FIGURE 7 (A) The first implanted biofuel cell operating in a living snail and generating electrical power by the consumption of physiologically produced glucose as a fuel. Reproduced with permission.[115] Copyright 2012, American Chemical Society. (B) Implanted single glucose biofuel cells in rats as power source devices with no immunological rejection. Reproduced with permission.[116] Copyright 2013, Springer Nature. (C) The miniaturised intravenous implantable biofuel cell based on modified flexible carbon fibre electrodes. Reproduced with permission.[31] Copyright 2013, Royal Society of Chemistry.
3.3. Wireless Power Transmission Technologies
Compared with internal energy harvesting devices, wireless power transmission technology through electromagnetic radiation, acoustic vibrations and optical cells et al. show higher output power up to 500 mW and better stability,[119-120] yet the flexibility and dimension are the main challenges for application in IMEs. Four main strategies of external wireless power transmission technologies are included in this section: Far-field RF radiation, near-field wireless power transfer (magnetic resonant coupling), photovoltaic power transfer and ultrasonic power transfer.
3.3.1. Far-field RF radiation
Far-field radio frequency power transfer can be achieved by emitting radio frequency radiation with a frequency ranging from 420 MHz to 2.4 GHz and a wavelength from 0.1 m to 1 m, from a transmitting antenna to a receiving antenna, and converting the harvested radio frequency radiation into direct current with a rectifier.[121] With specialized primary designs of transmission and receiving antennae, continuous and stable radio frequency power can be delivered over a long distance of up to several meters. With optimized designs of transmission and receiver coil, output voltages larger than 300 mV can be achieved at a distance of 4 mm, and higher voltages can be reached even at 10 V, which can provide enough power for various bioelectronic implants and even soft robots.[122] For example, Park S et al. introduced a strategy combining thin mechanically soft neural interfaces with fully implantable stretchable wireless radio power antenna and rectifying circuits into a fully implantable miniaturised optoelectronic system for optogenetic modulation of the spinal cord and of peripheral nerves, as illustrated in Figure 8A.[39] The antennas with the dimension of 3 mm harvest radio frequency power through capacitive coupling between adjacent serpentine traces, thereby enabling compact and lightweight devices (overall weight of ~16 mg) with low-modulus system-level mechanics that can accommodate irregular anatomical shapes and natural motions. With a minimally invasive and flexible structure, it can be expected to be used in chronic studies. Figure 8B shows a soft wireless bioresorbable neuromuscular stimulation platform for nerve regeneration with a radio frequency wireless receiver antenna as the power source.[24] After packaging with bioresorbable elastomers (polyurethane), implanted electronic stimulator could operate reliably without failure for more than one month, over periods related to recovery from traumatic nerve damage. According to the new Institute of Electrical and Electronic Engineers (IEEE) standard on human exposure to radio frequency radiation, the safe range of frequency is from 3 kHz to 100 GHz.[123] Based on the absorption rate of tissue in most parts of the human body, the maximum exposure of radio frequency radiation amount is about 2 W kg-1, and incident power densities range from 1000 W m-2 at 100 kHz to 10 W m-2 at 100 GHz with the minimum value of 2 W W m-2 between 30 and 400 MHz, which is established to protect the body from damage caused by tissue heating. Also, the transmission efficiency will be influenced by the orientations of the transmitting antenna and receiving antenna, and the surrounding obstacles such as metal and human tissue containing moisture will lead to heat generation and limited operating ranges from 0.1 m to 3 m.[124] To avoid these disadvantages, a specialized design is urgent needed for the implantable antenna. For IMEs using wireless far-field radio frequency power transfer as energy supply method, long-term applications should be considered carefully due to the safety issues that radio frequency radiation exposure would bring to living organisms.
3.3.2. Near-field wireless power transfer
The near-field wireless power transfer method adopts magnetic resonant coupling (non-radiative electromagnetic energy) and relies on inductive coupling between a transmitting coil and a receiving coil.[16] This strategy can transmit wireless power with high efficiency over short distances of about several centimetres. Due to the non-radiative nature of magnetic resonant coupling with frequencies ranging from 100 kHz to 200 MHz, the near-field wireless power transfer method is relatively insensitive to changes in dielectric environments such as moisture in tissues and to the presence of obstacles such as metals compared with far-field radio frequency power transfer. Also, near-field wireless power transfer working at a low working frequency applied in IMEs will generate less heat and reduce tissue absorption and therefore can be applied in complex biological surroundings, which minimizes safety concerns during long-term operation. Meanwhile, data transmission or remote wireless control can also be realized when using wireless near-field power transfer since near-field communication (NFC) protocols can be used at the same carrier frequency.[125] With near-field wireless power transfer, a fully implantable subcutaneous electronic system with an ultrathin probe and a micro light emitting diode for optogenetic stimulation of regions in the deep brain can be wirelessly powered with reliable operation and good chronic stability, as illustrated in Figure 8C.[37] Furthermore, the near-field wireless power transfer and NFC are also applied in the biomedical smart contact lens device with modules including ultrathin electrical circuits, microcontroller chip for real-time electrochemical biosensing and functions including on-demand controlled drug delivery, the near-field wireless power transfer and data communication (Figure 8D).[126] The smart contact lens system is demonstrated to be feasible for application in non-invasive and continuous diabetic diagnosis and diabetic retinopathy therapy. It is reported that near-field wireless power via magnetic resonant coupling is a reliable energy supply method with power up to 12 mW for small rodent-sized devices and about 13 mW cm-2 can be achieved.[127] With these features including low working frequency, less produced heat, minimized safety concerns, insensitivity to environments and data communication functions, near-field wireless power transfer method has consequently facilitated its applications in various wireless, battery-free and fully implantable electronics for localized tissue oximetry, for bioresorbable monitoring of intracranial pressure and temperature, for optogenetic stimulation in the central and peripheral nervous systems and for pharmacological modulation. In comparison, this energy supply strategy is superior to in vivo energy-harvesting strategies in terms of the amount and stability of output power.
3.3.3. Ultrasonic power transfer
The ultrasonic power transfer wireless energy harvesting method is an emerging energy transfer technology by converting ultrasound waves to electricity through piezoelectric semiconducting coupling.[128]Ultrasound is an acoustic sound wave with a frequency higher than 20 kHz but much shorter wavelengths than radio frequency radiation, focused power delivery to implantable medical devices can be achieved with high spatial resolution.[129] Therefore, compared with traditional wireless energy harvesting based on electromagnetic coupling, ultrasonic power transfer possesses several advantages in the applications of IMEs, such as small attenuation of ultrasonic power in biological tissues and excellent spatial resolution. For example, a biodegradable PENG driven by external ultrasound power without any transcutaneous leads was fabricated for sustained delivery of in vivo electrical stimulation to promote the repair of peripheral nerve injuries.[41] Under an ultrasound power intensity of 0.7 W cm-2 for short-term excitation, the current for stimulation driven by ultrasonic power is about 40 μA and the voltage of single stimulation is 10 mV with the pulse width of 1 ms demonstrating the feasibility of non-invasive monitoring of the nerve repairing dynamics (Figure 8E). However, this feature also brings disadvantages, for example, the ultrasonic waves propagate in a specific direction, and the slight misorientations between the external transducer and the implanted receiver will cause evidently reduced coupling efficiency.[35] To avoid a substantial impedance mismatch at the tissue-air interface, it is essential to make sure of close contact of the transducer with the skin. The relatively moderate absorption of ultrasound by soft tissues potentially enables large penetration depths,[130] but the presence of highly absorbing bone may also induce significant heating effects,[131] and low ultrasonic frequencies may induce cavitation which may also bring safety problems.[132] Also, ultrasonic power transfer devices are usually rigid and large in size, which is not suitable for curvilinear and soft tissue and organs. Recent advances in ultrasonic power sources with sufficient penetration depth and excellent spatial resolution represented a promising application in non-invasive power sources for IMEs and challenges remain to be solved regarding the flexibility and the coordination with drag force generated in harsh environments in human body.
3.3.4. Photovoltaic power transfer
Photovoltaic power transfer captures the energy from electromagnetic radiation in the form of visible and near-infrared light and converts them into electric energy by photodiodes.[133] For IMEs, photovoltaic power transfer devices need to be enfolded in soft living tissues, such as skin, fats and muscles, so within the near-infrared spectrum (700-2500 nm), high-scattering tissue can be penetrated more efficiently by the light. For optogenetic experiments, optical fibres were required to be inserted into the brain tissue with another end attached to a remotely located light source such as a laser or light-emitting diode, but the fibre tethers limited the movement of the animals and caused entanglement which led to the prohibition of neuroscience studies regarding the social interactions and home cage manipulations of small animals in complex environments.[134] Compared to previously reported systems, injectable optoelectronics under cellular-scale for wireless optogenetics has been reported with six times smaller dimensions and thirty-fold lighter weight.[51]In this case, wireless, ultra-miniaturised LEDs that can be implanted directly into the brain will well solve the constraints, the miniaturised photovoltaic cells can provide wireless power for the optogenetic electronics and can significantly expand the movement range of the experiment animals. The enhanced photovoltaic systems with dual junction gallium arsenide (GaAs) solar cells array have an open-circuit voltages of 2.31 V and short-circuit currents of 11.17 mA with the efficiency of 25%, and can provide 4 V to support the wireless power for control logic circuits and optogenetic stimulation under illumination with sunlight and desk lamp.[134] It can supply the power for blue and yellow micro light emitting diodes at intensities of 3.5 and 2.3 mW mm-2. Furthermore, optoelectronic devices based on semiconductor optoelectronic technologies have been developed for power harvesting in ultraminiaturised wireless implants for optogenetic neuromodulation.[40] A thin-film optoelectronic device combining an infrared double-junction photodetector and a visible LED was designed and realized near-infrared (∼810 nm) to visible (630 nm (red) or 590 nm (yellow)) up conversion (Figure 8F). It can capture photons from external incoherent low-power infrared LED bulbs and generates an upconverted red emission power density of about 1.1 mW mm-2 on the device surface, which can effectively manipulate the activated ChrimsonR-expressing neurons.[135] As an implantable photovoltaic power source for wireless optogenetic control of in vitro and in vivo neuroactivities, it can be used for deep-tissue light stimulation and provided the unprecedented potential for the application in optical bio interface. Compared with systems with far-field RF power, the photovoltaic power transfer can achieve high conversion efficiency with solar cells (10 times less power required compared with far-field power).[134] However, similar to all the external power transfer methods, the output power of solar cells strongly depends on incident angles,[136] additional optical imaging or tracking systems are necessary for the optics focusing, which will put a limitation on the experimental area and lead to constrained behaviours of experimental animals and human body using this power strategy for IMEs.