Direcciones estratégicas

our strategy in prolonging the residence of the contrast agent in the CPC matrix up to at least 8 weeks post-surgery [19-21,44,45]. One potential issue is the observed implant size overestimation on MR images, however, this property could be considered an advantage for detection especially when small amounts of the cement need to be identified in the body.

Histological assessment was performed 8 weeks after surgeries and showed a direct contact between bone and the cement, without sign of inflammation or fibrous encapsulation (see Figure 4c and Figure S3). BP-loaded CPCs have been used to increase bone augmentation after in vivo implantation in femora and vertebra of osteoporotic rats. Specifically, release of BP derivatives from the CPC phase resulted in an increased bone density in the immediate proximity of the implant (i.e. in an area from 0.4 to 0.7 mm far the cement) [46,47]. Our histological findings were in line with these previous studies and showed higher bone density around the implant when compared to the CPC composition without BP components (Figure 4c). However, statistical t-testing did not show significant differences in new bone formation between the experimental groups of this size and so further studies are necessary (Figure 4c).

One area of further study that is ongoing is to look at the release profile in vivo and the biodistribution of the GBCAs-BP when released from the CPC composite. Methods for radiolabeling are under investigation to determine a valid quantitative tracking. Previous studies have shown that GBCAs do not undergo to intracellular accumulation and are generally excreted by the hepatobiliary or renal systems [48,49]. The decrease in MRI and CT signal over time and the absence of background signals in the surrounding tissues indicate that any GBCAs-BP released from the materials did not accumulate and were eliminated from the body. The overall profile of the ultrasmall Gd2O3 nanoparticles that have been designed and

produced in this work offers a significant advance over the current state-of-the-art for longitudinal imaging of calcium phosphate cements. The key image acquisition features are effective multiple modality imaging (combining contrast in both MR and CT from a single agent) and high relaxivity across appropriate MR field strengths. A feature of equally high importance for longitudinal studies is the high affinity for the cement material which is due to the bisphosphonate coating added to the silica layer.

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Figure 4. CPC composite with and without GBCAs-BP after injection in a rat condyle defect. (a) the ZTE MR images and (b) the CT acquisitions are shown respectively. From the top to the bottom the axial view of the same leg after surgery, at 4 and 8 weeks post-surgery are shown respectively. Note yellow dashed circles that

indicate the difference in size between CPC with and without GBCAs-BP. Green arrows indicate the bright region that appears in the middle of the implant on the MRI acquisitions after 4 weeks from the surgery. The bright region corresponds on the CT images to a less dense material. Red arrow indicates the CPC that become indistinguishable from the surrounding bone after 8 weeks from implantation in vivo. In (c) histological sections

after EVG staining (scale bar 500 µm). The inserts show the new bone formation quantification based on the histological sections. The red dashed lines indicate the bone volume observed in the non-treated samples. No

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