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ScienceDirect Procedia Engineering 107 (2015) 205 – 214

Humanitarian Technology: Science, Systems and Global Impact 2015, HumTech2015

Empowering community health workers with inkjet-printed diagnostic test strips Allison Ranslowa,b, Daniel Cromptona,b, Khanjan Mehtaa *, Peter Butlerb, Jim Adairb a

Humanitarian Engineering and Social Entrepreneurship (HESE) Program. The Pennsylvania State University, 213U Hammond Building, University Park, PA 16802, USA b Biomedical Engineering Department, The Pennsylvania State University, 230 Hallowell Building, University Park, PA 16802, USA

Abstract Community health worker (CHW) programs have emerged as an effective way to address the growing double burden of acute and chronic diseases in developing countries. Affordable and ruggedized biomedical devices can enable CHWs to provide diagnostic and screening services to their communities. However, low profit margins make such devices and markets unattractive to large diagnostics companies. Diagnostic test strips, created with inkjet printers by depositing biochemical reagents on paper, are both practical and cost-effective. Such test strips can rapidly detect pathogens and other abnormalities through readilyinterpretable visual results, making them well-suited for use by CHWs in the field. © Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license ©2015 2015The The Authors. Published by Elsevier Ltd. (http://creativecommons.org/licenses/by-nc-nd/4.0/). Peer-review under responsibility of the Organizing Committee of HumTech2015. Peer-review under responsibility of the Organizing Committee of HumTech2015

Keywords: biomedical device; community health workers; diagnostic test strip; inkjet printing

1. Introduction 1.1. Community health workers and the double disease burden Lack of access to primary health care is one of the biggest challenges facing the world today. For instance, Kenya relies on just one doctor per 10,000 citizens—a stark disparity to the 26 physicians per 10,000 in the US [1]. Access to care is further limited when people need to travel long distances for basic medical care. Most clinics and major hospitals are located in, and near, urban areas. People rely on public transportation systems and spend a significant

* Corresponding author. Tel.: +1 814-863-4426 E-mail address: [email protected]

1877-7058 © 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license

(http://creativecommons.org/licenses/by-nc-nd/4.0/). Peer-review under responsibility of the Organizing Committee of HumTech2015

doi:10.1016/j.proeng.2015.06.075

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Allison Ranslow et al. / Procedia Engineering 107 (2015) 205 – 214

amount of time and money to reach primary care facilities. This health care situation is further compromised by the double burden of infectious diseases alongside the increasing prevalence of chronic illnesses. Community Health Worker (CHW) programs have emerged as one of the most effective ways to address these health disparities and improve health care. Successful programs, such as those in Brazil, Ethiopia, Bangladesh, Pakistan and Kenya have inspired almost every developing country to develop their own programs [2]. CHWs are dedicated members of their communities who receive basic health training in a variety of tasks including health education, sanitation precautions, malaria control, infectious disease management, acute care, family planning, birthing care, and medical record keeping [3]. After training, CHWs take on the responsibility of monitoring the health of a certain number of households (e.g. 20 households in Kenya) on a regular basis and thus serve as a link between communities and healthcare professionals. While CHW programs have proven their effectiveness, there are some fundamental barriers to realizing their full potential. CHWs are essentially volunteers and while that works in some places, there are accountability, uniformity and morale challenges in other locations. What kind of technology solutions can improve the efficacy and efficiency of CHWs? How can we transform CHWs from volunteers to entrepreneurs so as to improve accountability mechanisms and make such programs economically sustainable? In Central Kenya, our team has been working closely with the Ministry of Health to identify, and act on, opportunities where CHWs can provide health services to the general population for a small fee. Through our venture, Mashavu: Networked Health Solutions, CHWs offer a ‘know your numbers’ service in busy marketplaces as well as rural neighbourhoods. They provide customers with their height, weight, Body Mass Index (BMI), blood pressure, and heart rate with off-the-shelf biomedical devices [4]. This low-cost service is a starting point to determine if customers need further examination or treatment. Since residents are more likely to visit a local CHW with their concerns than travel to a clinic, programs like ‘know your numbers’ can help to warn of serious medical conditions before they become life-threatening [5]. For instance, late diagnoses typically lead to poorer prognoses for chronic conditions such as HIV/AIDS, malaria, and tuberculosis. Regardless of disease, earlier treatment typically means faster and cheaper recovery, allowing patients return to their productive livelihoods sooner with more of their savings intact [6]. 1.2. Rationale for inkjet-printed diagnostic devices Now entering its forth year, the Mashavu service has been widely accepted with several competitors offering similar services and collectively nudging patients to take an active interest in their health. Encouraged with humble but definite successes in bridging the last-mile health care challenges with Mashavu, our team is investigating other medical services that can be incorporated into the CHWs’ repertoire. In harmony with the overarching venture objectives, these services must improve access to pre-primary healthcare, provide active community health education, and enable the CHWs to improve their livelihoods. There is a large unmet need for screening and diagnostic services in the field. However, most biomedical devices available in developing countries like Kenya are not designed for the context. They cannot withstand the harsh climate and rough transportation systems, or are beyond the workers’ levels of training or technicians’ ability to repair them [7]. Over the past four years, our teams have designed and field-tested affordable and ruggedized biomedical devices including thermometers, blood pressure monitors, pulse oximeters, weighing scales, and dermascopes [8]. However, before these devices are ready for large-scale commercialization, they need to undergo industrial design for better usability and be optimized for mass manufacturability. They need regulatory approvals and larger clinical trials. These activities require greater amounts of capital and are better suited for industry to take over. We have been unable to engage biomedical device companies or start-ups interested in developing world markets and cross the chasm between academia and industry. The profit margins on low-cost devices are very small and hence, large sales volumes are needed to make up for the low per unit profits. This makes it significantly more difficult for low-cost diagnostics to reach the market. To help guide the design of diagnostic medical devices for developing communities, the World Health Organization (WHO) has developed a set of criteria called ASSURED: Affordable, Sensitive, Specific, Userfriendly, Rapid and robust, Equipment-free, and Deliverable to end-users. Tests should not only be affordable enough for users purchase, but they also need to be deliverable or accessible to users or customers. In the developing world, a medical device or test that has minimal electronics is advantageous, since many are not familiar with technology and technology can easily malfunction or break. A device that eliminates use of ‘equipment’ or


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excessive electronics is much more user-friendly. The devices also need to be rapid and robust in that they deliver results in less than thirty minutes. If it takes longer than thirty minutes to produce results, users may not be willing to wait around for the results, or even use the device. Sensitivity has to do with the test’s ability to detect positive results; the more positive results that a test correctly identifies, the more sensitive it is. Specificity on the other hand has to do with identifying negative results; a test is more specific if it can correctly identify those test results that are actually negative. With all these criteria in mind, an ideal device is simple and easy to use and fix, while still providing accurate results to users for a low cost [9]. Given the ground realities described earlier, we have revisited the kinds of screening and diagnostic devices that we attempt to design and commercialize. The new emphasis is on accurate and reliable devices that can be manufactured locally without large capital investments. Specifically, we are exploring paper test strips with different biochemical reagents that change color when exposed to certain pathogens or abnormalities. Different biochemical reagents can lead to a wide variety of sensitive and specific tests for various acute and chronic diseases. Further, since the test causes a visual color change, interpreting the results is essentially equipment-free and much more userfriendly than interpretations that require advanced electronic equipment. One potential way of mitigating the high costs and equipment levels associated with producing ASSURED test strips is to repurpose an existing technology: the inkjet printer. Typically, inkjet printers are used to create hardcopies of images or documents by propelling small droplets of pigment onto paper sheets [10]. However, this same process can be harnessed to deposit biochemical reagents onto paper test strips simply by replacing the ink in the ink cartridges. The combined cost of the printer and reagent cartridges is significantly less than most other modern diagnostic devices. Additionally, the test strip printing process is much simpler than current manufacturing alternatives, allowing even previously untrained workers to produce them within the existing infrastructure of many developing countries. Adopting the in-country production of inkjet-printed diagnostic test strips could empower local entrepreneurs while enhancing the healthcare services of CHWs, clinics and hospitals. In particular, it would allow CHWs to provide better and more valuable pre-primary care in their communities by lowering prices and offering more and better ASSURED diagnostic services. In short, if the price is low enough and the distance to service is short enough, residents will be more willing to pay for the tests and visit the healthcare center, ultimately leading to a better state of health for the entire community. This article discusses how inkjet printing can be used to make low-cost diagnostic test strips available in lowresource contexts. The opportunities and barriers to the design, manufacturing and integration of this technology into CHW programs are discussed. In addition, the article closes by discussing some of the practical challenges and opportunities to integrating strips into the existing CHW system and to developing the technology and related entrepreneurial ventures. 2. Inkjet printing and test strip technology 2.1. Adapting inkjet printing technology Inkjet printing technology emerged in the 1970s for industrial application as a new way to convert images from digital files to hard copy documents without having to use photochemical processes [11,12]. By the 1980s though, drop-on-demand technology allowed ink to be introduced only when necessary, leading to a decrease in the price and size of printers and their introduction into homes and offices [13]. The two main types of drop-on-demand inkjet printing are thermal and piezoelectric. A thermal inkjet printer operates at elevated temperatures and works by quickly heating ink contained inside of the cartridge to temperatures high enough to produce ink vapour bubbles. As the bubble grows inside of the cartridge, it forces a small amount of the surrounding ink out of the cartridge and onto the paper. A piezoelectric inkjet printer instead utilizes a piezoelectric material in the back of the ink cartridge which has the unique ability to change its shape when placed under an electric charge. With a charge placed on it, a piezoelectric diaphragm in the back of the cartridge changes shape and ejects a small amount of ink out of the printing nozzle [11]. Piezoelectric printing has been successful in printing a variety of enzymes and proteins, as the process does not use high heat or rapid changes in temperature [14]. The piezoelectric mechanism is displayed in Figure 1.

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Figure 1. Piezoelectric method of inkjet printing [11].

Creating images via inkjet printers is very efficient, easy to use, and cost-effective, which makes this a realistic option for producing diagnostic test strips. The production process is fairly simple, and not particularly different from current applications of inkjet printers. A regular, ink-filled, cartridge can be used; however, it must be cleaned before any other solutions can be injected into it. Next, a syringe is used to inject a different biochemical reagent into each compartment of the cartridge, just as the different ink colors are usually inserted. Once each compartment is full, the cartridge can be capped and placed back into the printer. The newly-loaded printer can then be used to print pages of test strips, such as those depicted in Figure 2. Each strip can include up to three tests, each using a different reagent corresponding to the three traditional colored inks (yellow, magenta and cyan). When printing multiple tests, it is critical that the ‘colors’ (reagents) do not mix. This is done by separating each test block and coding them to precisely the pre-set ink colors. Note that although color printers contain four cartridges, the black cartridge cannot be replaced with testing chemicals, as the black ink is used for printing the outlines, lot numbers and expiration dates as shown in Figure 2. Typical test strip dimensions are 9 x 100mm, which means that 101 strips will fit on a standard A4 sheet of paper (210 x 297mm, the closest standard to 8.5 x 11in), leaving roughly 9cm2 of blank space. Based on the template in Figure 2, each sheet would use approximately 81 mm2 of each of the three colors of ink. 2.2. Technical limitations of printed test strips Although inkjet-printed diagnostic test strips are affordable and easy to manufacture, inherent in the technology are some potential diagnostic limitations. First and foremost, the accuracy of each test is dependent on the sensitivity and specificity the reagents’ reactions to pathogens. False positives will occur if the reactions are not specific enough, for instance if they respond to a biological agent other than what the strip was intended to detect. A false negative will occur if the reaction is not sensitive enough, often if the patient’s sample has too low of a concentration of the identifying component. Sensitivity and selectivity errors can be further minimized using a multiplex test approach. Multiplex tests examine multiple analytes for a disease on a single strip—for instance the ‘yellow’, ‘magenta’ and ‘cyan’ tests in


Figure 2. The premise is that while one test may be wrong, the probability of all three tests being simultaneously wrong is significantly lower. In addition to multiplexing, each newly developed strip would be tested under controlled conditions to determine the reagent’s false positive and negative ratios.

Figure 2: Sample computer-generated template for a series of test strips.

A certain limitation for these tests strips that may result in false positive or false negative responses is the necessary skill of the worker required to correctly read color changes. This however, should not be a significant problem in the implementation of these strips because those that would use the strips would be CHWs who are well capable of reading a simple test strip. In addition, user skill should not be considered as a limiting factor because the status quo alternatives to inkjet-printed test strips also utilize simple visual changes as indicators. Therefore, the only competition should be the sensitivity and selectivity of each inkjet-printed test strip in comparison to current test strips. A review done on dipstick tests shows the sensitivity and selectivity of several tests that are commercially

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available; it gives several likelihood ratios of each test that is commonly included on a three-assay dipstick [15]. In order for inkjet printing test strips to be considered successful, they must perform better or equally as well as dipsticks presently on the market. Or, if their performance is slightly inferior but still of practical use, the ease and benefits of locally produced inkjet-printed test strips must outweigh the marginal sensitivity or selectivity of the test strips. There are also a few technical requirements for some printed test strips that could be challenging in rural developing communities. (Other non-technical issues are discussed at length in Section 4.) First, some tests require additional chemicals to function, e.g. to rehydrate a reagent. Second, some tests require refrigeration of materials before printing. While this can be difficult to accomplish in the field in remote rural areas in developing countries, refrigeration systems can certainly be maintained in small factories where these test strips are manufactured. 3. Types of test strips There are many different types of diagnostic test strips that are currently being used. Test strips that come into contact with fluids utilize the porosity of the paper or polymeric backing of the strip and allow the fluid(s) to be transported, by means of capillary action and microfluidics, and come into contact with embedded sensing reagents. Microfluidic test strips can easily be manufactured using inkjet printing technology and are becoming recognized as a viable avenue for test strip applications, and can be easily manufactured using an inkjet printer. Many novel layouts have been designed to detect a variety of substances and properties including pH [16], hydrogen peroxide [17], small molecule dyes [18], proteins [19], immunoglobulins [20, 21, 22] and neurotoxins [23]. The ability to detect a variety of substances such as these enables future diagnostic test strips to be utilized in multiple applications and diagnose an array of acute and chronic illnesses. This section will overview three types of test strip designs with significant potential as inkjet-printed strips: immuno-chemical (IgG) sensors, strips printed with active biological reagents, and urinalysis dipsticks. 3.1. Immuno-chemical sensors In 2010, Abe, et al., created an inkjet-printed microfluidic device that could both visually indicate the pH of an aqueous sample while simultaneously signaling the presence of human immunoglobulin G (human IgG) in a single test strip. The test utilizes three immunosensing inks, each occupying a single color compartment of the ink cartridge and each printed in a different zone of the test strip. These tests can be both highly specific and highly sensitive, as they utilize disease-specific anti-IgG particles, which bind only to the IgG and gold-labelled anti-IgG particles in the sample—the latter of which cause the color change. This means that test strips could be printed to detect any infectious disease by way of select IgG antibodies (HIV IgG, malaria IgG, measles IgG, etc.). If implemented at-scale, this breakthrough could provide for the low-cost detection of infectious diseases such as HIV, malaria, or hepatitis B throughout the developing world. The current standard for production of immunosensing tests is the Enzyme-Linked Immunosorbent Assay (ELISA). However, this method is much more expensive and uses more consumable materials than the inkjet version pioneered by Abe, et al. The inkjet printing process for this new design is somewhat more complicated than the basic procedure described in Section 2: it is a four-pass process in which each sheet is first made hydrophobic before the printer etches hydrophilic lines, reprints with the immunosensing inks, and etches further. Finally, the technician micropipettes on the pH indicators and gold-labelled anti-IgG. Despite these added levels of complexity, it is still much more feasible than the ELISA within the current infrastructure of much of the developing world. Another technology similar to that by Abe, et al., is the ‘POCKET immunoassay’, or ‘portable and cost effective’ assay designed by Sia, et al. [21]. It also aims to shortcut the costly and equipment-heavy ELISA tests, but this time using HIV or rabbit IgG antibodies coupled with gold colloids onto a solution of silver nitrate. Reaction with IgG or HIV creates a silver film that can be visually or electrically measured on a polystyrene strip. This has been shown to approach comparable standards of sensitivity, limit of detection, and reproducibility as those of an ELISA test. In addition, these strips are promising in terms of shelf-life because of the relative stability of silver. While Sia, et al., did not use inkjet printing in their design, the method could potentially be reproduced using a method similar to the work of Abe, et al. by using inkjet printing to manufacture the strips.


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3.2. Strips printed with active biological substances Another technique, demonstrated by Hossain et al., detects acetylcholinesterase (AChE) inhibitors by printing AChE and the Ellman’s reagent [25] on a test strip to lay out a reaction that forms a visible yellow anion [23]. This test can be used to detect organophosphates and mycotoxins such as those in neurotoxins, insecticides, pesticides and chemical warfare agents. They can even detect carcinogenic mycotoxins that are commonly a sign of food spoilage [26]. These test strips can be created entirely on paper strips in four layers of inkjet printing: the first, polyvinylamine, to capture the yellow reaction anion, the second a silica biocompatible sol-gel to allow for chemical activity retention, the third of AChE and Ellman’s reagent to detect the organophosphates, and finally an additional top coat of sol-gel to complete the ‘sandwiching’ of the enzyme for protection. While the test does not have a high degree of selectivity between neurotoxins—several inhibit AChE in the same way—it has a high sensitivity for detection even in small samples with short incubation. Further, the study demonstrated that the strips’ active enzyme remained active after two months of storage in 4 degrees C, which shows the ability for successfully printing active biological substances onto test strips. In 2010, Mazumdar, et al. introduced an easy-to-use dipstick that utilizes catalytic DNA (DNAzymes) [27] and gold-nanoparticles to detect lead in paints. The dipstick uses gold-labelled DNAzymes to detect traces of heavy metals, including lead ions in 1 mg/cm2 and higher—the US Department of Housing and Urban Development’s cutoff for classifying paint as lead-based. Given that inkjet printing has already proven viable in depositing preserved DNA, further research and development could lead to the practical printing of these lead biosensors on a costeffective scale [28]. A potential ASSURED weakness of this product, however, is the need to rehydrate the goldDNAzyme complex in a specific buffer solution: each test would require an additional small amount of consumable solution. 3.3. Urinalysis dipsticks Dry phase reagent test strips for use in urinalysis have been on the commercial market for some time now, in both three-assay and ten-assay versions [29]. They are widely used in laboratories in both the developed world and the developing world as an early test for potential indicators of kidney disease, urinary tract infections, diabetes and liver problems [18]. Although they are cheap, accessible and moderately sensitive and specific, they must be imported into most developing countries and used by a trained lab technician—severely limiting the number of patients who can access them. However, recent advances have raised the possibility of inkjet printing these tests, allowing them to be produced in-country. 4. Implementation challenges in developing countries 4.1. Overall benefits of inkjet-printed test strips Although each of the devices described in Section 3 do not strictly and/or solely use commercial piezoelectric inkjet technology in their manufacturing process, these degradable biochemicals could potentially be printed to create ASSURED diagnostic tests for developing countries. Inkjet printing offers a number of advantages for the production of test strips. First, it requires fewer and cheaper materials since only a small amount of reagent is needed per strip, and only basic substrates are required. In addition, the automation of printing as opposed to handdabbing or micro-pipetting can decrease the time, capital, personnel, and facilities necessary for production. Printed test strips also have the potential to be easier to use, particularly by semi-skilled workers such as CHWs. Finally, the technology is highly adaptable. More complex units such as ‘three-dimensional’ devices or strips with switches, valves, separators, reaction chambers, etc. can be developed by printing directly onto the same filter paper [14, 24]. Micro-fluidic test strips also offer multiple methods of interpreting results. Some tests can be designed to produce a readily-visible color change directly interpretable by the CHW or other healthcare providers. However, if more insight is desired, many test strip results can be further analyzed with cameras (including cell phone cameras) to

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detect color intensity [16]. Other analytic techniques include detecting opacity or fluorescence [21] and measuring electrochemical current or voltage [30]. 4.2. Integrating test strips into the CHW system Means to support livelihoods: These test strips have the potential to integrate well with CHW programs, fulfilling the ‘D’ (deliverable) in ASSURED. Since these programs already have established distribution channels, it would be easier to bring the strips to a large market. From our specific perspective, the ‘know your numbers’ program offered by the Mashavu CHWs can be further expanded with the addition of test strips. The test strips would augment our health workers’ livelihoods while improving pre-primary healthcare for the community. Usability: In order for the strips to be ASSURED and successful, they must be easy for semi-trained workers to operate without the need of a laboratory or excessive additional equipment. All outputs of a test strip must either be an obvious visual color change in the testing areas or an immediate display from an inexpensive portable electronic device that reads test results. In order to be considered usable by health workers, the tests must be able to run, and be completed, rapidly without the need for much interpretation after the test is given. The micro-fluidic test strip research described in Section 3 has shown the strips’ potential to meet all these usability requirements, but they must be continually considered during development. Training: For CHWs to be willing to use the strips, they first need to be trained on how the product works, as well as become comfortable with the testing process and using the tests on patients. Since the tests are ultimately ‘equipment free’, the training will be fairly simple and will work around correct identification of results. CHWs will need to be able to look at a test strip and correctly identify whether or not it has produced a color change or other result. In the instances where a specific color change does not result, or there may be some discrepancy in the color, the CHW needs to be trained on how to act. CHWs and test strip distributors must also understand how to correctly care for the strips before and during testing, as well as how to dispose them. These training systems will need to be comprehensive not only in communicating the required skills, but in conveying the importance of proper testing and handling. Environmental issues: The physical environment plays a role in the accuracy and durability of the test strips. The strips will need to be packaged in an airtight container that protects them from the sun, humidity, dust and outside air. The design of this case is critical to the overall effectiveness of the test strips. Not only must it be robust enough to protect strips from contaminants, it must be user-friendly enough that CHWs will correctly use it every time. For instance, removing a single strip must be simple and easy while also not risking the contamination of the rest of the lot. Short-term exposure to high temperatures or humidity will generally not damage the reagents, but long-term exposure could render the strips unusable as these contaminants can lead to oxidation of chemicals or an alteration in the chemical properties of printed solutions. CHWs must know how to identify and treat such destroyed strips. Shelf life of strips: The US FDA Standard in the absence of longer term testing is a 6-month shelf life for drugs and/or contrast agents. Humidity is likely the greatest degradation agent. The plan is to incorporate small silica desiccant packs in each group of test strips. However, the shelf life and changes in response (limit of detection, end point, etc.) will be determined in pre-clinical evaluations [1]. 4.3. Business development issues Supply chains: Along with issues of integrating the test strips with CHW programs, there are also issues involving the manufacture and business development of the test strips. Manufacturing the strips locally has the benefits of eliminating post-production shipment costs and of creating jobs to stimulate the local economy. Local entrepreneurs could purchase printers, paper and chemicals to produce the strips and sell them at dispensaries. This leverages dispensaries’ existing supply chains to access public and private labs, and CHWs. Using appropriately sized inkjet printers, this model is fully scalable as more healthcare providers request the strips. Further, given the expected lower manufacturing cost of the strips, each stakeholder along the supply chain could make the necessary profit without increasing the final price-point beyond the end user’s price-point. However, this model may not be viable in all countries as some materials, particularly reagents, are not always available in some regions. Although


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most reagents are not particularly scarce and can be obtained either online or via local chemical/biological supply houses, some may need to be imported. Importing the chemicals could decrease affordability and some chemicals might be hard to obtain due to export restrictions from western countries. Access to capital: Entrepreneurs interested in initiating test strip printing businesses will likely need capital to fund their start-up costs. Fortunately, many developing communities already have microfinancing systems leveragable to local entrepreneurs. The raison d’être for this approach to manufacturing test strips are low capital costs. Informal lending systems like Savings and Credit Cooperative (SACCOs) can be leveraged to fund the startup of such ventures [32] Regulation and quality control: Strips cannot be sold if they do not produce accurate results. This makes quality control in the manufacturing and testing process absolutely critical. Random selections from each batch must be tested against known positive and negative samples, before leaving the manufacturing location, to determine if the tests produce accurate results. In addition, since strips may lose accuracy over-time after leaving the manufacturing site, they will need to be equipped with a specific expiration date. Development-stage testing would be required to determine the correct expiration dates based on how long the reagents last and the conditions in which they will be used in. Setting the specific safety factor and enforcing the prohibition on expired strips also become cultural and training issues. A bias towards higher sensitivity over higher specificity would be preferred since the goal of the test strip is to provide a cost-effective screening mechanism. Intellectual property considerations: Opportunities for patenting and licensing the test strips must be considered. Ownership of an idea is vital for the purveyed authenticity of a product and can help to discourage and prevent cases of counterfeit test strip manufacture, which is a serious problem in the developing world [33]. Since there are few protections against counterfeiting in the developing world, trust relationships with the major customers like CHW programs are crucial to success. Disposal: Since these strips are consumable and disposable they will need to be discarded after each use. This is another training and implementation issue: some test strips may contain potentially hazardous chemicals, and as such cannot be buried or discarded with other waste. Incineration is another alternative, but contextually-appropriate methods will need to be determined before the introduction of any new reagent. Again, integration of test-strips with CHW programs presents a compelling opportunity because CHWs can collect the used test strips and bring them back to a central office where they can be safely discarded. 5. Conclusion Inkjet-printed test strips have the potential to integrate into existing CHW programs in rural areas of developing countries and conform with the ASSURED framework. Printing the strips makes them much more affordable than current alternatives (e.g. ELISA). However, more country-specific research is necessary to develop true cost models. The wide variety of available reagents and the possibility of multiplex testing using each of the three colored ink compartments means many (albeit not all) tests can be both sensitive and specific. The simplicity of the inkjet printer versus more technologically-advanced alternatives, and the ease of identifying a positive result by a color change or easily-interpretable electrical readout makes both production and testing user-friendly. While the strips themselves are not necessarily robust, they can be stored in appropriate protective cases. Many tests are rapid, with incubation periods of only minutes or seconds. Manufacturing the test strips by printing them is also quick and requires very little capital equipment. Many test strips do not need additional equipment through their supply chain, and those that do, only require basic refrigeration and/or affordable, portable electronics. Finally, the simplicity of the printing technology and the minimalism of the strips themselves make them more deliverable and accessible to the end-users. This is particularly true if businesses can leverage existing supply chains with dispensaries and/or can manufacture the strips locally. If these challenges can be addressed, inkjet-printed test strips have the potential to make testing cheaper and easier for CHWs, and in turn, benefit communities throughout the developing world. Acknowledgements The authors would like to thank Molly Eckman for editing assistance.

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