Feb 28, 2010
Elegant Solutions in Diagnostics.
Paper is a ubiquitous material, fundamental to our natural ability to communicate thoughts and document our past. Its origins can be traced back to ancient China (second century AD)1, and the value of paper as a carrier of information still permeates all aspects of society. In recent years, the intrinsic properties of paper – porous matrix of fibers, ability to bind functional chemical groups, and biocompatibility – have facilitated new advances in biomedicine that may meet the health care needs of the developing world. In the eyes of George Whitesides, University Professor of Chemistry at Harvard University, paper represents a powerful substrate for advanced diagnostic devices the size of postage stamps, in which a single blood droplet (microliter volume) could be used to detect and analyze multiple health problems (including liver disease, diabetes, and HIV) without requiring expensive, heavy laboratory equipment. Paper enables low-cost diagnostics at the point-of-care (POC), irrespective of available infrastructural resources like electricity and hazardous waste management. This synergy between paper and POC diagnostics exists because paper is inexpensive, biodegradable, combustible, light-weight, and has no severe power constraints for rapid fluid transport2.
The Whitesides Lab recently demonstrated intricate hydrophilic patterns in paper substrates that exploit the natural affinity of paper to absorb and wick small volumes of fluid2,3 via capillary action. As a result of this work, a new class of paper-based microfluidic devices for low-cost diagnostics has been realized. In principle, paper-based microfluidic devices are like other “lab-on-chip” devices, whose value is in their small size (smaller than a credit card) and ability to perform multiple laboratory functions. However, there is a clear distinction between paper-based microfluidics and other lab-on-chip devices, in that the foundational substrate is not a plastic mold or an elastomer like (poly)dimethylsiloxane (PDMS), both of which require external pumping or gravity to transport fluid. In contrast, paper devices contain arrays of channels that allow fluid to wick to multiple reservoirs pre-treated with reagents. Chemical reactions occur at these reservoirs and initiate color changes, whose reflectance intensities depend on the concentration of analytes (e.g., glucose and proteins) in the biological fluid samples (e.g., blood, urine, or saliva). The color intensities of the reflected light are then captured digitally with a camera or scanner and can be transmitted via a cellular device. These recording methodologies currently facilitate off-site diagnostics through transmission of digital information from locations where there is virtually no health care infrastructure to anywhere in the industrialized world. Although telemedicine with cell phone cameras is feasible, the lack of controllable lighting conditions, camera resolution, and image focusing2 present key challenges. Advancements in cell phone camera resolution, auto-focus and light emitting diode (LED) flash features are poised to improve imaging, enabling more accurate color analysis.
Alternatively, more quantitative tests may be achieved by integrating low-cost, high performance electronics directly into paper devices. The costs associated with manufacturing silicon-based electronics in bulk are considerably lower today, particularly in large lots (>100,000 units), which will enable the future convergence of these two technologies. Recent work by several research groups has introduced new ways to integrate electronics and energy storage elements into paper-based substrates4-7. With embedded electronics, the paper-diagnostics platform could expand to include electrochemical sensing with flexible electrodes and optofluidic detection with arrays of photodetectors and micro-LEDs. Much of this multi-functionality falls into the realm of future research and development. Nevertheless, given the breadth of the paper platform, there is some consensus that a myriad of commercial applications could arise even at this early stage. For example, Technology Review recognized Whitesides’ novel paper-based microfluidic systems as one of the top innovations of 2009.
Recent innovations in paper diagnostics have collectively spurred commercial interest from multiple entities. Several funding agencies, including government institutes (e.g., National Institutes of Health8), venture capitalists, and private non-profit foundations (e.g., Bill and Melinda Gates Foundation9), have already invested in paper diagnostic technologies that are currently being developed at universities and non-profit entities (e.g., Diagnostics For All; http:www.dfa.org), particularly because paper is a compelling platform for use in resource-limited settings, where electricity and water resources are unreliable.
Moving forward, wide adoption of paper diagnostic solutions will depend on market growth in POC health care as much as it will on technology. The POC market has grown steadily (11% rate of growth), exceeding $US12.5B in 2008 (ref. 10). However, this market growth and the general excitement in the industrialized world could also distract from the core vision and appeal of the technology, as envisioned by Whitesides – the deployment of vital health monitoring and diagnostics solutions in developing regions where profits may not be as large as in the US. Despite the lower profit margins, economists like C.K. Prahalad have argued that low-cost technologies can indeed be deployed via capitalistic, rather than philanthropic, mechanisms in poor regions where there are massive economies of scale whose needs have remained largely untapped11.
Alternatively, achieving the core mission of health care equality could require social entrepreneurial resolve to outweigh the profit-oriented mindset that prevails today. In the words of Muhammad Yunus: “Mindsets play tricks on us. We see things the way our minds have instructed our eyes to see.” This particular mindset is pervasive in capitalist markets where profit is king, but one that is worth breaking, given the potential for wide dissemination of a technology whose origins date back nearly 2000 years.
- Hart, M. (1978) Ts’ai Lun. In 100 A Ranking of the Most Influential Persons in History (pp36-41). New York: Hart Publishing Co.
- Martinez AW, Phillip ST, Whitesides GM, & Carrilho E. (2010) Diagnostics for the developing world: microfluidic paper-based analytical devices. Analytical Chemistry. 82, 3-10.
- Martinez AW, Phillips ST, Whitesides GM (2008) Three-dimensional microfluidic devices fabricated in layered paper and tape. PNAS. 105,19606–19611.
- Nie Z, Nijhuis CA, Gong J, Chen X, Kumachev A, Martinez AW, Narovlyansky M, Whitesides GM. (2010) Electrochemical sensing in paper-based microfluidic devices. Lab Chip. 10, 477-483.
- Siegel AC, Phillips ST, Wiley BJ, Whitesides GM. (2010) Thin, lightweight, foldable thermochromic displays on paper. Lab Chip. 9, 2775-2781.
- Hu L, Choi JW, Yang Y, Jeong S, La Mantia F, Cui LF, Cui Y. (2009) Highly conductive paper for energy storage devices, PNAS. 106, 21490-21494.
- Kim DH, Kim YH, Wu J, Liu Z, Song J, Kim HS, Huang Y, Hwang KC, Rogers JA. (2009) Ultrathin Silicon Circuits with strain-isolation layers and mesh layouts for high-performance electronics on fabric, vinyl, leather, and paper, Advanced Materials 21, 3703–3707.
- National Institutes of Health, Recovery Act Investment Reports RC1 EB010593-01 A sensitive multiplexed diagnostic platform using disposable 2D paper networks, University of Washington, Yager, P.
- Bill and Melinda Gates Foundation Research and Development Grant. To support the discovery of rapid economical point of care assay systems that can be utilized by the developing world. President and Fellows of Harvard College, Whitesides, GM.
- Prahalad, CK. (2009) The Fortune at the Bottom of the Pyramid: Eradicating Poverty Through Profits. Wharton School Publishing, New Jersey