One of the biggest concerns of human beings in all eras has been the diagnosis and treatment of different disorders and ultimately advancing quality of life. The remarkable progress in various scientific fields (physics, electronics, mechanics, chemistry, biochemistry, computer, and medicine) has led to the creation of new diagnostic and therapeutic methods and devices by employing the already-existing techniques and tools at hand. Biosensors have been one of the most successful outputs of supplementary science, especially after the first invention of a glucose biosensor in 1962 [1]. They found their proper place in various fields, including biomedicine, bioprocessing, homeland security, food safety, agriculture, environmental, and industrial monitoring. What is known today as pervasive computing (people interaction environment with various companions, embedded, and invisible computers) could bring the application and performance of biosensors to a higher level. Pervasive computing technology provides the automatic environmental reaction to the user’s computing needs without spending time and energy. The implantation of micro-sensors in the human body is an essential part of pervasive computing. This technology’s application undeniably provides high-performance, proportionally inexpensive, and people-centered solutions for health care and monitoring. Such a system, centralizing each patient individually, reduces the burden on society’s health systems, expended time and costs, and the risk of incorrect diagnosis and treatment while requiring low sample volumes and fewer testing reagents.

2. Implantable Biosensors and Their Design

Implantable devices were introduced in the early 20th century and with technological developments, the concept of implantable biosensors has seen many breakthroughs. 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][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][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][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 ^[11][12][12,13]. Moreover, the morphology and size of the device are important parameters. The chance of biological rejection is high for bulky devices ^[11][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.  Other than the host response of the human body to implantable biosensors, the chances of devices breaking down and malfunctioning in the body after a long time are high ^[13][18]. The most common reason is the repeated motion and size change of organs and tissues. To overcome this lack, self-healable materials with the ability to create energy dissipation mechanism-based reversible chemical bands and adaptable geometry are worthy of being utilized ^[14][15][19,20]. Another criterion to mention in the design of implantable sensors is their power suppliers, which often need to be out-of-body sources, that cause some drawbacks, including implantation complexity, discomfort of subjects, and infection risks ^[2][16][2,21].  The present solutions are designed around using two types of wireless communication tools: (i) passive devices (based on electromagnetic transmitters or readers) and (ii) chip-integrated devices (based on the measurement of electrical signals sent from the chip) ^[16][17][21,22]. However, the choice of devices should be meticulously selected depending on the intended use. The passive component-based devices are more favored due to the flexibility, self-healing ability, biocompatibility, and biodegradability of the applied substances and their lack of need for a hard and voluminous chip nor an inner power source (Figure 12) ^[2][3][2,3]. However, passive sensors have limited temporal resolution and poor performance when measuring multiple or complex parameters, limiting their use as implantable sensors in many medical applications. They also suffer from measurement frequency where they take minutes to acquire data compared to active sensors especially in situations where continuous or several measurements per second are necessary, as in the case of orthopedic monitoring ^[18][23]. Besides the concept of material design and device architecture, the insertion of the device into the body is one of the serious concerns for researchers in this field. There are huge numbers of complaints about conventional insertions by surgeries which cause physical suffering and infections, long recovery times, high cost, and possible psychological problems. To avoid such complaints, minimally-invasive surgery (MIS), such as catheter-based treatment and laparoscopic surgery, with considerably fewer side effects have been introduced as standard medical procedures ^[19][24]. The inspiration by the positive feedback of MIS has led to the introduction of an advanced version of the technique called the minimally invasive insertion of implantable devices. This approach consists of syringe-injectable devices that can be inserted into the body by MIS ^{[20][21][22][23]}[25,26,27,28].  In addition to the nature of the material used and the insertion strategies, another effective factor in the design is the ability of the implantable devices to adhere to the target tissues and organs. The adhesion subject can be seen from two points of view: (i) long-term and (ii) short term implantable devices. Short-term adhesion is achieved through pressure-sensitive adhesives or suction and is suitable for sensors that only need to be in place for a few hours or days. The advantages of short-term adhesion are the easy and painless removal of the sensor after use, without causing damage to the tissue or leaving residue, and lower cost than long-term adhesives. However, it may not hold the sensor in place during movement or physical activity and can cause skin irritation or allergic reactions. Long-term adhesion is achieved through biocompatible materials such as silicone, hydrogels, or other polymers that form strong bonds with the tissue. It is suitable for sensors that need to remain in place for extended periods of time, ranging from days to years. The main advantage of long-term adhesion is that it provides a more reliable and stable attachment, allowing for continuous monitoring without frequent repositioning or replacement. However, removing long-term adhesives can be more difficult and painful, and they can be more expensive than short-term adhesives ^[24][34].

3. Classification of Implantable Biosensors Based on Material Design

Undoubtedly, the development and application of biosensors, specifically wearable and implantable devices, significantly impacts the quality of life and, consequently, correct investment in biomedical systems. In general, biosensors and, later, implantable biosensors are classified based on the quantity to be measured, including physical, electrical, or chemical. The continuous measurement of such qualities without patients’ intrusion and patients’ physiological state (walking, rest, exercise, etc.) is an essential criterion for choosing the type of implantable biosensor. As mentioned before, the specific size and morphology of the device, as well as the long operational lifetime, should be precisely considered in material design and format. For instance, the destruction of the protective cover of the implantable sensors due to protein adsorption or cellular deposits and, as a result, releasing free chemicals between the body fluids and sensor, could cause inflammation of tissue, infection, or clotting in a vascular site reaction which results in un-trustable measurements ^[25][40]. Therefore, the materials used in implantable biosensors must be biocompatible and biodegradable.

3.1. Electrochemical Active-Based Implantable Biosensors

The two main constructive parts of each biosensor include a bio-recognition element that recognizes a target and a transducer that translates the molecular interaction into an electrical signal. Proteins, peptides, enzymes, antibodies, and nucleic acids are widely employed as detection components in biosensors. In electrochemical devices, electrodes that are transduction elements explore the intrinsic electron transfer nature of recognition elements throughout biochemical reactions. Electrochemical implantable devices are generally assembled on three-electrode or two-electrode systems with the latter having both the reference and counter electrodes combined into one. In such a system, the potential of the working electrode is influenced by a potentiostat to direct electrode reactions with immobilized enzymes for a complete catalytic turnover. The electrochemical biosensors, which can be divided into voltammetric and amperometric biosensors, can evaluate faradaic currents (fixed or varied potentials). They are ion-selective, conductometric, and field-effect transistor-based sensors. Amongst all metals, stainless steel or noble materials such as gold and other different alloys (i.e., platinum-tungsten or iridium oxide) are typically used as fundamental materials for forming strong metal electrodes. Regardless of the type of materials used, electrochemical implantable biosensors, based on their application, can be categorized into implantable glucose biosensors ^[26][41], implantable blood-gas, pH, electrolyte, and ion-selective field-effect transistor sensors ^[27][28][29][42,43,44]. In electrochemical implantable devices, using high-quality electrodes to diminish motion artifacts and record accurate, stable, and undistorted signals, are unavoidable and necessary. Other than changing the local analyte concentration at the sensing site due to the corrosive nature of the body liquid (provoking thrombus, inflammatory reactions, and capsule formation), they trigger a sequence of effects such as electrode passivation and membrane biodegradation, which limit the choice of materials. To avoid these issues, the most logical and practical solution is material biocompatibility improvement through the application of suitable bulk materials or modification of their derivatives to facilitate the adsorption of proteins and cells ^[30][45]. Among the developed biocompatible materials, polymers are coming in first place. Polymeric materials such as poly(ethyleneglycol), polyvinylchloride, polyurethanes, silicon rubber, Nafion, cellulose, chitosan, and phospholipids exhibit good performance in electrochemical implantable devices. It is important to mention that in converting materials to biocompatible compounds, some of the functionalities of the original materials will be lost. This mostly happens for polymeric materials used in potentiometric sensors. Conducting polymers, on the other hand, are another category of polymers that have been used as sensing elements in implantable biosensors due to their ability to transduce biological signals into electrical signals. Additionally, conducting polymers can be easily modified to improve selectivity and sensitivity, making them an attractive choice for biosensing applications. However, the use of polymers in implantable biosensors also poses some challenges, such as the potential for foreign-body response and the need for biodegradability or bioresorbability in some contexts ^[31][32][46,47].

3.2. Nanomaterial-Based Implantable Biosensors

It is shown that textured compositions are more suitable than smooth materials for enhancing the performance of biosensors in vivo applications due to vascularity improvement around the implant ^[33][48]. One of the well-described examples is incorporating a textured angiogenic layer over an implantable glucose sensor’s surface ^[34][49]. It is believed that a different hydrophobicity and hydrophilicity of the materials prohibits the proteins or cells’ adsorption over the surface. Another common phenomenon in in vivo biosensors is the clotting process caused by electrons exchange between blood proteins and cells on the implant surface (Figure 24) ^[35][50]. It is believed that the lower time constant of nanomaterials can decrease the clotting process when compared to metal-containing materials. However, the working mechanism of nanomaterials in in vivo systems is still debatable, but there are various studies where nanostructures used as an active material alleviate host body responses. Some of the regularly used nanostructures include nanoporous silicon ^[36][51], nanoporous titania ^[37][52], nanoporous carbon, etc. It is widely accepted that nanomaterials with controlled shapes and spaces can optimize drug delivery kinetics and improve anti-fouling characteristics ^[38][53].