Radiopaque 3D printed tissue engineered scaffolds for nerve generation

ABSTRACT Tissue engineered scaffolds (TES) are employed in regenerative medicine to induce tissue repair in a variety of organs. Over the last decade we have demonstrated that multichannel, polymer-based TES implanted in nerve injury sites facilitate functional recovery in rodent models. To augment the clinical utility of TES for peripheral nerve injury (PNI), we imparted radiopacity to these implantable devices, by doping the polymer devices with radiopaque tantalum oxide (TaOx) nanoparticles (NPs). With this process, biomedical devices could be monitored post-implantation by x-ray computed tomography (CT), a workhorse of clinical imaging due to its high resolution and accessibility. Indeed, implanted radiopaque TES are easily detectable in vivo by CT, enabling physicians to determine correct TES implantation site, and any displacement, damage and/or degradation. For PNI, this could reduce the delays to revision treatment that impair functional recovery for patients. Previously the upper bounds for tolerable TaOx concentration were determined in terms of biocompatibility, cellular growth, and device mechanics, and lower bounds by CT detection. The long-term goal is now to move the technology towards the clinic by 1) scaling production of a radiopaque TES using additive manufacturing, 2) confirming biocompatibility and NP tissue clearance following device degradation, and 3) validating CT as a method for longitudinal monitoring of nerve devices in a large animal model. To accomplish these goals, ultra-high resolution 3D printing of photoresin/NP composites will be used to create multichannel, radiopaque PNI devices. With homogeneous and well characterized radiopaque materials, the clearance of NPs will be evaluated in vivo, in a mouse model, to determine the effect of NP surface chemistry on biodistribution as implants degrade. A major hurdle in the translation of implants to the clinic is related to implant scale up, as changes in physical dimension of implants impact tissue repair, making large animal models key for justifying clinical use. Therefore, radiopaque PNI devices will be monitored in a swine model of sciatic nerve injury, quantifying device features via in situ imaging and relating imaged features to nerve regeneration and functional recovery over 8 months. Further, the benefits of an emerging clinical CT paradigm, photon counting spectral CT (PCCT), will be defined as it has the potential to enable more sensitive imaging, reducing TaOx content, while obtaining higher resolution images at lower X-ray doses. By demonstrating applicability of radiological monitoring to PNI devices on a human clinical scale, with no adverse events associated with the radiopaque nanoparticles, success of this project sets the stage for clinical translation, building on proven biocompatibility of TaOx NPs, customization of 3D printing, and demonstration of clinical utility in large animal models and with PCCT.