The inside story

9 June 2021

Neuromonitoring and neuromodulation technologies combine practical tools for patient care with what often seem like plot points from science fiction, and are on their way to erasing the traditional boundaries between medical devices and pharmaceuticals. The CEOs of two start-ups using new types of electrodes to define the space, Manfred Franke of Neuronoff and Luca Ravagnan of WISE, talk through their approaches to navigating the industry’s newest frontier.

Electrodes are getting avant-garde. They’re being stretched, softened, embedded and reformed into injectables, stents, neural ‘dust’ and brain ‘threads’ to interface with the human body. The potential is capturing the imaginations of the public and the pockets of investors. Those behind it just need to convince patients, doctors and regulators that it’s applicable to them today. Here Luca Ravagnan, CEO of WISE, and Manfred Franke, CEO of Neuronoff, offer first-person accounts of how they are trying to do so.

Brain power

Luca Ravagnan: We are solving what we consider one of the major problems in neurotechnology in general, and particularly in the neuromodulation and neuromonitoring fields, which is the mechanics of the electrodes. Currently, electrodes are generally made of hard metallic pieces that are embedded into thick polymeric films, typically silicone.

But you have to consider that the brain is like padding – it’s very soft. Our technology enables us to directly embed a conductive platinum layer into the silicone, which means we can make very conformable and stretchable electrodes that can adapt to the shape, and, in general, match the mechanical properties of the brain or a nerve, making for a much better connection.

Everything started from an experiment. I’m a materials scientist by training, and I was working at a university when we accidentally discovered this technology and understood we were able to embed a stretchable conductor into rubber. Our idea was to exploit this in the medical implant space and I left academia in 2011 to found the company.

I’m proud to say that we are doing exactly what we said ten years ago, but it took funding on the one hand and time on the other to carry the technology from something that works in the experimental setting, to a medical device that complies with all the requirements of European standards.

At the same time, it’s very dangerous to develop something that the customer is not looking for or doesn’t need. Clearly, we had to consolidate the technology, make it reproducible and very controlled, develop the device, and put together all the critical pieces necessary to make the electrodes and keep them – electrically and biologically – stable. But we also had to focus on what’s important for the user. There is a gap between the basic research I was doing in academia, which can seem a bit like science fiction, and current medical needs.

So, we simplified some aspects of our technology. Our first product, the Cortical Strip, just improves an electrode that already exists in terms of shape. It’s simple, but we decided to give the users – the surgeons – something they know, an electrode, and improve the conformability, which is what they wanted to have improved, while leaving the rest very similar to what they already had. Potentially, we could have made a completely new geometry or made a huge number of extremely small electrodes, which would be fascinating, but it’s too early for that to be adopted, because surgeons are trained to do the procedure with a particular number of electrodes.

For intraoperative neuromonitoring, we provide the same number of electrodes, in the same geometry and improve the one aspect that users were hoping could be improved. In the future, we know we can do a whole variety of fancy and strange geometries, but that’s an evolution – you have to bring the relevant innovation to the hands of the user for the needs of the patient first. Other companies have come to the market with innovations but remain in a niche because, in the end, you need to have a good reason to drill a hole in somebody’s head. If you want to play a game on your PC, you might prefer a better joystick before a hole in your skull.

When you’re in academia, it’s important that you stay in front of innovation. You work to push the line forward. I support all the people that are developing great science in Europe at the moment. But when you’re in business, what’s important is that you develop products that are relevant for the user, so one has to find the actual needs of the user they are serving. Science looks for what will happen in the next ten years and beyond, business has to focus on the next five, or maybe less.

Take out the risk

Manfred Franke: If you look at neuromodulation technology as a subset of medical devices, whether it’s being used to provide sensory input through an artificial hand, stimulate neuromuscular junctions with a pacemaker, or change how cells process signals to block pain, it always requires a highly invasive procedure. A surgeon has to open up a patient in an operating room to be able to place the electronics into the body and interface with nerves in a way that ensures those electrodes don’t move over the years. Add it all up and you have costs on a tenyear timescale of $100,000–150,000 for implanted neuromodulation devices, even for conditions that don’t require 24/7 stimulation.

“‘What’s the main hold up stopping neuromodulation from gaining treatment market share?’ It’s not efficacy, it’s not safety – it’s the perceived risk.” 

Manfred Franke

Due to these large costs for the healthcare system, you have to ensure a treatment will be effective before implanting it. State of the art treatments use so-called trial leads, which are leads with electrodes that are intended to be placed via needle, anchored with adhesive dressings where they exit the body, and connected to an external signal generator. The risk of infection means that the clinician has up to seven days for some indications and up to 30 days for others to confirm that a patient is a responder for the treatment. Unfortunately, in some cases, these trial leads and their electrodes move and, in others, the waveforms that may provide treatment are simply not found out in time. As a result, we are not finding every patient that is likely to benefit from neuromodulation.

We realised at Neuronoff that there must be a better way to do this, with a connector that conducts an electrical signal from right underneath the skin down to the nerve of interest. And we kept coming back to the basic principle that we needed something needle-injectable, with a needle of about 1mm in diameter, to create an electrode on the nerve that does not move after it’s put in place. This is how the Injectrode was born.

Because the Injectrode is needle-injectable and mechanically secures itself near a nerve target, it removes the need for sutures to secure it inside the body or to close up the needle puncture – and leaving the Injectrode just underneath the skin allows you to wirelessly provide a signal from the outside, with, for example, a TENS unit. So, you can use a relatively simple and versatile device, and you can figure out the best signal for a particular patient in a trial period that could now last ten years if you wanted, because you don’t have a wire crossing the skin anymore. Tens of thousands of people with chronic conditions may now be able to receive a therapy that is friendly for the patient, the physician and the payer.

The idea here really is asking, ‘What’s the main hold up stopping neuromodulation from gaining treatment market share?’ It’s not efficacy, it’s not safety – it’s the perceived risk. Patients are rightfully afraid of surgery, of the associated costs and the post-op pain. And if you can use a technology that uses a simple needle injection, which is as minimally invasive as possible, to place an easily removable device, then you move away from the fear of surgery – and scars, for that matter. It reduces the risk to something that we can wrap our minds around. And then the only question is ‘Can we find the right waveform?’

This means that the Injectrode is the only implanted component for treatments that rely on stimulation on demand. It’s similar to how a patient may take an aspirin to treat a headache instead of implanting a pain drug pump; we believe that on-demand treatments do not need a signal generator to be placed in a surgery (and replaced when its battery runs low). That said, for treatments that require 24/7 stimulation, the Injectrode allows for a much longer period to find the optimal stimulation waveform, likely drastically increasing the responder rates for neuromodulation. We are also developing adapters that allow us to connect to commonplace implantable pulseform generators (IPGs), ensuring compatibility with current treatment and reimbursement codes. It’s all coming.

With that in place, patients and clinicians can try out neuromodulation as a safe way of treating a chronic condition that they may no longer be able to treat with drugs on account of the side effects. An opioid taken as a pain suppressant may lead to addiction over time, but you can use neuromodulation to block pain without that risk. Electrical stimulation of nerves works by different mechanisms of action to drugs, so it can often be used in an additive manner while reducing the need for high drug doses. Importantly, reducing the dosage required to successfully treat a condition greatly extends the period that a drug may safely and effectively be used. Neuromodulation is a strategy for enhancing long-term patient benefit.

That is something that some drug companies, and initially only drug companies, have realised and started to invest in. In 2012, GlaxoSmithKline started going really deep into the neuromodulation pathways for pain. They have their own venture fund, Action Potential Venture Capital, which seems to be interested in the areas that GSK initially identified – where neuromodulation can make the biggest impact – because drugs that are used to treat rheumatoid arthritis, general inflammatory diseases, general pain diseases and many other conditions have immense side effects.

There are really significant benefits for patients that come from using neuromodulation in conjunction with a drug. Drug companies are realising that they have drugs sitting on the shelf that patients can’t take at a higher dosage anymore, because the side effects are overshadowing efficacious treatments. Now, those drugs may actually be applicable to a much larger patient base, because neuromodulation makes it possible to reduce the dosage while maintaining the same positive effects. This is where Medtronic, Abbott and other device manufacturers meet GSK, J&J and Pfizer. They all want to provide better treatments with fewer side effects and they all have to deal with patients’ fear of surgery. That’s what you have to take out.

Luca Ravagnan, CEO, WISE

Luca Ravagnan is CEO of WISE, a Milan and Berlin-based company developing a new generation of implantable leads for neuromonitoring and neuromodulation using a patented ‘supersonic’ manufacturing process. Its Cortical Strip, composed of platinum electrodes in a soft, thin film of medical-grade silicone, is the first highly-conformable intraoperative neuromonitoring electrode to achieve a CE mark.

Manfred Franke, CEO, Neuronoff

Manfred Franke is the CEO of Neuronoff, the California-based developer of the Injectrode platform, which is injected from a syringe and mechanically stabilises inside biological tissue to form a highly conforming, compliant neural electrode in vivo. As such, it can remove the need for surgery for many neuromodulation treatments.

The Cortical Strip, developed by WISE, is a highly-conformable intraoperative neuromonitoring electrode for brain tumour and epilepsy surgeries.
The Cortical Strip is the first neuromonitoring electrode of its kind to achieve a CE mark.
Luca Ravagnan, CEO, WISE
Manfred Franke, CEO, Neuronoff

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