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Bone is a natural mineral-organic nanocomposite protecting internal organs and allowing mobility. Through the ages, numerous strategies have been developed for repairing bone defects and fixing fractures. Several generations of bone repair biomaterials have been proposed, either based on metals, ceramics, glasses, or polymers, depending on the clinical need, the maturity of technologies, and knowledge of the natural constitution of the bone tissue to be repaired. The global trend in bone implant research is shifting toward osteointegrative, bioactive and possibly stimuli-responsive biomaterials and, where possible, resorbable implants that actively promote the regeneration of natural bone tissue. In this mini-review, the fundamentals of bone healing materials and clinical challenges are summarized and commented on with regard to progressing scientific discoveries. The main types of bone-healing materials are then reviewed, and their specific relevance to the field is reminded, with the citation of reference works. In the final part, we highlight the promise of hybrid organic-inorganic bioactive materials and the ongoing research activities toward the development of multifunctional or stimuli-responsive implants. This contribution is expected to serve as a commented introduction to the ever-progressing field of bone regeneration and highlight trends of future-oriented research.

Silicate-based bioactive glass nano/microspheres hold significant promise for bone substitution by facilitating osteointegration through the release of biologically active ions and the formation of a biomimetic apatite layer. Cu-doping enhances properties such as pro-angiogenic and antibacterial behavior. While sol-gel methods usually yield homogeneous spherical particles for pure silica or binary glasses, synthesizing poorly aggregated Cu-doped ternary glass nano/microparticles without a secondary CuO crystalline phase remains challenging. This article introduces an alternative method for fabricating Cu-doped ternary microparticles using sol-gel chemistry combined with spray-drying. The resulting microspheres exhibit well-defined, poorly aggregated particles with spherical shapes and diameters of a few microns. Copper primarily integrates into the microspheres as Cu 0 nanoparticles and as Cu 2+ within the amorphous network. This doping affects silica network connectivity, as calcium and phosphorus are preferentially distributed in the glass network (respectively as network modifiers and formers) or involved in amorphous calcium phosphate nano-domains depending on the doping rate. These differences affect the interaction with simulated body fluid. Network depolymerization, ion release (SiO 4 4- , Ca 2+ , PO 4 3- , Cu 2+ ), and apatite nanocrystal layer formation are impacted, as well as copper release. The latter is mainly provided by the copper involved in the silica network and not from metal nanoparticles, most of which remain in the microspheres after interaction. This understanding holds promising implications for potential therapeutic applications, offering possibilities for both short-term and long-term delivery of a tunable copper dose. STATEMENT OF SIGNIFICANCE: A novel methodology, scalable to industrial levels, enables the synthesis of copper-doped ternary bioactive glass microparticles by combining spray-drying and sol-gel chemistry. It provides precise control over the copper percentage in microspheres. This study explores the influence of synthesis conditions on the copper environment, notably Cu 0 and Cu 2+ ratios, characterized by EPR spectroscopy, an aspect poorly described for copper-doped bioactive glass. Additionally, copper indirectly affects silica network connectivity and calcium/phosphorus distribution, as revealed by SSNMR. Multiscale characterization illustrates how these features impact acellular degradation in simulated body fluid, highlighting the therapeutic potential for customizable copper dosing to address short- and long-term needs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

A large amount of research in orthopedic and maxillofacial domains is dedicated to the development of bioactive 3D scaffolds. This includes the search for highly resorbable compounds, capable of triggering cell activity and favoring bone regeneration. Considering the phosphocalcic nature of bone mineral, these aims can be achieved by the choice of amorphous calcium phosphates (ACPs). Because of their metastable property, these compounds are however to-date seldom used in bulk form. In this work, we used a non-conventional "cold sintering" approach based on ultrafast low-pressure RT compaction to successfully consolidate ACP pellets while preserving their amorphous nature (XRD). Complementary spectroscopic analyses (FTIR, Raman, solid-state NMR) and thermal analyses showed that the starting powder underwent slight physicochemical modifications, with a partial loss of water and local change in the HPO 4 2- ion environment. The creation of an open porous structure, which is especially adapted for non-load bearing bone defects, was also observed. Moreover, the pellets obtained exhibited sufficient mechanical resistance allowing for manipulation, surgical placement and eventual cutting/reshaping in the operation room. Three-dimensional porous scaffolds of cold-sintered reactive ACP, fabricated through this low-energy, ultrafast consolidation process, show promise toward the development of highly bioactive and tailorable biomaterials for bone regeneration, also permitting combinations with various thermosensitive drugs.

Biomimetic apatites exhibit a high reactivity allowing ion substitutions to modulate their in vivo response. We developed a novel approach combining several bioactive ions in a spatially controlled way in view of subsequent releases to address the sequence of events occurring after implantation, including potential microorganisms' colonization. Innovative micron-sized core-shell particles were designed with an external shell enriched with an antibacterial ion and an internal core substituted with a pro-angiogenic or osteogenic ion. After developing the proof of concept, two ions were particularly considered, Ag + in the outer shell and Cu 2+ in the inner core. In vitro evaluations confirmed the cytocompatibility through Ag-/Cu-substituting and the antibacterial properties provided by Ag + . Then, these multifunctional "smart" particles were embedded in a polymeric matrix by freeze-casting to prepare 3D porous scaffolds for bone engineering. This approach envisions the development of a new generation of scaffolds with tailored sequential properties for optimal bone regeneration.

In the challenging quest for a solution to reduce the risk of implant-associated infections in bone substitution surgery, the use of silver ions is promising regarding its broad spectrum on planktonic, sessile as well as multiresistant bacteria. In view of controlling its delivery in situ at the desired dose, we investigated its encapsulation in carboxymethyl cellulose (CMC) microparticles by spray-drying and included the latter in the formulation of a self-setting calcium phosphate bone cement. We implemented an original step-by-step methodology starting from the in vitro study of the antibacterial properties and cytotoxicity of two silver salts of different solubility in aqueous medium and then in the cement to determine the range of silver loading able to confer anti-biofilm and non-cytotoxic properties to the biomaterial. A dose-dependent efficiency of silver was demonstrated on the main species involved in bone-implant infection (S. aureus and S. epidermidis). Loading silver in microspheres instead of loading it directly inside the cement permitted to avoid undesired silver-cement interactions during setting and led to a faster release of silver, i.e. to a higher dose released within the first days combining anti-biofilm activity and preserved cytocompatibility. In addition, a combined interest of the introduction of about 10% (w/w) silver-loaded CMC microspheres in the cement formulation was demonstrated leading to a fully injectable and highly porous (77%) cement, showing a compressive strength analogous to cancellous bone. This injectable silver-loaded biomimetic composite cement formulation constitutes a versatile bone substitute material with tunable drug delivery properties, able to fight against bone implant associated infection. STATEMENT OF SIGNIFICANCE: This study is based on two innovative scientific aspects regarding the literature: i) Choice of silver ions as antibacterial agent combined with their way of incorporation: Carboxymethylcellulose has never been tested into bone cement to control its drug loading and release properties. ii) Methodology to formulate an antibacterial and injectable bone cement: original and multidisciplinary step-by-step methodology to first define, through (micro)biological tests on two silver salts with different solubilities, the targeted range of silver dose to include in carboxymethylcellulose microspheres and, then optimization of silver-loaded microparticles processing to fulfill requirements (encapsulation efficiency and size). The obtained fully injectable composite controls the early delivery of active dose of silver (from 3 h and over 2 weeks) able to fight against bone implant-associated infections., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

One major warning emerging during the first worldwide combat against healthcare-associated infections concerns the key role of the surface in the storage and transfer of the virus. Our study is based on the laser coating of surfaces with an inorganic/organic composite mixture of amorphous calcium phosphate-chitosan-tetracycline that is able to fight against infectious agents, but also capable of preserving its activity for a prolonged time, up to several days. The extended release in simulated fluids of the composite mixture containing the drug (tetracycline) was demonstrated by mass loss and UV-VIS investigations. The drug release profile from our composite coatings proceeds via two stages: an initial burst release (during the first hours), followed by a slower evolution active for the next 72 h, and probably more. Optimized coatings strongly inhibit the growth of tested bacteria ( Enterococcus faecalis and Escherichia coli ), while the drug incorporation has no impact on the in vitro composite's cytotoxicity, the coatings proving an excellent biocompatibility sustaining the normal development of MG63 bone-like cells. One may, therefore, consider that the proposed coatings' composition can open the prospective of a new generation of antimicrobial coatings for implants, but also for nosocomial and other large area contamination prevention.

In the field of bone regeneration, some clinical conditions require highly-resorbable, reactive bone substitutes to rapidly initiate tissue neo-formation. In this view, Amorphous Calcium Phosphates (ACP) appear as well suited bioceramics taking into account their high metastability. However, the metastability also leads to difficulties of sintering without transformation into crystalline compounds. In this work, various calcium phosphate samples (co)doped with carbonate (CO 3 2- ) and magnesium ions were synthesized by the double decomposition method in alkaline media using ammonium and potassium hydroxide solutions. The obtained amorphous powders possess an exceptionally-high carbonate content up to 18.3 wt%. Spark Plasma Sintering (SPS) at very low temperature (150 °C) was then utilized to consolidate initial powders with the view to preserve their amorphous character. The influence of the introduction of different apatite growth inhibitors such as carbonate (CO 3 2- ) and magnesium ions was studied. XRD and FTIR analyses revealed that sintered ceramics generally consisted in highly carbonated low-crystallinity apatites, which are expected to have higher solubility than conventional apatite-based systems. However, most interestingly, modulation of the doping conditions allowed us to retain, for the first time, the amorphous character of ACP powders after SPS. Such consolidated ACP compounds may now be considered as a new family of bioceramics with high metastability allowing the fast release of bioactive ions upon resorption.

Multifunctionalized biomaterials with enhanced bone antiresorptive properties were obtained through adsorption of a bisphosphonate, risedronate, on hydroxyapatite (HA) nanocrystals functionalized with zinc ions and polyethylenimine (PEI). Zn incorporation into the HA structure amounts to about 8 atom %, whereas the PEI content of the bifunctionalized material ZnHAPEIBP is about 5.9 wt %. The mechanism of adsorption and release of the bisphosphonate on ZnHAPEI is compared with that on ZnHA: risedronate adsorption isotherm on ZnHA is a Langmuir type, whereas the isotherm of adsorption on ZnHAPEI is better fitted with a Freundlich model and involved a higher amount of adsorbed risedronate. In vitro cell tests were carried out with a coculture model of osteoblasts and osteoclasts using a model simulating oxidative stress and consequent cellular senescence and osteoporosis by the addition of H 2 O 2 . The conditions utilized in the coculture model strongly affect osteoblast behavior. The results show that the composite materials allow an increase in osteoblast viability and recover impairment, revealing a novel characteristic of risedronate that is able to counteract the negative effects of oxidative stress when associated with differently functionalized samples. Both PEI and the bisphosphonate reduce osteoclast viability. Moreover, PEI, and even more risedronate, exerts an inhibitory effect on osteoclast activity.

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 (NH 2 /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.

The 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.

Bisphosphonates are widely employed drugs for the treatment of pathologies characterized by excessive bone resorption, and display a great affinity for apatitic supports. In this work we investigate how hydroxyapatite functionalization can influence the processes of adsorption and release of a bisphosphonate, namely risedronate. To this aim, pure hydroxyapatite (HA), hydroxyapatite with a partial substitution of Zn to Ca (ZnHA) and poly-ethylenimine-functionalized hydroxyapatite (HAPEI) were submitted to interaction with risedronate solution. The results indicate that the mechanisms of adsorption and release are greatly influenced by the type of the apatitic support. All the apatitic supports display Langmuir isotherms for risedronate adsorption. However in the case of HAPEI the plateau is not reached even at high equilibrium concentrations in solution. The data suggest that risedronate adsorption on HAPEI mineral-organic support occurs not only through chemisorption on apatitic phase, as on HA and ZnHA, but also through physisorption involved by PEI coating, which modulates also bisphosphonate release. These properties of tailor-made hydroxyapatite supports could be exploited to develop delivery systems for antiresorptive agents directly on osteoporotic sites., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The purpose of the study was to evaluate organogel nanoparticles as a drug delivery system by investigating their stability, according to the formulation strategy, and their release profile. The gelled nanoparticles were prepared by hot emulsification (above the gelation temperature) of an organogel in water, and cooling at room temperature. In the first step, we used DLS and DSC to select the most suitable formulations by optimizing the proportion of ingredients (HSA, PVA, castor oil) to obtain particles of the smallest size and greatest stability. Then, two lipophilic drug models, indomethacin and ketoconazole were entrapped in the nanoparticles made of castor oil gelled by 12-hydroxystearic acid. Thermal studies (DSC) confirmed that there was no significant alteration of gelling due to the entrapped drugs, even at 3% w/w. Very stable dispersions were obtained (>3 months), with gelled oil nanoparticles presenting a mean diameter between 250 and 300 nm. High encapsulation efficiency (>98%) was measured for indomethacin and ketoconazole. The release profile determined by in vitro dialysis showed an immediate release of the drug from the organogel nanoparticles, due to rapid diffusion. The study demonstrates the interest of these gelled oil nanoparticles for the encapsulation and the delivery of lipophilic active compounds.

Nanocrystalline calcium phosphate apatites are biomimetic compounds analogous to bone mineral and are at the origin of the bioactivity of most biomaterials used as bone substitutes. Their unique surface reactivity originates from the presence of a hydrated layer containing labile ions (mostly divalent ones). So the setup of 3D biocompatible apatite-based bioceramics exhibiting a high reactivity requests the development of «low» temperature consolidation processes such as spark plasma sintering (SPS), in order to preserve the characteristics of the hydrated nanocrystals. However, mechanical performances may still need to be improved for such nanocrystalline apatite bioceramics, especially in view of load-bearing applications. The reinforcement by association with biopolymers represents an appealing approach, while preserving the advantageous biological properties of biomimetic apatites. Herein, we report the preparation of composites based on biomimetic apatite associated with various quantities of microcrystalline cellulose (MCC, 1-20 wt%), a natural fibrous polymer. The SPS-consolidated composites were analyzed from both physicochemical (X-ray diffraction, Fourier transform infrared, solid state NMR) and mechanical (Brazilian test) viewpoints. The preservation of the physicochemical characteristics of apatite and cellulose in the final material was observed. Mechanical properties of the composite materials were found to be directly related to the polymer/apatite ratios and a maximum crushing strength was reached for 10 wt% of MCC.

Context: High-amylose sodium carboxymethyl starch (HASCA) was recently proposed as a material for oral, sustained drug-release tablets prepared by direct compression. It was produced on a pilot scale, but appeared to be unsuitable for tableting and sustained drug release. Pilot-scale dry powder HASCA was dispersed in hot water and then precipitated with ethanol to give a dry powder presenting the required properties, but very high volumes of ethanol were used to recover the product., Objective: A process was therefore designed to transform totally amorphous pregelatinized HASCA by spray-drying into a suitable sustained drug-release excipient for matrix tablets while decreasing ethanol quantities., Results and Discussion: During the first manufacturing step, that is, heating of the initial hydro-alcoholic suspension, powder and water concentrations are key parameters for the acquisition of excellent binding properties. Hence, a variable ratio of amylose Vh, a crystalline polymorph of amylose, to the amorphous form, is observed depending on the key parameter values. As the most crystalline samples give the weakest tablets, binding properties do not appear to be linked to the presence of a Vh form of amylose. On the other hand, a high water concentration results in excessive tablet strength, that is, inverse conditions leading to the appearance of a Vh form of amylose. Finally, variations in hydro-alcoholic composition appear to affect only tableting properties and do not influence the drug-release rate., Conclusion: A process designed to transform totally amorphous pregelatinized HASCA by spray-drying is proposed for easier, economical industrial HASCA production.

The aim of this work is to estimate the excipient percolation threshold for a new combined matrix native dextran (DT), series B110-1-2 (Mw 2 x 10(6)): HPMC K4M CR: lobenzarit disodium (LBD) system and demonstrate the advantages of this ternary system with respect to previously reported binary dextran:LBD and HPMC:LBD tablets. The formulations studied were prepared with different amounts of excipient (DT:HPMC, 4:1 (wt/wt) for all tablets and relative polymer/drug particle size of 4.17) in the range of 10-70% (wt/wt). Dissolution studies were carried out using the paddle method (100 rpm) and one face water uptake measurements were performed using a modified Enslin apparatus. The Higuchi's models as well as the non-linear regression were employed as empiric methods to study the released data. Values of diffusion exponent 0.588