Novel contributions on luminescent apatite-based colloids intended for medical imaging

The setup of colloidal hybrid nanosystems based on biomimetic calcium phosphate apatites doped with europium ions has recently raised great interest in the pharmacological community, especially due to their bio-inspired character. This is especially relevant in relation with medical imaging for cancer diagnosis. Questions however remain in relation to a number of applicability aspects, some of which have been examined in this contribution. In a first part of this work, we explored further the luminescence properties of such colloidal nanoparticles. We pointed out, upon excitation of europium, the existence of some non-radiative de-excitation via the vibration of O-H oscillators located at the vicinity of the Eu3þ luminescent centers. The replacement of Eu3þ by Tb3þ ions, less prone to non-radiative de-excitation, was then tested in a preliminary way and can be seen as a promising alternative. In a second part of this work, we inspected the possibility to store these colloids in a dry state while retaining a re-suspension ability preserving the nanometer size of the initial nanoparticles, and we propose a functional protocol involving the addition of glucose prior to freeze-drying. We finally showed for the first time, based on titrations of intracellular Ca2þ and Eu3þ ions, that folic acid-functionalized biomimetic apatite nanoparticles were able to target cancer cells that overexpress folate receptors on their membrane, which we point out here in the case of T-47-D breast carcinoma cells, as opposed to ZR-75-1 cells that do not express folate receptors. This contribution thus opens new exciting perspectives in the field of targeted cancer diagnosis, thus confirming the promise of biomimetic apatites-based colloidal formulations

Production par co-broyage de matériaux composites poreux biodégradables à usage orthopédique

L’article présente les résultats d’une étude sur la production de matériaux composites poreux biodégradables par co-broyage suivi d’une mise en forme. De l’acide polylactique et une apatite nanocristalline carbonatée analogue au minéral osseux, sous forme de poudres, ont été cobroyés dans un broyeur à boulets afin de disperser la charge minérale dans le polymère. Des implants poreux ont ensuite été réalisés en moulant à chaud le mélange des deux constituants et un agent porogène qui a ensuite été éliminé par lessivage. La résistance mécanique des implants a enfin été caractérisée. Il a été montré que des pourcentages de 30 % de charge et 70 % d’agent porogène permettent de produire des implants suffisamment poreux et résistants

Biomimetic nanocrystalline apatites: Emerging perspectives in cancer diagnosis and treatment

Nanocrystalline calcium phosphate apatites constitute the mineral part of hard tissues, and the synthesis of biomimetic analogs is now wellmastered at the labscale. Recent advances in the fine physicochemical characterization of these phases enable one to envision original applications in the medical field along with a better understanding of the underlying chemistry and related pharmacological features. In this contribution, we specifically focused on applications of biomimetic apatites in the field of cancer diagnosis or treatment. We first report on the production and first biological evaluations (cytotoxicity, proinflammatory potential, internalization by ZR751 breast cancer cells) of individualized luminescent nanoparticles based on Eudoped apatites, eventually associated with folic acid, for medical imaging purposes. We then detail, in a first approach, the preparation of tridimensional constructs associating nanocrystalline apatite aqueous gels and drugloaded pectin microspheres. Sustained releases of a fluorescein analog (erythrosin) used as model molecule were obtained over 7 days, in comparison with the ceramic or microsphere reference compounds. Such systems could constitute original bonefilling materials for in situ delivery of anticancer drug

Biomimetic Apatite-Based Functional Nanoparticles as Promising Newcomers in Nanomedicine: Overview of 10 Years of Initiatory Research

Biomimetic calcium phosphate apatites, analogous to bone mineral, may now be produced synthetically. Their intrinsic biocompatibility and the nanometer dimensions of their constitutive crystals not only allow one to envision applications in bone tissue regeneration, but also in other medical fields such as nanomedicine, and in particular in view of cell diagnosis. In this mini-review, we look back at 10 years of our dedicated research, and summarize the main advances made in terms of preparation, physical-chemical characterizations and biological evaluations of colloidal formulations of biomimetic apatite-based nanoparticles, which we illustrate here with the angle of cancer diagnosis. The confirmed exceptional biocompatibility of these engineered nanoparticles, associated to the possibility to confer them luminescence properties by way of controlled lanthanide doping, and their capacity to be internalized by cells, including with cancer cell addressing abilities (shown here as a proof of concept), underline that biomimetic apatite-based colloidal nanoparticles are particularly promising for nanomedicine applications, for example related to diseased cells diagnosis. Multidisciplinary research on these functional nanoparticles, initiated as described here, has now generated emulation in the scientific community where the concept of apatite nanoparticles for nanomedicine is being, gratifyingly, appropriated

Positive effects of hypoxic preconditioning of the extracellular matrix and stromal vascular fraction from adipose tissue

Background: Numerous approaches have been developed to decelerate the aging process of facial skin. Synthetic fillers and cell-enriched fat grafts are the main procedures employed to fill wrinkles. Objective: The aim of this study was to evaluate the in vitro and in vivo safety and efficiency of a new process developed by SYMBIOKEN: the AmeaCell, which facilitates the extraction of the stromal vascular fraction (SVF) and the associated hypoxia pre-conditioned matrix to promote fat graft survival. Methods: The AmeaCell device allows the extraction from adipose tissue of SVF and pre-conditioned MatriCS and promotes a hypoxic environment. Experiments were carried out on human cells and then in mice. Results: Characterization of cells and MatriCS showed that after their extraction using the new process developed by SYMBIOKEN, the extracted cells expressed stem-cell markers. The presence of characteristic proteins and lipid fractions found in the adipose matrix were confirmed in MatriCS. Cobalt chloride treatment of the matrix using the AmeaCell device induced modifications in the matrix composition with a decrease in laminin and without collagen modification, both of which promote adhesion and differentiation of SVF or adipose-derived stromal cells. The combination of MatriCS and SVF (1 × 106 and 5 × 106, respectively) is safe and efficient to fill winkles induced by UVB irradiation. The cross-talk between MatriCS and SVF can act a durable filler compared to the filling performed using cells or matrix or fat alone, which need to be replaced frequently. Conclusion: These results indicate that the combination of MatriCS and SVF is safe and effective as a biological filler for achieving skin rejuvenation and wrinkle filling

Adsorption onto nanocrystalline apatitic calcium phosphates. Applications to growth factors and drugs delivery

Interfacial properties of apatitic calcium phosphate play a crucial role in calcified tissues and biomaterials. Generally the adsorption of molecules on apatitic calcium phosphates is considered to obey to electrostatic interactions. The study of the adsorption of various active molecules such as albumin, heparin, bisphosphonate, and growth factors like BMP-2, VEGF and FGF-2 on such surfaces seems to follow a similar pathway. In all cases the adsorption process can be well described using Langmuir isotherms, although the adsorption process appears generally as irreversible. Further studies of the adsorption reaction reveal, in most cases, an ion exchange mechanism involving the replacement of mineral ions of the apatite surface by molecular ions from the solution. Considering biomimetic apatite nanocrystals, considerable variations of the adsorption parameters are observed depending on the maturation time of the nanocrystals. As the maturation time increases, the adsorption affinity constant increases and the maximum amount adsorbed decreases. The understanding of the adsorption process provides fundamental tools for the development of drug delivery system using apatite materials. Applications to the release of active molecules are examined in the case of apatite coatings