Your Own Pocket Laboratory
Topic Overview — Lab-on-a-Chip Devices & Micro-Total-Analysis System or μTAS
Wearable gadgets are on the rise, they are ubiquitous, you can find them everywhere nowadays from strictly fitness-oriented Fitbit to a beefed-up computer on your wrist like the iwatch, they provide non-medical/non-diagnostic vital signs information such as your heart rate, breathing, and activity levels. But none of them yet can tell you if you have a cold, an infection, or blood-borne diseases. That is because over 70% of the medical diagnostics come from biochemical testing of the blood itself, this is a well established medical standard that has garnered the reputation of being expensive, time-consuming, involving doctors, lab testing, and frequent back and forth that usually falls out of our favor when comes to maintaining a productive lifestyle. Fortunately, there is a thriving research field that is dedicated to bringing you portable, chip-sized, blood-testing-on-the-go devices to keep your health in the know.
So what is it about?
This exciting R&D (Research & Development) field is called Micro-Total-Analysis-Systems or μTAS which refers to the tiny (in micron-scale) assemblies capable of performing complete blood analysis using a very small number of testing reagents. The resultant stand-alone products are termed “Lab-on-a-Chip” or LOC devices because they are incredibly compact and efficient, able to carry out pre-programmed lab-test routines autonomously, automatically, rapidly, and cheaply. And their adaptation can be found in major research fields such as in Analytics (e.g. biological, chemical, environmental monitoring, medical diagnostics, and genomics) and pharmaceutics (e.g. drug discovery, screening, and manufacturing) as well as Detection Strategies (e.g. Single-cell detection, molecular sensors, and manipulators) and countless life science topics that aim to unravel this field further (e.g. fluid behavior at nano-scale, DNA interaction analysis and control, interfacial physics, and transport phenomena).
The rise of such amazing little machines did not happen overnight, it is research in the making for the past 6 decades. Motivated by visionaries who sought to bring lab testing closer to home and have a quicker turn-around time. Riding on the back wave of the microtechnology revolution around 1954 when semiconductor fabrication technology was invented for miniaturizing electronics and mechanical structures (termed Micro-Electro-Mechanical Systems or MEMS), it quickly found adaptation in handling liquid samples, a significant application that soon gave rise to μTAS. Since chemical reactions such as those occurring in a blood screening test are fluid-based, a series of controllable mini-valves, pumps, mixers, and other functional units are particularly helpful in handling biological liquid samples. Additionally, when a minute amount of fluids (less than a microliter) were confined to a small space (~ micrometer scale), a new set of physical laws kick in that dominates the interactive behavior of this liquid. This domain of research is termed “Microfluidics”, a topic that will be discussed in detail in another post. Today, μTAS and its resultant Lab-on-a-Chip devices is a thrilling research arena with a growing community constantly discovering new capabilities, integrations, and applications. Showing no signs of slowing, it continues to pick up pace in the translation of technology from laboratory space to the consumer markets, a maneuver that has been the pivotal challenge in gaining wide recognition.
Why is it so important?
The motivation for pursuing the development and advancement of μTAS type of devices are two folds. For one, their mission and accomplishment meets a human need and provides a potentially life-saving and disruptive market for consumers — that is us. As eluded to in the introductory, our modern medical examination still falls short of the desired outcome and efficiency, despite the advances we made and medical knowledge and experience gained. The doctor’s visit can never be just a one-time thing, even if you are perfectly healthy in every way, to be certain, the doctors would need to send you to specialists or labs for body imaging or blood, urine screening. After waiting for days to weeks for your results, you reschedule follow-up visits with the doctors to solidify his previous assumptions or suspicions. Then onto treatment prescription and more follow-ups to confirm healing progress or the lack of. And guess what, things can start over again if the prior diagnosis was incorrect. The cycle repeats once more. It is a time-consuming, discouraging, exhaustive, and expensive process that we have no choice but to live with. This can’t be the way of the future!
Wouldn’t it be easier if all the screening and diagnostics exist at the doctor’s office? And upon a suspicion, the doctor simply picks your finger for a drop of blood, and immediately confirms or rules out a disease? Would it be even greater for us commoners to have a set of these screening kits as well? When we suspect something is off, instead of waiting to see the doctor days away (did I mention how long it takes to get an appointment?!), you can run the autonomously operated device yourself and have the results automatically sent to a specialist for diagnosis, they will then confirm if something is wrong and you should go to the hospital immediately! Imagine the potential devastation we can avoid. Taking it even further, can you imagine how beneficial a cheap, fast, and portable screening device can be in a third-world country where a severe shortage of medical facilities and doctors is rampant? With μTAS in these supplies-deprived situations, lives can be saved by the thousands just by quickly knowing what pandemic is at work so solutions can be derived quickly.
Secondly, μTAS devices provide technological advantages in critical life science R&D domains such as the following:
Extremely Low Sample Requirements. Meaning that LOC devices consume a small number of samples, which in terms produce less waste, lower reagent costs, and less required volume for analysis. Think of the blood screening example, wouldn’t you want the Phlebotomists to draw as little blood from you as possible?! To give a number scale for the small volume, we are talking about an “nl” or a nanoliter for short. To give context, a drop of blood is about 50,000 nanoliter.
Faster Analysis and Turn-around Time. Because of the small scale, there is a very short diffusion distance for samples in liquids, energy dissipation becomes much faster, and surface-area-to-volume ratio and heat capacities start to increase significantly which collectively promotes an optimal chemical reaction environment for processes to proceed rapidly. To provide some context on fast the devices could run, the reaction will now occur in the sub-seconds range, going 1000th of a second and below. Compare this to the fastest shutter speed of a DSLR camera which I believe maxed at 8,000th of a second. The average human eye blinks at a 10th of a second.
Automated Control of Processes. Unlike working in a wet laboratory, where you may have a benchtop full of beakers, test tubes, and chemicals that need to be carefully, delicately, and accurately handled. In a μTAS environment, every physical construct, active units, and reagents are compartmentalized and isolated to only execute when a command is inputted manually. This level of controllability minimizes clutter and prevents mistakes. Additionally, faster process responses also aid in the swift control of key stages of chemical reactions as well. Imagine an automated factory, where every moveable part and passive elements are precisely programmed and manipulated, much like the Borg cubes in my favorite sci-fi franchise: Star Trek Next Generation, this is what it feels like inside the μTAS.
Compactness and Portability. It is a no-brainer, given such a small volume of fluid samples requirement and miniaturized physical structures, all functionalities are super tiny by our standard of daily comparison, even after they are fully compact up together. Think of the telephone from 50 years ago and the smartphone of today, a typical LOC device is frequently compared with the size of a penny. Small enough to tug into your pocket for on-the-go usage!
Cost-effectiveness. Have you noticed as your electronic gadgets get smaller, assuming all functions remain the same, their costs never spike up but went down instead? The fact is that we can now make incredibly small electronic components at a massive scale, a million of them at once (#microfabrication), on some 4, 8, or 12 inches silicon disk. So essentially, if you can make a lot of something quickly and effortlessly with materials that are abundant on this planet, you can have a cheap product per unit cost. The actual cost-of-manufacturing of a LOC device would be in the range of a few cents, but as we know, the reality is that capitalism will force you to pay a little more than that.
Multitasking Capability or Process Parallelization. Another byproduct of being so darn small is the ability to mirror functionalities. If one chemical reaction only takes up one-tenth of the space, then why not multiple it by 10 to fill up the whole space with the same or similar processes?! Such multiplication adds reproducibility as well as alteration to perform extra screening and analysis. In a penny-sized LOC device (19 mm in diameter by 1.5 mm in thickness), let’s assume one complex chemical function occupies a millimeter of space, then we can have 18 times more horizontal space and some room to ‘breath’ in the vertical space. This is not to mention stacking up the pennies to mount even more functions. The limitation would resort to how much is too much for the size of the device to start hindering your specific lifestyle, considered what this device can do for you — such as screening your saliva for all species of E-coli bacteria.
Safe Platform for Bio-hazards. No one wants any experimental technology to be tested in their backyard, for the potential hazards that may inflict on the safety and health of your loved ones. Bio-hazards can be very dangerous, in fact, chemists working in the lab run the highest risks of accidents, injuries, and even death in all other fields of scientific research. Unlike solid objects, chemicals can be unstable elements that can exist in all phases: sedimentary, gaseous, and liquid form. Their flexible existence in an open space can be a disaster waiting to happen if not properly handled. As a result, here comes the μTAS where everything can be physically confined, sorted, and compartmentalized to ensure no undue fuss and mess. It is certainly not storage space, since it is capable of executing your experiments all within its enclosed environment as well. It is genetic testing on the moon, when things do go wrong, we will just have zombies to look at from our telescopes, at the safety of our earth homes.
How does it work?
The fundamental fabrication technology behind μTAS and LOC devices is the photolithography process. Essentially a top-down fabrication strategy derived directly from semiconductor fabrication, it is based on silicon substrates to hold and create either the functional construct or a template for making copies of the imprinted design. In other words, opposite from 3D printers in which a construct is made from piece to piece assembly, photolithography ‘prints’ the construct directly on a block of the dissolvable scaffold, then etches away the extras to reveal the final features. A slide deviation from this method is the soft lithography fabrication method. It still requires an imprint on the block of the scaffold, but the resultant features serve as a template for making multiple copies using another soft material, commonly silicon-based to ensure biocompatibility and chemical inertness. These copies can then combine with themselves or other material to form an enclosed compartment ready for action. The specifics of the microfabrication technology are very interesting, I wrote another post on this here.
What are some of the applications?
There are countless adaption and applications of μTAS and LOC devices, they have been classified as “Point-of-Care (POC)” or “Point-of-Care Testing (POCT) diagnostic devices for their sample-to-results capability. One of the most common and day-to-day examples that successfully infiltrated the consumer market is the home pregnancy stick. It is a variant of the typical LOC devices which is based on paper rather than plastic or silicon materials. It runs a chemical reaction that screens specifically for a human hormone known as the chorionic gonadotropin (hCG) which presents in the urine of pregnant women. Upon detection, another chemiluminescent process enables the dashes to indicate the existence or lack of this hormone. And it all happens in a matter of minutes. A great deal of efforts is currently contributing to the immediate deployment of infectious diseases screening such as HIV and Malaria. The slow and steady pace is the result of accumulative technological hurdles to ensure device reliability, cost-effectiveness, result interpretation, and autonomous operation. They are no easy tasks, especially when comes to human lives on the stake, just think of the existence of the FDA in the United States, drugs invented decades ago are still being evaluated for potential dangers and negative consequences. So, I would stay patient, and wait for the dawn of a new era where pocket-able diagnostic devices are a common and daily commodity, and our health is no longer a guessing and waiting game at the doctor’s office.
The When & Who
Ángel Ríos, Mohammed Zougagh, Mónica Avila. Miniaturization through lab-on-a-chip: Utopia or reality for routine laboratories? A review. Analytica Chimica Acta, Volume 740, 2012, Pages 1–11.