Bacterial infection of implanted scaffolds may have fatal consequences and, in combination with the emergence of multidrug bacterial resistance, the development of advanced antibacterial biomaterials ...and constructs is of great interest. Since decades ago, metals and their ions had been used to minimize bacterial infection risk and, more recently, metal-based nanomaterials, with improved antimicrobial properties, have been advocated as a novel and tunable alternative. A comprehensive review is provided on how metal ions and ion nanoparticles have the potential to decrease or eliminate unwanted bacteria. Antibacterial mechanisms such as oxidative stress induction, ion release and disruption of biomolecules are currently well accepted. However, the exact antimicrobial mechanisms of the discussed metal compounds remain poorly understood. The combination of different metal ions and surface decorations of nanoparticles will lead to synergistic effects and improved microbial killing, and allow to mitigate potential side effects to the host. Starting with a general overview of antibacterial mechanisms, we subsequently focus on specific metal ions such as silver, zinc, copper, iron and gold, and outline their distinct modes of action. Finally, we discuss the use of these metal ions and nanoparticles in tissue engineering to prevent implant failure.
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•Distinct mechanisms concertedly contribute to the antibacterial effect of metal ions and nanoparticles in tissue engineering.•Metal-mediated antibacterial mechanisms include membrane disruption, ROS generation, and protein/DNA damage.•As different metals/nanoparticles prompt different antibacterial mechanisms, biomaterials may benefit from combinatorial use.•Application specific antibacterial biomaterials with controlled metal release rates are achievable by combining techniques.
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Scaffolds that secure and deliver therapeutic ingredients like signaling molecules and stem cells hold great promise for drug delivery and tissue engineering. Employing a core–shell ...design for scaffolds provides a promising solution. Some unique methods, such as co-concentric nozzle extrusion, microfluidics generation, and chemical confinement reactions, have been successful in producing core–shelled nano/microfibers and nano/microspheres. Signaling molecules and drugs, spatially allocated to the core and/or shell part, can be delivered in a controllable and sequential manner for optimal therapeutic effects. Stem cells can be loaded within the core part on-demand, safely protected from the environments, which ultimately affords ex vivo culture and in vivo tissue engineering. The encapsulated cells experience three-dimensional tissue-mimic microenvironments in which therapeutic molecules are secreted to the surrounding tissues through the semi-permeable shell. Tuning the material properties of the core and shell, changing the geometrical parameters, and shaping them into proper forms significantly influence the release behaviors of biomolecules and the fate of the cells. This topical issue highlights the immense usefulness of core–shell designs for the therapeutic actions of scaffolds in the delivery of signaling molecules and stem cells for tissue regeneration and disease treatment.
Biomaterials in the form of scaffolds hold great promise in the regeneration of diseased tissues. The scaffolds stimulate cellular adhesion, proliferation and differentiation. While the scaffold ...composition will dictate their biocompatibility, their porosity plays a key role in allowing proper cell penetration, nutrient diffusion as well as bone ingrowth. Porous scaffolds are processed with the help of a wide variety of techniques. Designing scaffolds with the appropriate porosity is a complex issue since this may jeopardize other physico-chemical properties. From a macroscopic point of view, parameters such as the overall architecture, pore morphology, interconnectivity and pore size distribution, have unique roles in allowing bone ingrowth to take place. From a microscopic perspective, the adsorption and retention of proteins in the microporosities of the material will dictate the subsequent cell adhesion. Therefore, the microstructure of the substrate can determine cell proliferation as well as the expression of specific osteogenic genes. This review aims at discussing the effect of micro- and macroporosity on the physico-chemical and biological properties of scaffolds for musculo-skeletal tissue regeneration.
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•Osteoconduction and osteoinduction of a biomaterial relies on its pattern of micro/macroporosity.•Size, morphology, distribution and interconnection of the pores influence both mechanical and biological properties.•Macroporosity (pores>50μm) determines cell colonization and therefore growth of vascular and bone tissue.•Micropores (<50μm) are crucial for proteins adsorption, which in turn can determine cell fate.
Biomaterials and scaffolds for Tissue Engineering are widely used for an effective healing and regeneration. However, the implantation of these scaffolds causes an innate immune response in which the ...macrophage polarization from M1 (pro-inflammatory) to M2 (anti-inflammatory) phenotype is crucial to avoid chronic inflammation. Recent studies have showed that the use of bioactive ions such as cobalt (Co
), copper (Cu
) and magnesium (Mg
) could improve tissue regeneration, although there is limited evidence on their effect on the macrophage response. Therefore, we investigated the immunomodulatory potential of Co
, Cu
and Mg
in macrophage polarization. Our results indicate that Mg
and concentrations of Cu
lower than 10 μM promoted the expression of M2 related genes. However, higher concentrations of Cu
and Co
(100 μM) stimulated pro-inflammatory marker expression, indicating a concentration dependent effect of these ions. Furthermore, Mg
were able to decrease M1 marker expression in presence of a mild pro-inflammatory stimulus, showing that Mg
can be used to modulate the inflammatory response, even though their application can be limited in a strong pro-inflammatory environment.
Protein-protein interactions (PPIs) mediate a large number of important regulatory pathways. Their modulation represents an important strategy for discovering novel therapeutic agents. However, the ...features of PPI binding surfaces make the use of structure-based drug discovery methods very challenging. Among the diverse approaches used in the literature to tackle the problem, linear peptides have demonstrated to be a suitable methodology to discover PPI disruptors. Unfortunately, the poor pharmacokinetic properties of linear peptides prevent their direct use as drugs. However, they can be used as models to design enzyme resistant analogs including, cyclic peptides, peptide surrogates or peptidomimetics. Small molecules have a narrower set of targets they can bind to, but the screening technology based on virtual docking is robust and well tested, adding to the computational tools used to disrupt PPI. We review computational approaches used to understand and modulate PPI and highlight applications in a few case studies involved in physiological processes such as cell growth, apoptosis and intercellular communication.
Tissue engineering focuses on the development of materials as biosubstitutes that can be used to regenerate, repair, or replace damaged tissues. Alongside this, 3D printing has emerged as a promising ...technique for producing implants tailored to specific defects, which in turn increased the demand for new inks and bioinks. Especially supramolecular hydrogels based on nucleosides such as guanosine have gained increasing attention due to their biocompatibility, good mechanical characteristics, tunable and reversible properties, and intrinsic self-healing capabilities. However, most existing formulations exhibit insufficient stability, biological activity, or printability. To address these limitations, we incorporated polydopamine (PDA) into guanosine-borate (GB) hydrogels and developed a PGB hydrogel with maximal PDA incorporation and good thixotropic and printability qualities. The resulting PGB hydrogels exhibited a well-defined nanofibrillar network, and we found that PDA incorporation increased the hydrogel's osteogenic activity while having no negative effect on mammalian cell survival or migration. In contrast, antimicrobial activity was observed against the Gram-positive bacteria
and
. Thus, our findings suggest that our PGB hydrogel represents a significantly improved candidate as a 3D-printed scaffold capable of sustaining living cells, which may be further functionalized by incorporating other bioactive molecules for enhanced tissue integration.
The use of copper (Cu2+) and cobalt (Co2+) has been described to stimulate blood vessel formation, a key process for the success of tissue regeneration. However, understanding how different ...concentrations of these ions affect cellular response is important to design scaffolds for their delivery to better fine tune the angiogenic response. On the one hand, gene expression analysis and the assessment of tubular formation structures with human umbilical vein endothelial cells (HUVEC) revealed that high concentrations (10μM) of Cu2+ in early times and lower concentrations (0.1 and 1μM) at later times (day 7) enhanced angiogenic response. On the other hand, higher concentrations (25μM) of Co2+ during all time course increased the angiogenic gene expression and 0.5, 5 and 25μM enhanced the ability to form tubular structures. To further explore synergistic effects combining both ions, the non-toxic concentrations were used simultaneously, although results showed an increased cell toxicity and no improvement of angiogenic response. These results provide useful information for the design of Cu2+ or Co2+ delivery scaffolds in order to release the appropriate concentration during time course for blood vessel stimulation.
Over the past few years, attention has been focused on the therapeutic roles in designing bone scaffolds for successful repair and regeneration. Indeed, biologically dynamic events in the bone ...healing process involve many of the molecules and cells adherent to the scaffold. Recent bone scaffolds have been designed considering intrinsic chemical and physical factors and exogenous/extrinsic cues that induce bone regeneration. Here, we attempt to topically review the current trends and to suggest featured strategies for the design of therapeutically relevant bone scaffolds taking into account recent studies and applications.
It is widely known that bone has intrinsic capacity to self-regenerate after injury. However, the physiological regeneration process can be impaired when there is an extensive damage. One of the main ...reasons is due to the inability to establish a new vascular network that ensures oxygen and nutrient diffusion, leading to a necrotic core and non-junction of bone. Initially, bone tissue engineering (BTE) emerged to use inert biomaterials to just fill bone defects, but it eventually evolved to mimic bone extracellular matrix and even stimulate bone physiological regeneration process. In this regard, the stimulation of osteogenesis has gained a lot of attention especially in the proper stimulation of angiogenesis, being critical to achieve a successful osteogenesis for bone regeneration. Besides, the immunomodulation of a pro-inflammatory environment towards an anti-inflammatory one upon scaffold implantation has been considered another key process for a proper tissue restoration. To stimulate these phases, growth factors and cytokines have been extensively used. Nonetheless, they present some drawbacks such as low stability and safety concerns. Alternatively, the use of inorganic ions has attracted higher attention due to their higher stability and therapeutic effects with low side effects. This review will first focus in giving fundamental aspects of initial bone regeneration phases, focusing mainly on inflammatory and angiogenic ones. Then, it will describe the role of different inorganic ions in modulating the immune response upon biomaterial implantation towards a restorative environment and their ability to stimulate angiogenic response for a proper scaffold vascularization and successful bone tissue restoration.
The impairment of bone tissue regeneration when there is excessive damage has led to different tissue engineered strategies to promote bone healing. Significant importance has been given in the immunomodulation towards an anti-inflammatory environment together with proper angiogenesis stimulation in order to achieve successful bone regeneration rather than stimulating only the osteogenic differentiation. Ions have been considered potential candidates to stimulate these events due to their high stability and therapeutic effects with low side effects compared to growth factors. However, up to now, no review has been published assembling all this information together, describing individual effects of ions on immunomodulation and angiogenic stimulation, as well as their multifunctionality or synergistic effects when combined together.
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The load transfer from metallic prosthesis to tissue plays an important role in the success of a designed device. From a mechanical behavior point of view, the load transfer will be favored when the ...elastic modulus between the metallic implant and the bone tissue are similar. Titanium and Ti-6Al-4V are the most commonly used metals and alloys in the field of dental implants, although they present high elastic moduli and hence trigger bone resorption. We propose the use of low-modulus β-type titanium alloys that can improve the growth of new bone surrounding the implant. We designed dental implants with identical morphology and micro-roughness composed of: Ti-15Zr, Ti-19.1Nb-8.8Zr, Ti-41.2Nb-6.1Zr, and Ti-25Hf-25Ta. The commercially pure Ti cp and Ti-6Al-4V were used as control samples. The alloys were initially mechanically characterized with a tensile test using a universal testing machine. The results showed the lowest elastic modulus for the Ti-25Hf-25Ta alloy. We implanted a total of six implants in the mandible (3) and maxilla (3) for each titanium alloy in six minipigs and evaluated their bone index contact (i.e., the percentage of new bone in contact with the metal-BIC%) after 3 and 6 weeks of implantation. The results showed higher BIC% for the dental implants with lowest elastic modulus, showing the importance of decreasing the elastic modulus of alloys for the successful osseointegration of dental implants.
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