In Vivo Microcomputed Tomography of Nanocrystal-Doped Tissue Engineered Scaffolds

Abstract

Tissue engineered scaffolds (TES) hold promise for improving the outcome of cell-based therapeutic strategies for a variety of biomedical scenarios, including musculoskeletal injuries, soft tissue repair, and spinal cord injury. Key to TES research and development, and clinical use, is the ability to longitudinally monitor TES location, orientation, integrity, and microstructure following implantation. Here, we describe a strategy for using microcomputed tomography (microCT) to visualize TES following implantation into mice. TES were doped with highly radiopaque gadolinium oxide nanocrystals and were implanted into the hind limbs of mice. Mice underwent serial microCT over 23 weeks. TES were clearly visible over the entire time course. Alginate scaffolds underwent a 20% volume reduction over the first 6 weeks, stabilizing over the next 17 weeks. Agarose scaffold volumes were unchanged. TES attenuation was also unchanged over the entire time course, indicating a lack of nanocrystal dissolution or leakage. Histology at the implant site showed the presence of very mild inflammation, typical for a mild foreign body reaction. Blood work indicated marked elevation in liver enzymes, and hematology measured significant reduction in white blood cell counts. While extrapolation of the X-ray induced effects on hematopoiesis in these mice to humans is not straightforward, clearly this is an area for careful monitoring. Taken together, these data lend strong support that doping TES with radiopaque nanocrystals and performing microCT imaging, represents a possible strategy for enabling serial in vivo monitoring of TES.

Design Considerations to Facilitate Clinical Radiological Evaluation of Implantable Biomedical Structures

“…A more versatile technique for adding contrast to almost any system is the incorporation of nanoparticles . Iron oxide nanoparticles are already in clinical use for therapeutic purposes, such as anemia treatment, and experimental uses such as tracking drug delivery and efficacy in cancer. − A wide range of nanoparticles with unique chemistries have been incorporated into matrices, allowing for monitoring via different imaging modalities. − Use of these novel materials has shown promise to track in vivo implanted device degradation and location in preclinical settings. , A downside to these studies is that imaging is performed using high-resolution preclinical systems, which are clinically incompatible, or the studies do not use protocols or techniques that are consistent with clinical practices.…”

“…14−16 Use of these novel materials has shown promise to track in vivo implanted device degradation and location in preclinical settings. 17,18 A downside to these studies is that imaging is performed using high-resolution preclinical systems, which are clinically incompatible, or the studies do not use protocols or techniques that are consistent with clinical practices.…”

Methacrylate‐Modified Gold Nanoparticles Enable Noninvasive Monitoring of Photocrosslinked Hydrogel Scaffolds

“…imaging (MRI), [24][25][26][27] and X-ray computed tomography (CT). [28][29][30] Among these, CT imaging is advantageous in providing low-cost, 3D, deep tissue imaging at high spatial and temporal resolution, but is limited by low soft tissue contrast. CT imaging contrast is derived from the X-ray attenuation of the scaffold material relative to adjacent tissue.…”

“…[ 13 ] Therefore, various imaging modalities have been investigated for noninvasive assessment of hydrogel degradation and drug delivery, [ 13,14 ] including ultrasound elasticity imaging, [ 15,16 ] photoacoustic imaging, [ 17,18 ] near‐infrared fluorescence imaging, [ 19–24 ] magnetic resonance imaging (MRI), [ 24–27 ] and X‐ray computed tomography (CT). [ 28–30 ] Among these, CT imaging is advantageous in providing low‐cost, 3D, deep tissue imaging at high spatial and temporal resolution, but is limited by low soft tissue contrast.…”

Methacrylate-Modified Gold Nanoparticles Enable Non-Invasive Monitoring of Photocrosslinked Hydrogel Scaffolds

“…13 Therefore, various imaging modalities have been investigated for noninvasive assessment of hydrogel degradation and drug delivery, 13,14 including ultrasound elasticity imaging, 15,16 photoacoustic imaging, 17,18 near-infrared fluorescence imaging, [19][20][21][22][23][24] magnetic resonance imaging, [24][25][26][27] and X-ray computed tomography (CT). [28][29][30] Among these, CT imaging is advantageous in providing low cost, three-dimensional (3D), deep tissue imaging at high spatial and temporal resolution, but is limited by low soft tissue contrast.…”