Abstract
As implantable medical electronics (IMEs) developed for healthcare monitoring and biomedical therapy are extensively explored and deployed clinically, the demand for non-invasive implantable biomedical electronics is rapidly surging. Current rigid and bulky implantable microelectronic power sources are prone to immune rejection and incision, or cannot provide enough energy for long-term use, which greatly limits the development of miniaturised implantable medical devices. Herein, a comprehensive review of the historical development of IMEs and the applicable miniaturised power sources along with their advantages and limitations is given. Despite recent advances in microfabrication techniques, biocompatible materials have facilitated the development of IMEs system toward non-invasive, ultra-flexible, bioresorbable, wireless and multifunctional, progress in the development of minimally invasive power sources in implantable systems has remained limited. Here we summarise three promising minimally invasive power sources, including energy storage devices (biodegradable primary batteries, rechargeable batteries and supercapacitors), human body energy harvesters (nanogenerators and biofuel cells) and wireless power transfer (far-field radiofrequency radiation, near-field wireless power transfer, ultrasonic and photovoltaic power transfer). The energy storage and energy harvesting mechanism, configurational design, material selection, output power and applications in vivo are also discussed. It is expected to give a comprehensive understanding of the minimally invasive power sources driven IMEs system for painless health monitoring and biomedical therapy with long-term stable functions.
1. Introduction
Since Hans Berger introduced electroencephalography (EEG) to record the electrical activity of the brain in 1929, electronics for physiological measurement and biological stimulation have been of interest for more than 90 years.[1-3] Over the past decades, numerous wearable and implantable electronics were designed for monitoring and measuring biological signals. According to Halperin et al., over 25 million United State citizens rely on implantable medical devices for life-critical functions in 2008,[4]the number of implantable cardioverter defibrillator implants 10-times increased between 1990 and 2002,[5-6] the demand for implantable medical electronics (IMEs) in 2015 in the United State is about $52B.[7] At present, the implantable medical device market is not just orientated to the growing geriatric population and associated prevalence of chronic degenerative diseases, younger populations pursuing a healthier and high-tech lifestyle also drive the lucrative wearable and implantable electronics market. The state-of-art technologies enabled biological signal recording including electrophysiological, physiological (pulse, temperature), mechanical (strain, pressure) and biochemical (glucose, pH) information.[8-10] Each of these biological signals is of vital importance for clinical research about physical functioning and various diseases.
However, it is still challenging to get access to bio-signals with high fidelity and stability from the target area of living organisms while conventional IMEs still stay rigid and bulky. The recent advanced technologies in microelectromechanical systems (MEMS), ultrathin electronic devices, sensors and biocompatible/bioresorbable encapsulating layers have broadened the application range of implantable electronics from traditional rigid and bulky devices to soft bioelectronics systems that interface with the complex geometries and curved surfaces of the human body.[8, 11] Compared with the first cardiac pacemaker invented and implanted in the human body in 1958,[12] bio-integrated electronics with good flexibility and stretchability shows huge progress and more benefits for precise signal recording and pain alleviation from patients. Nowadays, numerous miniaturised implants and wearable electronics have been developed. For instance, electrocorticography (ECoG) and electrocardiogram (ECG) sensors for neurological disorders study (e.g., Epilepsy, dementia, Parkinson’s disease and restless leg syndrome), angioplasty tools, prosthetic eye/skin, optoelectronic nerve stimulator, wearable pressure, strain, temperature sensors combined with drug delivery and data storage devices, signal recording and real-time treatment integrated with wireless data transmission, and wearable energy storage system for portable and remote healthcare.[8, 13-14] Though great progress has been made over the past decades to minimise the dimension of implants, a higher requirement towards more precise biomedical functions has also been set. The dimensions of the medical electronic system probing these signals are still orders of magnitude larger than those cells or tissues, thus developing minimally invasive or injectable micro and nanoscale medical electronic systems closely matching target tissues is necessary for the evolution of new-generation bioelectronics.
To provide energy for the new-generation minimally invasive bioelectronics system, the size and weight of the power source as a significant part of this system should also be taken into consideration. Batteries as the most used electrochemical energy storage devices developed for IMEs have enabled the successful operation for the treatment of human disease. Though energy requirements for the power sources vary with the IMEs functions, high volumetric energy density and minimised dimension are highlighted aiming to minimise discomfort for the patient.[15]However, conventional energy storage devices (such as Li-ion batteries) are usually large and bulky with inflexible packaging, leading to associated issues such as secondary invasive surgery for replacement due to limited capacity and potentially toxic substances leakage risk.[16] Therefore, new challenges have been present for power source devices to match with the soft, 3D and dynamically curved biological organisms while providing enough energy to the biomedical system.[17] To overcome the key limitations to the development of a minimally invasive IMEs system, the prospective implantable power sources should be developed towards the following features: minimally invasive, lightweight, durable, high-capacity, flexible, biocompatible or bioresorbable.
According to the different functional requirements of the IMEs, the designed and matched power source for the system varied. For short-term implantable electronics that are designed to be implanted and operate only for a prescribed time, biodegradable and bioabsorbable materials provide a unique opportunity. For instance, applications like muscle stimulation, bone growth stimulation, neurostimulation and wound healing require the power source to operate only for a short time compared with heart stimulation working over the whole patient’s life, biodegradable and bioabsorbable electronics can act as a desirable option to avoid the second surgery for device retrieving and tissue lesion.[18] As physically transient electronics, biodegradable power sources including biodegradable primary batteries,[19-22] biodegradable supercapacitors[23] and bioresorbable power harvesters,[24] can be fully dissolved into biologically benign byproducts in biofluids through hydrolysis and thus well resolve the problem of repeated surgery without secondary invasion. For long-term applications, durable energy storage devices with high energy density and energy harvesting devices with long-term stability are necessary. Compared with the primary battery, the rechargeable battery can provide a longer serves time and has been developed for neurostimulators operating in the milliwatt power range.[15] But for the minimally invasive implantable electronic system, secondary rechargeable batteries must also satisfy the requirements of bioabsorbable primary batteries, including reduced invasion and biocompatibility except for high energy density. In this case, miniaturised rechargeable batteries with high aspect ratio form can well solve the problem occurred with traditional bulky lithium-ion batteries and achieve charge/discharge cycling process in vivo such as sodium-ion batteries and fibre supercapacitors showed decent power capability and good biocompatibility.[25-27] Alternatively, the energy sources from the human body are also promising power options, which can provide a continuous stream of energy for medical devices such as pacemaker without restrictions like battery replacement and cumbersome daily charging.[28] Emerging biocompatible, ultra-flexible and miniaturised energy harvesters include piezoelectric nanogenerators (PENG) and triboelectric nanogenerators (TENG) for mechanical energy harvesting and biofuel cell for chemical energy harvesting.[29-34] The human body as a natural energy conversion factory can provide an abundant and constant flow of available biochemical and kinetic energy, it provides unlimited possibilities to support the IMEs during the whole lifetime of human and even to prolong the human lifespan.[28] In addition, wireless and battery-free technologies have also been widely studied for the application in miniaturised and ultralightweight devices probing signals with high chronic stability and signal fidelity.[35-36] For electronics such as optogenetic stimulator interfacing with neural tissues and micro injectable needles for multisite recording on the cellular scale, wireless power transmission technologies can provide reliable and constant power supply with versatile design and deployment options. At present, four main kinds of wireless power transmission technologies have been developed including near-field magnetic resonant coupling,[37] far-field radio frequency (RF),[38-39] photovoltaic (PV) power transfer,[40] and ultrasonic power transfer.[41] It can be applied as independent energy supply but also as complementary recharging technology to extend the lifespan of implanted energy storage devices.
In this review, we provided an overview of the state-of-the-art minimally invasive implantable electronics with an outlook of the smart and injury-reduced implantable electronics in the future, and aim to summarise various alternative miniaturised power sources for the implantable electronic system. Three broad categories of minimally invasive power sources were classified regarding their different energy supply mechanism: Energy storage devices, human body energy and wireless power transfer as summarised in Figure 1. The advantages and limitations of each kind of power strategy was reviewed in detail. Finally, the challenges and prospective future of minimally invasive electronics and corresponding applicable power sources were discussed.
2. Recent Progress in Implantable Electronics
Conventionally, implantable electronics with hardware modules such as bio-functional parts, circuits and energy storage devices are packaged and sealed within bulky metal cases, then implanted into the vacant area of the human body by open surgery.[42] Clinical implants such as drug delivery devices, pacemakers and ECG monitors are also in such conventional form. Figure 2 provides an overview of the milestones in the development history of implantable electronics since the first implantable battery-powered cardiac pacemaker was invented in 1958.[43] However, many complications including infection, thrombosis, lead failure and pneumothorax are related to this kind of construct of the cardiac pacemaker, the traditional implantation will cause large incisions and cannot exempt patients from secondary surgery to take implants out after the energy of the system is running out. Postsurgical complications caused by these invasive surgeries and bulky implants have also been reported.[44] In this case, an implantable device with an ultrathin structure and good conformability will be