Development of Reactive Freeze-Casting Applied to Calcium Phosphate Cements for the Fabrication of Macroporous Composite Materials for Bone Repair

Bone is a mineral-organic composite made up of collagen fibers mineralized by apatitic calcium phosphate nanocrystals [1]. Although bone tissue is capable of self-repair, reconstructive surgery using natural or synthetic bone fillers is often necessary [2]. Because of their structure and chemical composition, which are similar to those of the mineral phase of bone, phosphocalcic apatites are particularly suitable for bone reconstruction [3]. This physico-chemical analogy with bone mineral gives them excellent biocompatibility and bioactivity, and modulable resorbability, whether for releasing ions or biologically active molecules, or for promoting the adhesion, proliferation and differentiation of osteoprogenitor cells. The biomimicry of these substitutes can also be enhanced by combining them with an organic phase to give the material mechanical properties close to those of bone tissue [4,5].

Demand from clinicians is driving research into the personalization of these composite bone substitutes. This is achieved by: (i) patient-specific shapes/designs/resorption rates [6] and (ii) (multi)functionalization via (bio)active molecules or ions conferring specific biological properties [7,8]. To produce bone substitutes made from customized organic-inorganic composite biomaterials, it is therefore necessary to implement processes that operate at low temperatures [9, 10] to preserve their biological properties. The composition of the product (solubility of the mineral phase and biodegradability of the polymer) is also a key parameter that determines the modularity of the system, depending on the implantation site and the desired resorption rate [11, 12]. With regard to customized shaping, the development of reactive freeze-casting by coupling the freeze-casting process with a phosphocalcic cement system [13,14,15] appears to be a promising alternative to additive manufacturing processes that generally require high temperatures during printing or final consolidation post-processing [16].

As part of this PhD project, we will investigate the development of macroporous composites by combining the freeze-casting process with the reactivity of mineral and/or composite cement pastes (based on calcium phosphates and/or carbonates) for bone substitution applications which have been designed and developed in our laboratory (CIRIMAT, Phosphates, Pharmacotechnics, Biomaterials team – PPB). We aim to initiate this approach by leveraging the team's strong expertise in the physico-chemistry, formulation, and functionalization of mineral and composite bone cements, as well as the more recently developed know-how in freeze-casting processing within the PPB group. On one hand, recent work has focused on the fabrication and fine characterization of macroporous scaffolds produced via freeze-casting from non-reactive suspensions [17,18]; on the other hand, various mineral and composite cement formulations have been developed and studied in our group for over two decades [19,20,21].

The PhD thesis work will include:

• Studying the freezing behavior of reactive pastes,
• Fabrication of microporous composite scaffolds,
• Investigation of mechanical properties and degradation in acellular and cellular environments.

Some aspects of the work will be carried out in collaboration with other laboratories (in vitro cell studies, mechanical property evaluation).

References (in bold those of the PPB team):

1. Rey, C., et al., Physico-chemical properties of nanocrystalline apatites: Implications for biominerals and biomaterials. Materials Science and Engineering: C, 2007. 27(2): p. 198-205.

2. Gutermann, L., S. Roy, and T. Bégué, Synthetic bone substitutes: what specificities? Journal de Pharmacie Clinique, 2013. 32(2): p. 79-87.

3. Dorozhkin, S.V., Calcium orthophosphates as bioceramics: state of the art. Journal of functional Biomaterials, 2010. 1(1): p. 22-107.

4. Brouillet, F. et al. Biomimetic Apatite-Based Composite Materials Obtained by Spark Plasma Sintering (SPS): Physicochemical and Mechanical Characterizations. Journal of Materials Science: Materials in Medicine 2015 26(8): p.  1‑11.

5. Jacquart S, et al, Mechanical properties of self-setting composites: influence of the carboxymethylcellulose content and hydration state, J Mater Sci (2016) 51:4296-4305. DOI 10.1007/s10853-016-9739-4

6. Bose, S. and S. Tarafder, Calcium phosphate ceramic systems in growth factor and drug delivery for bone tissue engineering: a review. Acta biomaterialia, 2012. 8(4): p. 1401-1421.

7. Pascaud, P., et al., Interaction between a bisphosphonate, tiludronate, and biomimetic nanocrystalline apatites. Langmuir, 2013. 29: p. 2224-2232.

8. Iafisco, M., et al., Superparamagnetic iron-doped nanocrystalline apatite as a delivery system for doxorubicin. Journal of Materials Chemistry B, 2016. 4(1): p. 57-70.

9. Grossin, D. et al., Biomimetic Apatite Sintered at Very Low Temperature by Spark Plasma Sintering: Physico-Chemistry and Microstructure Aspects. Acta Biomaterialia 2010 6(2): p. 577‑85.

10. Kergourlay E. et al. First Cold Spraying of Carbonated Biomimetic Nanocrystalline Apatite on Ti6Al4V: Physical–Chemical, Microstructural, and Preliminary Mechanical Characterizations. Advanced Engineering Materials 2016 18(4): p. 496‑500.

11. Combes C. et al. Calcium carbonate-calcium phosphate mixed cement compositions for bone reconstruction, J Biomed Mater Res A. 2006, 79:318-328

12. Combes C. et al. Preparation, physical-chemical characterisation and cytocompatibility of calcium carbonate cements, Biomaterials 2006;27:1945-1954

13. Zhang H. et al. Enhanced compressive strength and in vitro degradation of porous pectin/ calcium phosphate cement scaffolds by freeze casting without sintered, Journal of Materials Research and Technology 34 (2025) 125–135.

14. Yang D. et al.  Effects of heat-dry curing temperature on porous silicate cement membranes fabricated by the coupling process of freeze casting and heat-dry curing, Ceramics International 50 (2024) 5411–5423

15. Gao K. et al. High-strength and multi-functional gypsum with unidirectionally porous architecture mimicking wood, Chemical Engineering Journal Advances 7 (2021) 100114

16. P. Navarrete-Segado, Masked Stereolithography of Hydroxyapatite Bioceramic Scaffolds: From Powder Tailoring to Evaluation of 3D Printed Parts Properties. Open Ceramics 2022 9: p. 100235

17. Merle M. et al. Freeze-Cast Composites of Alginate/Pyrophosphate-Stabilized Amorphous Calcium Carbonate: From the Nanoscale Structuration to the Macroscopic Properties. ACS Biomater. Sci. Eng. 2025, 11, 1198–1211

18. Lagarrigue P. et al. Poly(D,L-lactide)-Grafted Bioactive Glass Nanoparticles: From Nanobricks to Freeze-Cast Scaffolds for Bone Substitution, ACS Appl. Nano Mater. 2022, 5, 5278−5291.

19. Noukrati H. et al. Injectability, microstructure and release properties of sodium fusidate-loaded apatitic cement as a local drug-delivery system, MAT SCI ENG C-MATER, 2016 59: p. 177-184

20. Jacquart S, et al, Injectable bone cement containing carboxymethyl cellulose microparticles as a silver delivery system able to reduce implant-associated infection risk, Acta Biomaterialia 2022, 145: p. 342-357

21. Toufik E. et al. On the physicochemical properties, setting chemical reaction, and in vitro bioactivity of aragonite–chitosan composite cement as a bone substitute, New J. Chem., 2023, 47, 2771

The thesis will be carried out within the Phosphates, Pharmacotechnie, Biomatériaux (PPB) team of CIRIMAT in Toulouse (https://cirimat.fr/).

The candidate must have or be in the process of completing a Master 2 research and/or engineering degree in the field(s) of Materials Science or Chemistry. He/she must have skills in inorganic synthesis, physico-chemical characterizations and shaping processes. Knowledge of materials for healthcare would be an additional asset. The candidate must be open-minded, enjoy experimental work and be able to work as part of a team. Excellent oral and written communication skills (in English or French) are necessary.