FIGURE 2 Milestones in the development history of implantable electronics, and an illustration of the advanced minimally invasive electronics implanted in various parts of the human body and perspective outlook for the features of implantable electronics in the future. Reproduced with permission.[43] Copyright 2006, PubMed Central. Reproduced with permission.[46] Copyright 2008, IEEE. Reproduced with permission.[47] Copyright 2011, IEEE. Reproduced with permission. Copyright 2019, Medtronic. Reproduced with permission.[39] Copyright 2015, Springer Nature. Reproduced with permission.[24] Copyright 2020, Springer Nature. Reproduced with permission.[52] Copyright 2021, Science. Reproduced with permission.[53] Copyright 2022, Springer Nature. [55] . Reproduced with permission.[56] Copyright 2019, ARVO. Reproduced with permission.[57] Copyright 2021, Science. Reproduced with permission.[58] Copyright 2007, IEEE. Reproduced with permission.[59] Copyright 2018, Wiley-VCH GmbH.
3. Minimally Invasive Power Sources
Commonly a power source is contained in a fully implanted biomedical device, the demand for minimally invasive power sources will continue to increase as the minimally invasive bioelectronic applications have been well developed and will expand rapidly.[8] The commonly used power source for IMEs is bulky electrochemical power sources such as batteries and supercapacitors due to the mature technology and available hardware.[60-61] Conventional lithium-ion batteries can meet the requirement of energy supply due to their reliability and high energy density (~400 Wh kg-1).[15, 62] Nevertheless, lithium-ion batteries in the bulky, rigid and large-size form will not only result in the large total volume of the implant system but also nonnegligible issues such as irritation and infections after surgery. Additionally, issues such as battery replacement after charge depleting, toxic material leakage of electrodes and electrolytes, and rigid shape mismatched with 3D dynamically curved tissues may lead to the unprecise interpretation of experimental data.[17, 35]Obviously, the dimension and lifespan of power sources represent the major limiting factors for the development of the advanced biomedical implantable electronic system at present. Therefore, a qualified implantable power source for novel biomedical implants should possess the following features: miniaturised, light-weight, adequate capacity, and mechanically deformable properties that match well with soft biological organs and tissues, composed of biocompatible materials.[16] Since the power source plays a crucial part in the development of IMEs, many efforts and enormous enthusiasm of researchers have been dedicated to developing implantable power sources to extend the lifespan of IMEs.[63-64] With different functions and diagnostic purposes, IMEs show different requirements towards the power source. For short-term applications, biodegradable batteries with no need for secondary surgery will be a desirable choice.[65] For long-term applications, a power source with enhanced capacity such as batteries or energy source harvesting power wirelessly in-vivo and from the external of the human body will be more suitable. There are many forms of energy sources optional for IMEs such as thermal, kinetic, biochemical, electromagnetic, acoustic, and radiative forms of energy.[16] For example, energy derived from the human body including glucose oxidation,[66]heartbeats, and organ motion,[67-68] can be harvested by biofuel cells,[69] and piezoelectric/triboelectric energy harvesters.[70-71] Also, wireless power transmission technologies including inductive coupling/RF,[72]photovoltaic,[73] and ultrasound-induced power transfer[74] can be used as direct power or to assist in recharging the existing energy storage devices. Benefiting from these energy solutions, self-powered IMEs can be realised. To further discuss the practical application of different minimally invasive power sources based on the above mechanisms to power the IMEs, three categories were summarised: Energy storage devices (e.g., biodegradable primary batteries, rechargeable batteries, fibre supercapacitors), human body energy harvester (e.g., PENG, TENG, biofuel cell) and wireless power transfer (e.g., near-field magnetic resonant coupling, far-field RF radiation, PV power transfer, ultrasonic power transfer). Application contexts and advantages of each minimally invasive power source will be discussed in detail.
3.1. Energy Storage Devices
3.1.1. Biodegradable primary batteries
Batteries, including the single-use primary battery and rechargeable secondary battery, have been developed and can provide sufficient energy for IMEs with a lifespan of years.[62] Various IMEs including neurostimulators, cardiac pacemakers and cardiac defibrillators have applied batteries as energy sources. Not like batteries in other electronics, implantable batteries need to satisfy strict and considerable requirements including high energy density, stability, complete packaging, low self-discharge and a battery life of years to not only support vital functions in human bodies but also ensure the safe operation of devices. Also, small volumes and lightweight are required in the limited space inside the human body. Li-CFx (lithium-carbon monofluoride) and Li-SVO (lithium-silver vanadium oxide) batteries have been applied in the industry for cardiology applications for decades.[62] As an example, the Reveal LinQ insertable cardiac monitor fabricated by Medtronic in 2014 is a wireless and powerful small insertable cardiac monitor ideal for patients experiencing infrequent symptoms that require long-term monitoring or ongoing management, the device consisted of two titanium nitride-based recording electrodes, programmable electronic system and a Li-CFx battery that powers the entire system up to 3 years.[48] Except for Li-CFx[75] and Li-SVO batteries[76], lithium-iodine (Li-I2)[77] and lithium manganese dioxide (Li-MnO2) [78] have also been developed and widely applied in IMEs.
At the same time, the primary batteries have limitations such as rigid structure, capacity loss and battery failure, and therefore cause non-healing incisions as well as the risk of complications after insertion. With the emerging transient electronics technology, an alternative strategy is to develop biocompatible or biodegradable batteries.[79-82] Considering the safety issue which might be caused by the leakage of the metal-based material, metals like Mg and Zn are safer than Li inside the human body. In 2014, Yin et al. first reported fully biodegradable batteries consisting of dissolvable Mg-X (X = Fe, W, or Mo) foils as anodes and cathodes, and polyanhydrides for encapsulation. For short- and medium-term applications, biodegradable features are desirable so that a second surgical removal is not required.[16] Recently, Mg- and Zn-based batteries have made great progress. For instance, Mg and its alloys with high theoretical capacity (2.2 Ah g-1) are promising anode materials and represent excellent biocompatibility (daily allowance ≈300 mg d-1).[22] According to Huang et al., they designed a completely biodegradable primary magnesium-molybdenum trioxide (Mg-MoO3) battery with high performance as illustrated in Figure 3A. In their design, a single-cell battery with a stable output voltage (1.6 V) can achieve a high energy density of 6.5 mWh cm-2. The battery can work for about 13 days after encapsulation with biodegradable polyanhydride and poly(lactide-co-glycolide) (PLGA), and complete biodegradability of the battery can be observed in vivo experiments. With stable output voltage and a relatively long lifespan, this battery system could meet the requirements of short-term/medium-term and implantable electronics requiring ultralow power, which represents a promising method for self-powered IMEs. Similarly, Yin et al. reported a water-activated primary batteries with magnesium foils as anodes and metal foils based on Fe, W or Mo as the cathodes.[19] The primary battery was encapsulated by biodegradable polyanhydrides, it can provide a stable voltage output of about 1.6 V for up to 6 hours when discharging at a current density of 0.1 mA cm-2 as shown in Figure 3B. From the degradation process, it can be observed that the polyanhydride cover dissolved first followed by the degradation of Mg and Mo foils in phosphate-buffered saline (PBS) solution at 37 °C, and the primary battery was fully degraded after 19 days by increasing the temperature to 85 °C. Based on their transient batteries, the minimum dimension required to power the wireless implantable sensing is 5 mm with a thickness of 3.46 mm for operation for 1 year, which is a fully biocompatible and environmentally benign power source for IMEs. In addition, zinc primary battery is another option while Zn metal has a slower degradation rate, it can avoid local pH increases and alleviate the evolution of gaseous hydrogen. According to Dong et al., a bioresorbable zinc primary battery was constructed with zinc microparticle network coated with chitosan and Al2O3 double shells as the anode.[20] When discharged at a current of 0.01 mA in saline, the battery can generate stable voltage output of 0.55 V with a cross-sectional area of only 0.17 × 2 mm2. With 15 mm Zn anode, the battery can discharge stably for 200 h and can be fully dissolved in the saline solution, as can be observed in Figure 3C, indicating a significant potential for in vivo powering transient IMEs. In some cases, ionic liquids (ILs) with stable potential window and high ionic conductivity can be utilised as additives for biopolymers and biocompatible electrolytes.[83] As Jia et al., demonstrated, a biodegradable thin film magnesium primary battery was designed with biocompatible IL (choline nitrate) and ion-conducting free-standing membrane of biodegradable silk fibroin.[21] The silk protection layer can help protect and control degradation. With another layer of silk fibroin, stable open-circuit voltages above 1.21 V for more than 100 min can be observed and then finally be fully decomposed as can be seen in Figure 3D.
At present, bioresorbable electronics or transient electronics have been widely studied and have now achieved significant progress in mechanism and applications, it becomes an emerging technology in the field of innovative healthcare electronics.[84] Benefiting from the existing bioresorbable materials (e.g., Mg, Zn, Mo, polylactic acid, polyglycolic acid, polylactic-co-glycolic acid, carbon nanotubes, graphene),[85-89] biodegradable primary batteries can provide power for the bioelectronic functions such as post-surgical monitoring of organ, tissue, and wound healing for a period from seconds to months, and finally fully decomposed into biological safe byproducts through hydrolysis and enzymatic degradation, which significantly reduced the risk of irritations and complications caused by surgery. It is high expected to lead a revolutionary change in the field of power sources for minimally invasive IMEs, while at the meantime, there are some critical challenges including the high-cost fabrication techniques, uncontrollable packaging methods, and the dissolution mechanisms of bioresorbable electronics still exist and require further exploration.