The design and development of novel materials for biomineralized tissues is an extremely attractive field of research where calcium phosphates (CaPs)–based materials for biomedical applications play ...a leading role. The biological performance of these compounds can be enhanced through functionalization with biologically active ions and molecules. This review reports on some important recent achievements in creating functionalized biomimetic CaP materials for applications in the musculoskeletal field. Particular attention is focused on the modifications of these inorganic compounds with bioactive ions, growth factors and drugs, as well as on recent trends in some important CaP applications as biomaterials – namely, as bone cements, coatings of metallic implants and scaffolds for regenerative medicine.
Bisphosphonates (BPs) are the most utilized drugs for the treatment of osteoporosis, and are usefully employed also for other pathologies characterized by abnormally high bone resorption, including ...bone metastases. Due to the great affinity of these drugs for calcium ions, calcium phosphates are ideal delivery systems for local administration of BPs to bone, which is aimed to avoid/limit the undesirable side effects of their prolonged systemic use. Direct synthesis in aqueous medium and chemisorptions from solution are the two main routes proposed to synthesize BP functionalized calcium phosphates. The present review overviews the information acquired through the studies on the interaction between bisphosphonate molecules and calcium phosphates. Moreover, particular attention is addressed to some important recent achievements on the applications of BP functionalized calcium phosphates as biomaterials for bone substitution/repair.
Strontium is quantitatively incorporated into hydroxyapatite where its substitution for calcium provokes a linear increase of the lattice constants and a linear shift of the infrared absorption ...bands, coherent with the larger ionic radius of strontium. The effect of low levels of strontium on crystallinity, morphology and cationic site distribution is opposite to that observed at high strontium concentrations.
Among the many cations that can substitute for calcium in the structure of hydroxyapatite, strontium provokes an increasing interest because of its beneficial effect on bone formation, and prevention of bone resorption. We have synthesized calcium–strontium hydroxyapatite solid solutions in the whole range of composition by direct synthesis in an aqueous medium. The structural, morphological and chemical characterizations were carried out on the as-obtained products. Strontium is quantitatively incorporated into hydroxyapatite where its substitution for calcium provokes a linear increase in the lattice constants and a linear shift of the infrared absorption bands of the hydroxyl and phosphate groups, coherent with the greater ionic radius of strontium. At variance, the effect of relatively low levels of strontium concentration on the dimensions of the coherent length of the perfect crystalline domains and on the morphology of the nanocrystals is opposite to that observed at high levels of strontium concentration. Similarly, the results of the structure refinements carried out using the Rietveld method indicate that whilst in most of the range of concentration strontium displays a slight preference for the M(2) cation site coherently with its ionic radius, at very low concentrations its occupancy of the smaller M(1) site is slightly higher.
The development of suitable biomimetic three-dimensional scaffolds is a fundamental requirement of tissue engineering. This paper presents the first successful attempt to obtain electrospun gelatin ...nanofibers cross-linked with a low toxicity agent, genipin, and able to retain the original nanofiber morphology after water exposure. The optimized procedure involves an electrospinning solution containing 30wt.% gelatin in 60/40 acetic acid/water (v/v) and a small amount of genipin, followed by further cross-linking of the as-electrospun mats in 5% genipin solution for 7days, rinsing in phosphate-buffered saline and then air drying at 37°C. The results of scanning electron microscopy investigations indicated that the cross-linked nanofibers were defect free and very regular and they also maintained the original morphology after exposure to water. Genipin addition to the electrospinning solution dramatically reduced the extensibility of the as-electrospun mats, which displayed further remarkable improvements in elastic modulus and stress at break after successive cross-linking up to values of about 990 and 21MPa, respectively. The results of the preliminary in vitro tests carried out using vascular wall mesenchymal stem cells indicated good cell viability and adhesion to the gelatin scaffolds.
In this paper we used curcumin as a functionalizing agent of gelatin films with the aim to get antioxidant materials with modulated physico-chemical properties. To this aim, we prepared gelatin films ...at different contents of curcumin up to about 1.2 wt%. The as-prepared films, as well as glutaraldehyde crosslinked films, were submitted to several tests: swelling, water solubility, differential scanning calorimetry, X-ray diffraction, mechanical tests and curcumin release. The radical scavenging activity of the as-prepared films is similar to that of free curcumin, indicating remarkable antioxidant properties. All the other tested properties vary as a function of curcumin content and/or the presence of the crosslinking agent. In particular, the films exhibit sustained curcumin release in different solvents. Thanks to its biocompatibility, biodegradability and lack of antigenicity, gelatin uses span from food processing to packaging and biomaterials. It follows that the modulated properties exhibited by the functionalized materials developed in this work can be usefully employed in different application fields.
Sterilization through γ-irradiation has been reported to affect collagen mechanical properties, but its possible effects on gelatin based materials have not been investigated up to now. Herein we ...report the results of a mechanical, chemical and thermal study performed on gelatin films before and after γ-irradiation. The investigation was performed on uncrosslinked films as well as on crosslinked films. To this aim, two common crosslinking agents, glutaraldehyde and genipin, at different concentration (0.15, 0.30 and 0.67 %) were used. The results indicate that sterilization significantly affects the mechanical properties of uncrosslinked films, whereas it displays a modest effect on gelatin swelling, release in solution, thermal stability and molecular structure. Both glutaraldehyde and genipin enhance the mechanical properties and stability in solution of the gelatin films. In particular, the values of Young modulus increase as a function of crosslinker concentration up to about 10 and 18 MPa for genipin and glutaraldehyde treated samples respectively. The results of in vitro study demonstrate that the films crosslinked with genipin do not display any cytotoxic reaction, whereas glutaraldehyde crosslinking provokes an acute and dose dependent cytotoxic effect.
Bisphosphonates are widely employed drugs for the treatment of pathologies with high bone resorption, such as osteoporosis, and display a great affinity for calcium ions and apatitic substrates. ...Here, we aimed to investigate the potentiality of zoledronate functionalized hydroxyapatite nanocrystals (HAZOL) to promote bone regeneration by stimulating adhesion, viability, metabolic activity and osteogenic commitment of human bone marrow derived mesenchymal stromal cells (hMSCs).
we adopted an advanced three-dimensional (3D) in vitro fracture healing model to study porous scaffolds: hMSCs were seeded onto the scaffolds that, after three days, were cut in halves and unseeded scaffolds were placed between the two halves. Scaffold characterization by X-ray diffraction, transmission and scanning electron microscopy analyses and cell morphology, viability, osteogenic differentiation and extracellular matrix deposition were evaluated after 3, 7 and 10 days of culture.
Electron microscopy showed a porous and interconnected structure and a uniform cell layer spread onto scaffolds. Scaffolds were able to support cell growth and cells progressively colonized the whole inserts in absence of cytotoxic effects. Osteogenic commitment and gene expression of hMSCs were enhanced with higher expressions of
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Although some limitations affect the present study (e.g., the lack of longer experimental times, of mechanical stimulus or pathological microenvironment), the obtained results with the adopted experimental setup suggested that zoledronate functionalized scaffolds (GHAZOL) might sustain not only cell proliferation, but positively influence osteogenic differentiation and activity if employed in bone fracture healing.
Abstract This study demonstrates that zoledronate containing hydroxyapatite nanocrystals (HA-ZOL) can be synthesized as a single crystalline phase up to a zoledronate content of about 7 wt% by direct ...synthesis in aqueous solution, at variance with what previously found for alendronate-hydroxyapatite nanocrystals (HA-AL). On increasing zoledronate incorporation, the length of the coherent crystalline domains and the crystal dimensions of hydroxyapatite decrease, whereas the specific surface area increases. Full profile fitting of the powder X-ray diffraction patterns does not indicate major structural modifications, but an increase of the hydroxyapatite unit cell, on increasing zoledronate content. These data, together with a structural similarity between hydroxyapatite and calcium zoledronate, suggest a preferential interaction between zoledronate and the hydroxyapatite faces parallel to the c -axis direction. Osteoblast-like MG-63 cells and human osteoclasts were cultured on HA-ZOL nanocrystals and as a comparison on HA-AL nanocrystals containing almost the same (about 7 wt%) bisphosphonate amount. The beneficial influence of bisphosphonates on osteoblast proliferation and differentiation is enhanced when the tests are performed in co-cultures. Similarly, the reduction of osteoclast proliferation and the increase of Caspase 3 production are dramatically enhanced in co-cultures, which highlight an even greater influence of HA-ZOL than HA-AL on osteoclast apoptosis.
Both calcium and alendronate functionalization improves octacalcium phosphate deposition on the surface of gelatin microspheres. Display omitted
► Gelatin microspheres coated with octacalcium ...phosphate. ► Functionalization of microspheres with calcium ions. ► Functionalization of microspheres with a bisphosphonate (alendronate). ► Calcium phosphate porous shell modulates gelatin and alendronate release. ► Biomimetic mineralization based on molecular recognition.
Calcium phosphate/polymeric microparticles synthesized through a biomimetic approach are regarded with increasing interest for their various potential applications, including tissue engineering and regenerative medicine. Herein we report the synthesis and characterization of gelatin/octacalcium phosphate core/shell microspheres. Deposition of the calcium phosphate shell on the polymeric microspheres was obtained through bio-inspired mineralization on the surface of functionalized gelatin microparticles. Gelatin microspheres stabilized by alginate dialdehyde were prepared using an inverse microemulsion. Functionalization was achieved by enriching the microspheres composition with calcium ions or, alternatively, with alendronate, a bisphosphonate widely employed for the treatment of bone diseases. Functionalization and synthesis of the inorganic phase in the microemulsion environment were key factors for the achievement of a complete coating of the microspheres with calcium phosphate. The inorganic shell is constituted of small crystals of octacalcium phosphate, which control gelatin and alendronate release.
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