Using a rice-grain sized wireless implant to stimulate peripheral nerves from within blood vessels could potentially treat drug-resistant neuropathic pain, according to a study published in Nature Biomedical Engineering.
After receiving a grant, a team set out to create implantable, wirelessly powered nerve stimulators that can be used in place of opioids for pain management. The 1-millimetre large implants are small enough to be placed on stents and delivered within blood vessels adjacent to specific areas of the central and peripheral nervous system.
Co-principal investigator of the study, Sunil A. Sheth, MD, explained: “We’re getting more and more data showing that neuromodulation, or technology that acts directly upon nerves, is effective for a huge range of disorders—depression, migraine, Parkinson’s disease, epilepsy, dementia, etc. – but there’s a barrier to using these techniques because of the risks associated with doing surgery to implant the device, such as the risk of infection. If you can lower that bar and dramatically reduce those risks by using a wireless, endovascular method, there are a lot of people who could benefit from neuromodulation.”
Neuropathic pain can be a disabling disorder that accounts for nearly 40% of chronic pain sufferers, often leading to anxiety, depression, and opioid addiction. Previous studies showed that electrical stimulation is an effective treatment for reducing pain when doctors target the spinal cord and dorsal root ganglia (DRG), a bundle of nerves that carry sensory information to the spinal cord. However, existing DRG stimulators require invasive surgery to implant a battery pack and pulse generator.
According to the researchers, this new type of technology offers a way to perform minimally invasive bioelectronic therapy that helps with more precise placement of the implant and more predictable outcomes. The team are hoping to move forward with regulatory approval, which Dr Sheth estimates may take a few years.
Researchers have found that a number of deaths related to medical device adverse events were improperly categorised in the FDA’s Manufacturer and User Facility Device Experience (MAUDE) database, according to a new study.
Flagging terms commonly associated with death, the study investigators used a natural language processing algorithm to identify 290 141 reports where serious injury or death was reported; 52.1% of these events were reported as deaths, and 47.9% were classified as either malfunction, injury, or missing (report was uncategorised), reported Christina Lalani, MD, of the University of California San Francisco, and colleagues, in JAMA Internal Medicine.
Overall, 23% of reports with a death were not placed in the death category, amounting to some 31 552 reports filed from December 31, 1991, to April 30, 2020.
Whether to classify the event as a malfunction, injury, death, or ‘other’ is up to the physician or manufacturer. According to the FDA, the reporter is required to categorise an adverse event as an official death if the cause of death is unknown, or if the device “may have caused or contributed to a death.”
The three most common product codes among the adverse event reports were for ventricular assist bypass devices (38 708 reports), dialysate concentrate for haemodialysis (25 261 reports), and transcervical contraceptive tubal occlusion devices (14 387 reports).
The natural language processing algorithm scanned through reports, identifying terms such as “patient died,” “patient expired,” “could not be resuscitated,” and “time of death.” Of the 70 terms that were associated with a death, 62 (88.6%) were found among miscategorised adverse event reports involving a patient death. And, out of all 62, there were 17 terms that had an estimated percentage of 100%, meaning that “every time that term was used, the patient had died, even though the reporter had not classified the report as death,” the team wrote.
Only 18 terms had sample sizes large enough for researchers to calculate confidence intervals; among them, the words “death” or “deaths” were linked to 12% of adverse event reports in which a patient died, but were classified as malfunction, other, or missing — the highest rate of all the analysed terms.
The researchers acknowledged a major limitation in that only reports with at least one death-associated term were included, in contrast to all the reports from the MAUDE database. Improperly categorised deaths likely contribute to an underestimate.
“The classification chosen by the reporter is vital, as the FDA must review all adverse events reported as deaths, which is not the case for other reporting categories,” the authors wrote. Improving the reports’ accuracy is crucial, since patient death frequency can prompt the FDA to pursue investigations into the device’s safety, they added.
The researchers pointed out an inherent conflict of interest as 95.9% of the reports evaluated in the study were submitted by manufacturers.
“It may not be in their interest to facilitate identification of serious problems with their own devices in a timely manner,” they wrote. “There have been multiple instances of delays by manufacturers in reporting serious malfunctions and deaths that were associated with medical devices, as well as complete failures to report.”
Therefore, it’s likely that a significant number of patients have been unknowingly treated with devices that were later revealed to be dangerous, Dr Lalani and colleagues noted. For example, they referenced the reporting failures that occurred from 2002 to 2013, when 32 000 women reported adverse events associated with the permanent birth control device Essure while the FDA only received 1023 adverse event reports from the manufacturer.
They concluded that patients and care providers should submit reports directly to the FDA as well as or instead of the manufacturer.
Journal information: Lalani C, et al “Reporting of death in US Food and Drug Administration medical device adverse event reports in categories other than death” JAMA Intern Med 2021; DOI: 10.1001/jamainternmed.2021.3942.
A tiny, implantable carbon fibre electrode has the potential to provide a long-term brain-computer interface which can record electrical signals over lengthy periods of time.
The carbon fibre electrodes were developed at the University of Michigan and demonstrated in rats. The new research shows the promise of carbon fibre electrodes in recording electrical signals from the brain without damaging brain tissue. Directly implanting carbon fiber electrodes into the brain allows the capturing of bigger and more specific signals than current technologies.
This technology could lead to advances that could give amputees and those with spinal injuries control of advanced prosthetics, stimulate the sacral nerve to restore bladder control, stimulate the cervical vagus nerve to treat epilepsy and provide deep brain stimulation as a possible treatment for Parkinson’s. Â
“There are interfaces out there that can be implanted directly into the brain but, for a variety of reasons, they only last from months to a few years,” said Elissa Welle, a recent PhD graduate from the U-M Department of Biomedical Engineering. “Any time you’re opening up the skull for a procedure involving the brain, it’s a big deal.”
Brain implants are typically made from silicon due to its ability to conduct electricity and its historic use in cleanroom technology. But silicon is not very biocompatible and leads to the formulation of scar tissue over long periods. Such electodes will eventually degrade and no longer capture brain signals, requiring removal.
Carbon fibres may be the answer to getting high-quality signals with an interface that lasts years, not months. And by laser cutting and sharpening carbon fibers into tiny, subcellular electrodes in the lab with the help of a small blowtorch, U-M engineers have harnessed the potential for excellent signal capture in a form the body is more likely to accept.
“After implantation, it sits inside the brain in a way that does not interfere with the surrounding blood vessels, because it’s smaller than those blood vessels,” Welle said. “They’ll move around and adjust to an object that small, rather than get torn as they would when encountering larger implants.”
Part of the electrode’s compatibility in brain tissue is down to smaller size, but its needle-like shape may also minimise compacting of any surrounding tissue. Larger carbon-based electrodes have been shown to actually encourage neural tissue to grow instead of degrading. The team is hopeful that similar potential for their carbon fibre electrodes will be revealed by further testing.
Carbon fibre electrodes in a previous study dramatically outperformed conventional silicon electrodes with 34% of electrodes recording a neuron signal compared to 3%. Laser cutting then improved this number to 71% at 9 weeks after implantation. Flame sharpening has now enabled these high performance probes to be implanted directly into the cerebral cortex, negating the need for a temporary insertion aid, or shuttle, as well as into the rat’s cervical vagus nerve.
It is relatively easy to insert electrodes into the brain. But the researchers have also taken on the more difficult task of inserting the sharpened carbon fibre electrodes into nerves, with micrometre diameters.
Those findings show that potential for these electrodes goes beyond prosthetic manipulation, according to Cindy Chestek, a U-M associate professor of biomedical engineering, and principal investigator of the The Cortical Neural Prosthetics Lab.
“Someone who is paralysed may have no control over things like their bladder, for example,” Prof Chestek said. “We may be able to utilise these smaller electrodes to stimulate and record signals from areas that can’t be reached by larger ones, maybe the neck or spinal cord, to help give patients some level of control.”
A new 3D printing process developed by University of Nottingham researchers, allows customised production of artificial body parts and other medical devices with built-in functionality offering shape and durability, while also cutting bacterial infection risk.
“Most mass-produced medical devices fail to completely meet the unique and complex needs of their users,” explained lead researcher Dr Yinfeng He, Centre for Additive Manufacturing. “Similarly, single-material 3D printing methods have design limitations that cannot produce a bespoke device with multiple biological or mechanical functions.”
“But for the first time, using a computer-aided, multi-material 3D-print technique, we demonstrate it is possible to combine complex functions within one customised healthcare device to enhance patient wellbeing.”
The team’s hope is that their new design process can be applied to 3D-print any highly customised medical device.
For example, the method could be adapted to create a single-part prosthetic limb or joint with greater comfort and functionality; or printing customised pills containing multiple drugs – known as polypills – optimised to release their contents in a planned sequence.
What it can do
For this study, the researchers applied a computer algorithm to design and manufacture 3D-printed objects made up of two polymer materials with differing stiffness that also prevent bacterial biofilm build-up. Combining these two materials, they produced an implant with the required strength and flexibility.
Artificial finger joint replacements currently use both silicone and metal parts, offering the wearer a standardised level of dexterity but must be rigid enough to implant into bone. The team 3D-printed a finger joint as a demonstration, which offered these dual requirements in one device, while also being able to customise its size and strength to meet individual patient requirements. They can even make use of intrinsically bacteria-resistant and bio-functional multi-materials, combating infection without extra antibiotics.
A new high-resolution characterisation technique (3D orbitSIMS) was used to 3D-map the chemistry of the print structures and to test the bonding between them throughout the part. This showed that the two materials were intermingling at their interfaces; a sign of good bonding and therefore a stronger device.
The study was carried out by the Centre for Additive Manufacturing (CfAM) and funded by the Engineering and Physical Sciences Research Council. The complete findings are published in Advanced Science, in a paper entitled: ‘Exploiting generative design for 3D printing of bacterial biofilm resistant composite devices’.
Prior to making the technique commercialised, the researchers plan to try out more advanced materials with extra functionalities such as controlling immune responses and promoting stem cell attachment.
The HeartWare system, a left ventricular assist device (LVAD) for advanced heart failure patients, is being discontinued immediately, according to the Food and Drug Administration.
The manufacturer, Medtronic, is halting global distribution and sale of its HeartWare system in the wake of observational evidence of increased neurological adverse events and mortality for its LVAD compared with similar mechanical circulatory support (MCS) devices.
Last December, some HeartWare LVADs were recalled because of complaints that the pump may delay or fail to start. So far 100 of these complaints have been received, including 14 patient deaths and 13 cases where an explant was necessary, the FDA noted.
“We have been carefully monitoring the adverse events associated with this device and support its removal from the marketplace,” said Bram Zuckerman, MD, director of the Office of Cardiovascular Devices at the FDA’s Center for Devices and Radiological Health, in a statement.
Medtronic now advises physicians to immediately stop new implants of the HeartWare device, but does not recommend explants.
The company is working on a plan for ongoing support of the some 4000 patients around the world who currently have this LVAD. It received commercial approval for use in the US in November 2012.
The FDA named Abbott’s HeartMate 3 as one alternative LVAD for patients with end-stage heart failure. This device features a magnetic levitation system that keeps the rotor separate without mechanical contact.
“The FDA is working closely with both Medtronic and Abbott to ensure patient care is optimised during this transition period and that there is an adequate supply of devices available to provide this patient population with options for end-stage heart failure treatment,” said Dr Zuckerman.
In a separate press release, Abbott reassured the public that it has the ability to meet increased demand for MCS devices as a result of HeartWare withdrawal from clinical use.
A team of researchers have developed a miniscule device that allows them to implant insulin-secreting cells into diabetic mice, which secrete insulin in response to blood sugar without being destroyed by the immune system.
The findings are published in the journal Science Translational Medicine.
“We can take a person’s skin or fat cells, make them into stem cells and then grow those stem cells into insulin-secreting cells,” said co-senior investigator Jeffrey R Millman, PhD, an associate professor of medicine at Washington University. “The problem is that in people with Type 1 diabetes, the immune system attacks those insulin-secreting cells and destroys them. To deliver those cells as a therapy, we need devices to house cells that secrete insulin in response to blood sugar, while also protecting those cells from the immune response.”
Prof Millman, also an associate professor of biomedical engineering, had previously developed and honed a method to make stem cells and then grow them into insulin-secreting beta cells. Prof Millman previously used those beta cells to reverse diabetes in mice, but it was not clear how the insulin-secreting cells might safely be implanted into people with diabetes.
Prof Millman explained why the new device’s structure was so important.
“The device, which is about the width of a few strands of hair, is micro-porous—with openings too small for other cells to squeeze into—so the insulin-secreting cells consequently can’t be destroyed by immune cells, which are larger than the openings,” he said. “One of challenges in this scenario is to protect the cells inside of the implant without starving them. They still need nutrients and oxygen from the blood to stay alive. With this device, we seem to have made something in what you might call a Goldilocks zone, where the cells could feel just right inside the device and remain healthy and functional, releasing insulin in response to blood sugar levels.”
Millman’s laboratory collaborated with researchers from the laboratory of Minglin Ma, PhD, an associate professor of biomedical engineering at Cornell and the study’s other co-senior investigator. Prof Ma has been working to develop biomaterials that can help implant beta cells safely into animals and, eventually, people with Type 1 diabetes.
In recent years a number of implants have been tried to varying degrees of success. For this study, the team led by Prof Ma developed a nanofibre-integrated cell encapsulation (NICE) device. They filled those implants with insulin-secreting beta cells grown from stem cells and then implanted the devices into the abdomens of diabetic mice.
“The combined structural, mechanical and chemical properties of the device we used kept other cells in the mice from completely isolating the implant and, essentially, choking it off and making it ineffective,” Prof Ma explained. “The implants floated freely inside the animals, and when we removed them after about six months, the insulin-secreting cells inside the implants still were functioning. And importantly, it is a very robust and safe device.”
The cells in the implants continued to secrete insulin and control blood sugar in the mice for up to 200 days — even without any immunosuppressive drugs being administered. “We’d rather not have to suppress someone’s immune system with drugs, because that would make the patient vulnerable to infections,” Prof Millman said. “The device we used in these experiments protected the implanted cells from the mice’s immune systems, and we believe similar devices could work the same way in people with insulin-dependent diabetes.”
Profs Millman and Ma stress that a considerable amount of work is needed before the device can be trialled in a clinical setting.
Journal information:Â X. Wang et al., “A nanofibrous encapsulation device for safe delivery of insulin-producing cells to treat type 1 diabetes,” Science Translational Medicine (2021)
