Month: October 2018

Silicone implants have been widely used in medical applications, as orthopedic or breast implants, in catheters and drains, to name a few, however, the problem with silicone is that it causes excessive extracellular matrix formation around the implant, possibly because it does not allow for cell attachment and thus incorporation into the tissue. The fibrotic capsule that forms often has a higher Young’s modulus that the soft tissue and therefore is more stiff than the surrounding tissue (in the case of silicone breast implants for example the adipose tissue).

To address the problem of high inflammatory response resulting in fibrosis of tissue surrounding silicone implants, the group from ETH Zurich investigated the use of Bioglass 45S5® in combination with silicone to optimize the bioinert properties of implants and improve its integration into the tissue. They produced silicone composites containing micro- and nano-particles of Bioglass (45 wt% SiO2, 24.5 wt% Na2O, 24.5 wt% CaO, 6 wt% P2O5). Additionally, their particles were porous which allowed for increased “exposure” of tissue to the incorporated Bioglass, which the group actually showed when they compared adhesion and integration into the tissue of the different composites. It is also worth mentioning that the group even observed less fibrosis and even some vascularization in the close proximity to the implant!

As silicone is often used in bone graft implants, they found that incorporation of Bioglass allowed for transformation into hydroxyapatite on the surface of the composites. This makes the bioglass-silicone composites more biocompatible and suitable for use in bone implants.

Interestingly, the mechanical properties of these composites proved to be influences by the size of incorporated Bioglass particles. In class we learnt that decrease in size of glass and ceramic particles increases their strength, and affects their elastic modulus. The paper shows that incorporation of microparticles results in lower modulus of elasticity than for nanoparticles, when both are implanted into biological system (in this case their studies were done in ovo). This means that by incorporating bioglass into silicone implants we can increase their integration into tissue (the paper actually showed that Bioglass-silicone composites are more integrated into the tissue than silicone-only composites), and decrease the formation of fibrous capsule.

Their results seem to show that incorporation of Bioglass can help optimize the bioinert properties of silicone-based implants so that they allow for cell attachment, and improve integration into the tissue without causing chronic inflammation, and eventually inducing fibrosis.

Article:

Cohrs, N. H., Schulz‐Schönhagen, K., Mohn, D., Wolint, P., Meier Bürgisser, G., Stark, W. J., & Buschmann, J. (2018). Modification of silicone elastomers with Bioglass 45S5® increases in ovo tissue biointegration. Journal of Biomedical Materials Research Part B: Applied Biomaterials.

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.