CE19 - Technologies pour la santé

Bone REpair Assessment with K-edge Spectral imaging – BREAKSIT

Bone REpair Assessment with K-edge Spectral Imaging Technique (BREAKSIT)

The objective of the proposal is to investigate the potential of a brand-new imaging technique, Spectral Photon Counting Computed Tomography or SPCCT (currently in development, to detect, characterize and monitor neurovascular and cardiovascular disease), (i) for the in vivo visualization of injectable calcium phosphate cements (CPC) used in bone reconstruction surgery, (ii) for the monitoring of the replacement of the CPC implant by natural bone during the bone repair process.

Design of an optimized injectable CPC formulation which can easily be visualized by SPCCT in vivo

The use of injectable calcium phosphate cements (CPCs) for the repair or regeneration of bone tissues is expanding continuously, since (i) they are resorbable and replaced by natural bone in situ; (ii) they are injectable and suitable for minimally invasive surgery (the benefits of which are smaller incision, lower complication rates, local anesthesia, quicker patient recovery) and (iii) they offer an alternative to autograft which suffers from drawbacks such as a second surgical site which requires additional time spent in the surgical room and the occurrence of pain at the bone harvesting site along with increased risks of morbidity. Up to now CPCs are mainly used for moderate size bone void filling in traumatology. However, the fast improvement of imaging technologies should open new market perspectives for CPCs, including (i) the monitoring of the implant degradation and its replacement by bone (e.g., spine fusion, vertebral body augmentation); (ii) the implantation of CPCs under image-guided procedures for applications such as vertebral body augmentation. Since the opacity of CPCs is close to that of bone tissues, the inclusion of an adapted contrast agent (i.e., compatible with the bioresorption of the associated cement) is thus needed. In this context, the core and groundbreaking aspect of this proposal is to combine the expertise of complementary research teams and take benefits of a unique advanced imaging technique based on the K-edge, to design a new generation of CPCs with enhanced properties.

The BREAKSIT work plan is organized around 3 scientific work packages. The first work package (WP1) is focused on the design of optimized injectable CPC formulations which can be easily visualized by SPCCT. The research consists in the preparation of a series of SPCCT-detectable CPCs, each one based on a different contrast agent (i.e., rare earth fluoride-based nanoparticles) to select the two most suitable in terms of sensitivity, but also in terms of differentiation when considering simultaneous imaging of two different contrast agents. The purpose of WP2 is to conduct a proof of concept preclinical study to show that accurate in vivo monitoring of the replacement of the implanted CPCs by bone can be achieved thanks to SPCCT. Two types of CPC will be studied: a commercially-available injectable apatitic calcium phosphate cement and its blood composite analogue, which differ in their resorption kinetics in vivo. SPCCT-monitoring of the degradation of the corresponding materials once implanted will be investigated using two types of animal models: (i) bone critical-size defects in a small animal model (rabbit) and (ii) a large animal model (sheep) for lumbar arthrodesis. The objective of the third work package (WP3) is to design a CPC detectable by SPCCT and suitable to track the inflammatory process occurring during bone repair. This approach will require the use of two different contrast agents, with two new technical challenges to be addressed: (i) the appropriate surface biofunctionalization of the second contrast agent to make the related nanoparticles able to specifically target the inflammation at the bone - implant interface (decoration of the nanoparticles by a blend of PEG and folic acid moieties, which have been reported in the literature to target activated macrophages with high specificity; (ii) an appropriate strategy in the design of this specific CPC detectable by SPCCT to ensure release of the second contrast agent at the bone / implant interface.

-WP1 :
Given the stability issues observed for the first generation of SPCCT contrast agents in the liquid phase of our cements [aggregation driven by phosphate ions], a second generation has thus been developed. For that purpose, we have used a polymer bearing polyethylene glycol as well as phosphonic acid functions. The latter allow the efficient grafting of the polymer on the surface of the rare earth nanoparticles [gadolinium, yttrium] which results in a very good stability in phosphate medium. In addition, the mechanism of the reaction of phosphate ions with the nanoparticles has been investigated and we have progressed with the understanding of this phenomenon. Finally we have determined the appropriate dose of contrast agent to be combined to the cement to allow its easy visualisation by SPCCT (ideally between 5 and 20 mg per mL of cement paste).

-WP2 :
A preliminary experiment was performed using 4 rabbits that were implanted on critical-size femoral bone defects with calcium phosphate cements containing a SPCCT contrast agent (gadolinium fluoride-based nanoparticles). The anesthetized animals were scanned 1, 3 and 8 weeks after implantation, respectively. The SPCCT scanner allowed to obtain high resolution conventional images and a decomposition of the materials in water/calcium was performed to monitor the chemical evolution of the samples. The design of specific images processing was necessary for these highly attenuating materials and contrast agents. The image acquisition has shown the necessity to design an ex vivo model for the calibration of the water/calcium decompositions. The acquisition of this model is in progress.

-WP3 :
This last WP will be started as soon as the progress of WPs 1 et 2 will be sufficient.

-An unexpected and serious issue was observed at the early beginning of the project. Indeed the SPCCT contrast agents consisted of rare earth fluoride nanoparticles (NPs) grafted on their surface with a polyethylene glycol chain having a phosphonic acid end-group. In fact, this surface coating was found to be unstable once combined with the calcium phosphate cement paste, since rapid aggregation of the NPs occurred. An extensive study is in progress, in order to characterize and understand the chemical process responsible of this behaviour, and we are very confident in our capacity to successfully complete this study and valorise the results by means of publications and scientific communications.

-Thanks to efforts of the CEISAM, Laboratoire de chimie de l’ENS-Lyon and CEMHTI teams, a second generation of SPCCT contrast agents was designed, and the latter was stable when mixed with the CPC. The project is now focused on the use of this second generation of SPCCT contrast agents combined to the cement formulations.

-On the other hand, in spite of the above mentioned issue we have progressed on the other part of the study. Hence, preliminary experiments were successfully performed allowing to image our calcium phosphate cements by SPCCT, first using bone explants, then implanted living animals [rabbit]. These first results are very encouraging and confirm the high interest of the project. However, the arrival of a second generation prototype of SPCCT scanner required additional technical developments for the image reconstructions.

-Given the afore-mentioned issues, the progress of the project has been delayed by at least six months [excluding hazards related to the COVID-19 health crisis]. Moreover, the initially scheduled strategy for WP3 has to be reconsidered and this work is currently underway.

Two oral communications in scientific meeting dedicated to biomedical imaging

-Bujoli, B. et al. Formulation de substituts osseux à base de phosphates de calcium pour le suivi de leur résorption par imagerie spectrale à comptage photonique, 1er Workshop d'Imagerie Spectrale à Comptage Photonique, application en ostéo-articulaire, Lyon (France), 22 Novembre 2019

-S. Parola et al. Conception de nanoparticules hybrides de fluorures de terres rares pour l’imagerie Médicale, Journées Scientifiques France Life Imaging (FLI), nœud Lyonnais, Lyon (France) 20 Décembre 2019.

The objective of the proposal is to investigate the potential of a brand-new imaging technique, Spectral Photon Counting Computed Tomography or SPCCT (currently in development, to detect, characterize and monitor neurovascular and cardiovascular disease), for the visualization of injectable calcium phosphate cements (CPC) used in bone reconstruction surgery. Hence, combination of the contrast agents designed for SPCCT with CPC will be investigated to allow good visualization of the cement, while retaining suitable ergonomic, mechanical and biological properties for their practical use in bone surgery. Compared imaging results will be performed, to demonstrate that SPCCT provides unique advantages for the in vivo monitoring of the degradation of CPC implants, in comparison with other imaging techniques, in particular CT-scan. For that purpose, a preclinical animal model of spine fusion will be used, since the possibility to early detect fusion failures is a critical issue for this indication. The proposal will also investigate the potential of SPCCT to target and visualize the inflammatory process occurring during bone repair. Finally, the expected results might also open the way to the image-guided implantation of theses cements, via minimally invasive procedures.

Project coordination

Bruno BUJOLI (CHIMIE ET INTERDISCIPLINARITE : SYNTHESE, ANALYSE, MODELISATION)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

Unité de chirurgie - anesthésie
LCH LABORATOIRE DE CHIMIE
CREATIS CENTRE DE RECHERCHE EN ACQUISITION ET TRAITEMENT D'IMAGES POUR LA SANTE
GRAFTYS
CEMHTI Conditions Extrêmes et Matériaux : Haute température et Irradiation
CEISAM CHIMIE ET INTERDISCIPLINARITE : SYNTHESE, ANALYSE, MODELISATION
IBV Institut de biologie de Valrose

Help of the ANR 437,878 euros
Beginning and duration of the scientific project: November 2018 - 48 Months

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