Controlled release properties and final macroporosity of a pectin microspheres–calcium phosphate composite bone cement

The use of calcium phosphate cements (CPC) is restricted by their lack of macroporosity and poor drug release properties. To overcome these two limitations, incorporating degradable polymer microparticles into CPC is an attractive option, as polymer microparticles could help to control drug release and induce macroporosity after degradation. Although few authors have yet tested synthetic polymers, the potentiality of polysaccharides’ assuming this role has never been explored. Low-methoxy amidated pectins (LMAP) constitute valuable candidates because of their biocompatibility and ionic and pH sensitivity. In this study, the potentiality of a LMAP with a degree of esterification (DE) of 30 and a degree of amidation (DA) of 19 was explored. The aim of this study was to explore the influence of LMAP microspheres within the composite on the cement properties, drug release ability and final macroporosity after microspheres degradation. Three LMAP incorporation ratios, 2%, 4% and 6% w/w were tested, and ibuprofen was chosen as the model drug. In comparison with the CPC reference, the resulting composites presented reduced setting times and lowered the mechanical properties, which remained acceptable for an implantation in moderate-stress-bearing locations. Sustained release of ibuprofen was obtained on at least 45 days, and release rates were found to be controlled by the LMAP ratio, which modulated drug diffusion. After 4 months of degradation study, the resulting CPC appeared macroporous, with a maximum macroporosity of nearly 30% for the highest LMAP incorporation ratio, and interconnectivity between pores could be observed. In conclusion, LMAP appear as interesting candidates to generate macroporous bone cements with tailored release properties and macroporosity by adjusting the pectin content within the composites

Control of the injectability of calcium carbonate-calcium phosphate mixed cements for bone reconstruction

The purpose of this study was to improve injectability and cohesiveness of original calcium carbonate-calcium phosphate mixed (CaCO3-CaP) self-setting paste for bone filling and repair. With this aim in view dry co-grinding was implemented on the solid phase (vaterite and dicalcium phosphate dihydrate) of this cement. A protocol designed to quantify paste injectability has been established and pointed out the synergistic positive effects of solid phase co-grinding treatment on injectability, cohesiveness and setting time of the paste. The improvement of these properties are related to close and homogeneous association of reactive powders and to the decrease of specific surface area favoring the powders hydration process enhancing setting reaction rate. In addition, the particle size decrease and morphology modification improved flowability of the paste which results in a low and constant (320 g) force level to extrude the paste

Alginate Scaffolds for Mesenchymal Stem Cell Cardiac Therapy: Influence of Alginate Composition

Despite the success of alginate scaffolds and mesenchymal stem cells (MSCs) therapy in cardiac failure treatment, the impact of the physicochemical environment provided by alginate matrices on cell behavior has never been investigated. The purpose of this work was double: to determine the alginate composition influence on (1) encapsulated rat MSC viability, paracrine activity, and phenotype in vitro and (2) cardiac implantability and in vivo biocompatibility of patch shape scaffolds. Two alginates, differing in composition and thus presenting different mechanical properties when hydrogels, were characterized. In both cases, encapsulated MSC viability was maintained at around 75%, and their secretion characteristics were retained 28 days postencapsulation. In vivo study revealed a high cardiac compatibility of the tested alginates: cardiac parameters were maintained, and rats did not present any sign of infection. Moreover, explanted hydrogels appeared surrounded by a vascularized tissue. However, scaffold implantability was highly dependent on alginate composition. G-type alginate patches, presenting higher elastic and Young moduli than M-type alginate patches, showed a better implantation easiness and were the only ones that maintained their shape and morphology in vivo. As a consequence of alginate chemical composition and resulting hydrogel structuration, G-type alginate hydrogels appear to be more adapted for cardiac implantation

Optimization of spray-dried hyaluronic acid microspheres to formulate drug-loaded bone substitute materials

Wepresent here our first results concerning the evaluation of hyaluronic acid (HA) as a candidate to formulate an organic–mineral cement with sustained release properties. Incorporating drug-loaded microspheres in mineral bone cements is an alternative strategy to improve their ability as drug delivery materials. To synthesize microspheres according to a reproducible process and control at the same time their morphology and their encapsulation efficiency is one of the main challenges of the conception of such drug-loaded bone substitute. In this context, we investigated the potentialities of two HA, differing by theirmolecular weight, to form microspheres by a spray-drying technique. Erythrosin B (EB) was encapsulated as a model drug and spray-drying process conditionswere optimized. To performthis, the rheological behavior and viscosity of HA solutions have been related to their spray-drying ability, and then to the resulting microparticles morphological properties and size distribution. Reproducible microspheres, answering to the requirements in terms of size and encapsulation efficiency, have been obtained from both HA. However the HA exhibiting the lowest molecular weight, HA600, led to smaller microparticles, with a higher polydispersity index. Their swelling ability, related to their stability upon rehydration, also appeared reduced. In this context, HA850, with the highest molecular weight, was selected and the possibility to modulate drug release by HA850 microspheres incorporation into a mineral cement was explored. EB release kinetics from HA microspheres, HA microspheres loaded cement and reference cement were followed at 37 °C, in Tris buffer at pH 7.4, using European Pharmacopoeia flow-through cells. Results showed that HA microspheres incorporation into a mineral cement permitted to modify the cement drug release profile and led to a sustained release

Rheological properties of calcium carbonate self-setting injectable paste

With the development of minimally invasive surgical techniques, there is growing interest in the research and development of injectable biomaterials with controlled rheological properties. In this context, the rheological properties and injectability characteristics of an original CaCO3 self-setting paste have been investigated. Two complementary rheometrical procedures have been established using a controlled stress rheometer to follow the structure build-up at rest or during gentle mixing and/or handling on the one hand, and the likely shear-induced breakdown of this structure at 25 or 35 C on the other. The data obtained clearly show the influence of temperature on the development of a cement microstructure during setting, in all cases leading to a microporous cement made of an entangled network of aragonite-CaCO3 needle-like crystals. Linear viscoelastic measurements arriving from an oscillatory shear at low deformation showed a progressive increase in the viscous modulus (G0 0) during paste setting, which is enhanced by an increase in temperature. In addition, steady shear measurements revealed the shear-thinning behaviour of this self-setting paste over an extended period after paste preparation and its ability to re-build through progressive paste setting at rest. The shear-thinning behaviour of this self-setting system was confirmed using the injectability system and a procedure we designed. The force needed to extrude a homogeneous and continuous column of paste decreases strongly upon injection and reaches a weight level to apply on the syringe piston around 2.5 kg, revealing the ease of injection of this CaCO3 self-setting paste

Soy Protein Microparticles for Enhanced Oral Ibuprofen Delivery: Preparation, Characterization, and In Vitro Release Evaluation

International audienceThe objective of this work was to evaluate soy protein isolate (SPI) and acylated soy protein (SPA) as spray-drying encapsulation carriers for oral pharmaceutical applications. SPI acylation was performed by the Schotten–Baumann reaction. SPA, with an acylation rate of 41%, displayed a decrease in solubility in acidic conditions, whereas its solubility was unaffected by basic conditions. The drug encapsulation capacities of both SPI and SPA were tested with ibuprofen (IBU) as a model poorly soluble drug. IBU-SPI and IBU-SPA particles were obtained by spray-drying under eco-friendly conditions. Yields of 70 to 87% and microencapsulation efficiencies exceeding 80% were attained for an IBU content of 20 to 40% w/w, confirming the excellent microencapsulation properties of SPI and the suitability of the chemical modification. The in vitro release kinetics of IBU were studied in simulated gastrointestinal conditions (pH 1.2 and pH 6.8, 37°C). pH-sensitive release patterns were observed, with an optimized low rate of release in simulated gastric fluid for SPA formulations, and a rapid and complete release in simulated intestinal fluid for both formulations, due to the optimal pattern of pH-dependent solubility for SPA and the molecular dispersion of IBU in soy protein. These results demonstrate that SPI and SPA are relevant for the development of pH-sensitive drug delivery systems for the oral route

Factors influencing the erosion rate and the drug release kinetics from organogels designed as matrices for oral controlled release of a hydrophobic drug

This article proposes solid-like systems from sunflower oil structured with a fibrillar network built by the assembly of 12-hydroxystearic acid (12-HSA), a gelator molecule for an oil phase. The resulting organogels were studied as oral controlled release formulations for a lipophilic drug, Efavirenz (EFV), dissolved in the oil. The effects of the gelator concentration on the thermal properties of the organogels were studied by Differential Scanning Calorimetry (DSC) and showed that drug incorporation did not change the sol–gel–sol transitions. The erosion and drug release kinetics from organogels under conventional (filling gelatin capsules) or multiparticulate (beads obtained by prilling) dosage forms were measured in simulated gastric and intestinal fluids. EFV release profiles were analyzed using model-dependent (curve-fitting) and independent approaches (Dissolution Efficiency DE). Korsmeyer–Peppas was the best fitting release kinetic model based on the goodness of fit, revealing a release mechanism from organogels loaded with EFV different from the simple drug diffusion release mechanism obtained from oily formulations. From organogels, EFV probably diffuses through an outer gel layer that erodes releasing oil droplets containing dissolved EFV into the aqueous medium

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

Elaboration and evaluation of alginate foam scaffolds for soft tissue engineering

Controlling microarchitecture in polymer scaffolds is a priority in material design for soft tissue applications. This paper reports for the first time the elaboration of alginate foam-based scaffolds for mesenchymal stem cell (MSC) delivery and a comparative study of various surfactants on the final device performance. The use of surfactants permitted to obtain highly interconnected porous scaffolds with tunable pore size on surface and in cross-section. Their mechanical properties in compression appeared to be adapted to soft tissue engineering. Scaffold structures could sustain MSC proliferation over 14 days. Paracrine activity of scaffold-seeded MSCs varied with the scaffold structure and growth factors release was globally improved in comparison with control alginate scaffolds. Our results provide evidence that exploiting different surfactant types for alginate foam preparation could be an original method to obtain biocompatible scaffolds with tunable architecture for soft tissue engineering

Spray-Dried Succinylated Soy Protein Microparticles for Oral Ibuprofen Delivery

The potential value of succinylated soy protein (SPS) as a wall material for the encapsulation of ibuprofen (IBU), a model hydrophobic drug, by spray-drying was investigated. A succinylation rate of 93% was obtained for soy protein isolate, with a molar ratio of 1/1.5 (NH2/succinic anhydride). The solubility profile at 37°C showed that this chemical modification decreased the solubility of the protein below its isoelectric point, whereas solubility increased in alkaline conditions. Various SPS/IBU ratios (90/10, 80/20, and 60/40) were studied and compared with the same ratio of soy protein isolate (SPI/IBU). High encapsulation efficiency was achieved (91–95%). Microparticles were spherical and between 4 and 8 μm in diameter. The spray-drying of protein/IBU solutions appeared to be beneficial, as it resulted in an amorphous solid dispersion of IBU within the microparticles, coupled with an increase in the thermal stability of IBU. In vitro release was evaluated in acidic (pH 1.2 in the presence of pepsin) and neutral (pH 6.8) conditions similar to those in the gastrointestinal (GI) tract. IBU was released significantly more slowly at pH 1.2, for both proteins. However, this slowing was particularly marked for SPS, for which rapid (within 2 h) and complete release was observed at pH 6.8. These results validate the hypothesis that SPS is suitable for use as a coating material for hydrophobic active pharmaceutical ingredients (APIs) due to its pH sensitivity, which should delay IBU release in the gastrointestinal tract