Next evolutionary step

By definition, bioelectronics is the convergence of biology and electronics. We tend to think of it as a new term but the first reference was in 1912. According to a 2009 report by the US National Institute of Standard and Technology, this was in relation to the measurement of electrical signals generated by the body. We already have a number of applications of bioelectronics within common use, including pacemakers and medical imaging technology. Despite these developments, it was not until the mid- 1990s when the term became more commonly used within the scientific literature. Today, bioelectronics is used to describe a range of applications for electronics within biology and medicine.

A number of different types of devices have been developed using bioelectronics. This includes a large variety of diagnostic, monitoring and therapeutic electronic devices, from the organ level to the cellular or subcellular level. For example, there are devices that use biosensors to detect and characterise biological materials, such as DNA, protein and cells. In addition, there are implantable devices that interface with biological systems to repair, restore or enhance physiological functions. Biolectronics also includes implantable devices, such as pacemakers, deep-brain stimulators, cochlear implants, visual implants, electrical bladder controllers, muscle implants, spinal cord and peripheral nerve stimulators.

Lan Yue, assistant professor of research ophthalmology at University of Southern California (USC) is committed to advancing bioelectronics and is currently focused on retinal applications of this technology. Despite a great deal of progress made within the field and exciting future applications, there are also a number of challenges. This is exacerbated because of the inherent convergent nature of bioelectronics. Barriers can thus arise from a lack of technological advancement, biological understanding or a combination of the two. Although there is a requirement for innovation across a number of different fields, this also allows cross-discipline collaboration among researchers and a productive platform for creative thinking.

Small problems

In terms of technological difficulties, the inherent challenge is making devices small enough to be used inside the body and producing these at a high volume. “Device miniaturisation demands advancement in microelectronics and fabrication,” explains Yue.

Fabrication methods for other fields, such as the semiconductor industry, are optimised for minimising trace widths and feature sizes. A wide variety of materials have been incorporated into the fabrication processes to improve performance while reducing costs. However, in biology and medicine, methods for building microdevices are not well-established.

Reliability is a particular area of concern. The majority of micro-fabricated bioelectronic devices are either fabricated by small custom suppliers or are manufactured within academic facilities. While semiconductor technologies can be used to fabricate small features, they are not yet able to fabricate complex bioelectronics. However, with the rapid development of these technologies, it is likely only a matter of time before this is possible.

Another technological challenge is ensuring that a device is sustainable within the body. “Proper encapsulation is essential to the longevity of a device in the physiological environment,” explains Yue.

There are a number of strategies to improve biocompatibility. These include employing biocompatible materials, limiting implant rejection and minimising heat generation, which all help to achieve a healthy tissue-electronic interface. Optimising the battery lifetime, functional capacity and heat management of devices is also imperative in order to obtain power efficiency and data management capabilities.

Another key challenge for bioelectronics is customisation. “A closed-loop system is desired in many cases to customise a bioelectronics device for optimised therapeutic effects,” explains Yue. “This often demands advanced acquisition and interpretation of the biological signals.”

Similar to other personalised treatments, as gene therapy and cell tissue engineering, bioelectronics production could be decentralised with manufacturing taking place at sites close to specialist hospitals. However, achieving personalisation while navigating the pressure to reduce cost – through the high-volume manufacture of devices and their components – is inherently difficult.

One solution is 3D-printing technologies, which offer huge potential in their ability to produce devices that meet the needs of different users in a quick and cost-effective manner. Although these technologies are still in their relative infancy; they are likely to be an increased area of focus over the next few years because of their ability to drive progress, not only in bioelectronics, but within medical devices as a whole.

There are also physiological challenges within bioelectronics. “A better understanding of the fundamental issues of the target physiological systems, particularly the processing at the bioelectronic interface and beyond, is required,” says Yue. “This will enable design of the devices that better mimic the impaired functions of the target tissue while reducing biofouling.”

Biofouling is a process where a build-up of biological material accumulates on wetted surfaces. This is problematic in a number of bioelectronic devices, such as pacemakers. It affects their functionality by altering the electrical properties of the electrodes attached to the heart, making sensing and actuation difficult.

The key challenge is that bioelectronic devices must interact with living tissues that are not inherently compatible. Due to the high level of sophistication of digital electronics, the signal processing of these devices is far more advanced than the front-facing aspect of the device.

Such issues are likely to be solved by the increasing work within systems biology – the study of the interactions that occur within the body. Insights from this area will allow the development of devices that are more compatible with biological systems and tissue. In particular, there is an increasing amount of research in miniaturised and automated microfluidics and nanotechnology platforms, which is a key area of focus for Yue.

Eye for detail

Although Yue is passionate about advancing bioelectronics more generally, her particular area of expertise is in retinal medical devices. She began her research in this area when working towards her PhD, during which time she became fascinated with bioelectronic visual prostheses, often referred to as bionic eyes. After completion of her PhD, she joined the research team of Dr Mark Humayun, a world-renowned pioneer in retinal implants. For her postdoctoral studies, she evaluated the efficacy and safety of these devices. This experience had a profound impact on her research goals and motivation. “It inspired my current work in the development of new stimulation strategies and nanoelectronic prosthesis that will, hopefully one day, restore colour vision and high visual acuity in the blind,” Yue explains.

Yue is currently working with blind patients who have retinal implants. She is evaluating the implant-retina interface and their visual functions with the assistance of the device. Alongside this research, Yue is developing novel stimulation strategies to enhance the visual experience of the otherwise blind patients.

The aim when creating a complex bioelectronic device, such as visual prosthesis, is to harness electrical power to produce highly specific and localised stimulation. Although an area with a lot of potential, there have also been a number of challenges that Yue has had to navigate in her work. “A lot of the difficulties that we encounter stem from insufficient understanding of signal processing of human retina to electrical stimuli,” Yue explains. Further research is required to learn more about the different patterns of electrical stimulation in order to optimise the functioning of visual prosthesis.

In addition, as with all medical devices, safety is a top priority in visual prosthesis. However, this raises new challenges in the ability to improve its effectiveness. “It comes with the compromise in the fabrication capability and functional capacity of the device,” says Yue.

Yue is determined to stay focused on her current area of work. “The overarching goal of my research will remain to be enhancing visual ability of prosthetic vision in the blind,” Yue states. In order to achieve this, she intends to study two areas in parallel. The first of these is the development of new stimulation paradigms through continued investigation of electrical stimulation of the visual system. The second is creating and testing non-conventional bioelectronic prosthetic devices that use novel materials, such as organoelectronics and nanoelectronics.

In looking ahead in bioelectronics more generally, Yue remains optimistic, saying, “Advancement of material technology with fabrication and information technology will profoundly impact bioelectronics in the future, possibly leading to a revolutionary breakthrough.”

These material developments open up the possibility to make devices that are more flexible, biocompatible, immune tolerant and with a higher energy conversion efficiency. In addition, the progress in AI and related technologies will allow the decoding of biological signals at an impressive speed and depth. Together these provide the opportunity to address difficult questions in precisely harnessing electrical power to serve for biological purposes. The devices of the future may be able to not only match the level of human functioning but also improve upon it. “It is imaginable that with the advancement in bioelectronic technology, conventional devices that aim to monitor or mimic human physiological functions may one day progress to devices that can enable enhanced performance; for example, in sensory functions and memory,” says Yue. 

The current status of bioelectronics in the medical device industry

The rapid evolution within the field since the mid-1990s has been referred to as the ‘bioelectronic revolution’. This is characterised by large companies, which are currently making significant investments in the area. These include the big players in the medical device space, such as Medtronic and Boston Scientific, as well as those from other scientific disciplines, such as data mining and the pharmaceutical industry. Public and private organisations, such as the National Institute of Health, the Defense Advanced Research Projects Agency and GlaxoSmithKline, are dedicating substantial resources to drive efforts within bioelectronics worldwide, with a view towards building new markets, clinical translation and adoption.

Propelled by capital injection and by the discoveries of the scientific community, a growing number of start-ups are proposing new target diseases for intervention, releasing preliminary data that can demonstrate the validity of the bioelectronic medicine approach while accepting the risks associated with early stage technology development. As a result of these efforts from the private and public sector, it is becoming easier to envision continuous improvement of these devices, leading to new models of clinical care.

Source: ‘Bioelectronics: the promise of leveraging the body’s circuitry to treat disease.’