connecting compartmentalized environments in which different cells are cultured to mimic multiple organs that will be interconnected or isolated depending of the application in order to recreate a human body. This will have a big impact on the biomedical field, offering researchers a new test tool where new medicines and treatments can be tested.

As will be shown throughout this book, microfluidics and lab-on-a-chip devices offer a long list of attractive advantages for research in numerous fields requiring a low consumption of sample and reagents, portability, low-energy consumption, rapid response and multiplexing analysis, etc. However, challenges regarding its application at a large scale, the possibility of work with bigger volumes, the fabrication of low-cost and user-friendly devices and its integration with other analytical techniques are issues that need to be solved in order to accelerate the irruption of these technologies in our daily lives in a manner similar to that of smartphones and personal computers. In fact, there are many recent reports of LOC devices integrated in smartphones. The idea is to connect the microfluidic devices with the smartphone and take advantage of the features available in the latter, i.e., the power source, data transmission, and optical detection system (Mark et al. 2012; Yetisen et al. 2014).

As will be seen in the chapters ahead, several strategies to overcome these challenges are being successfully implemented and resulting in the commercialization and fabrication of new microfluidic, lab-on-a chip and microTAS devices (Araci and Brisk 2014; Chin et al. 2012) as presented in Table 1.1.

Table 1.1 Companies working on the design, fabrication and/or application of microfluidic, lab-on-a-chip and μTAS devices

Researchers that are interested in learning, discussing, and sharing experiences regarding the use of microfluidics have multiple options for this through journals, conferences, blogs, and forums focusing on microfluidics, some of which are presented in Tables 1.2 and 1.3. These alternatives offer a great environment to exchange ideas, tips, and experiences and hopefully create a community for starting new collaborations between scientists from different backgrounds (chemistry, physics, biology, material science). Such collaborations are one of the reasons that microfluidics has been able to expand its impact and should definitively increase this impact on our lives.

Table 1.2 Sources of information about microfluidics and lab-on-a-chip

Table 1.3 Conferences on microfluidics, lab-on-a-chip, and microTAS technology