Bioactive glass-based organic/inorganic hybrids: an analysis of the current trends in polymer design and selection.

Bioactive glass-based organic/inorganic hybrids are a family of materials holding great promise in the biomedical field. Developed from bioactive glasses following recent advances in sol-gel and polymer chemistry, they can overcome many limitations of traditional composites typically used in bone repair and orthopedics. Thanks to their unique molecular structure, hybrids are often characterized by synergistic properties that go beyond a mere combination of their two components; it is possible to synthesize materials with a wide variety of mechanical and biological properties. The polymeric component, in particular, can be tailored to prepare tough, load-bearing materials, or rubber-like elastomers. It can also be a key factor in the determination of a wide range of interesting biological properties. In addition, polymers can also be used within hybrids as carriers for therapeutic ions (although this is normally the role of silica). This review offers a brief look into the history of hybrids, from the discovery of bioactive glasses to the latest developments, with a particular emphasis on polymer design and chemistry. First the benefits and limitations of hybrids will be discussed and compared with those of alternative approaches (for instance, nanocomposites). Then, key advances in the field will be presented focusing on the polymeric component: its chemistry, its physicochemical and biological advantages, its drawbacks, and selected applications. Comprehensive tables summarizing all the polymers used to date to fabricate sol-gel hybrids for biomedical applications are also provided, to offer a handbook of all the available candidates for hybrid synthesis. In addition to the current trends, open challenges and possible avenues of future development are proposed.

Tailored therapeutic release from polycaprolactone-silica hybrids for the treatment of osteomyelitis: antibiotic rifampicin and osteogenic silicates.

The treatment of osteomyelitis, a destructive inflammatory process caused by bacterial infections to bone tissue, is one of the most critical challenges of orthopedics and bone regenerative medicine. The standard treatment consists of intense antibiotic therapies combined with tissue surgical debridement and the application of a bone defect filler material. Unfortunately, commercially available candidates, such as gentamicin-impregnated polymethylmethacrylate cements, possess very poor pharmacokinetics (i.e., 24 hours burst release) and little to no regenerative potential. Fostered by the intrinsic limitations associated with conventional treatments, alternative osteostimulative biomaterials with local drug delivery have recently started to emerge. In this study, we propose the use of a polycaprolactone-silica sol-gel hybrid material as carrier for the delivery of rifampicin, an RNA-polymerase blocker often used to treat bone infections, and of osteostimulative silicate ions. The release of therapeutic agents from the material is dual, offering two separate and simultaneous effects, and decoupled, meaning that the kinetics of rifampicin and silicate releases are independent from each other. A series of hybrid formulations with increasing amounts of rifampicin was prepared. The antibiotic loading efficacy, as well as the release profiles of rifampicin and silicates were measured. The characterization of cell viability and differentiation of rat primary osteoblasts and antibacterial performance were also performed. Gram-positive Staphylococcus aureus and Gram-negative Pseudomonas aeruginosa and Escherichia coli were selected due to their high occurrence in bone infections. Results confirmed that rifampicin can be successfully loaded within the hybrids without significant degradation and that it is possible to tailor the antibiotic release according to need. Once in a physiological environment, the rapid release of silicates was associated with optimal cell proliferation and the overexpression of osteoblastic differentiation. Simultaneously, rifampicin is delivered over the course of several weeks with significant inhibition of all tested strains. In particular, the materials caused a growth reduction of 7-10 orders of magnitude in Staphylococcus aureus, the major strain responsible for osteomyelitis worldwide. Our data strongly suggest that PCL/silica hybrids are a very promising candidate to develop bone fillers with superior biological performance compared to currently available options. Thanks to their unique synthesis route and their dual tailored release they can promote bone regeneration while reducing the risk of infection for several weeks upon implantation.

Polycaprolactone Electrospun Fiber Mats Prepared Using Benign Solvents: Blending with Copper(II)-Chitosan Increases the Secretion of Vascular Endothelial Growth Factor in a Bone Marrow Stromal Cell Line.

Inducing the formation of new blood vessels (angiogenesis) is an essential requirement for successful tissue engineering. Approaches have been proposed to enhance angiogenesis using growth factors and other biomolecules; however, this approaches present drawbacks in terms of high cost and patient safety. Copper is known to effectively regulate angiogenesis and can offer a more cost-effective alternative than the direct use of growth factors. With this study, a strategy to incorporate copper in electrospun fibrous scaffolds with pro-angiogenic properties is presented. Polycaprolactone (PCL) and copper(II)-chitosan are electrospun using benign solvents. The morphological and physicochemical properties of the fiber mats are investigated through scanning electron microscopy (SEM), static contact angle measurements, energy dispersive X-ray, and Fourier-transform infrared spectroscopies. Scaffold stability in phosphate buffered saline at 37 °C is monitored over 1 week. A bone marrow stromal cell line (ST-2) is cultured for 7 days and its behavior is evaluated using SEM, fluorescence microscopy and a tetrazolium salt-based colorimetric assay. Results confirm that PCL/copper(II)-chitosan is suitable for electrospinning. The fiber mats are biocompatible and favor cell colonization and infiltration. Most notably, the angiogenic potential of PCL/copper(II)-chitosan blends is confirmed by a three-fold increase in VEGF secretion by ST-2 cells in the presence of copper(II)-chitosan.

Chitosan/hydroxyapatite composite bone tissue engineering scaffolds with dual and decoupled therapeutic ion delivery: copper and strontium.

Therapeutic metal ions are a family of metal ions characterized by specific biological properties that could be exploited in bone tissue engineering, avoiding the use of expensive and potentially problematic growth factors and other sensitive biomolecules. In this work, we report the successful preparation and characterization of two material platforms containing therapeutic ions: a copper(ii)-chitosan derivative and a strontium-substituted hydroxyapatite. These biomaterials showed ideal ion release profiles, offering burst release of an antibacterial agent together with a more sustained release of strontium in order to achieve long-term osteogenesis. We combined copper(ii)-chitosan and strontium-hydroxyapatite into freeze-dried composite scaffolds. These scaffolds were characterized in terms of morphology, mechanical properties and bioactivity, defined here as the ability to trigger the deposition of novel calcium phosphate in contact with biological fluids. In addition, a preliminary biological characterization using cell line osteoblasts was performed. Our results highlighted that the combination of chitosan and hydroxyapatite in conjunction with copper and strontium has great potential in the design of novel scaffolds. Chitosan/HA composites can be an ideal technology for the development of tissue engineering scaffolds that deliver a complex arrays of therapeutic ions in both components of the composite, leading to tailored biological effects, from antibacterial activity, to osteogenesis and angiogenesis.

Polylactide-based materials science strategies to improve tissue-material interface without the use of growth factors or other biological molecules.

In a large number of medical devices, a key feature of a biomaterial is the ability to successfully bond to living tissues by means of engineered mechanisms such as the enhancement of biomineralization on a bone tissue engineering scaffold or the mimicking of the natural structure of the extracellular matrix (ECM). This ability is commonly referred to as "bioactivity". Materials sciences started to grow interest in it since the development of bioactive glasses by Larry Hench five decades ago. As the main goal in applications of biomedical devices and tissue scaffolds is to obtain a seamless tissue-material interface, achieving optimal bioactivity is essential for the success of most biomaterial-based tissue replacement and regenerative approaches. Polymers derived from lactic acid are largely adopted in the biomedical field, they are versatile, FDA approved and relatively cost-effective. However, as for many other widespread biomedical polymers, they are hydrophobic and lack the intrinsic ability of positively interacting with surrounding tissues. In the last decades scientists have studied many solutions to exploit the positive characteristics of polylactide-based materials overcoming this bottleneck at the same time. The efforts of this research fruitfully produced many effective tissue engineering technologies based on PLA and related biopolymers. This review aims to give an overview on the latest and most promising strategies to improve the bioactivity of lactic acid-based materials, especially focusing on biomolecule-free bulk approaches such as blending, copolymerization or composite fabrication. Avenues for future research to tackle current needs in the field are identified and discussed.

Synthesis and Characterization of Silver-Doped Mesoporous Bioactive Glass and Its Applications in Conjunction with Electrospinning.

Since they were first developed in 2004, mesoporous bioactive glasses (MBGs) rapidly captured the interest of the scientific community thanks to their numerous beneficial properties. MBGs are synthesised by a combination of the sol⁻gel method with the chemistry of surfactants to obtain highly mesoporous (pore size from 5 to 20 nm) materials that, owing to their high surface area and ordered structure, are optimal candidates for controlled drug-delivery systems. In this work, we synthesised and characterised a silver-containing mesoporous bioactive glass (Ag-MBG). It was found that Ag-MBG is a suitable candidate for controlled drug delivery, showing a perfectly ordered mesoporous structure ideal for the loading of drugs together with optimal bioactivity, sustained release of silver from the matrix, and fast and strong bacterial inhibition against both Gram-positive and Gram-negative bacteria. Silver-doped mesoporous glass particles were used in three electrospinning-based techniques to produce PCL/Ag-MBG composite fibres, to coat bioactive glass scaffolds (via electrospraying), and for direct sol electrospinning. The results obtained in this study highlight the versatility and efficacy of Ag-substituted mesoporous bioactive glass and encourage further studies to characterize the biological response to Ag-MBG-based antibacterial controlled-delivery systems for tissue-engineering applications.

Do bioresorbable polyesters have antimicrobial properties?

Biodegradable and bioresorbable polyesters (BBPEs) are a widespread class of aliphatic polymers with a plethora of applications in the medical field. Some reports speculate that these polymers have intrinsic antibacterial activity as a consequence of their acidic degradation by-products. The release of organic acids as a result of the hydrolytic degradation of BBPEs in vivo and the resulting pH drop could be an effective inhibitor of the growth of pathogens in the local environment adjacent to BBPE-based devices. However, there is no clear and conclusive evidence in the literature concerning the antibacterial activity of BBPE to support or refute this hypothesis. In this communication we address this point through an assessment of the antibacterial properties of six well-established commercially available BBPEs. Agar diffusion assays and optical density measurements at 600 nm were performed on all the polymer samples to characterize the growth of bacteria and any potential inhibition over an incubation period of 24 h. The results indicated that BBPEs do not possess an intrinsic and immediate antibacterial activity, which is consistent with the clear mismatch between the time-scales for bacterial growth and the rate of degradation of the polyesters.

Fabrication and characterization of copper(II)-chitosan complexes as antibiotic-free antibacterial biomaterial.

We produced and characterized copper(II)-chitosan complexes fabricated via in-situ precipitation as antibiotic-free antibacterial biomaterials. Copper was bound to chitosan from a dilute acetic acid solution of chitosan and copper(II) chloride exploiting the ability of the polysaccharide to chelate metal ions. The influence of copper(II) ions on the morphology, structure and hydrophobicity of the complexes was evaluated using scanning electron microscopy, energy-dispersive X-ray spectroscopy, attenuated total reflectance Fourier transform infrared spectroscopy and static contact-angle measurements. To assess the biological response to the materials, cell viability and antibacterial assays were performed using mouse embryonic fibroblasts and both Gram-positive and -negative bacteria. Combined analysis of cell and bacterial studies identified a threshold concentration at which the material shows outstanding antibacterial properties without significantly affecting fibroblast viability. This key outcome sets copper(II)- chitosan as a promising biomaterial and encourages further investigation on similar systems toward the development of new antibiotic-free antibacterial technologies.