FIGURE 1. Overview of various alternative minimally invasive power sources. “Biodegradable primary battery” Reproduced with permission.[19] Copyright 2014, Wiley-VCH GmbH. “Rechargeable battery” Reproduced with permission.[26] Copyright 2021, Royal Society of Chemistry. “Supercapacitors” Reproduced with permission.[27] Copyright 2018, Elsevier. “Triboelectric nanogenerator” Reproduced with permission.[30] Copyright 2014, Wiley-VCH GmbH. “Piezoelectric nanogenerator” Reproduced with permission.[29] Copyright 2021, Elsevier. “Biofuel cell” Reproduced with permission.[31]Copyright 2013, Royal Society of Chemistry. “Ultrasonic wireless power” Reproduced with permission.[41] Copyright 2022, Elsevier. “Photovoltaic wireless power” Reproduced with permission.[40] Copyright 2018, Proceedings of the National Academy of Sciences. “Far-field RF radiation wireless power” Reproduced with permission.[39] Copyright 2015, Springer Nature. “Near-field wireless power” Reproduced with permission.[37] Copyright 2017, Elsevier.
a better choice due to the minimised volume and better matching with target organs. Take cochlear implant electrodes as an example, the first-generation electrodes developed in the 1980s and 1990s demonstrated severe insertion trauma,[45] and the improved design of configuration can help avoid the severity of the injury. A pre-moulded spiral cochlear electrode implanted with the advanced off-stylet technique can reduce contact with the outer wall of the scala tympani, soft top and silicone rubber surface is also helpful to prevent internal tissue trauma.[46] Similarly, a hermetic vision prosthesis with a wireless-operated subretinal neurostimulator has been developed and implanted in a minipig eye in 2011.[47] To reduce the risk of infection caused by wireless transmission coils under the delicate conjunctiva, the coils were carefully wound on a spherical mandrel to match the curvature of the eye and moulded in biocompatible flexible poly(dimethylsiloxane) (PDMS) encapsulation. Another way to achieve minimally invasive implantation was developed in 2014 by Medtronic, a medical device company. A subcutaneous insertable cardiac monitor (the Reveal LinQ) with a high aspect ratio structure was designed for continuous cardiac monitor such as arrhythmia and atrial fibrillation, the parylene-based encapsulation and minimal dimension (44.8 × 7.2 × 4.0 mm3) allows it to be inserted subcutaneously through an incision size less than 1 cm without any post suturing process.[42, 48] With the programmable electronic system and lithium carbon monofluoride battery, the electronics system can be inserted into an infant’s chest and work independently for up to 3 years with wireless data communication with medical centres.[49] Even so, mechanically rigidness inducing stress to the interface between devices and tissue is still a nonnegligible issue, it’s still necessary to seek a flexible and thin-film configuration for such kinds of IMEs. Soft and stretchable materials with low modulus will be a desirable choice here. In 2015, Park et al. constructed a miniaturised, fully implantable soft optoelectronic system for wireless optogenetics consisting of radio frequency harvester antenna for wireless power and light-emitting diode (LED) arrays to activate opsins.[39] Inside the area of only 3 × 3 mm, the electrical interconnects and the circuits were sealed by flexible polyimide with thickness of 3 um and low-modulus silicone elastomer with thickness of 100 um. This design enabled the implanted system to accommodate anatomical shapes and natural motions, and to achieve minimally invasive fully implantation on multiple neural interfaces.[50-51] Furthermore, soft and wireless powered bioresorbable electronic were developed by Choi et al. for the neuromuscular regeneration stimulator.[24]Bioresorbable dynamic covalent polyurethane (b-DCPU) was synthesised and applied as substrate and biofluid barrier for deformable filamentary serpentine interconnects, the elastomeric mechanics and low levels of swelling in biofluids enable the implants to serve for over 30 days with long-term stability during the stimulation operation. With wireless power transmission technology and bioresorbable feature, the bioresorbable electronics can be implanted once for all and operate independently till full dissolution into benign products without residues, which avoids surgical extraction or secondary invasion for replacement. This kind of bioresorbable wireless powered electronics are also desirable options for bone healing treatment, spinal cord stimulation, brain therapy and cardiac pacing. Recently, minimally invasive spinal cord stimulation via simple needle puncture under local anesthetic instead of traditional bulky paddle-type devices requiring invasion under general anesthetic have been reported.[52] Since spinal cord implants are softer and soft robotics has made great progress regarding the surgical manipulators, Woodington et al. developed a minimally invasive spinal cord stimulation which can be loaded into needle for percutaneous implantation with low risk surgery.[52] A 14-gauge Tuohy needles were used for the loading and insertion of the rollable devices with dimension less than 2 mm including fluidic connections, electrical connections and supporting tubing. Due to the narrow footprint and flexibility, insertion trauma can be reduced, and on-demand shape actuation can be achieved. Compared with the previous rigid devices, it can offer far fewer surgical risks with simple epidural needle insertion. Till now, huge progress has been made towards the minimally invasive designation of implantable electronics as can be seen from the milestones in the development history.
Comparatively, biomedical electronics with a high aspect ratio structure such as a needle-like shape or integrated on a tubular carrier can solve the problems of a large incision, and enables accurate and minimally invasive injection of biomedical electronics into inhomogeneous tissues.[51] Nowadays, injectable biomedical devices were widely studied and applied in the field of brain sciences, percutaneous therapies, reading vital clinical signs, and healing diseases et al..[42] With a high aspect ratio form, injectable biomedical devices with various designs can be applied to almost every part of the human body. As illustrated in Figure 2 top left, various state-of-the-art minimally invasive electronics were developed and implanted in different parts of human body. For instance, tissue-like neurotransmitter sensor for neuronal recording in the brain and gut with minimal damage to other regions termed NeuroString were designed by Li et al..[53] As tissue-mimicking stretchable neurochemical biological interface sensors, it enables long-term in vivo real-time sensing in the brain and simultaneously serotonin dynamics detecting in the gut of a behaving mouse with high data recording fidelity. With easily stretched, twisted and even knotted structures, the ultra-flexible NeuroString can get access to the twisting colon of a mouse with no subsequent insertion trauma representing its high compatibility with soft and complex tissues. It is expected to be applicable for non-invasive biomolecular monitoring and dynamic signal study throughout the body in primates. The cochlear implant is another successful electronic prosthesis affecting millions of people worldwide, it changed the lives of people with profound hearing loss by long cable-like electrodes implanted into the spiral-shape cochlear area for hearing aid and restoration.[46, 54] According to Pinyon et al., cochlear implant electrode array integrated with neurotrophin gene therapy can produce directed regeneration of spiral ganglion neurite through stimulation in the guinea pig.[55] It provides minimal extraneous electrical stimulation for auditory nerve regeneration, nerve fibre can be restored to the pre-deafness values. Subretinal neurostimulators as a novel technology can also help individuals suffering from retinitis pigmentosa and macular degeneration to restore useful vision. The reported neurostimulation array based on a soft polyimide substrate was constructed and inserted through the scleral incision into the subretinal space with only a 3 mm wide incision.[56] After successful implantation, excellent retina apposition and intact inner layers of the overlying retina can be retained. For the cardiovascular system to deliver oxygen and nutrients to the body, implantable catheter-type oximeters can help to provide accurate real-time monitoring of vascular oxygen saturations. Compared with existing glass fibre-optic catheters leading to blood vessel damage and infection, the recently reported miniaturised wireless optoelectronic catheter system is more patient-friendly with good flexible construction and the absence of physical tethers, and especially, the diameter of the probe is only 1.5 mm.[57] With the addition of wireless data transmission, real-time local tissue oxygenation and respiratory activity can be monitored during continuous operation with accuracy and precision at clinical standards. Injectable subcutaneous chips like radiofrequency identification (RFID) tags in subcutaneous areas of the human body for recording and tracking personal healthcare information have also been reported.[58] Through a 2 mm incision, a mini transmitter about the size of a grain of rice can be implanted subcutaneously for the control of doors, lights, and computers, and can also provide personal medical information when patients are in emergency unconscious situations. Under the subcutaneous area, soft and flexible configurations can further alleviate irritations and chronic damage to surrounding tissues with enhanced mechanical compatibility with soft skin. To realise the minimally invasive subcutaneous implantation, a flexible-device injector was reported and an ultra-flexible optical pulse sensor was successfully implanted into a live pig animal model with the injector via a small incision of 4 mm.[59] Finally, spinal cord implants for neuronal activity measurement and stimulation as the oldest and most established neuromodulation therapeutic electronics have now developed towards injectable minimally invasive implants via simple needle puncture compared with traditional bulky devices.[52]Though in various forms and with different advantageous functions, these injectable biomedical devices are designed to be injected into aimed sites inside organisms with minimal invasions.
Enormous advancements and continuous breakthroughs have been achieved in implantable and injectable biomedical electronics, which hugely advanced the quality of surgical and monitoring tools. The future development tendency of the advanced biomedical implantable electronic system will shift towards minimally invasive, ultra-flexible, bioresorbable, wireless and multifunctional to achieve more pain-free surgical implantation and high-accuracy bio functional monitoring.