In vivo micro-computed tomography evaluation of radiopaque, polymeric device degradation in normal and inflammatory environments.

Polymeric biomedical implants are an important clinical tool, but degradation remains difficult to determine post-implantation. Computed tomography (CT) could be a powerful tool for device monitoring, but polymers require incorporation of radiopaque contrast agents to be distinguishable from tissue. In addition, immune response to radiopaque devices must be characterized as it modulates device function. Radiopaque devices and films were produced by incorporating 0-20 wt% TaOx nanoparticles into polymers: polycaprolactone (PCL) and poly(lactide-co-glycolide) (PLGA). In vitro inflammatory responses of mouse bone marrow-derived macrophages to polymer matrix incorporating TaOx nanoparticles was determined by monitoring cytokine secretion. Nanoparticle addition stimulated a slight inflammatory reaction, increasing TNFα secretion, mediated by changes in polymer matrix properties. Subsequently, devices (PLGA 50:50 + 20 wt% TaOx) were implanted subcutaneously in a mouse model of chronic inflammation, that featured a sustained increase in inflammatory response local to the implant site over 12 weeks. No changes to device degradation rates or foreign body response were noted between a normal and chronically stimulated inflammatory environment. Serial CT device monitoring post-implantation provided a detailed timeline of device collapse, with no rapid, spontaneous release of nanoparticles that occluded matrix visualization. Importantly, repeat CT sessions did not ablate the immune system or alter degradation kinetics. Thus, polymer devices incorporating radiopaque nanoparticles can be used for in situ monitoring and be readily combined with other medical imaging techniques, for a dynamic view biomaterial and tissue interactions. STATEMENT OF SIGNIFICANCE: A growing number of implantable devices are in use in the clinic, exposing patients to inherent risks of implant movement, collapse, and infection. The ability to monitor implanted devices would enable faster diagnosis of failure and open the door for personalized rehabilitation therapies - both of which could vastly improve patient outcomes. Unfortunately, polymeric materials which make up most biomedical devices are not radiologically distinguishable from tissue post-implantation. The introduction of radiopaque nanoparticles into polymers allows for serial monitoring via computed tomography, without affecting device degradation. Here we demonstrate for the first time that nanoparticles do not undergo burst release from devices post-implantation and that inflammatory responses - a key determinant of device function in vivo - are also unaffected by nanoparticle addition.

In vivo Biomedical Imaging of Immune Tolerant, Radiopaque Nanoparticle-Embedded Polymeric Device Degradation.

Biomedical implants remain an important clinical tool for restoring patient mobility and quality of life after trauma. While polymers are often used for devices, their degradation profile remains difficult to determine post-implantation. CT monitoring could be a powerful tool for in situ monitoring of devices, but polymers require the introduction of radiopaque contrast agents, like nanoparticles, to be distinguishable from native tissue. As device function is mediated by the immune system, use of radiopaque nanoparticles for serial monitoring therefore requires a minimal impact on inflammatory response. Radiopaque polymer composites were produced by incorporating 0-20wt% TaOx nanoparticles into synthetic polymers: polycaprolactone (PCL) and poly(lactide-co-glycolide) (PLGA). In vitro inflammatory response to TaOx was determined by monitoring mouse bone marrow derived macrophages on composite films. Nanoparticle addition stimulated only a slight inflammatory reaction, namely increased TNFα secretion, mediated by changes to the polymer matrix properties. When devices (PLGA 50:50 + 20wt% TaOx) were implanted subcutaneously in a mouse model of chronic inflammation, no changes to device degradation were noted although macrophage number was increased over 12 weeks. Serial CT monitoring of devices post-implantation provided a detailed timeline of device structural collapse, with no burst release of the nanoparticles from the implant. Changes to the device were not significantly altered with monitoring, nor was the immune system ablated when checked via blood cell count and histology. Thus, polymer devices incorporating radiopaque TaOx NPs can be used for in situ CT monitoring, and can be readily combined with multiple medical imaging techniques, for a truly dynamic view biomaterials interaction with tissues throughout regeneration, paving the way for a more structured approach to biomedical device design.