Clinical Research Directory

Burosumab and 1-25 (OH) Vitamin D on Human Osteoblasts

FGF23 is the cornerstone of phosphate / calcium / vitamin D metabolism: it is synthesized mainly by osteocytes and acts as a phosphaturizing agent, inhibitor of dihydroxyvitamin D, and inhibitor of synthesis and secretion of PTH in most tissues. The specific role of FGF23 on bone has yet to be demonstrated. In osteoblasts, overexpression of FGF23 in vitro suppresses not only osteoblastic differentiation but also the synthesis of the mineralized matrix independently of its systemic action on phosphate metabolism. In osteoblasts, FGF23 also regulates the secretion of osteopontin by directly suppressing transcription of alkaline phosphatase. In some diseases such as hypophosphatemic rickets (HR), the direct role of FGF23 on bone has not yet been studied to our knowledge, whereas these genetic hypophosphatemias are secondary to overexpression of FGF23, whether an activating mutation of FGF23 or inhibitory mutations of its inhibitors (DMP1 and PHEX). However, patients with X-linked hypophosphatemic rickets (XLH) have higher circulating FGF23 levels than healthy controls and these levels are higher in treated patients. Management of XLH consists primarily of correcting the native vitamin D defect by prescribing active vitamin D analogs as well as phosphate supplementation to improve bone mineralization and decrease dental complications, growth, and bone deformities. Recently, a new therapeutic option has been developed for XLH, burosumab, a human monoclonal antibody that binds and inhibits FGF23 activity. The use of burosumab is currently authorized in France in some pediatric patients with severe forms of XLH. Independently of the indirect bone effects of phosphate correction and vitamin D levels, the direct role of burosumab on bone cells has never been studied. The objective of this project is to study the osteoblastic biology of patients with RH compared to control patients, and to evaluate the direct impact of the treatments used in this pathology on human osteoblasts.

Hemodynamic Monitoring During Craniosynostosis Surgery: Comparing Traditional and Newer Technology Monitors (CRASY-PRAM)

Hemodynamic evaluation during pediatric anesthesia is essential to care management. Intraoperative cardiovascular instability is frequent in major surgeries, and appropriate monitoring is necessary to ensure safe anesthetic conduction and promptly detect changes in blood pressure, cardiac output, blood volume, and organ perfusion. In this context, advanced hemodynamic monitoring, continuous measuring, and estimating various parameters can allow a more specific hemodynamic profile and help identify the causal mechanisms of its variability. Moreover, the reference ranges of hemodynamic values in different pediatric ages and how to best monitor hemodynamic status in pediatrics are still debated. Surgical treatment of craniosynostosis is usually performed at an early age, between 3 and 8 months of age. The operation is burdened by a high risk of hemodynamic instability related mainly, but not only, to potential substantial hemorrhagic losses. This study aims to characterize the hemodynamic events occurring during corrective craniosynostosis surgery, recorded simultaneously with standard monitoring and Pressure Recording Analytic Method (PRAM), and to analyze the paired measurements.

Functionalized Bioink Delivering Biomolecules for the Treatment of Craniofacial Diseases

The study aims to address the challenges of craniofacial bone reconstruction in pediatric and adult patients affected by congenital craniofacial malformations (i.e. craniosynostosis), trauma or tumors, by developing an innovative biohybrid material with tunable rheological properties, serving as a sealing agent and defect filler. Craniectomy/craniotomy procedures often leave bone defects that require cranioplasty to protect the underlying dura mater and the brain from physical insults. Reconstruction of the viscerocranial skeleton poses additional challanges, due to the complex anatomy of the facial skull and significant esthetic and functional demands on its reconstruction. The study plans to develop a mouldable biosynthetic gelatin-methacrylamide (GelMA)-based hydrogel complexed with functionalized Poly (lactic-co-glycolic acid) (PLGA) nanoparticles for drug delivery. Osteoprogenitors cells (including mesenchymal stromal cells/osteoblasts and monocytes/osteoclasts) will be isolated from bone tissue fragments of enrolled patients and peripheral blood sample, respectively, to obtain 2D and 3D cultures mimicking the in vivo bone environment. High-throughput profiling of patients' samples will identify druggable targets for the bioactive compounds to be released by the bioink. In vitro validation will involve osteoprogenitor co-cultures derived from patients to assess uptake, release dynamics, biocompatibility, immunogenicity, and therapeutic effects of the developed complex. The final goal will be to develop a pre-prototype tissue engineering biocomposite for craniofacial bone reconstruction.

EPBONF : Evaluation of the Safety and Effectiveness of a Medical Device Aimed at Guiding Orbito-naso-frontal Band Surgery, for the Treatment of Craniostenoses

Craniostenosis is a congenital disorder caused by early fusion of the cranial sutures between the skull bones, resulting in orbito-naso-frontal deformities. The damage is primarily aesthetic, but intracranial hypertension may also be observed. The treatment of craniostenosis involves surgery, to restore harmonious growth between the skull bones and the brain, and proper development of the latter. There are various surgical techniques for correction, based on remodeling of the upper forehead and the orbito-naso-frontal band (BONF). However, BONF reshaping is difficult to tailor to each individual child. In most cases, the surgeon performs the reshaping "freehand", without a template. The result is therefore subject to the surgeon's experience and judgment. A surgical instrument (template) has been developed to guide the surgeon in the ideal reshaping of the BONF in patients with anterior craniostenosis (anterior plagiocephaly and trigonocephaly), according to each child's specific morphology. The aim of EPBONF research is to evaluate the benefits of using this template on the symmetry and angle of the BONF.