Synthetic Calcium Phosphate Ceramics for Treatment of Bone Fractures

Bone is a complex natural material with outstanding mechanical properties and remarkable self-healing capabilities. The mechanical strength is achieved by a complex structure of a mineral part comprising apatitic calcium phosphate crystals embedded in an organic matrix. Bone also contains several types of cells constantly replacing mature bone with new bone. These cells are able to seal fractures and fill gaps with new bone in case of structural damage. However, if a defect exceeds a critical size, surgery is necessary to fill the void with a spacer in order to prevent soft tissue from growing into the defect and delaying the healing process. The spacers, also known as bone grafts, can either be made of fresh bone from the patient, of processed bone from donor organisms, or of synthetic materials chemically similar to the mineral part of bone. Synthetic bone void fillers are also known as bone graft substitutes. This review aims at explaining the biological and chemical background that lead to the development of synthetic bone graft substitutes and gives an overview of the current state of development. It also highlights the multidisciplinary nature of biomaterials research, which combines cell biology and medicine with chemistry, mineralogy, crystallography, and mechanical engineering

Propriétés physico-chimiques et ostéogéniques d'un biociment hydraulique à base de phosphates de calcium

Biocements made from β-TCP - H3PO4 - H2O and β-TCP - MCPM - H2O mixtures were studied in order to obtain a better control of their setting time and mechanical strength (β-TCP = Ca3(PO4)2; MCPM = Ca(H2PO4)2.H2O). The effects of factors like the purity of the β-TCP powder, its particle size distribution, the carnet composition or the presence of additives were investigated. More fundamental studies were also done on the reactions controlling the setting time, i.e. β-TP dissolution and DCPD (CaHPO4.2H2O) precipitation. The influence of additives on the kinetics of these controlling reactions were studied in order to establish how they influenced the setting time. To complete these experiments, cements made from β-TCP - MCPM - CSH - H2O mixtures were implanted in rabbit tibias (CSH = CaSO4.l/2H2O). The aging behavior in vivo and in vitro were compared. Results show that many factors affect the physico-chemical properties of the cements, particularly setting time and tensile strength. However, these factors have only a very limited number of pathways in which they can act. For example, setting time can only change when either β-TCP dissolution rate, DCPD germination rate or interparticular free volume are modified. Tensile strength only depends on DCPD weight fraction (binder for β-TCP powder), porosity and microstructure. Sulfate, pyrophosphate and citrate ions delay the cement's setting time in the following order: sulfate < citrate < pyrophosphate. These three ions inhibit DCPD crystal growth in the same order. Therefore, these results suggest that all the ions which inhibit DCPD crystal growth are potential setting time delaying additives. The concentration range in which sulfate ions act on setting time is limited between 0 and 0.1 M; beyond this concentration sulfate ions precipitate as CSD (CaSO4.2H2O). As DCPD and CSD structures are nearly identical, the presence of CSD crystals speeds up the setting reaction by acting as seeds for DCPD crystals. This phenomenon provokes a decrease in the setting time and a refinement of the microstructure with a consequent increase in the tensile strength. Accurate control of the cement composition is very important, i.e. volume and concentration of the phosphoric acid solution. Results show that an excess of phosphoric acid provokes the recrystallization of DCPD into DCP, a process which strongly decreases tensile strength. A modification of the microstructure is also observed when initial β-TCP specific surface area is changed. An increase in the surface area gives an increase in the tensile strength and a decrease in the setting time. In our experiments, a fivefold increase of specific surface area decreases the setting time by a factor of three and doubles the tensile strength. These results show that β-TCP particle size distribution has a very strong effect on the physico-chemical properties of our cements. The comparison between in vitro and in vivo tests prove that in vivo results cannot be anticipated by in vitro experiments. However, in vivo results are extremely positive: our cement is biocompatible, bioresorbable and osteoconductive. These results show that after one month, our cements are closely bonded to living bone, and after four months, our cements are nearly completely resorbed and replaced by new bone (except for dense and large β-TCP particles)

Osteoinduction and osteoimmunology: Emerging concepts.

The recognition and importance of immune cells during bone regeneration, including around bone biomaterials, has led to the development of an entire field termed "osteoimmunology," which focuses on the connection and interplay between the skeletal system and immune cells. Most studies have focused on the "osteogenic" capacity of various types of bone biomaterials, and much less focus has been placed on immune cells despite being the first cell type in contact with implantable devices. Thus, the amount of literature generated to date on this topic makes it challenging to extract needed information. This review article serves as a guide highlighting advancements made in the field of osteoimmunology emphasizing the role of the osteoimmunomodulatory properties of biomaterials and their impact on osteoinduction. First, the various immune cell types involved in bone biomaterial integration are discussed, including the prominent role of osteal macrophages (OsteoMacs) during bone regeneration. Thereafter, key biomaterial properties, including topography, wettability, surface charge, and adsorption of cytokines, growth factors, ions, and other bioactive molecules, are discussed in terms of their impact on immune responses. These findings highlight and recognize the importance of the immune system and osteoimmunology, leading to a shift in the traditional models used to understand and evaluate biomaterials for bone regeneration

In Vitro Ceramic Scaffold Mineralization: Comparison Between Histological and Micro-Computed Tomographical Analysis

The porous structure of beta-tricalcium phosphate (β-TCP) scaffolds was assessed by conventional histomorphometry and micro-computed tomography (micro-CT) to evaluate the substitutability of time-consuming histomorphometry by rapid micro-CT. Extracellular matrix mineralization on human mesenchymal stem cell seeded β-TCP scaffolds was scanned by means of micro-CT after 6weeks in cultivation and evaluated morphometrically. For the histomorphometric analysis, undecalcified sections were prepared in the mediosagittal plane of the cylindrical tissue-engineered constructs. The sections were scanned at a nominal resolution of 8μm and stained with von Kossa and Toluidine Blue. Pores were analyzed with both methods for morphometrical parameters such as horizontal/vertical diameter and pore/mineralized tissue area. Results showed highly significant correlations between histomorphometry and micro-CT for pore horizontal length (r=0.95), pore vertical length (r=0.96), pore area (r=0.97), and mineralized tissue area (r=0.82). Mean percentage differences between histomorphometry and micro-CT measurements ranged from 1.4% (pore vertical diameter) to 14.0% (area of mineralized tissue). With its high image precision, micro-CT qualifies as an additional tool for endpoint evaluation measurements of mineralized tissue development within tissue-engineered constructs also in ceramic scaffold

Bisphosphonates reduce biomaterial turnover in healing of critical-size rat femoral defects.

Treatment of osteoporotic patients with bisphosphonates (BPs) preserves bone mass and microarchitecture. The high prescription rate of the drugs brings about increases in the numbers of fractures and bone defects requiring surgical interventions in these patients. Currently, critical-size defects are filled with biomaterials and healing is supported with bone morphogenetic proteins (BMP). It is hypothesized that BPs interfere with biomaterial turnover during BMP-supported repair of defects filled with β-tricalcium phosphate (βTCP) ceramics. To test this hypothesis, retired breeder rats were ovariectomized ( OVX). After 8 weeks, treatment with alendronate (ALN) commenced. Five weeks later, 6 mm diaphyseal femoral defects were applied and stabilized with locking plates. βTCP cylinders loaded with 1 μg and 10 μg BMP2, 10 μg L51P, an inhibitor of BMP antagonists and 1 μg BMP2/10 μg L51P were fitted into the defects. Femora were collected 16 weeks post-implantation. In groups receiving calcium phosphate implants loaded with 10 μg BMP2 and 1 μg BMP2/10 μg L51P, the volume of bone was increased and βTCP was decreased compared to groups receiving implants with 1 μg BMP2 and 10 μg L51P. Treatment of animals with ALN caused a decrease in βTCP turnover. The results corroborate the synergistic effects of BMP2 and L51P on bone augmentation. Administration of ALN caused a reduction in implant turnover, demonstrating the dependence of βTCP removal on osteoclast activity, rather than on chemical solubility. Based on these data, it is suggested that in patients treated with BPs, healing of biomaterial-filled bone defects may be impaired because of the failure to remove the implant and its replacement by authentic bone