It has long been recognized that particles are expelled during human expiratory events, such as sneezing, coughing, talking, and breathing. They serve as vehicles for respiratory transmission of the SARS-CoV-2 virus. Currently, there are two existing methods for virus detection : PCR, which indicates the infection, and serology which indicates that the patient has met the virus. There are no simple testing devices that quickly measure contagiousness through breath.
There is also an increasing concern that aerosols (airborne micrometric water droplets with a diameter <5µm) might be a significant route of infection. Indeed there is evidence that SARS-CoV-2 stays stable in aerosols (Neeltje van Doremalen et al., 2020) (Yuan Liu et al., 2020) (Santarpia et al., 2020) although the amount of virus necessary to infect a new subject is not not known yet. If a consensus on this point is achieved, our device appears as a powerful tool to measure the presence of viral particles in the environment.
What it does
Our aim is to develop a quick screening device to detect if humans exhale SARS-CoV-2 virus particles using an optical detection scheme.
As previously described, there are increasing concerns that aerosols could be a significant route of Covid-19 infection. But larger respiratory droplets are also recognized as a significant infection pathway. Our device would be able to process these droplets of different sizes to assess contamination potential through breath.
The person to test would exhale into a disposable tip leading into a tube, sending water droplets inside the device for processing and detection, indicating the presence of virus particles. If the droplets exhaled by the patients do contain SARS-Cov-2 virus particles, our device can detect them and warn that the patient might contaminate others through air.
How we built it
The patient would exhale into a disposable tip leading into a tube, through which the water droplets would be channeled into an optofluidic device which includes a sorting area. This sorting area uses the difference of inertial forces between bigger and smaller droplets to separate them in a spiral. The fluorescent probes, in an aqueous solution within a removable cartridge, would be nebulized and thus injected in the device as “probe droplets”. At the outlet of the spiral, the droplets flow into a merging area made of a simple “Y” channel which merges the exhaled droplets with "probe droplets" containing the fluorescent antibody.
We plan to use an antibody that will target specifically the spike protein of the SARS-CoV-2 virus. This antibody will be coupled to nanoparticles called Quantum Dots to serve as fluorescent probes. Our preferred option for the fluorescent label is to use a FRET pair of quantum dots (Chou and Dennis, 2015), or alternatively a pair of quantum dots and fluorescence quencher (Crisalli and Kool, 2011), both offering high fluorescence inhibition until binding to the virus.
The optical detection relies on the microresonator properties of water droplets. A tapered optical fiber will be placed inside or near the fluidic channel to exchange light with the water droplets by evanescent coupling (light "leaking" between the fiber and the droplets). A laser will be connected to one end of the fiber to excite the fluorescence of the probes bound to virus particles in the droplets. The other end of this fiber will lead to a fast photodetector or even a spectrometer, physically separated from the optofluidic circuit.
Challenges we ran into
While we have yet to decide on commercial arrangements such as licensing, or direct manufacture by collaborators, there is a need to think about how this new product can be integrated into a manufacturing regime that has been set up with pre-existing technologies.
1) Partnerships : We expect one of the main challenges to be finding suitable partners with the relevant expertise to supply some key elements for this high-tech device.
Here are a few preliminary ideas for partnerships:
Micro- / opto-fluidics: Biolidics (https://www.biolidics.com/clear-cell-fx1-system), as they have a similar spiral technology enabling to sort particles according to their size. They are also active in the covid-19 diagnosis market and developed their own antibody detection kit)
Photonic Integrated Circuits / optoelectronics: LioniX (https://www.lionix-international.com/) - International core competences are in Photonic Integrated Circuits (PIC), customized MEMS, and opto-fluidics.
Fluorescent probes: Hifibio (http://hifibio.com/) who has many common parts with our system (droplets microfluidics, antibody labeled with fluorophore, detection of fluorescence with a laser) who could share with us expertise. Centre of Applied Sciences for Health in Dublin (http://micra.ie/) - experts in microfluidic devices and new optical probe developments in their technology gateway MiCRA Biodiagnostics.
Certification of medical devices: We received an offer from ArrowFast.tech, which helps start-ups to develop and register medical devices or software as medical devices.
2) Regulatory aspects :
We keep in mind that this device may have to be registered, possibly as a medical device. This has implications in terms of clinical studies, as well as keeping full traceability of design documents, prototype build documents, prototype testing protocols, results and reports, etc.
The Centre for Devices and Radiological Health has deemed any breath test that involves a labeled (13)C substrate/drug and a device requires a Pre Market Approval (PMA), which is analogous to an approved New Drug Application. A PMA is, in effect, a private license granted to the applicant for marketing a particular medical device. The requirements are outlined in several documents, including the U.S. Food & Drug Administration’s Code of Federal Regulations (21CFR820.30, subchapter H) and the International Standards Organization’s ISO 13485:2016. Over the last decade non-invasive diagnostic breath tests have been researched extensively. However, only a handful of breath tests have been approved by the FDA over the last 20 years. The key to the successful outcome of any regulatory application is the performance study part of any report from the technology transfer and device development process.
3) Business plan :
BROVID is a device for real time detection of contagious people. The market is ready and there is no existing offer. There are no direct competitors but indirect competitors with PCR tests to detect if someone is infected by the COVID19.
Target customers and client segmentation: examples include hospitals (before entering for medical staff and visitors), ambulances, retirement and nursing homes, companies to check if their employees are not contagious before entering indoor spaces. Public sites: airports, malls, transports, cinemas, theatres, concert venues. Police and army.
There could be a huge market, as evident from the number of hospitals (2.9 hospitals per 100,000 inhabitants in Europe in 2014), nursing homes (50k in Europe) and airports (400 in Europe) as examples.
Revenue would be derived from : (a) sales of the device (b) disposable tips/tubes (c) maintenance.
Distribution channel : Biotech companies (i.e Thermofisher) and public markets. We note that it would be easier to enter a market if we enter by a distribution channel with all the contacts.
Accomplishments that we're proud of
We envisioned our BROVID-19 device to identify the contagious potential of both asymptomatic and symptomatic carriers of SARS-Cov-2 by their outbreath. This device is novel and not available on the market yet. Using established methods should make our device reliable and fast to develop, with scalable production, since the technology already exists and just needs to be adapted for our purposes. In addition our device provides rapid mass screening for different applications, including hospitals, schools and businesses. Such devices could potentially be used to monitor the spread of the covid-19 epidemic under the right circumstances.
Our device would be affordable and easy to operate* without biotechnology training. BROVID could be easily scalable. Moreover, it is versatile as it could be adapted to screen other viral mutants or pathogens, just by swapping the antibody cartridge. The advantages can be summarised as follows : (a) Few steps are necessary to get a result, no need for sample processing in a lab (b) Result in real-time © Minimal operator training.
If virus traces are detected by our device, further action could be taken to confirm this result using a more established procedure (PCR).
What we learned
As a team with very different academic and cultural backgrounds who met during the Hackaton, we joined our forces to imagine this novel device. One of the main lessons was that interdisciplinary work is needed more than ever before. On the other hand, difficulties naturally arise since no one can be an expert in all the scientific or technical aspects involved, and none of us could say outright “Yes, this works!”. Many discussions were needed to convince each other that ideas from different fields could do the job. Processing the ideas wisely and being open for discussion taught us patience as well. Always having in mind what society needs at this stage of the pandemic was a key factor that made all of us think beyond our horizon.
What's next for Instant SARS-CoV-2 breathalyzer
The next challenges for our project are to think ahead to bringing the device closer to market:
- Continue and finalize the Device Design (see project phases in Figure below)
- Identify business partners and collaborators (see grey inset in Figure below)
- Secure funding
- Technology transfer for scale-up
- Clinical Testing