CE17 - Recherche translationnelle en santé

3D printed customized composite cement for jaw repair – GIJAW

3D printed customized composite cement for jaw repair

In children, the interrupted bony loss (IBL) of jaws is mainly caused by malformation as cleft lip or palate at the maxilla. Jaw bone repair is very challenging due to some clinical specifications (complex shape of the defect, risk of infection in oral cavity, specific mechanical properties). Positive functional and aesthetical outcomes can be difficult to achieve. Autologous bone grafting, is the “gold standard” but this can add significant morbidities such as scarring and chronic pain.

General objective of GIJAW

Recently, thanks to 3D printed technology, we developed a customized calcium phosphate implant presenting interesting properties for bone repair. The morbidity of the commonly used procedure would be relieve thanks to the development of a customized biomaterials. Tridimensional (3D) printing is considered as a ground-breaking technology especially in surgery. This recent innovation could help to obtain a 3D printable cement with biomimetic properties able to replace bone graft. A project supported by BIOREGATE project, Région Pays de Loire (3D REFENTINE) allowed us to obtain some preliminary results regarding the challenging formulations we want to develop. Different composite calcium deficient hydroxyapatite cement close to the mineral part and cristallinity of bone has been tested. Chitosan and/or hyaluronic acid have been added to the cement for the printability. These two macromolecules are known to be bioresorbable. Moreover, chitosan offers antimicrobial properties of special interest in oral and nasal cavities. Indeed, in cases of a close relation of the implant to the mucosae of the upper airways (e.g. maxillary sinus) and the oral cavity, the risk of implant exposure and wound infection would be a real risk. This project aims to develop a cement : sterilizable, certified, resorbable regarding the context of lip and palate for promote bone regeneration, not brittle with good ductility making it user-friendly by surgeon, biocompatible, bioactive for a better cell adhesion and osseointegration, with a customized shape for a better bone defect filling. A clinical dog model which are dogs born with alveolar cleft, will allow us to establish a proof of concept. A clinical study is expected for in light of these results.

To meet the requirements of these clinical applications, we propose a 3-year project divided in 1 organizational work package (WP0) and 3 experimental WPs (WP1 to WP3):
- WP1: To elaborate 3D printed customized composite cement (Bio ink)
- WP2: To validate in vitro and in vivo different bio ink formulations
- WP3: To assess the optimal bio ink in a clinical model of cleft alveolus in dog.

The aim of WP1 was also to improve formulations and explore other 3D manufacturing methods.
Physico-chemical characterization has been performed as follows: rheology (Rheometer Haake, RS 300 and Mars) and injection methods with texture analyser (TAXT2 et TAHD; Stable Micro system) to characterize the bio ink in terms of flow properties and injectability. Bio inks formulations and 3D complex constructs have been printed and characterizations was done. We obtained implant with sufficient ductility, to be manipulated easily and correctly inserted into a complex bone defect. In this way, different formulations have been developed to improve ductility properties and other specific properties to increase safety and bioactivity of the constructs. One patent is published (EP3896048A1). In vivo evaluation of the first formulations covered by patent EP3896048A1 has been performed using a 5 mm calvarial defect in rat model. All scaffolds supported bone ingrowth (with or without total bone marrow addition). Scaffolds biodegradation could be modulated through scaffold composition.
We proposed thanks to Oniris partner, to the master of dogs with this cleft lip and palate, to do personalized 3D printed implant and to repair the deformity. Currently, we implanted 2 dogs and 4 are planed within 2 months. Tomography of the first dog is very encouraging showing bone ingrowth in pores of the implant and the tooth appears in the puppy's mouth that is a sign of functional success. Biopsy is planned and will show us the histological status of the bone healing.

The next steps are to keep on the recruitment and the clinical reconstruction of dog patients and in parallel the rat calvaria study.

1. Application of a Cryo-FIB-SEM-µRaman Instrument to Probe the Depth of Vitreous Ice in a Frozen Sample, Analytical Chemistry (2022)
2. The combined use of SEM, EPMA and FIB for the characterization of novel biomaterials for bone regeneration, Microscopy and Miscroanalysis (2021)
3. Probing the microporosity and 3D spatial distribution of calcium phosphate cement /hydrogel mixtures using FIB/SEM at cryogenic temperatures, submitted to Biomaterials Advances (2022)
4, Injectable macromolecules-based calcium phosphate bone substitutes, Material Advances (2022)

5, Brevet : EP3896048A1

In children, the interrupted bony loss (IBL) of jaws is mainly caused by malformation as cleft lip or palate at the maxilla, and tumor removal in mandible. Jaw bone repair is very challenging due to some clinical specifications (complex shape of the defect, risk of infection in oral cavity, specific mechanical properties). Positive functional and aesthetical outcomes can be difficult to achieve. Furthermore, facial growth can be significantly affected in cases without reconstruction. For maxillary critical sized defects, autologous bone grafting, mostly taken on tibial bone, is the “gold standard” but this can add significant morbidities such as scarring, lameness, and chronic pain. To avoid these disorders, one of the current research directions in bone tissue engineering (BTI) is to make bone tissue in vitro or in vivo with stem cells, growth factors and biomaterials. We have established a BTI procedure that is efficient, reproducible, minimally invasive, and easily implemented. This intraoperative procedure combined a biphasic calcium phosphate biomaterial (BCP) to autologous bone marrow (ABM). It has been compared to several BTI procedures in calvaria bone defect models in rats with promising results. However, the mixture of BCP and ABM did not allow the control of internal and external scaffold architecture, and lacked repairing complex bone defects. Recently, thanks to 3D printed technology, we developed a customized calcium phosphate implant presenting interesting properties for bone repair. The morbidity of the commonly used procedure would be relieve thanks to the development of a customized biomaterials. Tridimensional (3D) printing is considered as a ground-breaking technology especially in surgery. This recent innovation could help to obtain a 3D printable cement with biomimetic properties able to replace bone graft. A project supported by BIOREGATE project, Région Pays de Loire (3D REFENTINE) allowed us to obtain some preliminary results regarding the challenging formulations we want to develop. Different composite calcium deficient hydroxyapatite cement close to the mineral part and cristallinity of bone has been tested. Chitosan and/or hyaluronic acid have been added to the cement for the printability. These two macromolecules are known to be bioresorbable. Moreover, chitosan offers antimicrobial properties of special interest in oral and nasal cavities. Indeed, in cases of a close relation of the implant to the mucosae of the upper airways (e.g. maxillary sinus) and the oral cavity, the risk of implant exposure and wound infection would be a real risk. This project aims to develop a cement : sterilizable, certified, resorbable regarding the context of lip and palate for promote bone regeneration, not brittle with good ductility making it user-friendly by surgeon, biocompatible, bioactive for a better cell adhesion and osseointegration, with a customized shape for a better bone defect filling. A clinical dog model which are dogs born with alveolar cleft, will allow us to establish a proof of concept. A clinical study is expected for in light of these results.
To meet the requirements of these clinical applications, we propose a 3-year project divided in 1 organizational work package (WP0) and 3 experimental WPs (WP1 to WP3):
- WP1: To elaborate 3D printed customized composite cement (3DPC3)
- WP2: To validate in vitro and in vivo different 3DPC3 formulations
- WP3: To assess the optimal 3DPC3 in a clinical model of cleft alveolus in dog.

Project coordinator

Monsieur Pierre CORRE (Regenerative Medicine and Skeleton - Université de Nantes)

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

RMeS - Université de Nantes Regenerative Medicine and Skeleton - Université de Nantes

Help of the ANR 343,980 euros
Beginning and duration of the scientific project: October 2020 - 36 Months

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