# Novel In Silico Strategies to Model the In Vivo Nerve Scarring Around Implanted Parylene C Devices
## 1 Introduction  
Peripheral nerves provide the natural connection between the periphery of the body and the brain [1]. They are extremely complex structures, which, nonetheless, can be connected to external high-tech devices to record neural signals and evoke neural activity. These devices, which are commonly referred as neural interfaces, have been designed to be implanted around or directly inserted within the peripheral nerves [2; 3; 4; 5], optionally through microneedles [6; 7; 8]. Similarly, other kinds of electrodes (i.e., regenerative neural interfaces) were investigated [2; 9; 10] and found to benefit from the ability of axons to regenerate [11; 12; 13; 14]. In particular, intranearual interfaces, despite their relative invasiveness, were able to provide selective recording and stimulation. However, the foreign body reaction (FBR) normally affects the interaction between living tissues and synthetic materials [15; 16]. In this case, the FBR influences the interaction between peripheral nerve tissue [1; 17; 18; 19; 20; 21; 22; 23] and the intranearual interface [24; 25; 26], leading to the formation of a tissue capsule [27; 28] around the implanted device that hampers its functionality. Several works investigated the FBR and the main phases were described: first, blood and plasma proteins (e.g., fibrinogen, fibronectin, albumin, and antibodies)are absorbed to the implant surface [29; 30]; then, the adsorbed protein layer promotes monocyte and leukocyte extravasation, attraction, and adhesion to the surface, together with the coagulation cascade [31; 32; 33]. Furthermore, a matrix of fibrin was found to attract leukocytes and macrophages around the surface of the implanted material through the chemical attraction of chemokines [32; 34]. Again, the extravasated monocytes differentiate to macrophages and fuse together to form multinucleated foreign body giant cells (FBGCs), which start releasing further inflammatory cytokines, boosting the inflammatory response through a positive feedback mechanism [35; 36]. Thus, the myofiblasts trigger the secretion of extracellular matrix (ECM) components [16; 27; 37]. Finally, the scar tissue capsule was found to be impermeable to the nonspecific immune system and to many chemicals [15; 16; 27]. Currently, a reliable prediction of the scar capsule thickness around an inserted material is difficult because of the complexity of the FBR [15; 16; 27; 28; 29; 30; 31; 32; 33; 34; 35; 36; 37; 38] and the unclear physical and mechanical interactions with peripheral nerves [39; 40; 41; 42; 43; 44; 45; 46; 47; 48; 49]. Previous literature investigated the FBR evolution triggered by intraneural electrodes longitudinally implanted (e.g., LIFE electrodes [50; 51]) and studied the cellular composition and the thickness of the fibrotic capsule up to 8 months [52; 53]. These studies found that the increase in the thickness of the scar capsule was directly related to the increase in the electrical impedance, which resulted in the decrease in the signal-to-noise ratio [54], together with a drop in recording and stimulation capabilities [36; 55]. Again, the quantitative prediction of the scar tissue thickness emerged as crucial knowledge to improve both the design and the implantation techniques of intraneural interfaces, even if several interrelated FBR processes are partially hidden and their biophysical rules are not known in detail [15; 16; 27; 28; 29; 30; 31; 32; 33; 34; 35; 36; 37; 38]. Therefore, there is a pressing issue to investigate what kind of computational strategies could be able to model scar tissue evolution, also for small experimental data sets with close experimental time points, which are prone to be ill conditioned. In addition, the high complexity and the huge number of biophysical and biochemical processes may result in extremely complex and time-consuming computational models.