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As part of the Implantable Microsystems for Personalised Anti-Cancer Therapy (IMPACT) programme led by Alan Murray at the University of Edinburgh, UK, scientists hit on the idea of creating an implantable sensor to monitor cancer-cell oxygenation. “We know that solid tumours like breast and colon cancers can develop in areas of low oxygen,” says Mark Gray, a member of the IMPACT team1. He notes that cancer cells in a low-oxygen environment tend to develop “nasty, aggressive characteristics” which can promote their spread to other areas of the body. These hypoxic cancer cells are also more resistant to radiotherapy and chemotherapy. So if doctors knew the location of these hypoxic tumour environments, they could increase the radiation doses given to these areas or provide drugs that can increase the effectiveness of the radiotherapy.
But the trouble is that the tumour environment is far from static, says Gray. “One area can be hypoxic one second, and it suddenly gets a blood supply and another area becomes hypoxic. So it's constantly changing and evolving.” Current methods for detecting areas of low oxygen include magnetic resonance imaging and positron emission tomography, but these only provide a snapshot of the tumour environment at a specific moment. So the IMPACT group looked at creating an implantable sensor that could continuously monitor tumour oxygen levels in real time.
One area can be hypoxic one second, and it suddenly gets a blood supply and another area becomes hypoxic. So it's constantly changing and evolving.
Gray says that the IMPACT sensor is “basically a miniaturised version of a Clark electrode”, a device that has been used in research for decades to monitor oxygen levels. But Clark electrodes are large, and their liquid electrolyte makes them unsuitable for implantation. So the IMPACT group looked for ways to miniaturise the sensor and make it safe for in vivo use.
This is where multidisciplinary collaboration became important, says Gray. “One of the big advantages of the IMPACT project was that it brought together a diverse set of people working towards the same goal. It had veterinary surgeons like myself, medical doctors, and then it had scientists and engineers to design and manufacture the sensors.” The engineers fabricated electrodes using manufacturing techniques developed by the semiconductor industry, and made a protective coating from Nafion, a biocompatible ionomer that resists biofouling and acts as an electrolyte.
Gray, as a lecturer in large animal research surgery at the University of Edinburgh, also found that his background in veterinary medicine helped. “The advantage of having a veterinary surgeon on the team is you can develop animal models that are very applicable to human medicine,” he says. “For example, the sheep model that I developed was based on techniques commonly used in human lung cancer patients.”
An unexpected turn
But perhaps the biggest advantage of having such a multidisciplinary team was that it highlighted an application that wasn’t obvious at the outset. Gray says that the sensor was originally envisaged for use in cancer, but a member of the team who specialises in colorectal surgery, Mark Potter, realised that the sensor could also be used to monitor oxygen levels following intestinal surgery.
A range of medical conditions, including cancer, can result in the need to remove a segment of the intestine and then join the two ends back together. “And when you put staples or stitches in the intestine,” says Gray, “you need to have a good blood supply and adequate oxygen levels at the site where you've joined the intestine back together. If you haven't got oxygenation at the intestinal wall, the intestine may not heal correctly.”
Since doctors cannot visually inspect the intestine after surgery, they rely on things like raised temperature or inflammatory markers as indications that the intestine is not healing correctly. Unfortunately, by the time a patient has developed such clinical signs, says Gray, “it's very serious, and quite a lot of those patients will die.” But monitoring the oxygen levels around the repair using an implantable sensor could give an early warning signal that would prompt doctors to intervene before the patient becomes seriously unwell.
Although this use wasn’t envisaged at the start of the project, Gray now thinks it’s likely to be the first application of the device that will be tested in humans. The IMPACT team first tested the sensor materials for biocompatibility using human xenograft tumours grown in nude mice, and didn’t observe any significant foreign body response2. They then tested the device in an in vivo intestinal application in rats3, and in a newly developed sheep model of human lung cancer4,5, with encouraging results.
Gray says that the next step in developing the sensor for intestinal use will be to conduct experiments in pigs. “The pig has a remarkably similar gastrointestinal tract to humans and is a great translational model for human diseases,” he says. “Pigs will undergo the same intestinal surgical procedure as would be performed in human patients, and sensors will be placed onto the intestinal walls.” These studies will involve implanting the devices for longer periods than in previous experiments, probably leaving them in place for around a week. But to get to the stage where the device could be implanted into humans, Gray says that more refinements are needed, including improving the packaging, miniaturising it further, making it wireless and extending the sensor’s lifetime.
Still, Gray is pleased with the progress so far. And his advice for other would-be inventors? “You need a good question to start with, one which answers a specific, unmet clinical need. And a diverse group of researchers with expertise in each of their fields is important, but it’s the enthusiasm and drive of those involved in the project that will make it a success”.
Interview with Mark Gray, June 2020.
Gray, M. E. et al. Biocompatibility of common implantable sensor materials in a tumor xenograft model. J Biomed Mater Res B Part B. 2019; 107: 1620–1633.
Gray, M. E. et al. In vivo validation of a miniaturized electrochemical oxygen sensor for measuring intestinal oxygen tension. Am J Physiol Gastrointest Liver Physiol. 2019; 317: G242–G252.
Gray, M. E. et al. A Novel Translational Ovine Pulmonary Adenocarcinoma Model for Human Lung Cancer. Front Oncol. 2019; 9: 534.
Gray, M. E. et al. Ovine Pulmonary Adenocarcinoma: A Unique Model to Improve Lung Cancer Research. Front Oncol. 2019; 9: 535.