Lab on a Chip Blog

From space shuttles to military equipment, or even the kitchenware that we use on daily basis, lasers have found use in more places than we often realise. Interestingly, the solid-state lasers were believed to be a solution to an unknown problem after their invention in 1950s. In that time nobody—including their developer Charles Townes—noticed that the lasers were one of the game changer inventions in the world’s history. After tens of years, in 1964, the laser technology was awarded with a Nobel prize when its potential for diverse applications were realized.

So far we have only discussed solid-state lasers, but there is definitely capacity in the laser world to improve the performance and versatility with the help of little twists, such as optofluidic lasers. “Optofluidics” is a synergic combination of optical systems and microfluidics. In other words, optical systems are built or synthesized from liquids, aiming to serve as good as their solid-state equivalents. For example, two immiscible liquids form a smooth surface in their interface, leading to a laser cavity or an optical resonator with a very high Q-factor that allows for operating at low energy levels. This emerging field gains importance when considering most of the biochemical reactions that occur in aqueous environments. Optofluidic laser systems are flexible to change their optical properties by just replacing the liquid media; and with this twist, lasers have new application areas including diagnosis of genetic disorders at the cellular level and in vivo biosensing.

What is more exciting about the optofluidic lasers is that they can be biodegradable and easily tunable in microenvironments. Researchers in University of Michigan recently showed that one of the most abundant pigments on earth, chlorophylls, can maintain both biodegradability and tunability in optical systems owing to their fluorescence capabilities. Chlorophylls have a high Q-factor, dual-absorption bands in the visible spectrum, and a large shift between absorption and emission bands, suggesting that chlorophylls can be used as donors in fluorescence resonance energy transfer (FRET) laser (Figure 1). In this study, chlorophyll a was isolated from spinach leaf and used as the gain medium and the donor to develop a novel optofluidic laser. Two lasing bands of chlorophyll a was investigated by both theoretical and experimental means. Concentration-dependent studies enabled more insight for the mechanism determining when, where, and why the laser emission band appears. This new technique seems to gain increasing attention for applications in in vivo and in vitro biosensing, solar lighting and energy harvesting.

Before the 1700’s, when dissection techniques were not yet available, the cause of mood changes were thought to be the replacement of liquids and vapors in the body. The biology of the brain has been better understood since the discovery of research and test tools. However, occupying only about 1/50 of the body mass, the brain is perhaps the most complicated organ to study. National Institute of Neurological Disorders and Stroke’s list of over 400 neurological disorders can be seen as a sound proof of this exciting- and frustrating- fact.

Figure 1. The effects of biomechanical forces on the brain

Biomechanical forces on neurons play a fundamental role in neuronal physiology, which, in turn, affect brain development and disorders. During the growth of neurons, the tension created by the biomechanical forces are suggested to influence the cells’ motor activities, gene expression, neurotransmitter release, together with neurite growth and network connections (Figure 1). Research on the biomechanical forces can definitely help us to understand how the brain works, but many questions related to these forces remain unanswered. Quantitative measurements of the cell activity seem to be the only possible path to find satisfying answers to those questions.

A comprehensive list of experimental techniques involving both conventional and alternative micro&nanotechnology approaches have been recently brought to the attention of scientific community by Di Carlo and his coauthors. In their recent critical review, both advantages and disadvantages of conventional tools—namely motor-driven pressure, patch membrane pressure, osmotic pressure, fluid shear stresses, and deformation of flexible elastomers—, microtechnology tools—including atomic force microscopy, micropatterning, and some other potential techniques—, and nanotechnology tools—such as ferromagnetic and piezoelectric nanoparticles— are discussed.

The literature reports provided in the paper suggest that micro and nanotechnology tools offer better spatiotemporal resolution and throughput when compared to conventional techniques. The cellular functions and the possible technologies for the characterization of those functions are further described (Figure 2). For instance, behind-the-scene biological mechanisms for recovery in traumatic brain injuries can be determined by applying the biomechanical forces at the right place and right time to ultimately mitigate the injuries.

Figure 2. The influence of biomechanical forces on the neuron functions and available technologies for their investigation.

This article, published on 26 April 2016, is included in the Lab on a Chip Recent HOT Articles themed collection.

To download the full article for free* click the link below:

Micro- and nano-technologies to probe the mechano-biology of the brain
Andy Tay, Felix E. Schweizer, and Dino Di Carlo
Lab Chip, 2016,16, 1962-1977
DOI: 10.1039/C6LC00349D, Critical Review

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About the webwriter

Burcu Gumuscu is a PhD researcher in BIOS Lab on a Chip Group at University of Twente in The Netherlands. Her research interests include development of microfluidic devices for second generation sequencing, organ-on-chip development, and desalination of water on the micron-scale.

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William Sewell at Massachusetts Eye and Ear Infirmary and Harvard Medical School and Jeffrey Borenstein at the Charles Stark Draper Laboratory in Massachusetts have developed an automated micropump device for direct delivery of drugs into the perilymph fluid within the cochlea. This has potential for use in the treatment of sensorineural hearing loss and would remove the toxicity issues that are common when drugs are administered systemically. This is one of the most common forms of hearing loss and is caused by damage to the sensory hair cells or to the auditory nerve.

Components of the device and process flow for one drug delivery cycle

Due to the small volumes of perilymph fluid within the cochlea (~ 0.2 mL) and the sensitivity of the ear, the authors have developed a reciprocating delivery system, where an accurate volume of the concentrated drug can be infused and, once given time to distribute, the same volume of fluid can be withdrawn, resulting in zero overall net increase in cochlear fluid. The specific design also minimised the dead volume present in the device in order to reduce the amount of pumping needed, and by incorporating capacitors, prevented high flow rates during pumping, which can lead to cochlear damage.

The authors emphasise the need for a device that is small and lightweight enough to be implanted near to the cochlea and that is also able to administer precise sub-microliter volumes of fluid over several days or months. The microfluidic device presented in Lab on a Chip has been fabricated onto a ~4 x 3 cm chip and is capable of delivering accurate and repeatable volumes of fluid over more than 1000 pump strokes. The authors highlight that by incorporating the device onto a head mount, this particular design could be used in animal models for preclinical drug characterisation, where extensive studies are required.

All the fluidic components of this system have been incorporated into the chip, so that, if battery operated, it could be used as a stand-alone device. In this design, a separate controller was used; however, it is stated that the control circuitry could also be miniaturised and incorporated into the chip, for use with a battery. Efforts were also made to minimise the power consumption of the pump for this purpose. The main components of the device are a drug reservoir, a fluid storage capacitor which contains artificial perilymph for flushing the system, an infuse-withdraw line, and multiple valves to control the different steps of the drug delivery process, as shown in the diagram.

Dose control was successfully demonstrated by loading the pump with fluorescein as the test drug and monitoring the fluorescence of the aliquots collected following different dosage schemes. Several studies were also carried out on guinea pigs using a glutamate receptor antagonist as the test drug. This compound reversibly suppresses compound action potentials (CAPs) in the cochlea – monitoring changes in CAP amplitude and threshold can be used to test for hearing loss.

The results showed that fully reversible hearing loss was induced and this was used to estimate the optimum wait time between infusion and withdrawal for the reciprocating delivery. The distribution of the drug in the ear was also monitored by measuring changes to CAPs at different frequencies and comparing these to the known tonotopic organisation of the cochlea. To test for cochlear damage, the authors monitored another hearing response (distortion product otoacoustic emission) that was not expected to change, and determined that there was no acute mechanical damage.

This drug delivery system has excellent potential for use in clinical and preclinical trials and also for long term treatment of hearing loss using existing drugs. The potential for battery operation is particularly important, and is an aspect that the authors are now focusing on for future work.

To download the full article for free* click the link below:

Microfabricated reciprocating micropump for intracochlear drug delivery with integrated drug/fluid storage and electronically controlled dosing
Vishal Tandon, Woo Seok Kang, Tremaan A. Robbins, Abigail J. Spencer, Ernest S. Kim, Michael J. McKenna, Sharon G. Kujawa, Jason Fiering,  Erin E. L. Pararas, Mark J. Mescher, William F. Sewell, Jeffrey T. Borenstein
Lab Chip, 2016, 16, 829-846
DOI: 10.1039/C5LC01396H

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About the webwriter

Claire Weston is a PhD student in the Fuchter Group, at Imperial College London. Her work is focused on developing novel photoswitches and photoswitchable inhibitors.

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If the Lab on a Chip HOT articles are anything to go by, using microalgae as a feedstock for biofuel is definitely a flourishing research area.  Microalgae is a particularly attractive feedstock as it grows rapidly, has a large oil content, and can be grown pretty much anywhere.

David Sinton and co-workers at the University of Toronto have previously published in Lab on a Chip on this topic and have now reported their work on optimising the conditions for converting microalgae ‘biomass’ into crude biofuel (‘biocrude’). The process by which this is achieved is known as hydrothermal liquefaction. High temperatures and pressures are employed to break down the organic compounds from the biomass into the oils that make up biocrude.

a) Fluorescence images at increasing reaction time; b) Fluorescence and dark-field imaging of fluids at inlet and outlet.

The Sinton lab have developed a microfluidic chip in order to accurately control the reaction conditions of this process and also to study the effect of changing conditions on the biofuel that is formed. The continuous flow and small volume of the chip allow very fast heating of the algal slurry so reaction times can be accurately studied – in fact the heating rate achieved is the fastest reported to date. The slurry was analysed in situ by fluorescence imaging and changes to the fluorescence signature were monitored. Over the course of the reaction, the fluorescence signal due to chlorophyll disappeared and a new peak developed, indicating the formation of the aromatic compounds that are a characteristic component of crude oil and plant based oils.

Further analysis of the samples collected from the chip outlet found that the energy content (measured by the elemental composition) of the biocrude reached saturation after short reaction times – much before the fluorescence signal stopped changing. In addition to this, non-fluorescent droplets could be seen inside the reaction chamber, as shown in the diagram on the left, which were presumed to comprise of aliphatic oils. These findings indicate that analysis of the elemental composition alone is insufficient to measure chemical conversion to biocrude and methods such as fluorescence imaging should also be employed.

This work is the first example of using a microfluidic platform in hydrothermal liquefaction research and just goes to highlight the versatility of lab-on-a-chip systems.

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Biomass-to-biocrude on a chip via hydrothermal liquefaction of algae
Xiang Cheng, Matthew D. Ooms and David Sinton
Lab Chip, 2016, 16, 256-260
DOI: 10.1039/C5LC01369K

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About the webwriter

Claire Weston is a PhD student in the Fuchter Group, at Imperial College London. Her work is focused on developing novel photoswitches and photoswitchable inhibitors.

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*Access is free through a registered RSC account until 29/02/2016.

The Biomicrofluidics System Group at the Dalian Institute of Chemical Physics in China have published an exciting paper in Lab on a Chip where they have used paper as a material to grow and differentiate human pluripotent stem cells.

Recently, there has been much research into generating biocompatible materials for creating microenvironments for the growth of stem cells, with the aim of improving their regenerative potential. Using paper as the material has several advantages over the conventional polymers – it is cheap and readily available, it is biocompatible, and the bundles of cellulose microfibers that make up paper provide a porous 3D structure.

Identification of cardiomyocytes derived from pluripotent stem cells on paper

The authors used three different types of paper to identify which were best for stem cell growth – printing paper, filter paper, and nitrocellulose membrane. The paper was pre-coated with the required gels and the stem cells were seeded onto the surface. Initially, the stem cells were differentiated into cardiomyocytes prior to being added to the paper to test if the differentiated cells were able to grow on the different types of paper. The cells aggregated on both printing and filter paper and demonstrated spontaneous beating function, but not on the nitrocellulose membrane. These tissues also maintained their beating function for up to three months. The stem cells were then added to the paper prior to differentiation and the required cardiac differentiation procedures were carried out. The cells differentiated to the cardiomyocytes on all three paper types, however the cardiac-specific marker was only expressed weakly on the nitrocellulose membrane. Within two weeks a strong beating function was observed for the printing paper, but not the other paper types. The authors suggest the printing paper had a better pore size to support the cells than the filter paper, while the nitrocellulose membrane didn’t have a favourable microstructure to support growth of cardiac tissue.

Along with this article, there are some impressive videos showing the cardiac tissue beating that are well worth a watch!

To download the full article for free* click the link below:

Human induced pluripotent stem cell-derived beating cardiac tissues on paper
Li Wang, Cong Xu, Yujuan Zhu, Yue Yu, Ning Sun, Xiaoqing Zhang, Ke Feng and Jianhua Qin
Lab Chip, 2015, 15 , 4283-4290
DOI: 10.1039/C5LC00919G

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About the webwriter

Claire Weston is a PhD student in the Fuchter Group, at Imperial College London. Her work is focused on developing novel photoswitches and photoswitchable inhibitors.

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