#SCIENCE | Prognostic medical devices: The wave of the future in healthcare

by Reynaldo Parel

Imagine a world where diseases could be predicted before they happen, instead of diagnosed and cured by drugs or surgery. Where doctors could change a patient’s lifestyle, diet, and exercise, and prevent the disease.

A bishop once told me, long ago before the advent of the diagnostics revolution, that God designed the human body to produce very small amounts of antigens to signal the advent of diseases, and was just waiting for man to rise to the level of intelligence to create devices that would be able to detect these.

Flashback to 1989, when I met Kary Mullis, who won the Nobel Prize in Chemistry in 1993 for a technology called Polymerase Chain Reaction (PCR), and he said: “I want you to design a tube that is so thin and so uniform in thickness, it has never been done before in plastic!”

And we asked, why plastic?

The answer is because we will produce millions and millions of these “thermocycler tubes”, they have to be manufacturable, cheap, robust, and accessible to ordinary folks. It blew our minds, because the concept of amplifying (making copies) of DNA was not only foreign to us young plastics engineers, but mind-boggling as well.

The way he explained PCR to our simple minds was like this: Imagine our DNA chain as a railroad track twisted like a helix. Under heat, this railroad track unravels into a straight track. The polymerase enzyme takes base pairs from other sections of this railroad track and puts it in the same sequence as the DNA sequence you want to copy. And it can do this hundreds, millions, even billions of times.

He said the thermocycler tube wall thickness must be incredibly uniform — so uniform in fact that it was impossible to produce with the state of plastics technology at the time. As I said, it blew our minds!

Fast forward 3 years later, and the first GeneAmp PCR System was developed and the ultra-thin, ultra-uniform PCR thermocycler tube was a reality. I certified the polypropylene material that is still used today in all your labs.

I have a Polaroid photo of myself and the people from PerkinElmer (the [producers] of the PCR tubes) kicking the first box of PCR tubes out the door. One of its first applications, even before it was ever mass-produced, came about from a very tragic incident in Petaluma in 1993.

The FBI approached PerkinElmer and said: “We heard you have a new method for making copies of DNA. We have a very small spec of blood on the scene where a little girl by the name of Polly Klaas was abducted and subsequently murdered, and which we believe was of the perpetrator. The spec is so minute, we can’t identify it.”

The District Attorney held up that tube on TV and said, “This is Polly’s blood.” I ran up and down my neighborhood and yelled, “That’s my tube! That’s my tube!”

Fast forward to 2000. We made the very first microfluidics chip in plastic at Aclara Biosciences. Seventeen years ago, advances in materials, machinery, equipment, and software were still in their early stages to enable replication of micron plastic features. It was a struggle.

Fast forward some more to 2010. We were using injection-compression molding technology, borne out of the CD/DVD industry and morphed by Sony DADC Biosciences for applications in biotechnology, to mold at Illumina a credit-card sized PCR chip with 2.8 million wells, each well 30 microns in diameter. Who would have thought this was possible 25 years ago!

I tell this story about PCR because as the engine that revolutionized research to sprout new fields in DNA sequencing, genomics, bioinformatics and the like, this surging wave spurred the plastics industry to develop new techniques, machinery, tools, and polymers to meet the demanding challenges of replicating increasingly smaller and smaller features.

The result was the plastic microfluidic chip embedded in almost every diagnostic medical device today.

Polymer-based microfluidic chips: The engine that is driving a new generation of medical devices called prognostic point-of-care devices

The impact of the microfluidic chip in the life sciences is similar to that of the microchip in the Information Sciences. If the microchip reduced building-size computers to the size of your hand, the microfluidic chip is reducing building-size laboratories and hospitals to the size of your thumb.

Why plastic? Consider this: it costs around $0.30 (PHP 15) cents per sq cm for a silicon-glass chip and $0.03 (PHP 1.50) per square centimeter (cm) for the same chip molded in Cyclic Olefin Polymer. As Mullis said, it must be “manufacturable and cheap, robust and accessible” to the masses.

The push for accessible microfluidic chips over the last 15 years resulted in the transition from glass to polymer substrates, because of the latter’s scalability, manufacturability, lower cost, and biocompatibility. Microfluidics means smaller reagent volumes (some of which can cost several hundred or thousand dollars per liter), but also shorter reaction times and faster analyses results (from days in a lab, to hours or even minutes), on-site delivery of test results, smaller sample sizes (blood, cells, etc.), and greater number of iterations (from tens to several millions) — all of these translating to less cost, portability, and disposability.

Hence, the development of exciting new devices such as the ubiquitous Lab-on-a-Chip, and the more recent Organ-on-a-Chip and Body-on-a-Chip, each about the size of your thumb or palm. All of these devices take advantage of the unique fluidic flow properties at the microfluidic level, and most if not all are powered by micropumps and valves without external power sources except capillary pressure, all integrated into the plastic design. Plus, they were moldable!

These were accomplished due to a convergence of research teams with inventions for advanced immunoassay devices and dense arrays (from sample preparation, to amplification, to detection, to immunoassays, to sequencing), with teams of plastics engineers who developed these new techniques to make their scale-up a reality.

As healthcare moves away from curing diseases to predicting diseases via handheld POC (point-of-care) devices, the advent of the polymer-based microfluidic chip is the enabling technology that is making this happen. These new devices are called Prognostic Devices.

At the heart of these disease-predicting devices are novel developments in nano-biosensors and ultra-sensitive DNA detection.

One example: Imagine a microfluidics-based POC device that can detect BNP, a cardiac marker antigen that is produced by the heart in very minute quantities before the advent of Arrhythmia in a patient. Then the doctor can prevent the disease by changing the patient’s lifestyle, diet, and exercise.

There is such a device right now, in production by a China-based company, Micropoint Bioscience, which was initially funded by the Chinese government, as there are 100 million people with incipient arrhythmia-risk in the Chinese mainland, many without direct access to government hospitals.

The device is called mLabs® Precision POC Testing, which is an immunoassay diagnostic platform, based on their patented microfluidic technologies and advanced fluorescence detection.

According to Micropoint’s CEO, Nan Zhang, the device currently tests for D Dimer (a protein released by blood clots), but more cardiac markers are coming soon, including Troponin I (a marker for heart muscle damage), hs-Troponin I (a marker for acute thrombosis syndrome), and the aforementioned BNP.

One of the most exciting predictive tools that have come out of the pipeline is liquid biopsy, a technology that can detect very tiny bits of cancer DNA floating in a patient’s bloodstream, using a very small blood sample.

Its leading proponent is Silicon Valley start-up Guardant Health, whose CEO and Co-Founder, Helmy Eltoukhy (my old boss) said recently that “we aren’t far away from creating blood tests that can be used to detect the earliest stages of cancer.”

Liquid biopsy detects and interrogates cell-free DNA, not CTCs (circulating tumor cells), to detect very early stage cancers in the human body. The future of healthcare is predictive medicine and liquid biopsy is just one of the tools that are making this happen!

So why polymer-based microfluidic chips?

Over the last 25 years, microfluidics has been largely silicon-glass based, due to their micron-size features, which was difficult to replicate using conventional molding methods and materials.

The state-of-the-art has finally caught up with the exacting demands of the microfluidics field. There are exciting breakthroughs in the following technologies that are enabling microfluidic chip injection molding:

  1. Conformal cooling, microstructure and microfluidic tooling
  2. Microchannel molding, dense micro-array and replication processes
  3. Surface modification and surface treatment technologies
  4. State-of-the-art encapsulation and polymer welding techniques
  5. Advanced polymers and medical plastics
  6. Micro 3D printing and bioprinting

There are exciting developments in automation, simulation software, molding equipment, and micron-feature replication that have advanced in lock-step with the growth of the microfluidic chip field.

These new technologies are helping make PCR and microfluidics the two core technologies driving our biotech revolution and indeed our medical emancipation.

It’s a brave new world, enabled by the powerful engine of microfluidics!

Addendum:

This is me on this day back in October 15 1991, molding the very first PCR thermocycler tube that is ubiquitous today. PCR has come a long way since then. Glad to be a part of the beginning of this story!

Actual first-shot prototypes of the PCR thermocycler tubes I molded back in 1991. They are in a glass case for display, and I show it to my mentees and prospective plastics engineers, among other industry firsts.

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