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Calcium phosphates (CaPs) are widely accepted biomaterials able to promote the regeneration of bone tissue. However, the regeneration of critical-sized bone defects has been considered challenging, and the development of bioceramics exhibiting enhanced bioactivity, bioresorbability and mechanical performance is highly demanded. In this respect, the tuning of their chemical composition, crystal size and morphology have been the matter of intense research in the last decades, including the preparation of composites. The development of effective bioceramic composite scaffolds relies on effective manufacturing techniques able to control the final multi-scale porosity of the devices, relevant to ensure osteointegration and bio-competent mechanical performance. In this context, the present work provides an overview about the reported strategies to develop and optimize bioceramics, while also highlighting future perspectives in the development of bioactive ceramic composites for bone tissue regeneration.

The failure of the osteosarcoma conventional therapies leads to the growing need for novel therapeutic strategies. The lack of specificity for the Cancer Stem Cells (CSCs) population has been recently identified as the main limitation in the current therapies. Moreover, the traditional two-dimensional (2D) in vitro models, employed in the drug testing and screening as well as in the study of cell and molecular biology, are affected by a poor in vitro-in vivo translation ability. To overcome these limitations, this work provides two tumour engineering approaches as new tools to address osteosarcoma and improve therapy outcomes. In detail, two different hydroxyapatite-based bone-mimicking scaffolds were used to recapitulate aspects of the in vivo tumour microenvironment, focusing on CSCs niche. The biological performance of human osteosarcoma cell lines (MG63 and SAOS-2) and enriched-CSCs were deeply analysed in these complex cell culture models. The results highlight the fundamental role of the tumour microenvironment proving the mimicry of osteosarcoma stem cell niche by the use of CSCs together with the biomimetic scaffolds, compared to conventional 2D culture systems. These advanced 3D cell culture in vitro tumour models could improve the predictivity of preclinical studies and strongly enhance the clinical translation.

Small interfering RNAs (siRNAs) provide strong therapeutic potential due to their efficient gene-silencing properties; however, their instability limits clinical application. Nanoparticle carriers may overcome this problem; in particular, magnetic nanoparticles show great promise as they can be directed to the target sites by external magnetic fields, thus improving delivery efficiency and reducing off-target effects. In addition, magnetic nanoparticles offer a novel nanoplatform for theranostic applications, integrating siRNA delivery with magnetic resonance imaging and magnetic hyperthermia for synergistic diagnostic and therapeutic advantages. The present work reports the development of a novel platform based on biomimetic magnetic nanoparticles made of Fe(II)/Fe(III)-doped apatite (FeHA) nucleated and grown in the presence of cherry and pomegranate leaf extracts to enhance the colloidal stability and make it suitable for nucleic acid delivery under the guidance of magnetic fields. This approach allowed the obtention of FeHA suspension with increased negative zeta potential leading to very good stability. In addition, the functionalization with natural extracts conferred antioxidant properties also favoring the maintenance of the Fe(III)/Fe(II) ratio in the apatitic structure, inducing the superparamagnetic properties. To evaluate the delivery capability of the system, a model GAPDH-targeting siRNA molecule was employed. Its interaction with the nanoplatform was characterized by assessing loading capacity and release kinetics, which were further interpreted using mathematical modeling to elucidate the underlying release mechanisms.

Strontium-substituted apatitic bone cements enriched with sodium alginate were developed as a potential modulator of bone cells fate. The biological impact of the bone cement were investigated in vitro through the study of the effect of the nanostructured apatitic composition and the doping of strontium on mesenchymal stem cells, pre-osteoblasts and osteoclasts behaviours. Up to 14 days of culture the bone cells viability, proliferation, morphology and gene expression profiles were evaluated. The results showed that different concentrations of strontium were able to evoke a cell-specific response, in fact an inductive effect on mesenchymal stem cells differentiation and pre-osteoblasts proliferation and an inhibitory effect on osteoclasts activity were observed. Moreover, the apatitic structure of the cements provided a biomimetic environment suitable for bone cells growth. Therefore, the combination of biological features of this bone cement makes it as promising biomaterials for tissue regeneration.

Bioceramics are widely considered as elective materials for the regeneration of bone tissue, due to their compositional mimicry with bone inorganic components. However, they are intrinsically brittle, which limits their capability to sustain multiple biomechanical loads, especially in the case of load-bearing bone districts. In the last decades, intense research has been dedicated to combining processes to enhance both the strength and toughness of bioceramics, leading to bioceramic composite scaffolds. This review summarizes the recent approaches to this purpose, particularly those addressed to limiting the propagation of cracks to prevent the sudden mechanical failure of bioceramic composites.

The regeneration of bone fractures, resulting from trauma, osteoporosis or tumors, is a major problem in our super-aging society. Bone regeneration is one of the main topics of concern in regenerative medicine. In recent years, stem cells have been employed in regenerative medicine with interesting results due to their self-renewal and differentiation capacity. Moreover, stem cells are able to secrete bioactive molecules and regulate the behavior of other cells in different host tissues. Bone regeneration process may improve effectively and rapidly when stem cells are used. To this purpose, stem cells are often employed with biomaterials/scaffolds and growth factors to accelerate bone healing at the fracture site. Briefly, this review will describe bone structure and the osteogenic differentiation of stem cells. In addition, the role of mesenchymal stem cells for bone repair/regrowth in the tissue engineering field and their recent progress in clinical applications will be discussed.

Small interfering RNAs (siRNAs) are particularly attractive among the frontier drugs due to their high specificity of action, activity on disease-inducing genes, and small molecular weight, thus being one of the most studied agents for gene therapy. However, siRNAs are prone to fast enzymatic degradation in the bloodstream, as well as other limitations that challenge their clinical translation. Nanoparticle (NP) delivery of siRNA has been proposed as a potential solution, overcoming their intrinsic limitations. In this regard, the siRNA delivery by magnetic nanoparticles is of particular interest because, being susceptible to external magnetic fields, it may be guided remotely, maximizing transfection efficiency and minimizing side effects. In addition, magnetic NPs would also allow a theranostic combination of drug delivery, magnetic resonance imaging, and hyperthermia. In this work we have studied the uptake of a model therapeutic siRNA by iron-doped hydroxyapatite nanoparticles (FeHA NPs), which are known to have excellent biocompatibility and magnetic susceptibility. We discovered that FeHA NPs stabilized by citrate (Cit-FeHA NPs) uptake siRNA by adsorption quickly and with high efficiency (ca. 90%) without altering nanoparticles physicochemical properties or colloidal stability. SiRNA-loaded Cit-FeHA NPs are able to slowly release their payload, with a sustained release of 45 days without siRNA degradation. Our work is therefore the preliminary validation of the suitability of FeHA NPs for magnetically guided delivery of therapeutic siRNAs.

Bone is a complex biologic tissue, which is extremely relevant for various physiological functions, in addition to movement, organ protection, and weight bearing. The repair of critical size bone defects is a still unmet clinical need, and over the past decades, material scientists have been expending efforts to find effective technological solutions, based on the use of scaffolds. In this context, biomimetics which is intended as the ability of a scaffold to reproduce compositional and structural features of the host tissues, is increasingly considered as a guide for this purpose. However, the achievement of implants that mimic the very complex bone composition, multi-scale structure, and mechanics is still an open challenge. Indeed, despite the fact that calcium phosphates are widely recognized as elective biomaterials to fabricate regenerative bone scaffolds, their processing into 3D devices with suitable cell-instructing features is still prevented by insurmountable drawbacks. With respect to biomaterials science, new approaches maybe conceived to gain ground and promise for a substantial leap forward in this field. The present review provides an overview of physicochemical and structural features of bone tissue that are responsible for its biologic behavior. Moreover, relevant and recent technological approaches, also inspired by natural processes and structures, are described, which can be considered as a leverage for future development of next generation bioactive medical devices.

Bone regeneration in oral surgery remains a challenge, due to the features of the oral environment, characterized by the presence of saliva and extensive interaction with external pathogens. Recent advances in this field highlighted that biomimetic apatites in which Ca 2+ is replaced by Fe 2+ /Fe 3+ ions are promising candidates to guide bone regeneration with on demand activation control. In this study the Fe-doped apatite nanoparticles (FeHA) were developed and compared with magnetite nanoparticles, as new magnetic bio-activator, to be embedded in apatitic injectable paste/cement. Upon self-hardening, the new injectable cement generates a mechanically competent 3D superparamagnetic scaffold, endowed with remote activation by using static magnetic fields. We investigated the alkaline phosphatase expression and activity, as well as the behaviour of cells, when seeded onto the scaffold. The results show the ability of the cement to stimulate cell colonization and differentiation and how, when magnetized, they can further boost such phenomena. The proposed devices, in association with a magnetic aligner, can represent a new approach in oral surgery, able to tune the bone remodelling on demand, when the regenerative potential is impaired by physiological conditions such as aging or chronic diseases.

Over the past decades, age-related pathologies have increased abreast the aging population worldwide. The increased age of the population indicates that new tools, such as biomaterials/scaffolds for damaged tissues, which display high efficiency, effectively and in a limited period of time, for the regeneration of the body's tissue are needed. Indeed, scaffolds can be used as templates for three-dimensional tissue growth in order to promote the tissue healing stimulating the body's own regenerative mechanisms. In tissue engineering, several types of biomaterials are employed, such as bioceramics including calcium phosphates, bioactive glasses, and glass–ceramics. These scaffolds seem to have a high potential as biomaterials in regenerative medicine. In addition, in conjunction with other materials, such as polymers, ceramic scaffolds may be used to manufacture composite scaffolds characterized by high biocompatibility, mechanical efficiency and load-bearing capabilities that render these biomaterials suitable for regenerative medicine applications. Usually, bioceramics have been used to repair hard tissues, such as bone and dental defects. More recently, in the field of soft tissue engineering, this form of scaffold has also shown promising applications. Indeed, soft tissues are continuously exposed to damages, such as burns or mechanical traumas, tumors and degenerative pathology, and, thereby, thousands of people need remedial interventions such as biomaterials-based therapies. It is known that scaffolds can affect the ability to bind, proliferate and differentiate cells similar to those of autologous tissues. Therefore, it is important to investigate the interaction between bioceramics and somatic/stem cells derived from soft tissues in order to promote tissue healing. Biomimetic scaffolds are frequently employed as drug-delivery system using several therapeutic molecules to increase their biological performance, leading to ultimate products with innovative functionalities. This review provides an overview of essential requirements for soft tissue engineering biomaterials. Data on recent progresses of porous bioceramics and composites for tissue repair are also presented.