Difference between revisions of "Team:UCopenhagen/Implementation"

Revision as of 08:41, 26 October 2020

Introduction

Our work in implementation has been focused on the users, their perception of our solution and their safety. We have integrated expert advice and our own considerations in our process and the development is founded on concepts of an efficient user interface and clever device design. Our main outcomes have been:

• Safety by design

• Recognizing target diseases for proof of concept market entry

• Establishing the basis of real time tracking for patients

• Constructing a framework for analyzing our environmental impact

We recognize that challenges still exit that needs to be solved for our current solution.

The design of the patch

Our solution is a sweat-patch that the patient can wear on-the-go, immediately detecting concentration of inflammation biomarkers in the sweat. The patch is designed to work with really small amounts of sweat. Inside the patch, our modified yeast sensor will detect and react to the biomarkers. The patch consists of three different layers:

Porous nanofilm → A porous nanofilm will allow interleukins to diffuse into the patch and prevent the yeast cells from escaping.
Genetically modified yeast sensor → Our idea is, that in manufacturing the yeast will be dehydrated and placed in the patch in dry yeast format. This allows for easy storage and transportation of the patches at room temperature, which significantly reduces both cost and carbon emission related to the distribution of the patch.
Adhesive patch → Common transparent plastic or woven fabric (such as nylon) used by bandage manufacturers.

The patch is designed in a different way of current sweat patches, which usually collect sweat during days and then the biomarkers are concentrated. In our case, we are detecting biomarkers from sweat immediately, with little sweat needed.

Should the patch be tampered with, and the yeast exposed to the environment, extra safety measures will be put in place to ensure that the yeast cannot survive outside the patch. We present two options:

Safety

Life switch: Make the yeast dependent on a compound and coating the patch with this source of survival that is not easily found outside the patch.
Kill switch: In the patch a constitutive anti-toxin would be present to neutralize the toxins in yeast for as long as it is in the controlled environment. But if it leaves that environment, the anti-toxin would be inactivated, toxin would be activated, and the yeast would be killed.

Who will use it?

When launching a new product on the market, especially in the medical device category, getting approval can be tricky if the target group is too vague. We were thus advised by Caroline to choose appropriate target groups to provide the initial proof of concept of our solution before applying it to all CID patients. Although our device is designed to be a general inflammation monitor, we decided to focus our attention on three types of chronic inflammatory diseases. These patients can greatly benefit from using our patch, and they demonstrate the diversity of our monitoring-device.

• Crohn’s and Colitis are inflammatory bowel diseases giving inflammation in the digestive tract .
• It is estimated that ca. 3 million adults have Crohn’s disease or Ulcerative Colitis in the US .
• Around 80% of patients switch medication type within the first year -Doctor Johan Burisch

• Rheumatoid arthritis is a chronic disease that causes inflammation mostly in the joints.
• It is estimated that 1% of the world population has RA (nearly 80 million people!)
• Patients sometimes try as much as 20 different treatments Expert -Anna Fryxelius

• Eosinophilic esophagitis is a chronic, allergic inflammatory disease of the esophagus.
• The prevalence of EoE is around 0.1% cases worldwide .
• Patients can take some medication but most focus on managing and/or modifying their diet .

Why focus on these diseases?

Our research shows that patients with Crohn’s and Colitis would be ideal for our product and the survey we designed for this patient group corroborated this. Our survey indicated that patients with Crohn’s or Colitis underwent frequent medication change, and needed to test their inflammation levels often. Furthermore, In Denmark a new self-testing initiative has already been tried out on Crohn’s and Colitis patients, where they self-monitor their inflammation through stool samples at home. The results have been very promising so far according to Johan Burisch .

People with Rheumatoid arthritis (RA) can experience wild spikes in inflammation without symptoms and testing is therefore a prime concern for many. Unfortunately, testing for RA patients can be expensive as ultrasound and other expensive testing methods can be necessary. This often means that testing happens too infrequently, and when testing does occur it can be too late, and the disease has already done irrevocable damage. Our product could fit into the new “treat to target” treatment paradigm, which focuses on closely monitoring inflammation levels and administering drugs accordingly.

Lastly, Eosinophilic Esophagitis (EoE) represents a group of patients who undergo many very extensive and invasive tests in the period where they -together with their doctors- try to map their reactions to certain foods. It can often be a tedious process with various diet trials and many hospitals visits, especially for patients who are asymptomatic and not aware of their bodies' internal reaction to their sustenance. Easy inflammation monitoring at home could make a huge difference for this patient group during their long diagnosis process according to our conversation with EoE patient Jessica Chrzan.

The problems in short

Why are we the solution

CIDs are a largely invisible phenomenon. Often CIDs are not only hidden from public view, but the disease progression is often a mystery to the healthcare professionals in charge of treating them. In order to get a clear picture of the nature of a patient’s CID, frequent testing is required. Unfortunately traditional testing, often, cannot offer the frequency of testing required for the optimal disease picture. General inflammation can greatly fluctuate, and infrequent testing can give a misleading picture of a patient's inflammation status. As mentioned, rheumatoid arthritis patients can experience big inflammation changes between testing, leading to irrevocable damage. CIDosis will hopefully amend this problem. As a supplement to traditional testing, a CIDosis patch can aid in giving healthcare professionals and patients a clearer picture of their disease. The guiding philosophy of this approach is that more data is better, and more data provides a better guide for treatment. As such, we view ourselves as an information product. Using an app to track the results from the patch, CIDosis offers a way to fill the information gap created by infrequent testing . Hopefully, the CIDosis patch can help make a clearer picture of the disease.

Real time tracking

We envision the use of an app that would enable the users to read the inflammation results in a more precise manner. This tracking app removes the responsibility of correct interpretation from the users. Moreover, this app will track the inflammation results over time and show the progress. Thus inflammation levels can be saved and used for disease progression analysis. We would like to incorporate the feedback from Jakob Seidelin, developing an algorithm that would recognize whether the results should be seen by the doctor or the patient. Providing the patient with data overview helps them feel in control of their disease, however this data could also cause patient anxiety. In that case, information could instead always be sent to a doctor, that would go over the data to double check the results. Then the doctor could decide to call the patient in for a more exhaustive test or treatment change if needed. We plan to develop a color scale bar on the patch, physically divided in different gradients of the color generated by the yeast. This will provide the app with a color baseline against which it can analyze the color of the patch. This will minimize any misreadings due to differences in light affecting the image saturation.

User Guide

Proposed instructions for the home kit guide:

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Step 1

Wear this patch regularly to track your inflammation and monitor your treatment. The patch can be used for inflammation tracking 1-2 times a week. We recommend specifying the interval with your doctor. While monitoring a new treatment, frequent usage is optimal.

Step 2

Remove the thin translucent layer at the bottom, and without touching the adhesive, place the patch either on your upper arm, stomach, or chest - any place with easy access to sweat and minimal friction. Gently rub the patch after placement to ensure it sticks properly to your skin. Do not reuse the patch if it falls off.

Step 3

Wear the patch for approximately 6 hours. You will see the patch changing color depending on your inflammation level. Remove the patch, place it on a flat surface with a neutral background, and take a picture using the CIDosis app on your phone. If you observe drastic color change (dark pink, red), contact your doctor

Step 4

Storage: Room temperature Caution: Keep away from children below 10 years of age. Parental supervision when using the patch is mandatory if the child is under 10 years of age. Do not tamper with the patch by trying to tear it, open it, or putting it in your mouth. Do not bring flames near the patch or wetting it before use. Do not wear the patch in your shower or while swimming. Do not reuse a patch

How to get the product to the users

Initially, we believed that there were two potential users for our product. The first is the patient who as a private citizens would pay for the product themselves. However, the Danish government sometimes subsidizes medical devices and drugs, and could be considered as a potential end-user. If our device was deemed to be a necessary part of some treatment methods, then we could apply to Lægemiddelstyrelsen (Institution of Medication, Denmark) for subsidization of our device. The case for subsidization should not be too hard, as we can argue that our device functions as a direct substitute, or a necessary supplement, to already existing and subsidized medical devices. According to § 152 (3) of the health law (sundhedsloven), effective substitutes of already existing subsidized health devices will also be subsidized .

After doing some research we decided that our product could be marketed as a non-prescription device. A non-prescription marking would provide easier access to our device for interested CID patients. According to Sundheds- og Ældreministeriet (Ministry of Health and the Aged) there are four key considerations when deciding whether a medical device or drug should be prescribed.

• Can the device or drug pose a health risk to the patient if administered without medical supervision (even when used appropriately)
• Can the device or drug pose a health risk if used excessively and incorrectly
• Does the device or drug contain substances that need to be monitored?
• Does the drug need to be injected by a needle or similar

We believe that our device comfortably falls outside the aforementioned categories. Assuming that the user does not have any relevant allergies (such as yeast-allergies) the device should not pose a health risk when used without medical supervision. Similarly, excessive and incorrect use should not pose a health risk given that the device does not contain harmful substances. This also means that there is no need to monitor the materials of the device. Naturally, our device does not need to be injected, so it also falls outside the last category.

There is however some downsides to going for a non-prescription marking. Because prescription devices always needs a doctor’s approval, doctors will likely be more familiar with these options. Even today, where many patients go to the internet for medical recommendations, the doctor's opinion naturally carries some weight . Going non-description means that we can not necessarily count on doctor endorsement. As such, it is important to make a co-ordinated effort to get doctors’ endorsement.

User safety

During the Nordic Ethics Workshop, the Stockholm iGEM team enlightened us on the susceptibility of patients with celiac disease to yeast infections. We thought about incorporating that and troubleshooting on how we could ensure the safety of our patch in immunocompromised patients. Such patients could then use a specially designed, yeast-free patch. After wearing it on the skin for a certain period - long enough to collect the sweat - place the patch in a box containing yeast at the bottom. The rest of the mechanism would remain the same and the solution would produce a color change. This two-step process could benefit patients who could not use the patch due to gluten allergy, celiac disease or other diseases where one is immunocompromised. Unfortunately, patients with allergies to the patch materials and skin allergies may not be able to use the patch. However, at CIDosis, we hope to overcome this challenge with more research and design modifications.

Framework for environmental analysis

Making an environmental analysis is an important part of every project. CIDosis is not an exception. Thinking about your potential environmental impact is a complicated and multifaceted process. After doing some research we found some problem areas that should eventually be answered if CIDosis were to enter market.
The most obvious concern is the greenhouse emissions produced by a CIDosis patch. However, there is a lot of factors that one needs to consider when analyzing greenhouse emission impact . For example, one needs to consider the direct and indirect impact of our product, the potential cumulative impact and the risks associated with those potential impacts.
The direct impact of our product would be the emissions produced by production, transportation and disposal of the product. The indirect impact could be the potential shift in demand away from blood tests produced by our product. This could amount to reduced emissions due to fewer hospital visits, and reduced transportation need.

The cumulative impact could be the gradual increase in emission due to increased patch disposal. This type of impact can be either additive or synergistic, meaning that the impact is either equal to the sum of the individual parts, or greater than the sum of the parts. The goal is to ensure the patch creates emission only at minimal additive levels, without causing negative synergistic environmental effects.
In order to help us navigate the complexities of making such an analysis we had a talk with Hanne Dalsgaard Nicolaisen. She walked us through how to make a life cycle assessment. Click below to see the steps.

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Step 1 - Functional Unit

The first step is defining a functional unit for your product. Doing a life cycle assessment is usually a comparative process and one should start with figuring out how much of your product is needed to perform the same function as an alternative competing product. A natural comparison for our product is blood tests. However, comparing the two is not entirely fair as we are intended to be a supplement to blood tests. It is nevertheless a good aim to make our product less impactful than blood tests.

Step 2 - Inventory Analysis

The second step is making an inventory analysis for both the functional unit and the unit it is compared to. The inventory analysis should map out the environmental impact of each of the individual parts that feature in the functional unit or the unit it is compared to. There is usually some uncertainty about the exact amount of environmental impact Individual parts have, so estimations are usually needed. Given that we are dealing with uncertainties, we should also estimate the likelihood that an alternative environmental impact is associated with each of the parts. Each of these possibilities, along with their likelihood, should be featured in the final analysis.

Step 3 -Impact Assessment

The third step is the impact assessment. First one should decide which impact category one wishes to investigate. For example, is it relevant to know more about greenhouse emissions or is it more relevant to know the impact on the local environment? When this is done you can add up the environmental impact of each part featured in both units.

Step 4 - Sensitivity Analysis

In the fourth step we should already have an idea of the impact our product has on the relevant category. Now it is time to make a sensitivity analysis. This involves evaluating how the analysis changes if the value of one of the variables in the analysis changes. This is done to test the robustness of the analysis.

The implementation challenges

Other Inflammation: could provoke misreading, or virtually false readings of the inflammation (as the cause will be other than the caused by the disease). Could be local inflammation after a hit or systemic after doing physical exercise.

Precision: we should consider how to improve precision. We should investigate when exactly during the day the readings would be more precise, how much time should the patch be worn and how many readings would be necessary to get a proper idea of the levels.

Yeast survival or activation from dried yeast: We must study how to dry the yeast without damaging it, and how would it behave when getting in contact with the sweat. We should study how much time it would take to activate and start sensing biomarkers. Probably, we will have to optimize it for a faster reading.

Acceptance of GMO: The way we convey our message should be cautiously thought, as we have seen that a proper explanation of the modifications of the yeast would exponentially increase the acceptance rate of GMOs.

Price of the patch: We should calculate the price taking into consideration several aspects: market analysis (competitors), level of increased wellbeing (willingness for consumer to pay), and the business plan (consider the return on investment and the money needed for further steps).

How can other scientists use our project?

Several months were spent on CIDosis, and throughout the journey, we have identified and visualized how other scientists could use our project and science to make something useful for numerous target groups. One unique way of gathering data is crowdsourcing. We could not have validated the data on the concentration of interleukins in the sweat of a person without CID. We believe crowdsourcing would really help in getting more clarity on how to use sweat as a non-invasive method of diagnosis and monitoring.
Interleukin receptors play an important role in inflammation, infection, and immune reactions. Knowing how to utilize the IL-receptors to produce signals can help multiple patients with different diseases and improve their quality of life. Yeast, being eukaryotic, has certain morphological and certain functional similarities with human cells and genetic modifications can lead researchers in making better, precise medical tools.
The world has already come quite far in genetic engineering. We hope that, in parallel with advances in medicine, synthetic biology can one day help people live longer and comfortable lives by identifying genetic mutations and/or predicting disease occurrence early so that diseases can be cured and lives can be successfully managed.

Baumgart, D. C., & Sandborn, W. J. (2012). Crohn's disease. The Lancet, 380(9853), 1590-1605. ↩
Dahlhamer JM, Zammitti EP, Ward BW, Wheaton AG, Croft JB. Prevalence of inflammatory bowel disease among adults aged ≥18 years—United States, 2015. MMWR Morb Mortal Wkly Rep. 2016;65(42):1166–1169. ↩
World Health Organization. https://www.who.int/chp/topics/rheumatic/en/↩
Dellon E. S. (2014). Epidemiology of eosinophilic esophagitis. Gastroenterology clinics of North America, 43(2), 201–218. https://doi.org/10.1016/j.gtc.2014.02.002↩
American Academy of Allergy, Asthma and Immunology. https://www.aaaai.org/conditions-and-treatments/related-conditions/eosinophilic-esophagitis ↩
https://www.retsinformation.dk/eli/retsinfo/2019/9003↩
https://www.retsinformation.dk/eli/lta/2019/1297↩
Chernew, M., Cooper, Z., Larsen-Hallock, E., & Morton, F. S. (2018). Are health care services shoppable? Evidence from the consumption of lower-limb MRI scans (No. w24869). National Bureau of Economic Research ↩
Eccleston, C. H. (2011). Environmental impact assessment: A guide to best professional practices. Crc Press. ↩

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