Theologians once pondered how many angels could dance on the head of a pin.
Not to be outdone, Cornell researchers who build nanoscale electronics have developed microsensors so tiny, they can fit 30,000 on one side of a penny.
There’s more to these tiny sensors than just their diminutive size: They are equipped with an integrated circuit, solar cells and light-emitting diodes (LEDs) that enable them to harness light for power and communication.
And because they are mass fabricated, with up to 1 million sitting on an 8-inch wafer, each device costs a fraction of that same penny.
The team’s paper, “Microscopic Sensors Using Optical Wireless Integrated Circuits,” published April 17 in PNAS.
The collaboration is led by Paul McEuen, the John A. Newman Professor of Physical Science, and Alyosha Molnar, associate professor of electrical and computer engineering. Working with the paper’s lead author, Alejandro Cortese, Ph.D. ’19, a Cornell Presidential Postdoctoral Fellow, they devised a platform for parallel production of their optical wireless integrated circuits (OWICs) – microsensors the size of 100 microns (a micron is one-millionth of a meter), mere specks to the human eye.
“In a certain sense, it’s an old idea, building tiny sensors like this,” said McEuen, who co-chairs the Nanoscale Science and Microsystems Engineering (NEXT Nano) Task Force, part of Cornell’s Radical Collaboration initiative.
“But we pushed it another order of magnitude down in size and made it mass fabricate-able. A lot of times when people would make these little doodads, they would wire them all together by hand. You didn’t get a million at a time.
So we constrained ourselves and said we’re not going to do it unless we can make them by the million.”
The OWICS are essentially paramecium-size smartphones that can be specialized with apps. But rather than rely on cumbersome radio frequency technology, as cellphones do, the researchers looked to light as a potential power source and communication medium.
Placing tiny circuits on a silicon wafer is relatively easy in the nanotech arena, McEuen said, but adding LEDs is a special challenge because they are made with a different material: gallium arsenide.
In order to transfer the LEDs to a wafer with the electrical components and integrate them, the researchers developed a complicated assembly method that involved more than 15 layers of photolithography, 30 different materials and more than 100 steps.
“There are a lot of people working at larger scales where you can pick up things and see them with your eye and touch them. This is not that,” Cortese said. “It’s at a scale that you legitimately cannot see what you’re doing unless you’re under a microscope. So you really have to gain an intuition about the nanoscale and the microscale.”
Once the OWICs are freed from their substrate of silicon, they can be used to measure inputs like voltage and temperature in hard-to-reach environments, such as inside living tissue and microfluidic systems.
For example, an OWIC rigged with a neural sensor would be able to noninvasively record nerve signals in the body and transmit its findings by blinking a coded signal via the LED.
As a proof of concept, the team worked with the lab of Chris Xu, professor of applied and engineering physics and a co-author of the paper, and successfully embedded an OWIC with a temperature sensor in brain tissue and wirelessly relayed the results.
McEuen, Molnar and Cortese have launched their own company, OWiC Technologies, to commercialize the microsensors.
A patent application has been filed through the Center for Technology Licensing. The first application is the creation of e-tags that can be attached to products to help identify them.
The tiny, low-cost OWICs could potentially spawn generations of microsensors that use less power while tracking more complicated phenomena.
“The circuits in this paper were quite simple,” Cortese said. “But you can potentially fit thousands of transistors on one of these devices. And that means you can increase the range of things the device can sense, how the device communicates out, or it’s ability to complete more complex tasks. We really developed this as a platform so that a lot of people have space to develop new devices, new applications.”
Molnar and Xu are members of the Kavli Institute at Cornell for Nanoscale Science, which McEuen directs.
Contributing authors include doctoral students Conrad Smart, Michael Reynolds, Samantha Norris, Yanxin Ji, Fei Xia, Aaron Mok and Chunyan Wu; postdoctoral researchers Sunwoo Lee and Tianyu Wang; and Nathan Ellis, machine shop manager of the Laboratory of Atomic and Solid State Physics. The researchers developed their fabrication process with the assistance of the Cornell NanoScale Science and Technology Facility.
As we are approaching 20 years after the US National Nanotechnology Initiative has been announced, whereby most of that funding was spend to engineer, characterize and bring nanoparticles and nanosensors to the market, it is timely to assess the progress made. Beyond revolutionizing nonmedical applications, including construction materials and the food industry, as well as in vitro medical diagnostics, the progress in bringing them into the clinic has been far slower than expected.
Even though most of the advances in nanosensor and nanoparticle research and development have been paid for by disease-oriented funding agencies, much of the gained knowledge can now be applied to treat or learn more about our environment, including water, soil, microbes and plants. As the amount of engineered nanoparticles that enter our environment is currently exponentially increasing, much tighter attention needs to be paid to assessing their health risk.
This is urgent as the asbestos story told us important lessons how financial interests arising from a rapid build up of a flourishing industry has blocked and is still preventing a worldwide ban on asbestos, nearly 100 years after the first health risks were reported.
Assessing the progress made
Life evolved highly integrated biological nanosensors for a large range of applications, including to store and compute information, to sense the metabolic activities to ensure steady energy supply as well as to sense and respond to a broad range of environmental stimuli and threads. Such nanosensors include enzymes, antibodies, DNA, photochromic systems and many others whose functions and mechanisms, by which they often convert energy, are still to be deciphered.
In fact, the diversity found in microorganisms, plants and animals is so huge that atomistic insights into how these machineries work is not only academically intriguing, but has inspired already a diversity of new nanoscale designs.
Our ability to engineer nanosystems with tightly tailored functions has made rapid progress since nanotech tools became available to synthesize, visualize and characterize such systems. While the public often relates the term nanosensors with nanoparticles, the definition of nanosensors is much broader and includes all nanodevices that respond to physical or chemical stimuli and convert those into detectable signals.
Engineered nanoparticles and nanosensors have been made from inorganic or organic, from synthetic or biological materials. Their specificity to probe environmental or biomedical processes can be greatly enhanced by functionalizing them with biomolecules, for example in ways that molecular recognition events will cause detectable physical changes.
This Commentary forms part of a special issue, dedicated to “Nanosensors” as we approach 20 years of announcing that major funding will be poured into the advancement of nanotechnology, first by the US National Nanotechnology Initiative (NNI) [Roco MC. Nanotechnology: convergence with modern biology and medicine. Curr Opin Biotechnol. 2003;14(3):337–346. doi: 10.1016/S0958-1669(03)00068-5. ], followed closely by others in Europe and Asia.
The key promises driving such significant investments into the development of a new generation of nanoparticles and nano scale sensors was their anticipated low cost in production, their specificity to target biomolecules, microbial cells and tissues, as well as to detect toxins.
This opened the door to a range of medical applications, including transformative technologies for point of care monitoring and diagnostics devices. It’s thus a timely occasion to review the successes of nanoparticles and sensors tailored to serve highly specific functions, from medical applications [ Chen X, Zhu Y, Yang K, Zhu L, Lin D. Point of care testing for infectious diseases. Clin Chim Acta. 2019;493:138–147. doi: 10.1016/j.cca.2019.03.008–Nair M, Jayant RD, Kaushik A, Sagar V. Getting into the brain: Potential of nanotechnology in the management of NeuroAIDS. Adv Drug Deliv Rev. 2016;1(103):202–217. doi: 10.1016/j.addr.2016.02.008.] to sensing the environment [ Willner MR, Vikesland PJ. Nanomaterial enabled sensors for environmental contaminants. J Nanobiotechnology. 2018;16:95. doi: 10.1186/s12951-018-0419-1.– He X, Deng H, Hwang HM. The current application of nanotechnology in food and agriculture. J Food Drug Anal. 2019;27(1):1–21. doi: 10.1016/j.jfda.2018.12.002.], as well as to ask where and when caution is warranted [ Figueiredo Borgognoni C, Kim JH, Zucolotto V, Fuchs H, Riehemann K. Human macrophage responses to metal-oxide nanoparticles: a review. Artif Cells Nanomed Biotechnol. 2018;46(sup2):694–703. doi: 10.1080/21691401.2018.1468767. –Miernicki M, Hofmann T, Eisenberger I, von der Kammer F, Praetorius A. Legal and practical challenges in classifying nanomaterials according to regulatory definitions. Nat Nanotechnol. 2019;14(3):208–216. doi: 10.1038/s41565-019-0396-z. ].
Even though most of the advances in nanosensor and nanoparticle research and development have been paid for by funding agencies in the context of early detection and treatment of human diseases, much of the gained knowledge applies to natural nanoparticles as well, or can now be applied to learn more about our environment.
It is thereby interesting to note that the worldwide budgets of agencies that focused on nanotechnologies in the context of biomedical sciences addressing diseases are magnitudes higher than those dedicated to analyze their risks and to protect our environment. Yet, many insights and developments in biomedicine can be translated to addressing environmental challenges.
For example, the development of nanoparticles for diagnostic and therapeutic applications gave much insights into the plethora of schemes by which nanoparticles and sensors can be designed and furbished with specific functions, and how they need to be designed to allow them to pass major barriers of our bodies such as the skin, lung and intestine epithelia, or the blood–brain or blood–tissue barrier.
Much has also been learned regarding the pharmacokinetics of nanosystems once applied to the skin, swallowed, injected or inhaled [Nair M, Jayant RD, Kaushik A, Sagar V. Getting into the brain: Potential of nanotechnology in the management of NeuroAIDS. Adv Drug Deliv Rev. 2016;1(103):202–217. doi: 10.1016/j.addr.2016.02.008., Kolanjiyil AV, Kleinstreuer C, Kleinstreuer NC, Pham W, Sadikot RT. Mice-to-men comparison of inhaled drug-aerosol deposition and clearance. Respir Physiol Neurobiol. 2019;260:82–94. doi: 10.1016/j.resp.2018.11.003. ].
While nanosensors have already revolutionized nonmedical applications, including construction materials and the food industry, as well as the diagnostic medtech market, i.e. the use of sensors for in vitro diagnostics [Mahmoudpour M, Ezzati Nazhad Dolatabadi J, Torbati M, Pirpour Tazehkand A, Homayouni-Rad A, de la Guardia M. Nanomaterials and new biorecognition molecules based surface plasmon resonance biosensors for mycotoxin detection. Biosens Bioelectron. 2019 doi: 10.1016/j.bios.2019.111603. , Yadav S, Nair SS, Sai VVR, Satija J. Nanomaterials based optical and electrochemical sensing of histamine: progress and perspectives. Food Res Int. 2019;119:99–109. doi: 10.1016/j.foodres.2019.01.045.], the progress in bringing nanoparticles into the clinic has been far slower than expected.
Even though the majority of nanotechnology funding in bioengineering and medicine went into approaches to target tumor tissues with nanoparticles, a thorough meta-analysis of the literature from the last decade revealed that only a tiny fraction of the administered nanoparticles (< 1%) were actually delivered to solid tumours, whether based on organic or inorganic materials and with just minor differences based on their physical characteristics [Wilhelm S, Tavares AJ, Dai Q, Ohta S, Audet J, Dvorak HF, Chan WCW. Analysis of nanoparticle delivey to tumours. Nat Rev Mater. 2016;1:1–12].
More information: Alejandro J. Cortese et al, Microscopic sensors using optical wireless integrated circuits, Proceedings of the National Academy of Sciences (2020). DOI: 10.1073/pnas.1919677117