This week in class we briefly touched upon the body’s immune reaction to the foreign body implantation, and how this reaction is dependent on the characteristics of the material and the extent of injury. While looking for adequate literature in relation to fibrosis, I decided to elaborate on how different types of materials induce more or less severe inflammation which later on results in formation of fibrotic capsule around the implant, using a simple example from a recent publication by Bertrans et al. (2018).
Biomaterials used as implants should be designed in a way that allows for mitigation of the inflammatory response and their integration into the tissue. Otherwise, biomaterial implants frequently cause the so-called foreign body reaction, which comprises of 1) protein adsorption and formation of matrix around the implant, 2) acute phase inflammation with presence of mast cells and granulocytes, this can further develop into 3) chronic inflammation where macrophages play a central role, 4) granuloma with presence of giant cells, and finally, through the activation of fibroblasts, 5) formation of the fibrous tissue surrounding the implant and isolating it from the peri-implant cells.
The study of Bertrans et al. followed-up on patients with hip replacements made out of and coated with different materials (ceramic on ceramic – CoC, ceramic on polyethylene – CoP, and metal on metal – MoM), who required revision surgery. The ceramic materials used for these implants were alumina-toughened zirconia (nanosized alumina in zirconia) – ATZ, and zirconia-toughened alumina (nanosized zirconia grains in alumina) – ZTA.
Interestingly, they found that in the patients with CoC prosthetics, the peri-implant environment consisted of much denser fibrotic capsule than in patients with MoM or CoP implants, and that increase was elevated with time after implantation of artificial hip joint (see the graph below). They were also able to find worn CoC in the connective tissue matrix.
The group further investigated the mechanisms underlying the differences between cellular reactions to these materials in vitro, and performed studies on fibroblast cultures, where the cells were cultured on surfaces identical to the ones of CoC, CoP, and MoM prosthetics. As a measure of the fibroblast response they looked at the levels COX2, a marker of chronic inflammation, and found an increase of that marker only in fully ceramic implants (especially the ATZ), suggesting increase of fibroblast response in the inflammatory reaction. They also conducted studies on peripheral blood mononuclear cell cultures and saw an increase of pro-inflammatory cytokines (IL-1, IL-6, COX2) when in contact with ATZ, but not with the other materials.
Their results clearly show that the reaction of the body to the foreign material can vary depending on the chemical and physical properties of the biomaterial used as an implant. In this specific case, the increase in inflammatory reaction and, as a consequence, fibrosis could be due to the presence of the worn ceramic particles in the tissue surrounding implant which might be bioactive, even though the wear of ceramics in general is rather low. While in the case of joint replacement, extensive fibrosis might prove to be beneficial and reduce the implant dislocation, for instance in the case of heart valve replacements extensive inflammation and fibrosis can be lethal.
A way to reduce this effect in biomaterial implants or drug delivery systems is for example by coating the surface of materials with protein which would mediate the reaction to the material.
Examples of biomaterials coated with protein and ways of their production are described for instance in the US Patent Application # US20120114734A1. The authors of this invention also suggest using compositions with covalently attached anti-inflammatory compounds to decrease the foreign body reaction. To me, it seems the most promising now, and easy-to-apply into clinical use way to diminish tissue fibrosis following implantation.
References:
Bertrand, J., Delfosse, D., Mai, V., Awiszus, F., Harnisch, K., & Lohmann, C. H. (2018). Ceramic prosthesis surfaces induce an inflammatory cell response and fibrotic tissue changes. Bone Joint J, 100(7), 882-890.