Finite element analysis of vertebroplasty in the osteoporotic T11-L1 vertebral body: Effects of bone cement formulation.

Vertebral compression fractures are one of the most severe clinical consequences of osteoporosis and the most common fragility fracture afflicting 570 and 1070 out of 100,000 men and women worldwide, respectively. Vertebroplasty (VP), a minimally invasive surgical procedure that involves the percutaneous injection of bone cement, is one of the most efficacious methods to stabilise osteoporotic vertebral compression fractures. However, postoperative fracture has been observed in up to 30% of patients following VP. Therefore, this study aims to investigate the effect of different injectable bone cement formulations on the stress distribution within the vertebrae and intervertebral discs due to VP and consequently recommend the optimal cement formulation. To achieve this, a 3D finite element (FE) model of the T11-L1 vertebral body was developed from computed tomography scan data of the spine. Osteoporotic bone was modeled by reducing the Young's modulus by 20% in the cortical bone and 74% in cancellous bone. The FE model was subjected to different physiological movements, such as extension, flexion, bending, and compression. The osteoporotic model caused a reduction in the average von Mises stress compared with the normal model in the T12 cancellous bone and an increment in the average von Mises stress value at the T12 cortical bone. The effects of VP using different formulations of a novel injectable bone cement were modeled by replacing a region of T12 cancellous bone with the materials. Due to the injection of the bone cement at the T12 vertebra, the average von Mises stresses on cancellous bone increased and slightly decreased on the cortical bone under all loading conditions. The novel class of bone cements investigated herein demonstrated an effective restoration of stress distribution to physiological levels within treated vertebrae, which could offer a potential superior alternative for VP surgery as their anti-osteoclastogenic properties could further enhance the appeal of their fracture treatment and may contribute to improved patient recovery and long-term well-being.

Osteogenic Potential of Nano-Hydroxyapatite and Strontium-Substituted Nano-Hydroxyapatite.

Nanohydroxyapatite (nanoHA) is the major mineral component of bone. It is highly biocompatible, osteoconductive, and forms strong bonds with native bone, making it an excellent material for bone regeneration. However, enhanced mechanical properties and biological activity for nanoHA can be achieved through enrichment with strontium ions. Here, nanoHA and nanoHA with a substitution degree of 50 and 100% of calcium with strontium ions (Sr-nanoHA_50 and Sr-nanoHA_100, respectively) were produced via wet chemical precipitation using calcium, strontium, and phosphorous salts as starting materials. The materials were evaluated for their cytotoxicity and osteogenic potential in direct contact with MC3T3-E1 pre-osteoblastic cells. All three nanoHA-based materials were cytocompatible, featured needle-shaped nanocrystals, and had enhanced osteogenic activity in vitro. The Sr-nanoHA_100 indicated a significant increase in the alkaline phosphatase activity at day 14 compared to the control. All three compositions revealed significantly higher calcium and collagen production up to 21 days in culture compared to the control. Gene expression analysis exhibited, for all three nanoHA compositions, a significant upregulation of osteonectin and osteocalcin on day 14 and of osteopontin on day 7 compared to the control. The highest osteocalcin levels were found for both Sr-substituted compounds on day 14. These results demonstrate the great osteoinductive potential of the produced compounds, which can be exploited to treat bone disease.

Incorporation of strontium-containing bioactive particles into PEOT/PBT electrospun scaffolds for bone tissue regeneration.

The combination of biomaterials and bioactive particles has shown to be a successful strategy to fabricate electrospun scaffolds for bone tissue engineering. Among the range of bioactive particles, hydroxyapatite and mesoporous bioactive glasses (MBGs) have been widely used for their osteoconductive and osteoinductive properties. Yet, the comparison between the chemical and mechanical characteristics as well as the biological performances of these particle-containing scaffolds have been characterized to a limited extent. In this work, we fabricated PEOT/PBT-based composite scaffolds incorporating either nanohydroxyapatite (nHA), strontium-containing nanohydroxyapatite (nHA_Sr) or MBGs doped with strontium ions up to 15 wt./vol% and 12,5 wt./vol% for nHA and MBG, respectively. The composite scaffolds presented a homogeneous particle distribution. Morphological, chemical and mechanical analysis revealed that the introduction of particles into the electrospun meshes caused a decrease in the fiber diameter and mechanical properties, yet maintaining the hydrophilic nature of the scaffolds. The Sr2+ release profile differed according to the considered system, observing a 35-day slowly decreasing release from strontium-containing nHA scaffolds, whereas MBG-based scaffolds showed a strong burst release in the first week. In vitro, culture of human bone marrow-derived mesenchymal stromal cells (hMSCs) on composite scaffolds demonstrated excellent cell adhesion and proliferation. In maintenance and osteogenic media, all composite scaffolds showed high mineralization as well as expression of Col I and OCN compared to PEOT/PBT scaffolds, suggesting their ability to boost bone formation even without osteogenic factors. The presence of strontium led to an increase in collagen secretion and matrix mineralization in osteogenic medium, while gene expression analysis showed that hMSCs cultured on nHA-based scaffolds had a higher expression of OCN, ALP and RUNX2 compared to cells cultured on nHA_Sr scaffolds in osteogenic medium. Yet, cells cultured on MBGs-based scaffolds showed a higher gene expression of COL1, ALP, RUNX2 and BMP2 in osteogenic medium compared to nHA-based scaffolds, which is hypothesized to lead to high osteoinductivity in long term cultures.

A computational analysis of a novel therapeutic approach combining an advanced medicinal therapeutic device and a fracture fixation assembly for the treatment of osteoporotic fractures: Effects of physiological loading, interface conditions, and fracture fixation materials.

The occurrence of periprosthetic femoral fractures (PFF) has increased in people with osteoporosis due to decreased bone density, poor bone quality, and stress shielding from prosthetic implants. PFF treatment in the elderly is a genuine concern for orthopaedic surgeons as no effective solution currently exists. Therefore, the goal of this study was to determine whether the design of a novel advanced medicinal therapeutic device (AMTD) manufactured from a polymeric blend in combination with a fracture fixation plate in the femur is capable of withstanding physiological loads without failure during the bone regenerative process. This was achieved by developing a finite element (FE) model of the AMTD together with a fracture fixation assembly, and a femur with an implanted femoral stem. The response of both normal and osteoporotic bone was investigated by implementing their respective material properties in the model. Physiological loading simulating the peak load during standing, walking, and stair climbing was investigated. The results showed that the fixation assembly was the prime load bearing component for this configuration of devices. Within the fixation assembly, the bone screws were found to have the highest stresses in the fixation assembly for all the loading conditions. Whereas the stresses within the AMTD were significantly below the maximum yield strength of the device's polymeric blend material. Furthermore, this study also investigated the performance of different fixation assembly materials and found Ti-6Al-4V to be the optimal material choice from those included in this study.

Optimization of an Injectable, Resorbable, Bioactive Cement Able to Release the Anti-Osteoclastogenic Biomolecule ICOS-Fc for the Treatment of Osteoporotic Vertebral Compression Fractures.

Vertebral compression fractures are typical of osteoporosis and their treatment can require the injection of a cement through a minimally invasive procedure to restore vertebral body height. This study reports the development of an injectable calcium sulphate-based composite cement able to stimulate bone regeneration while inhibiting osteoclast bone resorption. To this aim, different types of strontium-containing mesoporous glass particles (Sr-MBG) were added to calcium sulphate powder to impart a pro-osteogenic effect, and the influence of their size and textural features on the cement properties was investigated. Anti-osteoclastogenic properties were conferred by incorporating into poly(lactic-co-glycolic)acid (PLGA) nanoparticles, a recombinant protein able to inhibit osteoclast activity (i.e., ICOS-Fc). Radiopaque zirconia nanoparticles (ZrO2) were also added to the formulation to visualize the cement injection under fluoroscopy. The measured cement setting times were suitable for the clinical practice, and static mechanical testing determined a compressive strength of ca. 8 MPa, comparable to that of human vertebral bodies. In vitro release experiments indicated a sustained release of ICOS-Fc and Sr2+ ions up to 28 days. Overall, the developed cement is promising for the treatment of vertebral compression fractures and has the potential to stimulate bone regeneration while releasing a biomolecule able to limit bone resorption.

Achievements in Mesoporous Bioactive Glasses for Biomedical Applications.

Nowadays, mesoporous bioactive glasses (MBGs) are envisaged as promising candidates in the field of bioceramics for bone tissue regeneration. This is ascribed to their singular chemical composition, structural and textural properties and easy-to-functionalize surface, giving rise to accelerated bioactive responses and capacity for local drug delivery. Since their discovery at the beginning of the 21st century, pioneering research efforts focused on the design and fabrication of MBGs with optimal compositional, textural and structural properties to elicit superior bioactive behavior. The current trends conceive MBGs as multitherapy systems for the treatment of bone-related pathologies, emphasizing the need of fine-tuning surface functionalization. Herein, we focus on the recent developments in MBGs for biomedical applications. First, the role of MBGs in the design and fabrication of three-dimensional scaffolds that fulfil the highly demanding requirements for bone tissue engineering is outlined. The different approaches for developing multifunctional MBGs are overviewed, including the incorporation of therapeutic ions in the glass composition and the surface functionalization with zwitterionic moieties to prevent bacterial adhesion. The bourgeoning scientific literature on MBGs as local delivery systems of diverse therapeutic cargoes (osteogenic/antiosteoporotic, angiogenic, antibacterial, anti-inflammatory and antitumor agents) is addressed. Finally, the current challenges and future directions for the clinical translation of MBGs are discussed.

Design and Performance of an Adsorption Bed with Activated Carbons for Biogas Purification.

Organic waste can be efficiently converted into energy using highly efficient energy systems, such as SOFCs coupled to the anaerobic digestion process. SOFC systems fed by biogenous fuels, such as biogas or syngas, suffer long-term stability due to trace compound impacts. It follows that, a mandatory gas cleaning section is needed to remove these pollutants at lower concentrations. This work investigates the adsorption mechanism for micro-contaminant removal through experimental results achieved using solid sorbents. Samples of different sorbent materials were analyzed in the laboratory to determine their performances in terms of sulfur (mainly hydrogen sulfide) and siloxanes (mainly D4-Octamethylcyclotetrasiloxane) adsorption capacities. The analysis shows that the chemical composition of the samples influences the adsorption of H2S (i.e., presence of calcium, iron, copper), while the effect of their textural properties mainly influences the adsorption of siloxane compounds, such as D4. A quantitative analysis was performed considering the influence of gas velocity on adsorption capacity. By increasing the biogas velocity (+45% and +89%), there was an indirect correlation with the H2S adsorption capacity (-27% and -44%). This identified an aspect related to the residence time required to be able to remove and retain the trace compound. The results obtained and summarized were used to develop a strategy for the removal of trace compounds in large-scale plants, e.g., for water purification.

Mesoporous Bioactive Glasses Incorporated into an Injectable Thermosensitive Hydrogel for Sustained Co-Release of Sr2+ Ions and N-Acetylcysteine.

An injectable delivery platform for promoting delayed bone healing has been developed by combining a thermosensitive polyurethane-based hydrogel with strontium-substituted mesoporous bioactive glasses (MBG_Sr) for the long-term and localized co-delivery of pro-osteogenic Sr2+ ions and an osteogenesis-enhancing molecule, N-Acetylcysteine (NAC). The incorporation of MBG_Sr microparticles, with a final concentration of 20 mg/mL, did not alter the overall properties of the thermosensitive hydrogel, in terms of sol-to-gel transition at a physiological-like temperature, gelation time, injectability and stability in aqueous environment at 37 °C. In particular, the hydrogel formulations (15% w/v polymer concentration) showed fast gelation in physiological conditions (1 mL underwent complete sol-to-gel transition within 3-5 min at 37 °C) and injectability in a wide range of temperatures (5-37 °C) through different needles (inner diameter in the range 0.4-1.6 mm). In addition, the MBG_Sr embedded into the hydrogel retained their full biocompatibility, and the released concentration of Sr2+ ions were effective in promoting the overexpression of pro-osteogenic genes from SAOS2 osteoblast-like cells. Finally, when incorporated into the hydrogel, the MBG_Sr loaded with NAC maintained their release properties, showing a sustained ion/drug co-delivery along 7 days, at variance with the MBG particles as such, showing a strong burst release in the first hours of soaking.

Electrospun Collagen Scaffold Bio-Functionalized with Recombinant ICOS-Fc: An Advanced Approach to Promote Bone Remodelling.

The treatment of osteoporotic fractures is a severe clinical issue, especially in cases where low support is provided, e.g., pelvis. New treatments aim to stimulate bone formation in compromised scenarios by using multifunctional biomaterials combined with biofabrication techniques to produce 3D structures (scaffolds) that can support bone formation. Bone's extracellular matrix (ECM) is mainly composed of type I collagen, making this material highly desirable in bone tissue engineering applications, and its bioactivity can be improved by incorporating specific biomolecules. In this work, type I collagen membranes were produced by electrospinning showing a fibre diameter below 200 nm. An optimized one-step strategy allowed to simultaneously crosslink the electrospun membranes and bind ICOS-Fc, a biomolecule able to reversibly inhibit osteoclast activity. The post-treatment did not alter the ECM-like nanostructure of the meshes and the physicochemical properties of collagen. UV-Vis and TGA analyses confirmed both crosslinking and grafting of ICOS-Fc onto the collagen fibres. The preservation of the biological activity of grafted ICOS-Fc was evidenced by the ability to affect the migratory activity of ICOSL-positive cells. The combination of ICOS-Fc with electrospun collagen represents a promising strategy to design multifunctional devices able to boost bone regeneration in osteoporotic fractures.

3D Printed Scaffold Based on Type I Collagen/PLGA_TGF-ß1 Nanoparticles Mimicking the Growth Factor Footprint of Human Bone Tissue.

In bone regenerative strategies, the controlled release of growth factors is one of the main aspects for successful tissue regeneration. Recent trends in the drug delivery field increased the interest in the development of biodegradable systems able to protect and transport active agents. In the present study, we designed degradable poly(lactic-co-glycolic)acid (PLGA) nanocarriers suitable for the release of Transforming Growth Factor-beta 1 (TGF-ß1), a key molecule in the management of bone cells behaviour. Spherical TGF-ß1-containing PLGA (PLGA_TGF-ß1) nanoparticles (ca.250 nm) exhibiting high encapsulation efficiency (ca.64%) were successfully synthesized. The TGF-ß1 nanocarriers were subsequently combined with type I collagen for the fabrication of nanostructured 3D printed scaffolds able to mimic the TGF-ß1 presence in the human bone extracellular matrix (ECM). The homogeneous hybrid formulation underwent a comprehensive rheological characterisation in view of 3D printing. The 3D printed collagen-based scaffolds (10 mm × 10 mm × 1 mm) successfully mimicked the TGF-ß1 presence in human bone ECM as assessed by immunohistochemical TGF-ß1 staining, covering ca.3.4% of the whole scaffold area. Moreover, the collagenous matrix was able to reduce the initial burst release observed in the first 24 h from about 38% for the PLGA_TGF-ß1 alone to 14.5%, proving that the nanocarriers incorporation into collagen allows achieving sustained release kinetics.

Incorporation of Superparamagnetic Iron Oxide Nanoparticles into Collagen Formulation for 3D Electrospun Scaffolds.

Nowadays, there is an ever-increasing interest in the development of systems able to guide and influence cell activities for bone regeneration. In this context, we have explored for the first time the combination of type-I collagen and superparamagnetic iron oxide nanoparticles (SPIONs) to design magnetic and biocompatible electrospun scaffolds. For this purpose, SPIONs with a size of 12 nm were obtained by thermal decomposition and transferred to an aqueous medium via ligand exchange with dimercaptosuccinic acid (DMSA). The SPIONs were subsequently incorporated into type-I collagen solutions to prove the processability of the resulting hybrid formulation by means of electrospinning. The optimized method led to the fabrication of nanostructured scaffolds composed of randomly oriented collagen fibers ranging between 100 and 200 nm, where SPIONs resulted distributed and embedded into the collagen fibers. The SPIONs-containing electrospun structures proved to preserve the magnetic properties of the nanoparticles alone, making these matrices excellent candidates to explore the magnetic stimuli for biomedical applications. Furthermore, the biological assessment of these collagen scaffolds confirmed high viability, adhesion, and proliferation of both pre-osteoblastic MC3T3-E1 cells and human bone marrow-derived mesenchymal stem cells (hBM-MSCs).

Polyelectrolyte-Coated Mesoporous Bioactive Glasses via Layer-by-Layer Deposition for Sustained Co-Delivery of Therapeutic Ions and Drugs.

In the field of bone regeneration, considerable attention has been addressed towards the use of mesoporous bioactive glasses (MBGs), as multifunctional therapeutic platforms for advanced medical devices. In fact, their extremely high exposed surface area and pore volume allow to load and the release of several drugs, while their framework can be enriched with specific therapeutic ions allowing to boost the tissue regeneration. However, due to the open and easily accessible mesopore structure of MBG, the release of the incorporated therapeutic molecules shows an initial burst effect leading to unsuitable release kinetics. Hence, a still open challenge in the design of drug delivery systems based on MBGs is the control of their release behavior. In this work, Layer-by-layer (LbL) deposition of polyelectrolyte multi-layers was exploited as a powerful and versatile technique for coating the surface of Cu-substituted MBG nanoparticles with innovative multifunctional drug delivery systems for co-releasing of therapeutic copper ions (exerting pro-angiogenic and anti-bacterial effects) and an anti-inflammatory drug (ibuprofen). Two different routes were investigated: in the first strategy, chitosan and alginate were assembled by forming the multi-layered surface, and, successively, ibuprofen was loaded by incipient wetness impregnation, while in the second approach, alginate was replaced by ibuprofen, introduced as polyelectrolyte layer. Zeta-potential, TGA and FT-IR spectroscopy were measured after the addition of each polyelectrolyte layer, confirming the occurrence of the stepwise deposition. In addition, the in vitro bioactivity and the ability to modulate the release of the cargo were evaluated. The polyelectrolyte coated-MBGs were proved to retain the peculiar ability to induce hydroxyapatite formation after 7 days of soaking in Simulated Body Fluid. Both copper ions and ibuprofen were co-released over time, showing a sustained release profile up to 14 days and 24 h, respectively, with a significantly lower burst release compared to the bare MBG particles.

3D Printing in Alginic Acid Bath of In-Situ Crosslinked Collagen Composite Scaffolds.

Bone-tissue regeneration is a growing field, where nanostructured-bioactive materials are designed to replicate the natural properties of the target tissue, and then are processed with technologies such as 3D printing, into constructs that mimic its natural architecture. Type I bovine collagen formulations, containing functional nanoparticles (enriched with therapeutic ions or biomolecules) or nanohydroxyapatite, are considered highly promising, and can be printed using support baths. These baths ensure an accurate deposition of the material, nonetheless their full removal post-printing can be difficult, in addition to undesired reactions with the crosslinking agents often used to improve the final structural integrity of the scaffolds. Such issues lead to partial collapse of the printed constructs and loss of geometrical definition. To overcome these limitations, this work presents a new alternative approach, which consists of adding a suitable concentration of crosslinking agent to the printing formulations to promote the in-situ crosslinking of the constructs prior to the removal of the support bath. To this aim, genipin, chosen as crosslinking agent, was added (0.1 wt.%) to collagen-based biomaterial inks (containing either 38 wt.% mesoporous bioactive glasses or 65 wt.% nanohydroxyapatite), to trigger the crosslinking of collagen and improve the stability of the 3D printed scaffolds in the post-processing step. Moreover, to support the material deposition, a 15 wt.% alginic acid solution was used as a bath, which proved to sustain the printed structures and was also easily removable, allowing for the stable processing of high-resolution geometries.

Biomimetic Scaffolds Obtained by Electrospinning of Collagen-Based Materials: Strategies to Hinder the Protein Denaturation.

The use of biomaterials and scaffolds to boost bone regeneration is increasingly gaining interest as a complementary method to the standard surgical and pharmacological treatments in case of severe injuries and pathological conditions. In this frame, the selection of biomaterials and the accurate assessment of the manufacturing procedures are considered key factors in the design of constructs able to resemble the features of the native tissue and effectively induce specific cell responses. Accordingly, composite scaffolds based on type-I-collagen can mimic the composition of bone extracellular matrix (ECM), while electrospinning technologies can be exploited to produce nanofibrous matrices to resemble its architectural organization. However, the combination of collagen and electrospinning reported several complications due to the frequent denaturation of the protein and the variability of results according to collagen origin, concentration, and solvent. In this context, the strategies optimized in this study enabled the preparation of collagen-based electrospun scaffolds characterized by about 100 nm fibers, preserving the physico-chemical properties of the protein thanks to the use of an acetic acid-based solvent. Moreover, nanoparticles of mesoporous bioactive glasses were combined with the optimized collagen formulation, proving the successful design of composite scaffolds resembling the morphological features of bone ECM at the nanoscale.

PEG-Coated Large Mesoporous Silicas as Smart Platform for Protein Delivery and Their Use in a Collagen-Based Formulation for 3D Printing.

Silica-based mesoporous systems have gained great interest in drug delivery applications due to their excellent biocompatibility and high loading capability. However, these materials face challenges in terms of pore-size limitations since they are characterized by nanopores ranging between 6-8 nm and thus unsuitable to host large molecular weight molecules such as proteins, enzymes and growth factors (GFs). In this work, for an application in the field of bone regeneration, large-pore mesoporous silicas (LPMSs) were developed to vehicle large biomolecules and release them under a pH stimulus. Considering bone remodeling, the proposed pH-triggered mechanism aims to mimic the release of GFs encased in the bone matrix due to bone resorption by osteoclasts (OCs) and the associated pH drop. To this aim, LPMSs were prepared by using 1,3,5-trimethyl benzene (TMB) as a swelling agent and the synthesis solution was hydrothermally treated and the influence of different process temperatures and durations on the resulting mesostructure was investigated. The synthesized particles exhibited a cage-like mesoporous structure with accessible pores of diameter up to 23 nm. LPMSs produced at 140 °C for 24 h showed the best compromise in terms of specific surface area, pores size and shape and hence, were selected for further experiments. Horseradish peroxidase (HRP) was used as model protein to evaluate the ability of the LPMSs to adsorb and release large biomolecules. After HRP-loading, LPMSs were coated with a pH-responsive polymer, poly(ethylene glycol) (PEG), allowing the release of the incorporated biomolecules in response to a pH decrease, in an attempt to mimic GFs release in bone under the acidic pH generated by the resorption activity of OCs. The reported results proved that PEG-coated carriers released HRP more quickly in an acidic environment, due to the protonation of PEG at low pH that catalyzes polymer hydrolysis reaction. Our findings indicate that LPMSs could be used as carriers to deliver large biomolecules and prove the effectiveness of PEG as pH-responsive coating. Finally, as proof of concept, a collagen-based suspension was obtained by incorporating PEG-coated LPMS carriers into a type I collagen matrix with the aim of designing a hybrid formulation for 3D-printing of bone scaffolds.

Sr-Containing Mesoporous Bioactive Glasses Bio-Functionalized with Recombinant ICOS-Fc: An In Vitro Study.

Osteoporotic bone fractures represent a critical clinical issue and require personalized and specific treatments in order to stimulate compromised bone tissue regeneration. In this clinical context, the development of smart nano-biomaterials able to synergistically combine chemical and biological cues to exert specific therapeutic effects (i.e., pro-osteogenic, anti-clastogenic) can allow the design of effective medical solutions. With this aim, in this work, strontium-containing mesoporous bioactive glasses (MBGs) were bio-functionalized with ICOS-Fc, a molecule able to reversibly inhibit osteoclast activity by binding the respective ligand (ICOS-L) and to induce a decrease of bone resorption activity. N2 adsorption analysis and FT-IR spectroscopy were used to assess the successful grafting of ICOS-Fc on the surface of Sr-containing MBGs, which were also proved to retain the peculiar ability to release osteogenic strontium ions and an excellent bioactivity after functionalization. An ELISA-like assay allowed to confirm that grafted ICOS-Fc molecules were able to bind ICOS-L (the ICOS binding ligand) and to investigate the stability of the amide binding to hydrolysis in aqueous environment up to 21 days. In analogy to the free form of the molecule, the inhibitory effect of grafted ICOS-Fc on cell migratory activity was demonstrated by using ICOSL positive cell lines and the ability to inhibit osteoclast differentiation and function was confirmed by monitoring the differentiation of monocyte-derived osteoclasts (MDOCs), which revealed a strong inhibitory effect, also proven by the downregulation of osteoclast differentiation genes. The obtained results showed that the combination of ICOS-Fc with the intrinsic properties of Sr-containing MBGs represents a very promising approach to design personalized solutions for patients affected by compromised bone remodeling (i.e., osteoporosis fractures).

Understanding Selectivity of Mesoporous Silica-Grafted Diglycolamide-Type Ligands in the Solid-Phase Extraction of Rare Earths.

Rare earth elements (REEs) and their compounds are essential for rapidly developing modern technologies. These materials are especially critical in the area of green/sustainable energy; however, only very high-purity fractions are appropriate for these applications. Yet, achieving efficient REE separation and purification in an economically and environmentally effective way remains a challenge. Moreover, current extraction technologies often generate large amounts of undesirable wastes. In that perspective, the development of selective, reusable, and extremely efficient sorbents is needed. Among numerous ligands used in the liquid-liquid extraction (LLE) process, the diglycolamide-based (DGA) ligands play a leading role. Although these ligands display notable extraction performance in the liquid phase, their extractive chemistry is not widely studied when such ligands are tethered to a solid support. A detailed understanding of the relationship between chemical structure and function (i.e., extraction selectivity) at the molecular level is still missing although it is a key factor for the development of advanced sorbents with tailored selectivity. Herein, a series of functionalized mesoporous silica (KIT-6) solid phases were investigated as sorbents for the selective extraction of REEs. To better understand the extraction behavior of these sorbents, different spectroscopic techniques (solid-state NMR, X-ray photoelectron spectroscopy, XPS, and Fourier transform infrared spectroscopy, FT-IR) were implemented. The obtained spectroscopic results provide useful insights into the chemical environment and reactivity of the chelating ligand anchored on the KIT-6 support. Furthermore, it can be suggested that depending on the extracted metal and/or structure of the ligand and its attachment to KIT-6, different functional groups (i.e., C═O, N-H, or silanols) act as the main adsorption centers and preferentially capture targeted elements, which in turn may be associated with the different selectivity of the synthesized sorbents. Thus, by determining how metals interact with different supports, we aim to better understand the solid-phase extraction process of hybrid (organo)silica sorbents and design better extraction materials.

Collagen Hybrid Formulations for the 3D Printing of Nanostructured Bone Scaffolds: An Optimized Genipin-Crosslinking Strategy.

Bone-tissue regeneration induced by biomimetic bioactive materials is the most promising approach alternative to the clinical ones used to treat bone loss caused by trauma or diseases such as osteoporosis. The goal is to design nanostructured bioactive constructs able to reproduce the physiological environment: By mimicking the natural features of bone tissue, the cell behavior during the regeneration process may be addressed. At present, 3D-printing technologies are the only techniques able to design complex structures avoiding constraints of final shape and porosity. However, this type of biofabrication requires complex optimization of biomaterial formulations in terms of specific rheological and mechanical properties while preserving high biocompatibility. In this work, we combined nano-sized mesoporous bioactive glasses enriched with strontium ions with type I collagen, to formulate a bioactive ink for 3D-printing technologies. Moreover, to avoid the premature release of strontium ions within the crosslinking medium and to significantly increase the material mechanical and thermal stability, we applied an optimized chemical treatment using ethanol-dissolved genipin solutions. The high biocompatibility of the hybrid system was confirmed by using MG-63 and Saos-2 osteoblast-like cell lines, further highlighting the great potential of the innovative nanocomposite for the design of bone-like scaffolds.

In Vivo Validation of Spray-Dried Mesoporous Bioactive Glass Microspheres Acting as Prolonged Local Release Systems for BMP-2 to Support Bone Regeneration.

Bone morphogenetic protein-2 (BMP-2) is a known key mediator of physiological bone regeneration and is clinically approved for selected musculoskeletal interventions. Yet, broad usage of this growth factor is impeded due to side effects that are majorly evoked by high dosages and burst release kinetics. In this study, mesoporous bioactive glass microspheres (MBGs), produced by an aerosol-assisted spray-drying scalable process, were loaded with BMP-2 resulting in prolonged, low-dose BMP-2 release without affecting the material characteristics. In vitro, MBGs were found to be cytocompatible and to induce a pro-osteogenic response in primary human mesenchymal stromal cells (MSCs). In a pre-clinical rodent model, BMP-2 loaded MBGs significantly enhanced bone formation and influenced the microarchitecture of newly formed bone. The MBG carriers alone performed equal to the untreated (empty) control in most parameters tested, while additionally exerting mild pro-angiogenic effects. Using MBGs as a biocompatible, pro-regenerative carrier for local and sustained low dose BMP-2 release could limit side effects, thus enabling a safer usage of BMP-2 as a potent pro-osteogenic growth factor.

Multifunctional Copper-Containing Mesoporous Glass Nanoparticles as Antibacterial and Proangiogenic Agents for Chronic Wounds.

The physiological wound healing process involves a cascade of events which could be affected by several factors resulting in chronic, non-healing wounds. The latter represent a great burden especially when bacterial biofilms are formed. The rise in antibiotic resistance amongst infectious microorganisms leads to the need of novel approaches to treat this clinical issue. In this context, the use of advanced biomaterials, which can enhance the physiological expression and secretion of the growth factors involved in the wound healing process, is gaining increasing attention as a robust and appealing alternative approach. Among them, mesoporous glasses are of particular interest due to their excellent textural properties and to the possibility of incorporating and releasing specific therapeutic species, such as metallic ions. One of the most attractive therapeutic ions is copper thanks to its proangiogenic and antibacterial effects. In this contribution, copper containing mesoporous glass nanoparticles were proposed as a multifunctional device to treat chronic wounds. The developed nanoparticles evidenced a very high specific surface area (740 m2/g), uniform pores of 4 nm and an almost total release of the therapeutic ion within 72 h of soaking. The produced nanoparticles were biocompatible and, when tested against Gram positive and Gram negative bacterial species, demonstrated antibacterial activity against both planktonic and biofilm bacteria in 2D cell monolayers, and in a 3D human model of infected skin. Their proangiogenic effect was tested with both the aortic ring and the chick chorioallantoic membrane assays and an increase in endothelial cell outgrowth at a concentration range between 30 and 300 ng/mL was shown. Overall, in this study biocompatible, multifunctional Cu-containing mesoporous glass nanoparticles were successfully produced and demonstrated to exert both antibacterial and proangiogenic effects.