Biomedical and Tissue Engineering Strategies to Control Foreign Body Reaction to Invasive Neural Electrodes

Abstract

Neural-interfaced prostheses aim to restore sensorimotor limb functions in amputees. They rely on bidirectional neural interfaces, which represent the communication bridge between nervous system and neuroprosthetic device by controlling its movements and evoking sensory feedback. Compared to extraneural electrodes (i.e., epineural and perineural implants), intraneural electrodes, implanted within peripheral nerves, have higher selectivity and specificity of neural signal recording and nerve stimulation. However, being implanted in the nerve, their main limitation is represented by the significant inflammatory response that the body mounts around the probe, known as Foreign Body Reaction (FBR), which may hinder their rapid clinical translation. Furthermore, the mechanical mismatch between the consistency of the device and the surrounding neural tissue may contribute to exacerbate the inflammatory state. The FBR is a non-specific reaction of the host immune system to a foreign material. It is characterized by an early inflammatory phase eventually leading to the formation of a fibrotic capsule around intraneural interfaces, which increases the electrical impedance over time and reduces the chronic interface biocompatibility and functionality. Thus, the future in the reduction and control of the FBR relies on innovative biomedical strategies for the fabrication of next-generation neural interfaces, such as the development of more suitable designs of the device with smaller size, appropriate stiffness and novel conductive and biomimetic coatings for improving their long-term stability and performance. Here, we present and critically discuss the latest biomedical approaches from material chemistry and tissue engineering for controlling and mitigating the FBR in chronic neural implants.

Medical Applications of Porous Biomaterials: Features of Porosity and Tissue‐Specific Implications for Biocompatibility

“…A modern definition of biocompatibility put forth by Crawford et al., is “the ability of a material to locally trigger and guide the proteins and cells of the host toward a non‐fibrotic, vascularized reconstruction and functional tissue integration.” [ 1 ] The effect of material porosity on biocompatibility has been extensively studied, repeatedly showing that porosity improves tissue healing responses and decreases scar tissue growth. [ 4,10,13,33,38,39,80,142–144 ] Considering our tissue‐specific focus here, we have broadened our definition of biocompatibility to consider the other factors which are critical to the success of the medical device. Beyond the FBR, this includes hemocompatibility, biofilm formation, and calcification – all of which have nuanced impacts by porosity.…”

Physically Consistent Scar Tissue Dynamics from Scattered Set of Data: A Novel Computational Approach to Avoid the Onset of the Runge Phenomenon

“…Furthermore, it was described as the way extravasated monocytes differentiate to macrophages and fuse together to form multinucleated foreign body giant cells (FBGCs). These cells started releasing further inflammatory cytokines, boosting the inflammatory response through a positive feedback mechanism [35,36]. Then, it was described as myofibroblasts triggered a massive secretion of extracellular matrix (ECM) components [15,27,37].…”

“…Both the complexity of the FBR [14,15,[27][28][29][30][31][32][33][34][35][36][37][38] and the unclear relationship between the physical properties of peripheral nerves [7,[39][40][41][42][43][44][45][46][47][48] and the amount of scar tissue production makes a reliable prediction of the capsule thickness a challenging task.…”

“…These investigations revealed that the contacts between the nerve fibers and the electrode active sites were partially lost because of the outgrowth of the encapsulating tissue. In particular, the increase of the scar capsule was directly related to the increase of the electrical impedance, resulting first in the decrease of the signal to noise ratio [53] and possibly in a sensible drop of registration and stimulation capabilities [36,54].…”

“…Therefore, a correct and quantitative assessment of the capsule thickness over time is crucial information to improve the design of intraneural interfaces as well as their implantation technique. However, the development of the FBR involves several interrelated complex processes [14,15,[27][28][29][30][31][32][33][34][35][36][37][38] which are partially hidden since their explicit and physically based rules are not known in all details.…”