A calming influence

In 1954, cardiovascular surgeon Dr Michael DeBakey successfully implanted the first prosthetic graft into a patient with weakened arteries. The novel graft was made from the widely available synthetic material called Dacron, which DeBakey had stumbled across almost by chance in his local department store. “He wanted to develop an artificial heart and he knew that vascular grafts were needed to create this connection,” explains Omid Veiseh, assistant professor of bioengineering at Rice University. “He was looking for different materials that he could use and he was inspired by what he was finding in the fabric stores. He was literally sewing [the Dacron] together and trying it out on patients.” As Veiseh says, “There was an urgent need for patients and people had to come up with something… The field wasn’t as systematic or as structured as it is today.”

DeBakey got lucky: through iterative testing, and a dose of serendipity, he was able to discover a material that didn’t provoke an immune reaction in the body. But this is not the case with all implantable medical devices (IMDs). “For all the really exciting breakthrough ideas, designers often underestimate the challenge of foreign body response – and that’s usually where these ideas die,” Veiseh notes. “You come up with your perfectly designed device, you put it in the body, and then the body rejects it. This barrier has curtailed a lot of innovation when it comes to implantables.”

An attuned threat response

Foreign body response (FBR) is the term used to describe the body’s immune reaction to a foreign object. As Veiseh explains: “The immune system is really good at identifying things that don’t belong there, and it has a number of different mechanisms for trying to eliminate them. But when the immune cells are physically unable to ‘chew up’ and eliminate an implant, then they start adhering to the surface of it and they initiate a cascade, which is what we call the foreign body response.”

When this happens, different types of immune cells “orchestrate”, building up scar tissue around the implant in order to wall it off from the rest of the body. For some medical devices, such as knee and breast implants, this is not a big deal. “The devices are somewhat inert and don’t need to physically interact with the body,” says Veiseh. “But for active devices that have sensing or actuated components, such as a pacemaker or a neural recording device, this is a major barrier, which limits the utility of these [applications] in the body.”

Veiseh has recently concluded a study into lipid deposition on the surfaces of implants, as one strategy for targeting FBR. “We identified small molecule coatings,” he explains. “One of the things that we realised is that these molecules tend to attract a suppressive type of macrophage immune cell. As these immune cells crawl on the surfaces of implants, we realised that they leave behind lipid vesicles – these extracellular kind of blobs of cells that are chock full of cytokines.”

Veiseh observed that these vesicles could tag material with either an “attack” or “do not attack” signal. “We did quite a lot of work on this in different contexts with different types of coatings, as well as looking at explanted human devices, and we noticed that, indeed, there is a correlation between the composition of these extracellular vesicles that are deposited on to these implants, and whether you get foreign body responses or not,” he adds.

Veiseh describes the results of the study as “an overarching mechanistic insight” which is relevant for devices that exist on the market today, as well as a guide to the future development of devices. “We’ve tested these small molecule coatings in large animals and we’re working on advancing them to the clinic in different contexts,” he says.

Fighting the immune system

Veiseh’s study is just one amongst a number of innovative approaches that are currently being tested and deployed in the fight against FBR. At the University of Cambridge, for example, Dr Damiano Barone, clinical lecturer in the Department of Clinical Neurosciences and a practising neurosurgeon, has been working on a study that explores the prevention of FBR through something called “inflammasome inhibition”.

Barone’s expertise is in bioelectronics, exploring the relationship between neural interfaces – electronic devices that interact with the nervous system – and the body. For this application, the ideal device is “one that goes into the brain”, he says. “You want as much information as you can get, and the only way to get this is to be close [to the brain]. Unfortunately, there are lots of problems with this, and one of the major ones is the fact that every time you implant something into the brain it gets kind of rejected.”

When it comes to neural interfaces, FBR becomes a serious obstacle because, as Barone explains, once the scar tissue begins “building up between the brain and the electrodes”, the signal doesn’t pass anymore, and eventually it stops altogether. “That’s one of the main reasons why many advanced brain-computer interfaces have not translated into humans,” he adds.

Barone’s study takes a pharmaceutical approach to FBR, examining the effects of dexamethasone – the immunosuppressant anti-inflammatory drug often used to treat cancer patients – on inflammation.

“What we found is that if you use such a potent immunosuppressant anti-inflammatory drug, you don’t just stop inflammation and scarring, you also damage and stop neuroregeneration,” he explains. “It’s not a feasible translatable action. So, our question was: ‘How do we bring down inflammation to reduce the scarring without bringing down regeneration of the nervous system?’”

Bothersome inflammasome

The answer, as Barone discovered in a study using mice, was to inhibit inflammasome – the innate macromolecular signalling platform that induces inflammation. “What we found is that by working on the inflammasome, which is this molecule inside the macrophages, you could reduce the secretion of interleukin-1, which causes the bad inflammation [scarring] but doesn’t affect the good inflammation [regeneration].” Like Veiseh’s study, Barone’s research will have wider application in conjunction with existing devices and in combination with other strategies, such as the use of flexible electrodes and soft interfaces. “There is no one single strategy that really is going to be the strategy for translation,” he says.

There are still obstacles ahead in the path to overcoming FBR, but with innovative studies like Veiseh’s and Barone’s underway, there could eventually be methods that make new IMD innovations viable in the clinic. “When it comes to chronic sensing,” Veiseh says, “there’s a big need for glucose with diabetes patients – but I think there are other biomarkers that could really inform people of their health status.” Veiseh also mentions the emerging concept of “electroceuticals”, wherein, by activating certain neurons in the body – within the brain or even the peripheral nerves – a similar therapeutic effect to that of drugs can be achieved.

Barone, meanwhile, is looking into how inflammasome inhibition could be used to further the emerging field of neuroprosthetics. “At the moment”, he says, “bioelectronic devices are mostly used to modulate function”. He gives the example of a brain stimulator used in patients with Parkinson’s disease. “You implant electricity to disrupt the network in order to make patients shake less,” he says. “Or you have the spinal cord stimulation, where we interfere with the signal going through the spinal cord for people to feel less pain. But it’s all about neuromodulation rather than disruption.” The new generation of neural interfaces, however, may be able to “restore function that has been lost”, Barone says. “So people who aren’t able to talk could talk again; people who can’t see could see again; and people who are able to unable to walk could walk again.”

Miraculous as these solutions sound, Barone believes that we will begin to see them in the not-too-distant future. “It’s not movie sci-fi [stuff],” he says. “There are already company staffed clinical trials – this is what Elon Musk is targeting with Neuralink. So I think the next 10 years will be a revolution. Probably more will happen in the next 10 years than we have seen in the last 100. It’s extremely exciting.”

First, though, we’ve got to remove the barrier of FBR. Once we’ve achieved that – and Veiseh and Barone are confident that we will – miracles really might happen.