Team:Aalto-Helsinki/Implementation
End-User Analysis
The end-users of our capsule are researchers who aim to understand the connections between our gut microbiota and our brain, known as the gut-brain axis. We want to provide the researchers a new and innovative tool that overcomes the limitations of current sampling methods and enables the study of gut microbiota interactions in vivo. In the future, our capsule design could also be expanded to detect a variety of other metabolites, thus paving the way for further diagnostic and therapeutics explorations as well. The limitations and preliminary associations established about the gut-brain axis are described in more detail on Description. The possible development opportunities of our capsule are discussed in Future Prospects.
To understand our potential end-users and their needs, we met with researcher Kaisa Linderborg and gastroenterologist Marko Kalliomäki from the University of Turku. The meeting with Kaisa Linderborg provided us valuable insights on the user experience of ingestible capsules. Based on the meeting, we identified several limitations in current capsule technologies which shaped our design to best fit the actual needs of a researcher. The comparison of capsule properties and reasoning of optimal choices is provided in the Hardware section. The meetings and their impact have been described in detail on our Human Practices section.
Research is the key to finding new solutions to global problems we are facing. We envision our capsule to be used to tackle the current knowledge gap that exists in the research of the gut-brain axis. GutLux enables better research with real-time measurement of metabolites inside the gut. GutLux targets two metabolites within the tryptophan metabolism pathway, which is regulated by the gut microbiota and associated with several different states of health. Tryptophan metabolism is one key mechanism of the gut-brain axis, but the correlations and causations of its different metabolite concentrations to health need further investigation. By providing researchers with a new type of research tool, we will take a step forward to revealing the underlying mechanisms of the gut-brain axis. This paves the way for new diagnostic and therapeutic solutions.
GutLux in Action
The GutLux capsule is used under professional medical supervision to ensure participant safety and quality of the measurements. Before ingesting our capsule, the participants of the research undergo a screening process to eliminate potential risks of retention during the process and potential bias in the measurement. A fasting period is conducted before the start of the experiment to ensure smooth propagation of the capsule in the digestive system. The required fasting period would be approximately 10 hours, based on previous research with ingestible capsules (Hakkola et al., 2021). A fibre-rich diet during the measurement also helps to move the capsule along with the digestive system (Hakkola et al., 2021), which can be ensured by providing nutritional tips for the participant to follow the whole duration of the experiment.
Our capsule will be ingested by the research participant under medical supervision to ensure proper entering of the capsule into the digestive system. The safe capsule dimensions and design choices are discussed in our Hardware section. The capsule moves with peristaltic movement, which is the motion that moves food in our gastrointestinal tract naturally. The capsule materials and coating are designed to endure the harsh and changing conditions of the gastrointestinal tract, such as fluctuating pH and temperature.
Once our capsule reaches the small intestine and metabolites are present in the luminal fluid, the biological and electronic systems function together to transmit the measurement of the metabolite concentration into a readable signal and outside of the body through radio frequency. The biological detection mechanism is discussed further in Design and components of our electronic system are described in Hardware. The measurement continues throughout the intestines where our target metabolites, kynurenic acid and tryptamine, can be found. The receiver device carried by the participant detects the incoming radio signal and stores the data locally.
At the end of the experiment, the capsule will be excreted naturally and we record the exit of the capsule from the body as a drop in the temperature of the capsule environment. The capsule is collected and properly disposed, and the receiver device is then returned to the researcher who is able to view, process and analyse the measurement data in order to establish correlations and mechanisms underlying the tryptophan pathway. The GutLux journey through the digestive system is visualized in video 1.
Product Development
To implement our project in the real world and understand the legislation that applies to our design, we met with expert Rosa Tengvall, a lead quality engineer from Kasve. Kasve is a Finnish company that helps organizations in the field of healthcare to develop their expertise and commercialize healthcare products that help our society. We realized after this meeting that, despite being a research tool, our device would be legally considered a medical device, and as such, it is subject to medical device regulations. As a result, we identified the key steps for entering the market of medical devices. A roadmap of these steps is presented in Figure 1.
Additionally, we have conducted thorough business analysis and market research to support the existing itinerary. Our business plan is described in more detail in Entrepreneurship. The legislative and regulatory considerations are further discussed below in Medical Device Regulation.
Safety Considerations
In order to ensure the safety of our GutLux capsule for the researcher, participant and our community, we have taken into account several safety considerations throughout our project. The safety aspects are carefully considered on our Safety page. In addition, we need to follow the existing EU regulations for medical devices to make sure our device is compatible with the current legislation and enable the further development of our capsule as a clinical research tool. The regulations are described in detail in the following section.
Medical device regulation
Before GutLux can be manufactured as a research tool, it would need to undergo strict evaluation as a medical device. The key considerations in medical device regulation are outlined below.
General Requirements for Manufacturers
The manufacturers of medical devices need to comply with the general requirements set out in the EU Medical Device Regulation (MDR). The main requirements are:
- compliance with the MDR regulation as a whole,
- establishment and maintenance of a risk management system,
- conducting clinical evaluation according to the MDR,
- establishment and updating the technical documentation of the device,
- establishment of a post-market surveillance system,
- establishment of a quality management system,
- establishment of a system for recording and reporting incidents and field safety corrective actions and
- acquiring an EU Declaration of Conformity.
In addition to the general requirements, we have examined the specific regulations that apply to our designed research tool. The detailed requirements of the regulation for our device is described below. (OJ L 117, 2017).
Classification
According to our discussion with expert Rosa Tengvall and the classification guidelines from EU Regulation on Medical Devices (OJ L 117, 2017), our Gutlux capsule was verified as a class IIa medical device. The regulations of class IIa medical devices require the maintenance and production of specific documentation by manufacturers. The necessary elements to fulfil the legislative requirements are: technical documentation, a periodic safety update report, a quality management system and specific information to be supplied with the device. The details of these elements are described below. By understanding these legislative requirements, we are able to plan the next steps of our project in a feasible manner and can propose legitimate guidelines for the implementation of our research tool in the real world.
Technical Documentation
The manufacturer of the medical device needs to establish and update the technical documentation related to the device. The technical documentation needs be presented in a clear, organized and easily searchable manner, and needs to include the following elements:
- device description and specification
- reference to previous and similar generations of devices,
- information supplied with the device to the user,
- design and manufacturing information,
- general safety and performance requirements,
- benefit-risk analysis and risk management,
- product verification and validation,
- pre-clinical and clinical data.
In the case of our research tool, technical documentation is required to also include a description of methods to ensure measurements accuracy and description of the device combination (our measurement capsule and the data collection device), including proof of conformity with the safety and performance requirements. (OJ L 117, 2017).
Periodic Safety Update Report
Class IIa medical device manufacturers need to prepare a periodic safety update report (PSUR) for each device summarizing the results and conclusions from the analysis of post-market surveillance data gathered according to the post-market surveillance plan. The PSUR sets out the conclusions of the benefit-risk determination, the main findings of the PMCF, the volume of sales of the device, and an estimated evaluation of the characteristics of the population using the device, throughout the lifetime of the device concerned. Manufacturers of class IIa devices shall update the PSUR when necessary, at least every two years. (OJ L 117, 2017).
Information Supplied with the Device
Manufacturers of class IIa medical devices need to provide instructions of use with the device to ensure safe use of the devices. (OJ L 117, 2017). For example, our GutLux device would need to include information regarding safe ingestion, data collection, and capsule excretion in order for manufacturing of this class II a medical device.
Quality Management System
The quality management system (QMS) is a description of all the elements related to a manufacturer's quality of processes, procedures and devices. It is a key document that governs the structure, processes and management resources that are required to implement the principles and actions that are necessary to achieve compliance with the MDR. The minimum requirements for a QMS are (OJ L 117, 2017):
- a strategy for regulatory compliance,
- identification of applicable general safety and performance requirements,
- responsibility of the management,
- resource management,
- risk management,
- clinical evaluation,
- product realisation,
- verification of the Unique Device Identification system assignments,
- implementation of a post-market surveillance system,
- communication with competent authorities and other stakeholders,
- serious incidents and field safety corrective actions reporting system,
- management of corrective and preventative actions,
- processes for monitoring and measurement of output, data analysis and product improvement.
Challenges of Implementation
In addition to the complexity of entering the market for medical devices due to legislative requirements, our research tool contains genetically modified organisms (GMO) as a part of our detection mechanism. This requires careful safety considerations regarding the engineered cells and foreign DNA within the capsule, and also consideration of national laws on gene technology. In our primary market within Finland, the use of GMOs is controlled, reviewed and approved by the Board for Gene Technology. The safety aspects of GMO and foreign DNA leakage, both inside the body and into the environment, are discussed in detail on our Safety page. Other possibly hazardous materials in the capsule would be properly handled once they are returned to the professionals.
References
1. Hakkola, S., Nylund, L., Rosa-Sibakov, N., Yang, B., Nordlund, E., Pahikkala, T., Kalliomäki, M., Aura, A. M., & Linderborg, K. M. (2021). Effect of oat β-glucan of different molecular weights on fecal bile acids, urine metabolites and pressure in the digestive tract - A human cross over trial. Food chemistry, 342, 128219. https://doi.org/10.1016/j.foodchem.2020.128219
2. MDCG 2019-15 rev1: Placing Class I medical devices on the market: https://ec.europa.eu/health/sites/health/files/md_sector/docs/md_guidance-manufacturers_en.pdf
3. Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC . OJ L 117, 5.5.2017, p. 1–175.
