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Entrepreneurship

Because of the innovative nature of our device, we decided to launch our new technology as a product. To do so, we investigated how our device would be viewed by experts in the world of medical devices and what potential market there would be for our aptasensor. In order to ensure the maximal relevance and use of our product, we took into account the general needs of the global population to decrease the deaths due to sepsis, as well as more nuanced aspects of our project that would make it a popular product. Below, we outline the considerations that were most important in developing our product for the appropriate market and the adjustments we made to improve it:

Understanding the Need

First, we researched the prevalence of sepsis. Sepsis accounts for 20% of all deaths worldwide.¹ Unfortunately, according to the Sepsis Alliance, less than 30% of people worldwide are aware of sepsis as an condition. Studies done by affiliated institutions show not only the prevalence but also the inequality of successful treatment of sepsis in the US. Specifically, Black patients bear nearly twice the number of sepsis deaths, relative to the size of the Black population, as compared to whites (80%-92% higher).² This data is especially important to the development of our product because Rochester, NY has a majority black population, accounting for 40% of the city’s population.^3,4

When developing our product and connecting with professionals and hospitals, we had to take racial disparities into consideration at every step. To read more about our partnerships with Sepsis Alliance, please visit our Human Practices page. In terms of the production and marketing of our aptasensor, the large minority population in the Rochester area led us to do research of medical care disparities that are present in Rochester. As Dr. Pietropaoli, Director at the Critical Care Unit at the University of Rochester Medical Center informed us, physicians can let their subconscious biases about a certain race or ethnicity impact their diagnosis. Because of this, the less room there is for human error, the more accurate the diagnosis will be. Dr. Pietropaoli was excited to see the development of a quantitative rather than a qualitative method for sepsis detection. He believes this will allow us to not only improve the accuracy of the diagnosis but also mitigate any racial biases that may frequently arise in the Rochester hospitals between predominantly white physicians and minority patients. Furthermore, three patients admitted post-surgery to the ICU at the University of Rochester Medical Center anonymously contributed insight about their experience with sepsis. They shared that they would feel safer and better about their diagnosis if there were a quantitative parameter in addition to medical intuition to indicate their state of health.

To be certain of the medical need and utility of our device to hospitals, we connected with more medical professionals who told us about the point of care perspective and patient experience in hospitals. First, Dr. Nagel from the University of Rochester Medical Center told us that roughly 20% of patients diagnosed with sepsis are post surgery patients. In fact, most post-surgery patients are admitted to the ICU after surgery and need to be closely monitored for signs of sepsis. Kate Valcin, Director of Adult Critical Care Nursing at the University of Rochester Medical Center, stressed the need for timely administration of antibiotics to patients diagnosed with sepsis, ideally within one hour of diagnosis. The antibiotics help battle the infection caused by bacteria. Currently, medical teams at hospitals mostly base the diagnosis of sepsis on qualitative signs and professional intuition. Our device would enable a quicker and more accurate determination of sepsis risk. Ms. Valcin gave us a tour of the Intensive Care Unit (ICU), provided us with samples of the best materials to use for the sleeve, and advised us on the best way of incorporating our device into the existing setup in the ICU. The best material for our sleeve, according to the patients in the ICU and Kate, is silicon because it is a transparent material that is easy for nurses to see through and does not irritate the patient's skin.

Additionally, because of the ability to put our aptasensor sleeve onto the patient directly after the surgery, we decided to market our device as a sepsis aptasensor strictly for post-surgical patients. According to Ms. Valcin, this specification would mitigate confusion about when to use the device and on which patients - nurses can be instructed to put the device on every patient leaving the surgical room.

Lastly, since our main consumers are the hospital systems, our device needs to be able to be integrated with the current equipment already installed in the patients’ rooms. This was a major focus of our product development and resulted in the decision to develop a bluetooth-friendly software for nurses to track patients remotely, and incorporating aptasensor readouts into the Philips or General Electric monitors used by the hospitals to display other vital signs such as blood pressure and heart rate. This would allow for easier use of our device by medical professionals, increasing the likelihood of hospitals investing in more devices like ours.

Confident in the positive social and medical impact that our product has the potential for, we started determining the details of the production and distribution of our innovative device.

Production

Our main concern was making the sleeve as cost-effective as possible. In order to do that, we consulted various engineering professors, such as Dr. James McGrath and Dr. Benjamin Lehner, to create a cost-effective framework for the device. We used silicon as the material because it is easy to obtain, clear, and bendable; a similar material is used for brain wave monitoring post-surgery. This meant that the material was already tested in the healthcare setting and approved by nurses for easy use and visibility of the patient skin.

Furthermore, we designed our device so that one device could be adjusted to various sizes, including bariatric and pediatric.

To summarize, to make our device cost-effective we:

Made a single sleeve adjustable for a wide range of sizes.
Used accessible and inexpensive materials such as silicon.
Designed the core of the sleeve to be reusable from patient to patient. The aptamers and electrodes can be switched out to make sure the signal is as accurate as possible, but the rest of the device can be reused.

The breakdown of the cost is in the list below: The total cost of manufacturing is around $375.

Microfluidics and electrode cover: $162

PDMS: $132
Glass: 10$
3D printing of master mold: $10
Misc. materials (dye, syringe, etc.): $10

Potentiostat: $90

Circuit components: $40-$50
PCB: $27
3D printing of components: $0.1/g, up to approximately $30

Sleeve Design: $20

Silicon: $15
Glue: $5

Electrodes: $0.99 ($200 per pack of 286)
Circuits: $70

Arduino Uno: $20
Different Parts: $50

Total= $375.67

To make sure that the aptasensor is a truly innovative device, safe for patient use, and cleared for distribution, we will have to go through the Food and Drug Administration (FDA) clearance process. To anticipate the steps we will need to take in this procedure, our team attended a workshop on FDA approval hosted by VelocityXT entitled “Foundations of FDA Regulations for Medical Devices and Diagnostics” and contacted a former FDA regulator in the Center for Biologics Evaluation and Research (CBER), Dr. Joan Adamo. Below we will discuss the advice of both of these sources and how we plan on implementing their advice into our production process.

Foundations of FDA Regulations for Medical Devices and Diagnostics:

At this workshop, the experts at VelocityXT outlined the process of obtaining FDA clearance in order to be able to produce and sell/distribute our device. According to the information shared with us, there are several ways to obtain clearance depending on the classification the FDA assigns to the product. In Figure 1, you can see the various classifications and requirements.

Figure 1: Device classification distinctions and the requirements for their clearance by FDA⁵

Class 1 examples:tongue depressor, scalpel, or an app sending blood pressure data to a clinician.

Class 2 examples:contact lens, pregnancy test kit.

Class 3 examples: pacemaker, heart valve, or an algorithm diagnosing meningitis.

Determining the Classification of our Device

This is what we would have to do to determine our medical device classification:

Search the FDA product classification database.
Search by the trade name of an existing product (FDA Establishment Registration).
Find existing product classification.
Find similar product classification.
Document your classification and rationale.
Submit 513(g) request for FDA approval.

After considering the classification criteria and going through the determination steps, we classified our aptasensor device as a Class 2 device (special controls needed, low/medium risk). According to this classification, we would have to file a 510(K) or a deNovo if our device was a completely new idea. Dr. Adamo agreed that our device is innovative in its details, but the idea of a biosensor is not new, since various biosensors have been used for the detection of illnesses, such as the Hepatitis B Virus biosensor.⁶ Because not all the individual components of our device but the original combination of the components is the novelty of our device, we would be able to go through the 510(K) procedure. This procedure is shorter and would get our device approved quicker. We then followed the steps required for clearance of our device through the 510(K) process.

Regulatory Pathway: 510(K)

Demonstrate that the device is substantially equivalent to one or more existing devices (a Predicate Device)

The predicate device that we have is the Hepatitis B Virus electrochemical biosensor and a Sweat Test for Cystic Fibrosis.

The combination of technological parts in the devices above are present in our aptasensor, however, the assembly of these parts has never been seen before.
As long as the different parts of the device are similar enough to various predicate devices, the 510(K) form is the strategy that will allow us to produce the product as quickly as possible.

May or may not require clinical study data.

Our aptasensor will probably require a clinical trial as a device that hopes to use a novel medium (sweat) from patients.

90-day review cycle by FDA.
Additional data may be requested.

As we created this plan for the clearance of our device, we wanted to have another professional look over our procedure as well as give us further advice on the success of our device in the point of care setting. For this reason, we contacted Dr. Joan Adamo.

Approval of our device and Implications for marketing it to Hospitals

Dr. Joan Adamo

Dr. Joan Adamo is Director for Regulatory Support Services at the University of Rochester. Prior to this, she worked for the FDA and held a researcher/regulator position in the Center for Biologics Evaluation and Research (CBER). We reached out in order to gauge how the approval process would work if we wanted to get our device sold and implemented in hospitals. She looked over our initial plan for FDA clearance through 510(K) and gave us further advice on the improvement of this form, which we implemented in the form.

Main Takeaways

Our aptasensor device will be an FDA-regulated device.
It is important to search for predicate devices-- or similar products-- that have been classified by the FDA.

Similar devices can give us an option to only have to go through FDA clearance for the novel parts of our device (ones that are not similar in mechanism), saving time and money for production.

Product clearance by the FDA is the only required step towards being able to sell our product.

After clearance, our product can be advertised and bought by hospitals. However, FDA clearance may require a successful clinical trial of our product.

Progress of the project development is very important for FDA clearance

We keep a timeline of our actions and changes.

Adjustments Made

As per Dr. Adamo’s recommendation, we came up with a definitive “intended use” statement for our product. She informed us of the importance of this statement, both for finding predicate devices and for getting clearance by the FDA.

Our definitive use statement is the following: Our aptasensor device will use continuous monitoring of sweat biomarkers to provide medical professionals with a quicker and more accurate quantitative diagnosis of the risk of sepsis development in post-operative patients.

We learned about the process of searching for predicate devices and the importance of highlighting similarities, differences, and indications of use for the FDA.

Even though we are using this technique to induce sweat continuously and not just one time, since this technique to conceive biomarkers through swea has already been used. These nuances are very useful to know to get our device approved as quickly as possible.

A part that was novel for our project was the aptamer sensor part and the microfluidic aspect of sweat collection - for these parts, we would need to create a separate 510(K) application so that it can be checked for safety and be cleared.

Distribution

The distribution of our product will be targeted to hospitals all over the world. After FDA clearance, we will be able to produce the product and advertise it to hospitals as an innovative tool for usage in the Intensive Care Unit for post-surgical patients. In addition to a lower cost of production in contrast to similar devices, the hospital professionals will be provided more specific additional data to judge patient condition. Representatives from the Innovations Center and the University of Rochester Medical Center advised us on providing the clearest instructions on how to use our device, including step-by-step instructions on how to put the sleeve on the patient, replacing the inside parts (aptamers and electrodes on a glass slide), connecting the sleeve to the software, and cleaning the silicon core for use by the next patient. Detailed instructions will ensure the proper use of our aptasensor, higher user satisfaction, as well as minimize the external technology support our team would need to provide to customers.

Instructions for Aptasensor Use:

Unwrap the sleeve device.
Insert the sensors into the sleeve device.
Clean the patient’s forearm with sanitary wipes.
Apply the sleeve to the patient's forearm and tighten until snug.

Make sure to put the sleeve on the patient as soon as possible after surgery.

Plug the device into the software to enable readout of the data.
Keep the aptasensor on patients for as long as deemed necessary by medical professionals - until there is no concern for development of immune reaction to an infection.
Take the aptasensor off and clean thoroughly with ethanol to make sure no germs are left on the sleeve.

Milestones

First, we need to obtain FDA clearance of our prototype.

This may require a clinical trial and a gathering of volunteers for a study.

Second, we will apply for funding to venture capital firms and other investors.
Third, we will start manufacturing our product.

Simultaneously, we will advertise the product to hospitals and send representatives from our company to promote the benefits of our device for patient outcomes.

Once hospitals agree to try the device, we will send a team of supervisors to the hospitals in order to make sure that the aptasensor is used properly by the medical staff.

If the hospitals like our aptasensor, we will keep producing and expanding to other areas of the hospital, such as the Emergency Department.

Evaluating potential negative impacts

One potential negative impact could result in false advertisement or miscommunication of our product. Hospitals may think that the device will actually definitively tell medical staff if the patient has sepsis. However, that is not the case, our device has to serve in tandem with the intuition of the medical professionals and serves as an extra point of reference when making a diagnosis.
Another potential negative implication could be the distribution of the device to only specific regions and hospitals.

We want to make this device as accessible as possible to any region in the world, especially since we learned that less developed regions need more quantitative support due to lack of medical staff.

Overall, we believe that our device has a much greater potential for improving the lives of millions of people than of hurting patients. For this reason, we plan to keep improving our device and fighting for worldwide accessibility.

Do we need more stakeholders to develop this further?

In order to develop this project to its fullest potential, we would need to consume more with patients and learn from them first hand what it is like to have sepsis, what devices were attached to them and what is the best location for the aptasensor.
We would also reach out to the hospital technology advancement teams to promote our device and also hear from them what features are valued by them.

For example, Dr. Pietropaoli told us that the University of Rochester Medical Center is transitioning to a wireless system. This advancement would increase the appeal of our device to hospitals.

We would also want to talk to representatives from less funded hospitals and figure out how much more we can decrease the cost of production without sacrificing quality of the aptasensor.

Since hospitals are our main customers, the market for our product is very extensive, taking into account that our device is truly innovative, without competitors in the biomarker detection field of sepsis.

In addition, the cost-effectiveness of our device will allow us to distribute the device to underprivileged regions of the US and worldwide, where there may be a shortage of experienced physicians and other medical staff. The quantitative data from our device will improve diagnosis in these regions as well, even if there is a shortage of physicians or the intuition of less experienced medical professionals fails. The clear directions of use will also enable many medical professionals to apply the aptasensor correctly to the patient and interpret the data provided by our software. In addition, this medical option for a more accurate diagnosis will be less expensive for patients with a lower income and the underinsured. Our entrepreneurial efforts demonstrate that our device will benefit patients both through the low cost of production and the reusability of the aptasensor parts.

References

Chris Dall | News Reporter | CIDRAP News | Sep 10, 2020. (2020, September 10) Who says sepsis causes 20% of global deaths. CIDRAP.
Kempker, J. A., Kramer, M. R., Waller, L. A. and Martin, G. S. (2018) Risk Factors for Septicemia Deaths and Disparities in a Longitudinal US Cohort, Open Forum Infectious Diseases, 5(12), ofy305.
U.S. Census Bureau quickfacts: Rochester City, New York.
The Sepsis Alliance Institute. The Sepsis Alliance Institute | Sepsis Education.
(2021, June 15) Manufacturing concepts for medical devices. Velocity.
Yao, C.-Y., and Fu, W.-L. (2014, September 21) Biosensors for hepatitis B virus detection. World journal of gastroenterology. Baishideng Publishing Group Inc.
Sweat test. CF Foundation.

Team:Rochester/Entrepreneurship