Medicine and the Life Sciences

MARIE FREEBODY, CONTRIBUTING EDITOR, marie.freebody@photonics.com

Imagine testing for a host of diseases and conditions in a single sample of blood, saliva, urine or even a few tear drops. Cancers, heart conditions, viruses, food allergies and sepsis are just some of the tests that could be carried out using next-generation lab-on-a-chip concepts that are being explored and patented by today’s top researchers.

Such disposable chips could be loaded with the sample and then quickly analyzed using a computer, tablet or even a smartphone for fast diagnostic testing and simple disease monitoring and management.

It’s not just health care worldwide that could be transformed; a host of other applications stand to benefit from such scalable photonics — from environmental monitoring and food sorting to fingerprint detection and lighting to enhance health.

Compared with today’s often bulky lab equipment, which requires either the patient to visit a clinic or sending samples away for testing, integrated photonics could transform the health care system, reduce waiting times and costs as well as provide better care for patients worldwide. For those in rural or underdeveloped areas, it may bring direct access to doctors for the first time.

“What is really important is that such lab-on-chip sensors have been applied for real diagnostic applications of pathologies and conditions employing only few drops of bodily fluids such as blood, saliva, urine or tears,” said Laura Lechuga, leader of the Nanobiosensors and Bioanalytical Applications Group at the Catalan Institute of Nanoscience and Nanotechnology (ICN2), Barcelona, Spain. “This is opening the route to an instantaneous diagnostic for the identification of many diseases — such as cancer or infection — at a very early stage in a fast, simple and cost-effective way.”

Example of a tunable external cavity laser containing a tunable reflective mirror with hybrid attachment of two chips of different material — in this case an InP gain chip and TriPleX chip. Courtesy of XiO Photonics.

Hurdles: integration and demonstration

Translating any new technology from basic science into products always poses challenges. This is particularly true for devices intended for life sciences or clinical applications where living things — and people in particular — are involved.

Crucial obstacles must first be overcome: One significant effort is gathering the relevant statistics for evaluation of success. Since there are so many variables in medical procedures, it is often not easy to gather success rates. Therefore, translating new technologies into existing clinical settings would require a convincing argument to improve success rates that are challenging to statistically determine.

“In the aspect of the real bioapplication, the key challenges are to attain enough selectivity and sensitivity in the detection when using only few drops of body fluids without any pre-cleaning or conditioning of the sample,” Lechuga said. “This aspect is common for other transduction schemes, not only to optical sensors, [therefore] the improvements are coming by the hand of other disciplines, such as chemistry or biotechnology.”

Another crucial challenge is full integration in compact platforms: Efficient in- and out-coupling of light in tiny waveguides is needed, as is a reliable solution for multiplexed actuation — detecting more than 25 biomarkers in the same patient’s sample, for example.

The combination of electronics with photonics also is an important aspect for the future, which will make further miniaturization feasible, with potential new innovative solutions for all kind of applications.

“With the continuous improvements and research in the field of integrated photonics and microfluidics, we are confident that such challenges will be soon surpassed,” said assistant professor Amy Foster at Johns Hopkins University, Baltimore, Maryland. “Hopefully in the next few years, integrated photonic systems and devices will continue to mature and find little windows of opportunities in life sciences and medical markets to enable more widespread adoption.”

From shrinking OCT to early cancer detection

Putting some solutions to the test is LioniX International, a leading global provider of customized microsystem solutions, which has developed a specific set of assembly and packaging capabilities for visible light photonic integrated circuits (PICs). This year LioniX, XiO Photonics, Satrax and others merged to form LioniX International, based in Enschede, the Netherlands.

Multicolor laser system (marketed by Integrated Optics as ARA) based of four Matchbox lasers and a visible PIC. The PIC combines the four wavelengths to one output as well as stabilizes the output power using a feedback measurement. Courtesy of XiO Photonics.

“The main challenge for integrated photonics is that no customer wants to deal with the PIC alone. Turning the PIC into a photonic module requires a complete additional set of capabilities besides the microsystem technology capabilities for creating the PIC,” said Douwe Geuzebroek, sales and marketing manager at XiO Photonics. “Making a photonic module that can be used by photonic OEM companies like Carl Zeiss and Pacific Bioscience requires assembly and packaging as well as electronics integration expertise.”

LioniX International has been addressing the life sciences and medical markets for over 10 years and is currently engaged with many companies with its TriPleX chips in which fibers are attached to a visible light PIC for wavelengths in the range of 400 to 700 nm.

An example of a visible light PIC. Photos show the PIC with the waveguides visible, as well as the fiber connection and driving electronics. Courtesy of XiO Photonics.

“Since last year we feel that the market is really beginning to understand the potential of integrated photonics. We see this both in an increased number of new contacts in this field as well as in the number of existing customers that reach production volumes with PIC modules,” said Geuzebroek. “Furthermore we see more companies and institutes starting to work with PIC in life science applications in general and more specifically in PIC technology for visible light.”

One example is the company’s collaboration with the Academic Medical Center, one of Netherland’s largest hospitals and research institutions, in which PIC technology is being incorporated into optical coherence tomography (OCT) devices.

“Together with LioniX, we have designed and characterized an OCT chip in which eight parallel sample arms with different arm lengths were fabricated, making parallel OCT with one swept source feasible,” explained Ton van Leeuwen, chairman of the Biomedical Engineering & Physics department. “We showed that it was possible to make cross-sectional images of layered tissue phantoms with these interferometers on a chip.”

Ongoing demonstrations show that even the lens could be integrated on the chip. By combining the interferometer with a swept source based on integrated photonics, built by 2 M sensors, van Leeuwen and colleagues are making the whole system much cheaper.

“The next steps are to combine the swept source, the interferometer and the detectors on a chip, thereby reducing the footprint and costs even more,” van Leeuwen said. “I envision that the combination of various imaging or sensing techniques, like for instance Raman/fluorescence spectroscopy, are combined with OCT, in order to reveal chemical or functional information next to images of the tissue structure.”

Other avenues of research apply OCT to monitor industrial processes such as the flow and diffusion of bead solutions as well for contactless determination of fingerprints based on the epidermal-dermal junction.

At optics sensor solutions specialist AMS, based in Premstaetten, Austria, circadian lighting is gaining greater acceptance whereby lighting is controlled to enhance the health and productivity of workers. The company recently acquired Mazet, integrated circuit and filter design experts, and now offers CMOS image sensors such as its NanEye 2D, a fully digital system-on-a-chip camera head.

“A small lens is assembled to the chip, making it the world’s most compact digital camera for applications such as medical endoscopy,” said Otilia Ayats-Mas, senior marketing communications manager.

Scheme of a BiMW sensor. Courtesy of ICN2.

Biophotonic probes are of particular interest in minimally invasive real-time imaging and sensing applications where tools such as micro-endoscopes can be used to observe behavior, perform pathology, or even provide guidance for surgical tools. Beyond imaging and sensing, biophotonic probes can deliver optical power at high spatial resolution for stimulation of nerves or neurons, or be used in targeted drug delivery.

An example is the innovative nanophotonic biosensor based on silicon photonics technology, developed by Lechuga’s ICN2 group, known as the Bimodal Waveguide interferometer (BiMW). The BiMW has shown promise in the early detection of colorectal cancer, which could avoid the need for a colonoscopy; dietary control of celiac patients through a simple test of the presence of gluten consumption by analyzing a few drops of urine; early detection of infectious diseases such as tuberculosis or sepsis using body fluids such as urine or serum, among others.

BiMW working principle, showing the two modes of the light propagating in the single and bimodal section and interacting in the sensor area. Courtesy of ICN2.

“There are clinical evidences that when a person is initiating a colorectal cancer, the cancer cells segregate antigens which trigger our immunosystem. As a consequence, our immunosystem produces proteins (autoantibodies) which circulate in our blood,” explained Lechuga.

By detecting the presence of these autoantibodies, this type of cancer could be detected up to four years earlier than using current diagnostic methods.

“As the concentrations are very low, we need a very sensitive sensor device, such as the one provided by integrated optics, to perform the analysis,” she said. “We believe that we will be able to deliver in the future, a hand-held device able to do the testing — employing a few drops of a person’s blood — contributing to the comfort of the population and decreasing the cost on the health system.”

As part of the European project BRAAVOO (www.braavoo.org), Lechuga and LioniX are employing biosensors for early warning of dangerous ocean pollution. On the coast of Ireland, an integrated optics-based lab-on-a-chip biosensor, which has been fitted inside a buoy, is monitoring sea pollutants including antibiotics, algae toxins, hydrocarbons and biocides. The aim is to explore the potential of large-scale marine quality surveillance and allow sustainable multi-usage of the marine environment.

BiMW biosensor embedded in a microfluidics cartridge and connected by optical fibers. The sensor is intended to be allocated inside a buoy for real operation to monitor the ocean pollution. (Work done under the EU BRAAVOO project.) Courtesy of ICN2.

Borrowing from telecoms

Integrated photonics is making great strides in areas such as telecoms and computing with the development of high-speed interconnections and devices such as transceivers, modulators and detectors. But the application of integrated photonics for the life sciences and medical markets is only just being explored.

Although disparate industries, the fabrication techniques to integrate multiple platforms as well as access to increasing foundry processes geared toward integrated photonic fabrication means that medical and life sciences researchers are able to create larger arrays of photonic devices with higher yield.

Scheme of the ideal point-of-care BiMW biosensor using full integration of PICs. Courtesy of ICN2.

With extensive clinical trials requiring thousands of disposable chips, high yield will enable more cost-effective research.

Apart from fabrication techniques, technological advances in free-space optical communication also lend themselves well to biophotonics applications. Integrated photonic devices and arrays for beam steering and beam shaping have recently been demonstrated. Many applications depend on the ability to quickly and accurately steer a laser beam, ranging from the fiber endoscope in biological imaging to lidar scanning in large-scale landscape surveying.

Traditional approaches are often mechanical, requiring bulky motors and gimbals to physically move the entire laser system, or alternatively use tilted mirrors through micromechanical or galvanometer-based devices. The problem is, these solutions can be relatively slow and achieve limited angular range.

BiMW biosensor operating in visible light connected by optical fibers for multiplexed diagnosis. Courtesy of ICN2.

“We are working on integrated silicon OPAs [optical phased arrays] in end-fire configuration. We have demonstrated a one-dimensional OPA device on an integrated silicon platform capable of edge-emitting light in the plane of the chip with apertures spaced at half the operational wavelength,” said Johns Hopkins’ Foster. “Our aperture spacing is the smallest to-date, thereby enabling the largest total steering range. We have thus far demonstrated up to an angular steering range of 52°.”

As PICs continue to advance, powerful point-of-care diagnosis and treatment will be driven from acute care settings through to community care and eventually to home care, using simple-to-use lab-on-a-chip technology.