Abstract
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.
Highlights
An effective bone tissue engineering (BTE) scaffold must own several key properties: interconnected porosity with adequate pore size distribution (10–400 mm), biocompatibility, biodegradability and/or bioresorbability over longer time periods, adequate mechanical properties in the short-term and physicochemical cues for the cells.[4,5] The success of BTE scaffolds in clinical applications for bone repair and regeneration is linked to the fulfillment of this complex array of properties simultaneously, which implies that a composite PaperJournal of Materials Chemistry B approach, combining organic and inorganic biomaterials could be of great advantage.[6]
Quantification was made by capillary electrophoresis:[40] this method combines the in situ complexation of free copper ions with ethylenediaminetetraacetic acid (EDTA) in the electrophoresis column to the subsequent detection and quantification of the complexes by UV radiation.[40]
In previous works it was shown by energy dispersive X-ray spectroscopy (EDX) that copper is present in copper(II)– chitosan samples without significant contaminations from other elements.[39]
Summary
An effective BTE scaffold must own several key properties: interconnected porosity with adequate pore size distribution (10–400 mm), biocompatibility, biodegradability and/or bioresorbability over longer time periods, adequate mechanical properties in the short-term and physicochemical cues for the cells.[4,5] The success of BTE scaffolds in clinical applications for bone repair and regeneration is linked to the fulfillment of this complex array of properties simultaneously, which implies that a composite PaperJournal of Materials Chemistry B approach, combining organic and inorganic biomaterials could be of great advantage.[6]. Hydroxyapatite (HA) has been widely studied and used for bone tissue engineering applications.[10] The production of 3D HA scaffolds from precursor powders was demonstrated using several methods, including thermal bonding, phase leaching, foam replica and additive manufacturing.[11] Inorganic HA scaffolds have optimal morphology and porosity, but are usually characterized by insufficient mechanical properties.[11] For this reason, a composite approach aiming at the combination of HA powders with natural polymers was often preferred, proving to be a great candidate method for the development of scaffolds.[9,12,13] Composite scaffolds based on HA powder dispersed in collagen, silk fibroin, gelatin and chitosan have been all extensively studied.[14] Chitosan/HA scaffolds, in particular, are expected to present competitive biocompatibility, osteoconductivity and biodegradation together with sufficient mechanical strength for orthopedic use.[9] HA (Ca10(PO4)6(OH)2) is a natural choice when designing novel bone TE approaches: it is a major component of vertebrate hard tissues and it makes up 60–70% of the mass of bone and 98% of the mass of dental enamel. Desired ions can be added to a simulated body fluid (SBF) solution and precipitated to obtain ion-substituted HA19 with biomimetic potential.[20,21] Notably, the work published by Bonfield, Best and collaborators on the synthesis of silicon substituted HA showed improved attachment, growth and production of extracellular matrix by osteoblasts.[22,23] Substituted HA has already been combined with polymeric matrices in previous studies.[24]
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