Overview

From the start, our iGEM team wanted to do something to address questions of distributive justice. That is, we wanted our project to advance an idea that could help bring the power of modern biotechnology and synthetic biology to the broadest group of people possible. This is why we chose to work on a paper-based project, especially since paper has already been used and deployed to address biomedical issues in low-resource areas.

Working with paper has many advantages, including low cost, ease of transport, and chemical stability. However, designing a solution with paper meant first understanding the root of the problem. Here we chose to focus on Mozambique because we had connections to experts with deep experience in the structure of the healthcare system and clinical experience in clinics around the country and region. We spoke to Ruth Bechtel, Mozambique Country Director of Village Reach, an organization that works to improve health systems capacity and efficiency through improvements in supply chain logistics, about the structure and function of the Mozambican healthcare system. We also spoke to Kebba Jobarteh, a clinician and healthcare entrepreneur with decades experience in southern African health systems, about healthcare structure, as well as his experience working in clinics in Malawi and Mozambique. Given the dearth of data concerning healthcare questions in Mozambique, we relied heavily on the experiences and descriptions of the experts with whom we spoke for information on these issues.

Below is an account of what we learned from our research and conversations, how that learning influenced our design ideas on how to address these issues, and how we contributed to growing connections between researchers in the lab and experts in the field.

Logistics in Mozambique

When it comes to healthcare systems in Mozambique, “most issues are logistical, or stem from a lack of knowledge,” says Ruth Bechtel. To better address the question of how a paper-based system could alleviate some of the issues, we first sought to understand the structure of the Mozambican healthcare system.

The logistical system for import and distribution of biologics in Mozambique consists of three main systems :

“The problems begin at the point of purchase,” says Kebba Jobarteh. The vast majority of pharmaceuticals in the Mozambican health system are purchased from India, where there is variable quality control and reliability. They are transported on boats, where storage conditions are also known to be variable, which can damage the product. When they arrive in Mozambique, they are stored in a centralized warehouse in the capital Maputo. Notably, there is no facility for testing the quality of the imported products.

From the central warehouse, the products are transported to the district level in refrigerated trucks, which offers another opportunity for spoilage ; many biologics, such as vaccines, have strict storage requirements, and can spoil if frozen ( http://www.who.int/immunization/documents/IIP2015_Module2.pdf). “We had to teach healthcare workers that the vaccines should not come in contact with the cold packs, in order to avoid freezing and spoiling them,” describes Ms. Bechtel. Village Reach also worked to improve awareness of simple tests for whether or not the vaccines had frozen beyond the point of safety, such as the shake test. If a vial has frozen and thawed, shaking the vial will show the solution is cloudy, and that the vial is unfit for use.

From the district level, samples are once again transported by truck to individual facilities, which are fraught with their own set of cold-chain, logistical, and training problems

Facility-level Storage and Administration

As imperfect as the logistic system is, many problems arise only once biologics have reached facility-level. Storage conditions at the level of the individual clinic vary enormously, from facilities with good electrical and refrigeration infrastructure to more remote clinics with only unreliable solar or generator power.

A lack of training and information exacerbate these problems at the facility level. Undertrained and overworked staff often miss small details that can impact the effectiveness of a medication. One common issue that Village Reach found was that staff were leaving medication out of refrigeration for too long, resulting in spoiling.

At-Home Storage

Beyond even the “last mile” of biologic delivery and storage, a final hurdle exists between having a medication in hand and treating a patient. When a patient is prescribed a regular medication or treatment regimen, often they are given the medicine to take home, store, and use as directed. However, this raises two more problems : inadequate cold storage and inadequate instructions for administration.

This poses a troubling ethical question for clinicians and medical professionals in the field: Should they prescribe or dispense medication if they think or know that it will not be used safely? This is a decision that no medical professional should have to make, especially not in a day and age when we have the technology to completely obviate such questions. The real need, then, is to design solutions using relevant technologies that can directly address these problems.

Paper Can Help Overcome Storage and Information

Paper-based cell-free products help address the multitude of issues facing Mozambican healthcare in two ways: they can be a source of biologics and contain instructions on how to use them safely.

The stability of the paper systems (Pardee et al. 2016) obviates the need for the most stringent transportation and storage conditions. While paper still must be handled carefully, and could not be exposed to high heat for extended periods, it is a much more flexible and forgiving substrate. This increased flexibility would help reduce losses along the logistic pipeline and help ensure the quality of the final product delivered to patients.

Coupling the actual biologics with information on how to use them compounds the impact of both. One cannot travel without the other, and if the paper system is well-designed, the end user will never be without the information they need to safely and correctly use the product. This could help both the healthcare professional in the clinic to administer and store the product correctly, and the patient at home to do the same.

As an example of what a paper-based therapy for home use might look like, we created a mock-up of a Kaletra treatment passport for individual, long-term use. Kaletra is an HIV medication used to slow the progression of the disease. It is a combination of lopinavir and ritonavir, two protease inhibitors that are the standard of care for suppressing HIV activity and are known to be the best combination medication for treating children.

The draft booklet shown above is meant to be given to the patient by the prescribing doctor, who would fill in the details about the number of tablets per day, and any other notes they wish to include. The patient would drip water onto the target, which would initiate the reaction. They would then secure it against their body for the specified time, then simply consume the paper.

The title page contains paper sensors to indicate if the product has been damaged with heat or water. It contains a unique barcode for identification and inventory. The names of the doctor and patient can be written in on the front page, as well as the date of the prescription.

The first page inside contains instructions in Portuguese, Mozambique’s official language, and English. The instructions are simple and easy to follow, meant to give the patient only as much information as they need to successfully consume the medication.

The remaining pages are use pages. They are meant to be hydrated, cut, and consumed by the patient. The design of the page is simple and the images on the page are easily understood. Each line contains a slot for the date to be written, to help the patient keep track of how much medication they have taken and when. One issue of the system is to contain the reaction to a specified area. This can be achieved by including a wax ring that does not allow water to permeate, and can also help seal in the reaction when the page is folded over.

The whole booklet contains holes on the left side to allow multiple medications in similar booklets to be stored in the same binder along with all of their instructions for use.

Citations

• Pardee, K., Slomovic, S., Nguyen, P. Q., Lee, J. W., Donghia, N., Burrill, D., . . . Collins, J. J. (2016). Portable, On-Demand Biomolecular Manufacturing. Cell, 167(1), 248-259.e212. doi:https://doi.org/10.1016/j.cell.2016.09.013 http://www.sciencedirect.com/science/article/pii/S0092867416312466