# Material Design in Implantable Biosensors toward Future Personalized Diagnostics and Treatments
## 2 Implantable Biosensors and Their Design  
Implantable devices were introduced in the early 20 th century and with technological developments, the concept of implantable biosensors has seen many breakthroughs (Figure 1). Implantable biosensors consist of (i) a wireless sensing network inside the human body and (ii) some external entities outside of the body that are responsible for data collection and dissemination, respectively [2; 3]. For instance, implantable biosensors in the subcutaneous skin layer, nasal area, and tongue can recognize toxins in ingested food and inhaled air. Depending on the biosensor infrastructures, these devices can take corrective action after toxin detection or inform the host about it. The retina implantable biosensors are another success, where the biosensor collects light signals from outside and stimulates the optical cells to give partial vision [4]. Since the invention of implantable biosensors, many of them have been approved by the FDA and reached industrialization, such as cochlear, heart pacemakers, and vagus nerve stimulators [5; 6; 7; 8]. Despite all the positive impacts of implantable devices on medical care and treatment, their side effects and high cost are still thought-provoking [9]. Changing materials and manipulating devices' architectures are among the primary strategies selected to reduce or eliminate such consequences [10]. The materials used in implantable biosensors must have in vivo biocompatibility, mechanical suitability, flexibility, and biodegradability. The in vivo biocompatibility experimentation is hardly recommended due to the different body responses to foreign materials [5; 6; 7; 8]. Introducing foreign materials into the human body causes some biological reactions (i.e., host response) that lead to tissue or organ malfunction. Other than biocompatibility, the flexibility of the materials is an important criterion due to the soft nature of tissues and organs and the ability of the device to adhere to its allocated and targeted region [12; 13]. Moreover, the morphology and size of the device are important parameters. The chance of biological rejection is high for bulky devices [12]. Although implantable devices with good biocompatibility and soft materials are suitable for clinical application, the long-term presence of foreign substances in the body can increase the risk of malfunction, inflammation, and deformity of tissues. In most cases, a second surgery is needed to externalize the implanted instruments, which has its own concerns and risks. In addition, there are limitations in terms of accuracy and effectiveness in certain clinical applications, such as the treatment of large or metastatic tumors (Table 1). Post-market surveillance and human factor studies are important tools in ensuring the safety and effectiveness of implanted devices, but they also face challenges such as limited resources and funding, difficulties in identifying and reporting adverse incidents, and potential for bias in reporting and data collection. Overall, while implantable sensors have great potential  
Figure 1: Timeline of implantable sensors developments. Reproduced with permission from ref. [11]. ©2021 Wiley Periodicals LLC. for improving healthcare outcomes, their development and use must be approached with caution and careful consideration of the risks and benefits [14; 15]. As such, devices composed of biodegradable materials have become favored to overcome these issues [16]. These devices can be degraded through the metabolic processes that happen in the body (complete or partial degradation) [2; 17]. Some materials, such as metals (e.g., zinc, molybdenum, and magnesium) have been used as conductors. Other materials such as silicon, zinc oxide, or silicon oxide and nitride (SiNx) are used as nanomembranes, semiconductors, or insulators, respectively. Additionally, polymers containing an ester group (RCOOR), including polycaprolactone (PCL), poly(lactic-co-glycolic acid) (PLGA), or poly(glycerol seba