Viviana Mouriño

Metallic ions as therapeutic agents in tissue engineering scaffolds: an overview of their biological applications and strategies for new developments

This article provides an overview on the application of metallic ions in the fields of regenerative medicine and tissue engineering, focusing on their therapeutic applications and the need to design strategies for controlling the release of loaded ions from biomaterial scaffolds. A detailed summary of relevant metallic ions with potential use in tissue engineering approaches is presented. Remaining challenges in the field and directions for future research efforts with focus on the key variables needed to be taken into account when considering the controlled release of metallic ions in tissue engineering therapeutics are also highlighted.

Single-step electrochemical deposition of antimicrobial orthopaedic coatings based on a bioactive glass/chitosan/nano-silver composite system

Composite orthopaedic coatings with antibacterial capability containing chitosan, Bioglass® particles (9.8μm) and silver nanoparticles (Ag-np) were fabricated using a single-step electrophoretic deposition (EPD) technique, and their structural and preliminary in vitro bactericidal and cellular properties were investigated. Stainless steel 316 was used as a standard metallic orthopaedic substrate. The coatings were compared with EPD coatings of chitosan and chitosan/Bioglass®. The ability of chitosan as both a complexing and stabilizing agent was utilized to form uniformly deposited Ag-np. Due to the presence of Bioglass® particles, the coatings were bioactive in terms of forming carbonated hydroxyapatite in simulated body fluid (SBF). Less than 7wt.% of the incorporated silver was released over the course of 28days in SBF and the possibility of manipulating the release rate by varying the deposition order of coating layers was shown. The low released concentration of Ag ions (<2.5ppm) was efficiently antibacterial against Staphyloccocus aureus up to 10days. Although chitosan and chitosan/Bioglass® coating supported proliferation of MG-63 osteoblast-like cells up to 7days of culture, chitosan/Bioglass®/Ag-np coatings containing 342 μg of Ag-np showed cytotoxic effects. This was attributed to the relatively high concentration of Ag-np incorporated in the coatings.

Therapeutic inorganic ions in bioactive glasses to enhance bone formation and beyond

Bioactive glasses (BG) are being widely used for bone tissue engineering applications due to their bioactivity (ability to form strong bonds to bone) and their stimulating effects on bone formation. Recently, progress has been made to enhance the biological impact of BGs by incorporating specific metallic ions in silicate (or phosphate) glasses, including boron, copper, cobalt, silver, zinc and strontium. This review summarizes the newest developments on novel compositions of bioactive glasses in the field of bone tissue engineering related to osteogenesis and angiogenesis. Furthermore, new applications areas for bioactive glasses, including nerve regeneration and cancer treatment, are highlighted.

Electrophoretic deposition of gentamicin-loaded bioactive glass/chitosan composite coatings for orthopaedic implants.

Despite their widespread application, metallic orthopaedic prosthesis failure still occurs because of lack of adequate bone-bonding and the incidence of post-surgery infections. The goal of this research was to develop multifunctional composite chitosan/Bioglass coatings loaded with gentamicin antibiotic as a suitable strategy to improve the surface properties of metallic implants. Electrophoretic deposition (EPD) was applied as a single-step technology to simultaneously deposit the biopolymer, bioactive glass particles, and the antibiotic on stainless steel substrate. The microstructure and composition of the coatings were characterized using SEM/EDX, XRD, FTIR, and TGA/DSC, respectively. The in vitro bioactivity of the coatings was demonstrated by formation of hydroxyapatite after immersion in simulated body fluid (SBF) in a short period of 2 days. High-performance liquid chromatography (HPLC) measurements indicated the release of 40% of the loaded gentamicin in phosphate buffered saline (PBS) within the first 5 days. The developed composite coating supported attachment and proliferation of MG-63 cells up to 10 days. Moreover, disc diffusion test showed improved bactericidal effect of gentamicin-loaded composite coatings against S. aureus compared to control non-gentamicin-loaded coatings.

Composite polymer-bioceramic scaffolds with drug delivery capability for bone tissue engineering

Introduction: Next-generation scaffolds for bone tissue engineering (BTE) should exhibit the appropriate combination of mechanical support and morphological guidance for cell proliferation and attachment while at the same time serving as matrices for sustained delivery of therapeutic drugs and/or biomolecular signals, such as growth factors. Drug delivery from BTE scaffolds to induce the formation of functional tissues, which may need to vary temporally and spatially, represents a versatile approach to manipulating the local environment for directing cell function and/or to treat common bone diseases or local infection. In addition, drug delivery from BTE is proposed to either increase the expression of tissue inductive factors or to block the expression of others factors that could inhibit bone tissue formation. Composite scaffolds which combine biopolymers and bioactive ceramics in mechanically competent 3D structures, including also organic–inorganic hybrids, are being widely developed for BTE, where the affinity and interaction between biomaterials and therapeutic drugs or biomolecular signals play a decisive role in controlling the release rate. Areas covered: This review covers current developments and applications of 3D composite scaffolds for BTE which exhibit the added capability of controlled delivery of therapeutic drugs or growth factors. A summary of drugs and biomolecules incorporated in composite scaffolds and approaches developed to combine biopolymers and bioceramics in composites for drug delivery systems for BTE is presented. Special attention is given to identify the main challenges and unmet needs of current designs and technologies for developing such multifunctional 3D composite scaffolds for BTE. Expert opinion: One of the major challenges for developing composite scaffolds for BTE is the incorporation of a drug delivery function of sufficient complexity to be able to induce the release patterns that may be necessary for effective osseointegration, vascularization and bone regeneration. Loading 3D scaffolds with different biomolecular agents should produce a codelivery system with different, predetermined release profiles. It is also envisaged that the number of relevant bioactive agents that can be loaded onto scaffolds will be increased, whilst the composite scaffold design should exploit synergistically the different degradation profiles of the organic and inorganic components.

Development of bioactive glass based scaffolds for controlled antibiotic release in bone tissue engineering via biodegradable polymer layered coating

Highly porous 45S5 Bioglass(®)-based scaffolds coated with two polymer layers were fabricated to serve as a multifunctional device with controlled drug release capability for bone regeneration applications. An interior poly(d,l-lactide)/poly(ethylene glycol)-(polypropylene glycol)-poly(ethylene glycol) triblock copolymer (Pluronic P123) coating improved the mechanical stability of Bioglass-based scaffolds, while an exterior natural polymer (alginate or gelatin) coating served as an antibiotic drug carrier. The results showed improved mechanical properties of Bioglass-based scaffolds by the bilayer polymer coating. In addition, hydrochloride tetracycline loaded in either alginate or gelatin coatings was released rapidly at the initial stage (∼1 h), while the released rate subsequently decreased and was sustained for 14 days in phosphate buffered saline. Therefore, these layered polymer coated scaffolds exhibit attractive characteristics in terms of improved mechanical properties and controlled drug release, simultaneously with the added advantage that the drug release rate is decoupled from the intrinsic scaffold Bioglass degradation mechanism. The layered polymer coated scaffolds are of interest for drug-delivery enhanced bone regeneration applications.

Novel nanocomposite biomaterials with controlled copper/calcium release capability for bone tissue engineering multifunctional scaffolds

This work aimed to develop novel composite biomaterials for bone tissue engineering (BTE) made of bioactive glass nanoparticles (Nbg) and alginate cross-linked with Cu2+ or Ca2+ (AlgNbgCu, AlgNbgCa, respectively). Two-dimensional scaffolds were prepared and the nanocomposite biomaterials were characterized in terms of morphology, mechanical strength, bioactivity, biodegradability, swelling capacity, release profile of the cross-linking cations and angiogenic properties. It was found that both Cu2+ and Ca2+ are released in a controlled and sustained manner with no burst release observed. Finally, in vitro results indicated that the bioactive ions released from both nanocomposite biomaterials were able to stimulate the differentiation of rat bone marrow-derived mesenchymal stem cells towards the osteogenic lineage. In addition, the typical endothelial cell property of forming tubes in Matrigel was observed for human umbilical vein endothelial cells when in contact with the novel biomaterials, particularly AlgNbgCu, which indicates their angiogenic properties. Hence, novel nanocomposite biomaterials made of Nbg and alginate cross-linked with Cu2+ or Ca2+ were developed with potential applications for preparation of multifunctional scaffolds for BTE.

Nanocomposite scaffolds with tunable mechanical and degradation capabilities: co-delivery of bioactive agents for bone tissue engineering

Novel multifunctional nanocomposite scaffolds made of nanobioactive glass and alginate crosslinked with therapeutic ions such as calcium and copper were developed for delivering therapeutic agents, in a highly controlled and sustainable manner, for bone tissue engineering. Alendronate, a well-known antiresorptive agent, was formulated into microspheres under optimized conditions and effectively loaded within the novel multifunctional scaffolds with a high encapsulation percentage. The size of the cation used for the alginate crosslinking impacted directly on porosity and viscoelastic properties, and thus, on the degradation rate and the release profile of copper, calcium and alendronate. According to this, even though highly porous structures were created with suitable pore sizes for cell ingrowth and vascularization in both cases, copper-crosslinked scaffolds showed higher values of porosity, elastic modulus, degradation rate and the amount of copper and alendronate released, when compared with calcium-crosslinked scaffolds. In addition, in all cases, the scaffolds showed bioactivity and mechanical properties close to the endogenous trabecular bone tissue in terms of viscoelasticity. Furthermore, the scaffolds showed osteogenic and angiogenic properties on bone and endothelial cells, respectively, and the extracts of the biomaterials used promoted the formation of blood vessels in an ex vivo model. These new bioactive nanocomposite scaffolds represent an exciting new class of therapeutic cell delivery carrier with tunable mechanical and degradation properties; potentially useful in the controlled and sustainable delivery of therapeutic agents with active roles in bone formation and angiogenesis, as well as in the support of cell proliferation and osteogenesis for bone tissue engineering.

Multifunctional scaffolds for bone tissue engineering and in situ drug delivery

Abstract: This chapter provides an overview about the development of bone tissue engineering scaffolds with the ability to provide the controlled delivery of therapeutic drugs. Typical drugs considered include gentamicin and other antibiotics generally used to combat osteomyelitis as well as anti-inflammatory drugs and bisphosphonates. Special attention has been given to the technology used for controlling the release of the loaded drugs. A detailed summary of drugs included in bone tissue scaffolds is presented and the many approaches developed to combine organic and inorganic biomaterials in composites for drug-delivery systems are discussed. The remaining challenges in the field are summarized, suggesting also future research directions.

Development and Validation of a Capillary Zone Electrophoresis Method for the Determination of Calcium in Composite Biomaterials

Fil: Cattalini, Juan Pablo. Universidad de Buenos Aires. Facultad de Farmacia y Bioquimica. Departamento de Tecnologia Farmaceutica; Argentina; Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay; Argentina;