Team:UCopenhagen/Implementation
Introduction
Our work in implementation has been focused on the user perception of our product and user safety. We have integrated expert advice and our own considerations in our process. Our work in this area 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
The design of the patch
Our solution is a sweat-patch that the patient can wear on-the-go. The patch detects concentration of inflammation biomarkers in the sweat. The patch is designed to work with 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 → The idea is, that during manufacturing the yeast will be dehydrated and placed in the patch in dry yeast form. This allows for easy storage and transportation of the patches at room temperature. This 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.
Safety
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:- Life switch: Making the yeast dependent on a compound and coating the patch with it ensures that the yeast can not survive 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. If it leaves that environment, the anti-toxin would be inactivated, and the toxin would be activated. This would ensure that the yeast is killed.
Who will use it?
When launching a new product, especially in the medical device category, getting regulatory approval can be tricky if the target group is too vague. Thus we have chosen appropriate target groups to provide the initial proof of concept of our solution before marketing 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.
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 extensive and invasive tests in the period where they 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.
- • Crohn’s and Colitis are inflammatory bowel diseases causing 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
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 extensive and invasive tests in the period where they 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 phenomena. 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 getting the optimal disease picture. General inflammation can greatly fluctuate, and infrequent testing can give a misleading picture of a patient's inflammation status, due to the snapshot nature of these tests. 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, with the CIDosis patch we can go from a blurred to a clear 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 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. In this way, inflammation levels can be saved and used for disease progression analysis.
Incorporating the feedback from Jakob Seidelin, we wish to develop an algorithm that would recognize whether the results should be seen only by the doctor or also the patient. Providing the patient with a data overview helps them feel in control of their disease. However, this data could also cause patient anxiety. In such cases, the information could only be sent to a doctor, who would go over the data to double-check the results. The doctor could then decide to call the patient in for a more exhaustive test or treatment change if needed.
On the patch, a color scale bar, physically divided into different gradients will provide clarity of the yeast generated color. This will be the color baseline against which the app can analyze the color of the patch. This will minimize any misreadings due to differences in light affecting the image saturation. Below you see a representation of our app with a slider that allows the user to save the patch color to their calendar. This app represents our first step toward our medical app, and does not showcase the use of algorithms to analyse the patch color or inflammation data.
Incorporating the feedback from Jakob Seidelin, we wish to develop an algorithm that would recognize whether the results should be seen only by the doctor or also the patient. Providing the patient with a data overview helps them feel in control of their disease. However, this data could also cause patient anxiety. In such cases, the information could only be sent to a doctor, who would go over the data to double-check the results. The doctor could then decide to call the patient in for a more exhaustive test or treatment change if needed.
On the patch, a color scale bar, physically divided into different gradients will provide clarity of the yeast generated color. This will be the color baseline against which the app can analyze the color of the patch. This will minimize any misreadings due to differences in light affecting the image saturation. Below you see a representation of our app with a slider that allows the user to save the patch color to their calendar. This app represents our first step toward our medical app, and does not showcase the use of algorithms to analyse the patch color or inflammation data.
User Guide
Proposed instructions for the home kit guide: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 wet 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 the Institution of Medication, Denmark (Lægemiddelstyrelsen) 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 the Ministry of Health and the Aged (Sundheds- og Ældreministeriet) 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 need 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 coordinated 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 the market.
The most obvious concern is the greenhouse emissions produced in the production of 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.
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. This also involves deciding what unit the emissions will be measured in. 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. It also involves defining the system boundaries. The boundaries are defined by the chosen target areas, such a production, transport, and distribution.
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. It is important that the value of each unit is characterized in the same way, such that every unit is measured in for example co2 per kg.
Step 4 - Normalization
In the fourth step, we attempt to normalize the impact of our functional unit. We have determined the individual impact of a unit, but now we should multiple it by the number of units we expect there to be. For us, this would be how many patches would be used.
Step 5 - Sensitivity Analysis
In the fifth 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.
Step 6 - Expansion
In the sixth step, we expand on our analysis. In order to get a comprehensive analysis, we should reiterate our sensitivity analysis with different assumptions. We should also reevaluate the initial boundaries we set for our analysis. Maybe different geographical or temporal boundaries would give a different result.
The implementation challenges
Here we present some of the challenges that we recognize still needs to be solved before our product can be implemented:
- Other types of Inflammation: This could provoke misreadings, or false readings of the inflammation (as the inflammation will not be caused by the disease). This could be local inflammation caused by local tissue damage, or systemic inflammation after doing physical exercise.
- Precision: We should consider how to improve precision. We should investigate when exactly during the day the readings would be most 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 out, 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 factors: 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 identified and visualized how other scientists could use our project and the science behind it 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.
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