The expanding role of paper in point-of-care diagnostics

Abstract

This editorial discusses the expanding role of paper as a platform on which to build new point-of-care assays, particularly those intended for use in resource-limited settings. Successful diagnostics for use in these environments require a low-cost platform (possibly paper) as well as new assay strategies, reagents and materials for achieving selectivity and sensitivity. Paper provides a common platform for bringing these components together and serves as a low-cost medium for prototyping new point-of-care assays.

Keywords::

• bioactive paper
• diagnostics
• paper diagnostics
• paper microfluidics
• point-of-care diagnostics

Since the 1970s, nitrocellulose and plastics have been the materials of choice for building point-of-care diagnostics [1]. Although paper is used too, for the most part it serves primarily as a container of sorts, for holding dry reagents (pH paper or dipsticks) or for collecting solids (filters) or liquids (blood spots). In recent years, the focus in some academic laboratories has shifted to using paper as the key material on which to build new types of point-of-care assays, particularly those intended for use in extremely resource-limited settings such as remote villages [1–3]. In this editorial, we offer our personal views on the role of paper in advancing the area of low-cost point-of-care diagnostics. We define paper broadly as a variety of porous materials, although the emphasis often is on traditional cellulosic forms.

There was a dramatic rise in the use of paper in point-of-care diagnostics after two reports in 2007 demonstrated that paper could be patterned with hydrophobic polymers to create defined hydrophilic and hydrophobic regions [4] and that aptamer-based detection reagents are compatible with paper [5]. The micropatterned paper enables distribution of a single sample into multiple regions on a piece of paper for conducting multiple assays simultaneously. More importantly, this first publication crystallized the idea that fairly sophisticated sample distribution capabilities, which previously were the domain of plastic- and glass-based microfluidics, could be imparted to paper. In principle, advances in sample distribution should support more selective and sensitive assays, and the aptamer work (the second publication) provided reagents that could be used to satisfy these analytical goals.

These two discoveries suggested that paper could play a larger role in point-of-care diagnostics than it had in the preceding 30+ years. Two properties of paper that are beneficial in this context are its abundance (it is available nearly everywhere) and low cost [6]. Beyond these logistical advantages, it also has interesting surface functionality and adsorption and absorption properties. It can be folded [7], stacked [8], printed on [9] and otherwise manipulated easily. Moreover, it absorbs a fixed volume of fluid (thereby providing a defined volume of sample to an assay region), transports fluids by capillary action (with rates of transport that can be modified by altering the paper) and serves as a filter [10]. In other words, paper has moved well beyond its traditional role as a container.

Some applications provide low-hanging fruit for paper diagnostics. These are situations where only qualitative results are needed, the analytes are fairly abundant and existing assays can be reformulated for use on paper. Still, a smart systems approach is needed to ensure proper performance and ease of use [11,12]. One successful example of a systems approach is the paper-based liver function tests developed by Diagnostics for All [13].

More advanced paper diagnostics will provide quantitative results, and a common approach has been to pair external instruments with assays on paper [1–3,14]. While useful for exploring new ideas, benchtop instruments are impractical for point-of-care assays. Successful assays employ inexpensive, mass-produced, readily available handheld readers, such as a glucose meter (for electrochemical assays) [15] or a handheld multimeter (for assays that generate power as the readout) [16].

Even handheld instruments, however, may be too expensive and complicated for use in extremely resource-limited environments such as remote villages [10,17]. For these settings, we need other strategies that provide the desired level of performance at very low cost. In fact, some of the most difficult challenges for point-of-care diagnostics are these resource-limited environments where the relevant analytes often are present in limited quantities, and/or where quantitative results are needed. These are situations that provide opportunities for new science and for paper to take a leading role as a low-cost platform for assays. There have been clever and promising innovations in this context, some of which are highlighted in the references section [18,19].

It is becoming apparent that dramatic advances in point-of-care diagnostics for use in these settings are unlikely to arise from simply combining known assays with paper. More likely, advances will occur at the interface of several disciplines, such as analytical, organic and materials chemistry [10]. Paper is playing an important role in bringing these communities together, and already we are beginning to see new types of analytical systems that have benefitted from cross-disciplinary arrangements [12,18,19]. These multidisciplinary approaches have provided new, thermally stable reagents [18]; strategies for controlling when and in what order reagents interact [20]; preprocessing reagents and materials to remove components that may interfere with the assays [18]; and new types of readouts that enable quantitative assays without using instruments [18,19]. They also have led to new systems perspectives that consider how a user applies the sample and obtains an unambiguous result [12,13,18,19].

Thus, while paper is a useful and promising material, it is not simply a replacement for existing materials. Its role in the context of point-of-care diagnostics is as a tool, as a medium for exploring new ideas and as a subject for motivating collaborative research. Is paper the best material on which to build a diagnostic for use in resource-limited settings? Not necessarily. The best material depends on the assay: how it is configured, how it will be performed, what tolerances are acceptable for device-to-device variations, and in many cases, cost. Paper is not a solution by itself; it is one of many materials that are needed for creating an effective point-of-care assay. Nevertheless, it is an interesting starting point, particularly for exploring new ideas.

Financial & competing interests disclosure

The authors’ work in this area was supported by NSF (CHE-1150969), the Bill & Melinda Gates Foundation (subcontract No. 01-270716-00), the Arnold and Mabel Beckman Foundation, the Camille and Henry Dreyfus Foundation, the Alfred P. Sloan Foundation and Louis Martarano. The authors have filed the following patent application: US Provisional Patent application No. 61/838,097, ‘Qualitative and Quantitative Point-of-Care Assays’. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.