# Challenges for the Implantation of Symbiotic Nanostructured Medical Devices
## 3 Biocompatibility is the Major Challenge for Symbiotic Implanted Medical Devices  
Indeed, the issues of biocompatibility have remained largely unsolved since scientists such as [PERSON], [PERSON], [PERSON], and [PERSON] pioneered the fields of modern biomaterials and biocompatibility issues [8; 9; 10; 11; 12; 13; 14]. Current thinking about biocompatibility pathways for a biomaterial have included the ways in which the components of the biomaterial actually interact with cells of the body [15]. [PERSON] (2014) identified those components acting on the cell as having an origin from the biomaterial (e.g., metal ions, polymer additives, nanoparticles, and contaminants), mechanical and biophysical mediators of interactions (e.g., electromagnetic fields and structural/fluid stresses), internalization mechanisms (e.g., phagocytosis, endocytosis, and pinocytosis), or material mediators of interactions (chemical structure, elasticity, shape, volume, and topography). However, those mediating components were considered as originating from, or derived from, the biomaterial. Nonetheless, such a concept of biocompatibility subsumes a collection of individual phenomena that make it impossible to consider that biocompatibility can be graduated into some form of a scale. Furthermore, even by referring to a \"biocompatible system\" rather than a \"biocompatible material,\" [PERSON] concluded that the term \"biocompatible system\" remained imprecise and potentially misleading [16]. We suggest that such imprecision can be avoided if biocompatibility is defined by the intended functional properties of the implanted device. Such a definition implies that the implanted device would need the characteristics of duplex communication with the body in order for it to be a symbiotic device and, hence, biocompatible. The value of re-defining the framework of a \"biocompatible system\" is in considering the next generation of such symbiotic devices where long-term function is the focus of the implanted system. An example of such a symbiotic device is a biofuel cell that can also produce potentially irritant chemicals from its catalytic reactions. The enzymatic biofuel cell needs to be designed to include a stable and permeable interface with the body. Nonetheless, an implanted enzymatic biofuel cell will inevitably be enclosed by a fibrous capsule that follows the usual foreign-body reaction (FBR), as is the case for all non-biodegradable implanted devices [17]. The formation of a fibrous capsule could be initiated by adsorption of a cluster of inflammatory proteins [18]. However, that hypothesis does not completely explain the differences in biocompatibility amongst all types of biomaterials. Indeed, the same material can initiate an in vivo reaction that may not only include the encapsulation that follows the FBR [17]. [PERSON]'s group found that an implanted non-porous slab of poly(hydroxymethylmethacrylate) hydrogel heals via the prototypical FBR. In comparison, an implanted 34-\(\upmu\)m porous poly(hydroxyethylmethacrylate) hydrogel has the additional feature that the pores are infiltrated with a mostly cellular and slightly fibrous tissue substance, but the implant is surrounded by a fibrous capsule, albeit one that is thinner and less dense than the capsule surrounding the non-porous implant. For larger pores of 160-\(\upmu\)m, there was a greater fraction of fibrous tissue inside the pores [19]. Those observations provide a snapshot of the FBR, since the different hydrogel samples were implanted for only three weeks. Nonetheless, those results raised several interesting directions for finding a solution to minimize and/or eliminate the fibrous encapsulation of the enzymatic biofuel cell in order to maintain a stable and permeable interface for the exchange of molecules of fuel. The consideration of such directions is also important for the more general issue of implanting a symbiotic device where there is the need to maintain a stable and porous interface between the device and the body.