Team:UPF Barcelona/Human Practices
Human Practices
- Peter Carr, Director of Judging
Human Practices
Providing a solution to the hypothyroidism treatment problems could be the key to reduce patients’ adverse effects and health care costs. Then, why not make Hormonic that very own solution? In order to do so, an exhaustive bibliographic research was done, followed by a human-centered solution search process.
Identification of the medical need
Thyroid disease is one of the most common endocrine disorders, affecting millions of individuals throughout Europe and a 5% of the general population [1]. Over 99% of affected patients suffer from hypothyroidism and are mainly prescribed levothyroxine: a medication that has a narrow range of doses at which is effective without adverse effects [2]. As a consequence, one-third of the patients who receive this treatment still exhibit symptomes.
Proposed solution: Hormonic
Several studies have concluded that there is a clear need for patient-specific dosage optimization [1]. Consequently, the aim of this project was set as the development of an alternative treatment that remotely restores the whole thyroid feedback system, allowing to automatically adapt the dosage depending on each patient’s hormonal state. This way, Hormonic intends to reduce the number of visits to the doctor, while guaranteeing a correct and safe monitoring of the patients that does not depend on self-diagnosis methods.
Integrated Human Practices
It is clear that background information gathered from books and articles was essential to gain a first sight of Hormonic’s possible impact, helping us identify the previously mentioned objective towards which we started working thanks to the help of multidisciplinary scientists. However, we found a huge gap between the academic world and the real one. A gap that ought to be connected by a trustworthy and robust bridge: a human-centered solution search process.
At this point, we understood that concerns related to current hypothyroidism therapies were as numerous as the number of different stakeholders.
Therefore, once we obtained a better understanding of the disorder by interviewing several doctors, we decided to go a step further and identify the concerns of local, national and european endocrine associations. Since they are representative bodies of patients, scientists and doctors, their demands, which were included into our solution, turned out to be very diverse. Moreover, once their medical needs were identified, concerns over the ethical and safety aspects that the demands’ implementations required arose; issues that were solved together with experts.
All in all, thanks to this human-centered process, Hormonic started out as a simple hormonal level controller in order to later become a complex patient-specific therapy, designed to mimic hormonal circadian rhythms and characterize the currently unknown thyroid hormone metabolism and action pathways. Take a look at our Future implementation section, in which you will find the solution to all the clinical, security and ethical concerns.
Now is the time to follow the journey of our UPF_Barcelona team as we got closer and closer to what Hormonic has become!
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April 2020
First Brainstorming sessions
Letting our mind think of any crazy and ambitious idea to help solve a problem using synthetic biology tools.
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Marc Güell Cargol
The head of Translational Synthetic Biology laboratory in the Biomedical Research Park of Barcelona
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May 2020
Final brainstorming session with advisors
May 17, each team member voted for one of the candidate projects and the winner was...
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June 2020
Javier Macia Santamaria
The head of the laboratory of Synthetic Biology for Biomedical Applications in the Biomedical Research Park of Barcelona.
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Guillermo Nevot
PhD candidate at the Translational Synthetic Biology group in the Biomedical Research Park of Barcelona.
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July 2020
Dr Ricard Torras
Former head of department of the Endocrinology Service at Hospital Mutua Terrassa.
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Dr Albert Goday
The head of department in the endocrinology unit of Parc de Salut Mar Hospital in Barcelona.
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August 2020
SCEN
Catalan Society of Endocrinology and Nutrition.
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September 2020
ETA
European Thyroid Association
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SEEN
Spanish society of endocrinology and nutrition
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October 2020
Vanesa Daza
Member of the Wireless Communication Group within the department of Information and Communication Technology at the UPF, Barcelona.
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Clinical Research Ethic Committee
Managed by IMIM, the Hospital del Mar Institute for Medical Research.
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Noemí Pont Noguero
Expert in regulation and legislation of medical devices in the European Union. Director of Qualitec-scp business.
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Carles Taulé Flores
Business Development Manager in Biotech.
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Giant
Jamboree
2020!
Brainstorming
Scientific
approach
definition
Exploring
physiological
and clinical
aspects
Gathering
multidisciplinary
stakeholders
demands
Biosafety,
biosecurity and
bioethical
concerns
Medical Device
regulations and
business plan
References
[1] Chiovato, L., Magri, F. & Carlé, A. (2019) Hypothyroidism in Context: Where We’ve Been and Where We’re Going. Adv Ther 36, 47–58. DOI:10.1007/s12325-019-01080-8
[2] Fliers, E., Demeneix, B., Bhaseen, A., & Brix, T. H. (2018). European Thyroid Association (ETA) and Thyroid Federation International (TFI) Joint Position Statement on the Interchangeability of Levothyroxine Products in EU Countries. European thyroid journal, 7(5), 238–242
[3] Ernst, F., Barr, P., Elmor, R., Sandulli, W., Thevathasan, L., & Sterman, A. et al. (2016). The Economic Impact of Levothyroxine Dose Adjustments: the CONTROL HE Study. Clinical Drug Investigation, 37(1), 71-83. doi: 10.1007/s40261-016-0462-3
[4] Gorgojo Martínez, J., Zugasti Murillo, A., Rubio Herrera, M. and Bretón Lesmes, I., 2020. TELECONSULTA En Endocrinología Y Nutrición En Tiempos De La Pandemia COVID-19 Y Más Allá. [online] Seen.es. Available at: https://www.seen.es/ModulGEX/workspace/publico/modulos/web/docs/apartados/1433/160620_105727_7128864936.pdf [Accessed 22 October 2020].
First brainstorming sessions
We went through several brainstorming sessions where we discussed local problems that affected real people and real-life situations. Needs finding is a long and profound process. During these sessions we talked with our advisors as well as other researchers in our university.
Some of the discussed topics were:
- Lindane detection with a biosensor
- A bioremediation approach to detect lindane insecticide levels in water so as to know if it is safe to be consumed by humans.
- Non-invasive early diagnosis of melanoma
- An approach contemplating the design of a microneedle array capable of detecting specific miRNA overexpressed in melanomas in the skin interstitial liquid.
- Phtalates detection with a biosensor
- Phtalates is a composite present in the air near industrial areas which is potentially damaging for the human body. The aim of this approach was to degrade phtalates into some innocuous molecules.
Marc Güell Cargol
A researcher, the head of Translational Synthetic Biology laboratory in the Biomedical Research Park of Barcelona. He has been working on a variety of areas including mammalian genome editing, gene therapy and human skin microbiome engineering.
Input: He gave us some of the results of a study they did related to skin microbiome and Cutibacterium acnes bacteria. These results showed a list of some skin biomarkers, among them T3 hormone!
Output: From this, we continued investigating and came up with the idea of what our project is right now, but still there were many unsolved questions and some gaps we needed to fill. We could say that our first steps towards our final project started here.
Final brainstorming session with advisors
On May 17th we had the final elections to decide the project we wanted to dedicate the whole summer to. We discussed the feasibility, advantages, disadvantages, limitations and applications of the topics that we would work on and learn.
Output: We finally balanced our preferences towards Hormonic because currently there is not much research on thyroid system problems. There was a society need and because our group, formed by biomedical engineering students, wanted to develop an innovative and groundbreaking approach to solve this problem we decided to center our project on thyroid homeostasis.
Javier Macia Santamaria
The head of the laboratory of Synthetic Biology for Biomedical Applications, in the Biomedical Research Park of Barcelona. He has been currently working on the recovery of polluting waste through its transformation by various consortiums of microorganisms.
Input: He gave us the ideas of accomplishing an automated feedback system with a lactone circuit as a proof of concept.
Output: Our wetlab team focused on engineering E.Coli so that it could act as a biosensor to detect the amount of produced lactone. A second bacterial strain that produced lactone in a controlled manner was given to us by this lab.
Guillermo Nevot
Researcher, a PhD candidate at the Translational Synthetic Biology group in the Biomedical Research Park of Barcelona. He had previous experience on building a DIY turbidostat, an automated and continuous cell culture device.
Input: He gave us some tips and guidance to build out DIY turbidostat.
Output: Our drylab team focused on the design optimization of the electronic circuits and the self-regulation systems behind a turbidostat.
Dr Ricard Torras
Former head of department of the Endocrinology Service at Hospital Mutua Terrassa and at the General Hospital of Catalunya.
Input: We had a video call in which we broadened our knowledge on the physiology of the endocrine system, its pathology, and what are the main diagnosis and treatments processes used nowadays. We also discussed the viability of our approach in the clinical world. Moreover, he proposed another possible implementation for an automatic control of post-surgery thyroid cancer.
Output: Our team was encouraged to continue investigating and working on Hormonic. It promised to be a project with a high potential.
SCEN
Catalan Society of Endocrinology and Nutrition. It promotes the development of tasks of medical and scientific interest within the endocrinology, metabolism and nutrition fields. We asked them for an overall sight over the project.
Input: They stated that sweat is a variable and unstable secretion which makes it extremely challenging to relate the amount of T3 detected to a proper thyroid disease diagnosis and treatment. Moreover, they emphasized the importance of an individualized treatment because a low level of T3 is not always a consequence of hypothyroidism. However, they showed interest in our approach, especially for future application in patients suffering from malabsorption who cannot take the drug in pill form but through a weekly intramuscular puncture.
Output: The idea of detecting T3 hormone at skin level was discarded. Instead, a microneedle capable of reaching interstitial liquid (or blood) was contemplated.
ETA
European Thyroid Association. The European Thyroid Association's aims are to promote knowledge in the thyroid field (fundamental and clinical) and improve knowledge of the thyroid gland and its diseases. We carried out an interview with Eric Fliers, member of the executive committee and co-author of the European Thyroid Association (ETA) and Thyroid Federation International (TFI) Joint Position Statement on the Interchangeability of Levothyroxine Products in EU Countries article. Together with him we designed an insertion and monitoring plan for our new treatment.
Input: He stated that each tissue has its own organ-specific regulation by a deionization of T4 into T3, depending on its local enzyme concentration. Hence, we should take into consideration that we are detecting T3 locally and it does not need to involve the same levels of hormone in other tissues. He advised us to protect the levothyroxine pump from external light because otherwise it would degrade and confirmed that plasma is a reliable source to detect hormones. Regarding the content of the previously mentioned article, he gave us advice on how to fulfill their demands on bioequivalence. Overall, he strongly believed that even though the technology needed to accomplish a device like “Hormonic” is super complex, it is worth to investigate on it and give it a try. It would have a huge impact on helping the human body regulate its metabolic needs.
Output: Reinforcement of the statement made by the members of the SCEN, which affirms that the local hormonal condition of the skin cannot be extrapolated to the global condition of the patient. Together with Dc. Fliers we designed a test to ensure bioequivalence between current treatments and Hormonic; and a subsequent monitoring plan to keep the patient’s evolution under observation. Both can be found within the Future Implementation section.
Carles Zafon (SEEN)
SEEN: Spanish Society of Endocrinology and Nutrition
Input:He remarked the existence of a circadian rhythm of T3 and its delayed response to the infusion of levothyroxine due to levothyroxine’s (L-T4) long half-life and its slow uncharacterized metabolization into T3. He explained that analytic determinations are done via the quantification of free hormone concentration, every 6 months, but that the time at which the real effect of the dosage adjustment is unknown, and maybe it should be done earlier. On top of that, he pointed out that there are several factors such as age, other diseases and drugs that play a role on thyroid hormone levels. Finally, a list of possible patients that could benefit from the use of Hormonic was made.
Output:It was concluded that pre-clinical studies should be carried out in order to characterize the circadian rhythm that should be set as the reference value of our PID control system and another one that characterized the conversion of T4 to T3 in response to different levothyroxine injections. Moreover, the optimal time between dosage adjustment should be identified. In relation to the possible factors that alter hormone levels, population studies should be carried out in order to characterize subgroups. Finally, a more detailed list of beneficiaries was defined. All of these considerations were used to define the future implementation of Hormonic.
Dr Albert Goday
Head of department in the endocrinology unit of Parc de Salut Mar Hospital in Barcelona.
Input: Expertise on the field, physiological impact, clinical viability, device implementation and possible introduction to patients. Although Dr. Goday stated that the current treatment works well in the clinic, he was aware of the need to deeply investigate this field and automatize the therapy. He stated that 40% of the patients do not have a proper attachment to the treatment. Moreover, he proposed to us the idea of a possible application in patients suffering from Euthyroid Sick Syndrome, with the aim to monitorize these patients and prevent them from relapsing to a worse state.
Output: Our team considered redirectioning the clinical application of Hormonic. That is, not only it could be used for a diagnosis-treatment tool, but it could also show great performance in the monitoring of patients.
Vanesa Daza
Member of the Wireless Communication Group within the department of Information and Communication Technology at the UPF. We contacted her with the aim of adapting the possible future implementation so that the wireless transmission of health related data is secure.
Input: she recommended the implementation of a symmetric-key algorithm, which makes use of cryptographic keys for the encryption of the incoming and outgoing data (concentration of T3 hormone and subsequent activation signal of the levothyroxine injection pumps) and the decryption of that same information (for PDI control computation and pump activation). In particular, she emphasized the high compatibility and good performance of the Advanced Encryption Standards (AES) 256. Furthermore, she suggested implementing the cryptography processes within the medical device, so that the patient does not have direct access to its key and the data transmission has one less open door. However, the corresponding endocrinologist should receive its own key from its department. In order to prevent external agents from injecting data, she suggested the use of digital signatures, at cost of a higher computational load.
Output: security aspects were gathered and summarized into the possible future implementation plan.
Clinical Research Ethic Committee - IMIM
The committee on the ethics of medicines research ensures ethical and legal correctness of any investigation project dealing with physical or psychological risk to a human being. It is managed by IMIM, the Hospital del Mar Institute for Medical Research. We contacted them to know about bioethics and biosafety issues related to the future implementation of Hormonic device.
Input: When it comes to the process of approval, the committee informed us that the first step is to accomplish a clinical trial on humans after obtaining the approval from the ethics committee itself and the AEMPS (Spanish agency for medicines and medical devices). Further steps would imply achieving the CE mark.
Output: Bioethical aspects were gathered and complemented with current European Regulation legislative aspects. It was all summarized and included into the possible future implementation plan.
Noemí Pont Noguero
Expert in regulation and legislation of medical devices in the European Union. Director of Qualitec-scp business.
Input: In order to place a device in the market, the regulatory aspects of the EU for medical devices needs to be taken into account. She provided us information and guided us in order to classify Hormonic.
Output: The device was classified as a class III device according to 2017/745 reglament.
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