Abstract Body:

Implantable medical devices are often used to repair tissue after trauma. Despite widespread use, polymeric biomedical devices are difficult to monitor post-implantation to ensure proper positioning and determine subsequent device damage or degradation. With the incorporation of radiopaque nanoparticle contrast agents, polymers can be distinguished from tissue using computed tomography (CT) [1-2], which significantly improves radiologists’ success rate for identifying implant location and damage [3]. In this study, serial monitoring was utilized as a way to understand inflammatory responses to nanoparticles in vitro and how local in vivo inflammation and mechanics affect device properties over time, to better design implants.

Methods: Three biocompatible polymers with differing degradation rates were used as matrices: poly(lactide co-glycolide) (PLGA) 50:50, PLGA 85:15 and polycaprolactone (PCL). Radiopaque porous films and phantoms mimicking tissue engineering devices were produced via salt leeching incorporating CT-visible hydrophobic TaO_x nanoparticles at 0-20 wt% [2]. Mouse bone marrow derived macrophages (BMDM) were cultured on radiopaque films for 1 week and inflammatory response was probed via cytokine expression (TNFα, TGFβ1, IRF5, CCL17). To measure in vivo degradation, radiopaque phantoms (20wt% TaO_x) were implanted into mice intramuscularly (IM), interperitoneally (IP) and in a subcutaneous site with chronic inflammation induced by 1.7wt% carrageenan injection. Phantoms were imaged in situ using micro-computed tomography (µCT) at 90keV, 88 µA for 20 weeks and features (matrix volume, gross volume, attenuation) were extracted using MATLab.

Results & Discussion: Incorporation of a hydrophobic radiopaque nanoparticle created phantoms visible in µCT, with a homogeneous distribution of x-ray attenuation that increased as the wt% TaO_x increased. In vitro, TaO_x nanoparticles stimulated only a slight inflammatory reaction from macrophages, namely increasing TNFα secretion. The effect was mediated by changes in polymer properties, such as increased surface roughness and matrix susceptibility to hydrolyzation. In vivo, chronic inflammation did not alter the degradation profile of phantoms produced from fast degrading polymers, despite a significant increase in macrophage number over 12 weeks.

Serial CT monitoring of implanted phantoms provided a detailed timeline of degradation, with no significant effect on the systemic immune system or degradation kinetics. Phantom degradation was primarily controlled by the properties of the polymer matrix. Phantoms implanted intramuscularly were more constrained, with less swelling than IP implantation. Over 20 weeks, implantation site was most relevant for the mid-degrading polymer (PLGA 85:15), with faster matrix dissolution in IP, likely due to the high number of inflammatory cells [4]. In all cases, degradation of PLGA was faster in vivo than in vitro [2]. As phantoms collapsed, X-ray attenuation increased, as the hydrophobic TaO_x nanoparticles were physically concentrated at the implant site, due to either macrophage action or interaction with hydrophobic extracellular matrix. Although not completely removed from the implant site, nanoparticles also reached the liver and spleen, without inducing tissue damage. Importantly, there was no burst release of nanoparticles from phantoms, supporting the use of radiopaque nanoparticles to conveniently facilitate in situ monitoring of medical devices in a way that does not interfere with other medical imaging techniques.

Conclusion: A better understanding of how materials interact with living tissue could usher in a new age of medical devices. However, this necessitates better methods for monitoring degradation and device damage post-implantation. Importantly, CT is an imaging technology that can transition from bench to bedside. The incorporation of 5-20wt% TaO_x nanoparticles induce only a mild inflammatory reaction but enable longitudinal monitoring of devices. Over 20 weeks, in vivo degradation profiles were distinct for polymer type and implantation site. In combination with other medical imaging techniques to track dynamic biological changes, the use of serial CT monitoring opens new opportunities to engineer biological response through medical devices.