Team:TUDelft/Implementation

AptaVita AptaVita

Proposed Implementation

Applying new (technological) innovations in the real world brings about a whole set of challenges that must be considered. Here, a proposition is presented that discusses the application, the intended end-users, safety considerations, and other challenges regarding the implementation of AptaVita in healthcare facilities in Uganda.

Introduction

AptaVita is a modular detection system to diagnose vitamin deficiency at the point of care. This rapid diagnostic test (RDT) will allow physicians and local healthcare workers to analyze patients' samples at the point of care through a simple workflow. To implement AptaVita in the real world multiple hurdles must be overcome, including legislation, certifications, data regulation, safety issues, medical trials, scaling-up procedures, and environmental impact. Here, the proposed implementation of AptaVita is discussed and the challenges that arise from this proposition are addressed.

Application and end-users

This section demonstrates how we envision the application of AptaVita and how the end-users are involved. In addition, it demonstrates how other stakeholders, such as the government and health organizations, engage with AptaVita. Fig. 1 is a graphical representation of this proposed application.

Infographic of Proposed Implementation
Fig. 1 Implementation infographic. Infographic displaying the proposed application and end-users of AptaVita.

Government approval

The first step towards the application of our RDT is governmental approval. Countries uphold requirements and regulations to ensure the safe implementation of medical devices and innovations. To be able to implement AptaVita in Uganda, Ugandan safety regulations and requirements must be met. According to the Ugandan National Drug Agency (NDA), "any instrument, apparatus, implement, machine, appliance, implant, reagent for in vitro use, software, material or other similar or related article, intended by the manufacturer to be used, alone or in combination, for human beings and animals for […] diagnosis" [1] is seen as a medical device and should therefore be certified under the "ministerial decree ADM.140/323/01 of 20th July 2020 and statutory Instrument no 77 of the Surgical Instruments and appliances Regulation 2019" [2]. Furthermore, the sharing of medical data through our read-out device must adhere to the National Information Technology Authority Uganda (NITA-U) "Data Protection and Privacy Regulations, 2021" to prevent any misuse of information [3].

In addition to the regulations provided by the Ugandan government, we aim to adhere to additional regulations upheld in the European Union (EU) and the United States of America (USA), resulting in a test that is not only technologically but also geographically modular. This will facilitate further stages of the implementation of AptaVita in future target countries. These additional regulations consider medical technology certifications such as the CE Marking and the U.S. Food & Drug Administration (FDA) approval, and electrical certifications like the FCC (electromagnetic radiation), IEC 62133 (lithium batteries), and RoHS certification (lead-free) [4, 5].

End-users

By engaging with stakeholders we identified a clear niche for our test in the public and private hospitals. Upon governmental approval and obtention of all required certifications, the test can be purchased by the public health system and private institutions, making trained physicians the end-users of AptaVita. According to the Ministry of Health of Uganda, 86% of the Ugandan population has access to either a public or a private healthcare facility within five kilometers [6]. Therefore, we believe that by providing the tests across this network, the majority of the Ugandan population will have access to our product.

The end-users will perform the test on patients to screen for vitamin deficiencies at the point of care, which in our application we define as the patient’s bedside at healthcare facilities. This ensures that the end-user has a sufficient level of training and has access to appropriate waste disposal infrastructure.

Stakeholders provided this and more significant insights, which can be further consulted in our Integrated Human Practices page.

We envision our test to be affordable and accessible to the general public, regardless of socioeconomic status, reducing dependency on charity or health insurance. To achieve accessibility, certain design choices were made to reduce the costs of the test. Currently, the production costs of an AptaVita vitamin detection test is €4.39 per reaction using only commercial kits. This cost can be reduced by using the OnePot PURE and the scaling-up of production procedures. Furthermore, the test can be freeze-dried, so logistic expenses on cold transportation can be avoided. To see the full cost structure of AptaVita, please review the Business Model Canvas on our Entrepreneurship page.

Testing workflow

To use the AptaVita test kit, first, a blood sample should be drawn through a finger prick with, for example, a lancet needle [7]. AptaVita is based on a colorimetric read-out, so it is essential that the plasma is separated from the red blood cells to prevent any background noise by the color of the blood. Based on literature research, we found evidence that this can be done at the point of care, which is demonstrated in the workflow in Fig. 2. For future research, the design of this workflow should be adapted to AptaVita and validated. After blood collection and plasma separation, the sample is added to the paper discs located in the test cassette. Subsequently, the healthcare worker uses the dedicated hardware to evaluate the test results and give dietary advice (or immediate treatment if required for more severe cases). To read more about the technical details of the test and hardware, please visit the Design and Hardware page.

Workflow of Proposed Implementation
Fig. 2 Test workflow.(1) Sample extraction through finger prick with lancet needle[7]. (2) Sample collection with a pipette-like device such as a UniSampler™ [8, 9, 10]. (3) Plasma separation from red blood cells by centrifugation via Paperfuge or similar device[11, 12]. (4) Sample loading, read-out measurement, and results interpretation.

Improving data availability

Health organizations have been taking action to prevent malnutrition. Examples of such action programs are the IMMPaCt program and the IFSS portal [13, 14]. Despite these previous efforts, change has been slow and unequal across different countries and regions in the world [15]. To improve intervention strategies and to guide governments in the process of eradicating malnutrition, access to up-to-date and quality data on the prevalence of malnutrition is essential [16]. With AptaVita, our aim is to increase data availability on the prevalence of one of the forms of malnutrition: vitamin deficiencies.

To reach this goal, we want to make the data generated by the hardware available to health organizations through the use of existing databases such as the VMNIS and NLIS databases from the World Health Organization (WHO) [17, 18]. By analyzing this data, health organizations will be able to identify which regions are at higher risk of a deficiency in particular vitamins. This enables health organizations to advise governments and healthcare networks on strategies for intervention programs, resulting in the efficient use of (financial) resources and a healthier population.

One of the issues that arises from sharing medical data is privacy. As mentioned before, the Ugandan government upholds regulations on data protection and privacy. Adhering to these rules will ensure communicating the data without compromising patients’ safety and privacy. To read more about the misuse of personal data and how we address this, visit the Safety page.

Dietary advice & treatment

Besides its use to make well-informed intervention strategies, data is also valuable to healthcare workers as a tool to make well-informed and accurate treatment decisions (if required for severe cases) and/or to give personalized dietary advice. This is based on the fact that vitamin requirements can differ among demographic groups, where factors such as type of biomarker, age, gender, medical conditions, and pregnancy play a major role. Therefore, in order to generate the desired impact, AptaVita will require sufficient trials in the target populations to identify the corresponding thresholds [19, Interview nutritional expert working at a global health care/monitoring organization].

Safety considerations

Safe by design, biosecurity, and lab safety

Throughout the development of AptaVita, the different aspects of safety and security were researched, discussed, and adapted into the final design, the proposed implementation, and our own behavior while conducting experiments. The main measures that were taken to achieve safety and reduce any risks of AptaVita are:

  • The use of genetically modified organisms (GMOs) is avoided by adopting a cell-free system to achieve expression of the reporter gene.
  • A reporter gene (LacZ) that catalyzes a reaction based on a non-toxic substrate was chosen over an alternative (XylE) that utilizes a toxic substrate (pyrocatechol).
  • GMOs are required for scaling up plasmid and cell-free system production. Therefore, production in the Netherlands was chosen over local production in Uganda, seeking more robust regulations that assured better control and quality of the production processes.
  • The paper discs that contain the cell-free expression system are freeze-dried during transport, ensuring the test remains sterile and abiotic during transportation.
  • To prevent gain of function by antibiotic resistance genes in the plasmid or the risk of spreading blood infectious diseases, proper waste disposal must be applied after using the test. In the future, it is proposed to provide a disposal manual with the test kit to make sure that all biological material is collected and treated in the same way.
  • The risk of misuse of data is reduced by anonymizing the data and by using a dedicated read-out device instead of a mobile read-out.

To read more about the details of the safety consideration of AptaVita, go to the Safety page.

MAUDE database

In addition to the risks identified by the AptaVita team, errors, safety issues, and misuse of similar rapid diagnostic tests and read-out devices may be documented in the Manufacturer and User Facility Device Experience (MAUDE) database of the FDA. No reports on RDTs for vitamins were found. However, it is also advised that before conducting any trials or implementing the product, a thorough search of this database should be conducted to look for problems with similar products. This ensures that the AptaVita design does not contain flaws or problems reported for other types of RDTs [20].

Other challenges

Before AptaVita can be implemented as an RDT, the test must be validated. As with all medical innovations, this should be done through medical trials. A medical trial is an extensive, resource-consuming process. Especially for diagnostics development, different rules and legislation apply for different countries and regions across the world making global market strategies complicated. Data collection through clinical trials to evaluate and assess the prototype and/or product is essential to obtain the right certifications to realize AptaVita as an RDT in the real world [21].

There are four phases in the development and clinical evaluation of a diagnostic test. Phase I is the discovery phase where technical requirements of the test are designed and established. This is the current status of the developmental age of AptaVita. Following this stage is Phase II: the introductory phase. The performance of the first working prototype is validated in clinical settings. For AptaVita this would mean that the test and read-out device’s current design would be tested at a small scale by end-users with patient samples. In Phase III, the maturing phase, these early quantifications must be compared to current diagnostic procedures such as high-performance liquid chromatography (HPLC) and mass spectrometry (MS). Finally, during Phase IV, the dissemination stage, the product is tested at large scale and utilization by the intended end-users is assessed. Thus, AptaVita will eventually be tested on a large scale at public and private healthcare facilities throughout Uganda [22].

Currently, AptaVita is in the proof-of-concept phase. To go from this proof-of-concept prototype to an actual working prototype that can be applied in the second phase of the trials and later to Phase III and Phase IV, AptaVita must be scaled-up. This procedure comes with its own hurdles to overcome. For example, although scaling-up results in a reduction in material costs due to bulk consumption, many big one-time purchases must be made. These include molds for the hardware and test cassettes and reactors for the in-house production of the cell-free system and plasmid through the use of microorganisms. Therefore, for clinical trials and the corresponding scale-up procedures sufficient funding must be acquired and partners to assist in these processes are essential.

A final challenge that AptaVita faces upon implementation is the environmental impact of the product. To avoid any cross-contamination of blood samples or contamination of the environment with biological parts, all components that come in contact with biological material (paper discs, lancet needle, and UniSamplerTM) must be single-use products that can be easily disposed of. This, however, affects the environment in a negative way. To relieve this pressure on the environment, biodegradable plastics and recycled materials should be considered to be used in all other components of the test that allow for it (e.g. secondary packaging, manuals, etc.).

At the current stage, the parts that do not come into contact with biological material, such as the casing of the hardware, were made by 3D printing. For the future production of AptaVita on a larger scale, more robust materials can be used to ensure a long ‘lifetime’ of the parts. To reduce the environmental impact of the biotechnological production upon scaling-up, biochemical engineers can optimize the production process by diversifying substrate sources, reducing by-products formation, and optimizing resource usage.

Conclusion

To conclude, we envision for AptaVita to be implemented at the point of care in Uganda. Upon governmental approval, the test can be purchased and applied by physicians at the patients’ bedside. To achieve this proposed implementation there are hurdles to overcome and risks to be taken into account. These include legislation, certifications, data regulation, safety issues, medical trials, scaling-up procedures, and environmental impact. However, the data generated by analyzing the paper-based test with a dedicated read-out device can be used by health organizations to assist and guide the government and private and public healthcare networks to give personal dietary advice and treatment and set up well-informed intervention strategies to improve the health of the Ugandan population.

References

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  3. NITA-U. (2021). Data Protection and Privacy Regulations, 2021 | NITA-U. National Information Technology Authority - Uganda. https://www.nita.go.ug/publication/data-protection-and-privacy-regulations-2021
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  5. U.S. Food & Drug Administration. (n.d.). Medical Device Safety. Retrieved October 2, 2021, from https://www.fda.gov/medical-devices/medical-device-safety
  6. Ministry of health - Uganda. Ministry of Health- Uganda [@MinofHealthUG]. (2021, April 7) 86% of the population is now within a 5km reach of either a public or a private health facility. This[Tweet]. Twitter. https://mobile.twitter.com/minofhealthug/status/1379770295800696833?lang=ca
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