Although doped bioceramics have been widely investigated for biomedical applications, the codoped bioceramics remain mostly unexplored for bone regeneration applications. For example, the impact of codoping of Sr2+ and Fe3+ ions on the phase stability and cytocompatibility is not explored so far. In this perspective, the objective of the present study is to quantitatively understand this aspect in case of Fe/Sr codoped biphasic calcium phosphate (BCP). Following sol–gel synthesis, codoped BCP samples with Sr/Fe dopant concentrations of 2, 10, 20, 30, and 40 mol % as well as doped BCPs with single dopant (Sr or Fe) with similar compositions were calcined at 800 °C in air. Using extensive Rietveld analysis, the dopant content dependent crystallographic properties (e.g lattice parameters) and phase stability of HA/TCP are quantitatively assessed. In vitro cytocompatibility of codoped samples has been assessed using mouse osteoblast cells. An important observation is that, while singular dopant of Sr/Fe at 20 mol % or higher amount reduces cell viability significantly, osteoblast viability is not compromised to any significant extent on Sr/Fe codoped BCP, compared to undoped BCP. Our results indicate that one can tailor osteoblast functionality by controlling the codopant content. More importantly, all the codoped BCPs support cell proliferation, when single doped BCP exhibits significant reductionin cell viability, at dopant content of 10 mol % or higher. Cell morphological analysis supports extensive cell spreading on codoped BCPs. An attempt has been made to correlate the variation in cellular response with HA/TCP ratio and ion dissolution behavior. Taken together, the present work establishes unique advantage of Sr/Fe codoping approach toward realizing their bone replacement application.
We report the first synthesis of Cu doped in the core region of ZnO nanocrystals and fluorescing in the blue region, establishing the novel possibility of using these as fluorescent probes.
Hydroxyapatite, tricalcium phosphate, and a mixture of these, i.e biphasic calcium phosphate (BCP), are widely employed as ceramic materials in hard tissue engineering, despite their poor mechanical and functional properties. The method of ionic substitution inside their lattice structures has been examined extensively by researchers in their long efforts to develop materials, that closely resemble natural hard tissues. The presence of dopants has a deep impact on the phase assemblage, structural, and functional behaviors of BCP. In this context, the goal of the current article is to cover different aspects of ongoing research on doped biphasic calcium phosphate. Apart from providing brief descriptions of different synthesis routes for producing ion-modified BCPs, the limitations of each technique are also discussed. In addition, particular emphasis has been given to describing the key experimental results, which elucidate the structural changes occurring due to doping. In particular, the preferable substitution sites of different dopant ions and the resulting crystallographic changes are depicted quite elaborately. Finally, the effects of substitution on biological and mechanical properties of BCP are briefly mentioned. In summary, the present review focuses on the ionic substitutions in BCP systems and their collective effects on material behaviors.
Among synthetic biomaterials, calcium phosphate (CaP)-based bioceramics, specifically hydroxyapatite (HA) and tricalcium phosphate (TCP) as well as biphasic calcium phosphate (BCP), are widely investigated in the biomedical community. The arrangement of different ions in the CaP crystal structure allows one to dope with metal ions, while tailoring the properties. The present article reviews some of the multifaceted research in the field of (multi)-ion-doped BCP, particularly on the aspects of biomedical applications. After summarizing different synthesis methods, a brief overview of experimental techniques and results to probe the dopant site and local structure surrounding the dopants has been provided, with an emphasis on the XRD-based Rietveld refinement and EXAFS (extended X-ray absorption fine structure) method. The effect of ion substitution on the functional properties, such as dielectric and magnetic behavior, of BCP has also been discussed. Importantly, in vitro and in vivo biocompatibility of doped BCP has been elucidated along with in silico studies on the biomaterial−biomolecule interaction. Toward the end, the results of the published clinical trial study and limited commercialization efforts will be illustrated.
In the perspective of dental restorative applications, co-doped bioceramics have not been explored much. From the clinical perspective, a successful dental implant is expected to interact with peri-prosthetic bones, gingival tissue, and surrounding connective tissues. The interaction of implant and implant coating materials with bone tissue is well studied. However, their interaction with surrounding epithelial components needs scientific validation. In this context, the present study aims at quantitative evaluation of the electrical properties of Fe/Sr co-doped biphasic calcium phosphate (BCP) samples and assessment of their cytocompatibility with epithelial (vero) cells. Sr/Fe co-doped BCPs were prepared by sol-gel synthesis technique, with different dopant concentration. Impact of co-doping on conductivity was assessed and interestingly an increase in conductivity with dopant amount was recorded in different co-doped BCPs. Cellular study showed the significant ( p = 0.01) increase in both cellular viability and functionality with increasing conductivity of samples. Higher epithelial cell adhesion indicates that (Sr/Fe) co-doped BCP would be favorable for faster epithelial sealing and also would reduce the chances of infection. Real-time PCR and immunofluorescence studies indicated that the expression of the epithelial marker (E-cadherin) significantly ( p = 0.01) increased in 10, 30 and 40 mol% co-doped samples in comparison to undoped BCP. In contrast to E-cadherin, fold change of β-catenin remains unchanged amongst the co-doped ceramics, implying the absence of tumorigenic potential of (Sr/Fe) co-doped BCP. In addition, immune-fluorescence signatures for cellular polarity are established from enhanced expression PARD3 protein, which has major relevance for cellular morphogenesis and cell division. Summarizing, the present study establishes the efficacy of Sr/Fe co-doped BCPs as a dental implant coating material and its ability to modulate vero cell functionality.
In experimental research-driven biomaterials science, the influence of different material properties (elastic stiffness, surface energy, etc.) and, to a relatively lesser extent, biophysical stimulation (electric/magnetic) on cell−material interactions has been extensively investigated. Despite the central importance of protein adsorption on cell−material interactions, the quantitative analysis to probe into the role of physicochemical factors in protein adsorption remains largely unexplored in biomaterials science. In recent studies, the critical role of electric field stimulation toward the modulation of cell functionality in implantable biomaterials has been experimentally demonstrated. Given this background, we investigated the influence of external electric field stimulation (upto 1.00 V/nm) on fibronectin (FN) adsorption on a hydroxyapatite (HA) (001) surface at 300 K using the all-atom molecular dynamics (MD) simulation method. FN adsorption was found to be governed by attractive electrostatic interactions, which changed with the electric field strength. Nonmonotonous changes in the structural integrity of FN were recorded with the change in the field strength and direction. This can be attributed to the spatial rearrangement of the positions of local charges and the global structural changes of proteins. The dipole moment vectors of FN, water, and HA quantitatively exhibited a similar pattern of orienting themselves parallel to the field direction, with field strength-dependent increase in their magnitudes. No significant change has been recorded for the radial distribution function of water surrounding FN. Field-dependent variation in the salt bridge nets and the number of hydrogen bonds between FN and HA were also examined. One of the important results in the context of cell−material interaction is that the RGD (Arg-Gly-Asp) sequence of FN was exposed to the solvent side when the field was applied along an outward direction perpendicular to the HA (001) surface. In summary, the present study provides molecular insights into the influence of electric field stimulation on phenomenological interactions involved in FN adsorption on the HA surface.
In experimental research driven biomaterials science, the influence of different material properties (elastic stiffness, surface energy, etc.), and to a relatively lesser extent, the biophysical stimulation (electric/magnetic) on the cell-material interaction has been extensively investigated. Considering the central importance of the protein adsorption on cell-material interaction, the role of physiochemical factors on the protein adsorption is also probed. Despite its significance, the quantitative analysis of many such aspects remains largely unexplored in biomaterials science. In recent studies, the critical role of electric field stimulation towards modulation of cell functionality on implantable biomaterials has been experimentally demonstrated. Given this background, we investigated the influence of external electric field stimulation (upto 1.00 V/nm) on fibronectin (FN) adsorption on hydroxyapatite, HA (100) surface at 300K using all-atom MD simulation method. Fibronectin adsorption was found to be governed by the attractive electrostatic interaction, which changed with the electric field strength. Non-monotonous changes in structural integrity of fibronectin were recorded with the change in field strength and direction. This can be attributed to the spatial rearrangement of local charges and global structural changes of the protein. The dipole moment vectors of fibronectin, water and HA quantitatively exhibited similar pattern of orienting themselves parallel to the field direction, with field strength dependent increase in their magnitudes. No significant change has been recorded for radial distribution function of water surrounding fibronectin. Field dependent variation in the salt bridge nets and number of hydrogen bonds between fibronectin and hydroxyapatite were also examined. One of the important results in the context of the cell-material interaction is that the RGD sequence of FN was exposed to solvent side, when the field was applied along a direction outward perpendicular to HA (001) surface. Summarizing, the present study provides quantitative insights into the influence of electric field stimulation on biomolecular interactions involved in fibronectin adsorption on hydroxyapatite surface.
Hyperphosphorylated guanosine nucleotide (p)ppGpp, synthesized by Rel proteins, regulates the stringent response pathway responsible for biofilm growth and persister cell formation in the stationary phase of mycobacteria. The discovery of vitamin C as a potent inhibitor of Rel protein activities raises the prospect of such a tetrone lactone to prevent biofilm growth and persister cell formation. The closely related isotetrone lactone derivatives are identified in the present study as potent inhibitors of the above processes in a mycobacterium. Isotetrone lactone derivatives are synthesized from appropriate α-ketocarboxylic acids, derived from the a-amino acids. Aldol condensation with formaldehyde, followed by the lactone formation, completes synthesis of isotetrone derivatives, possessing varied substituents atC-4 carbon, in good yields. A series of biochemical evaluations of biofilm growth and persister cell formation inM. smegmatisis conducted. Among the derivatives, isotetrone possessing phenyl substituent atC-4 carbon completely inhibit the biofilm formation at 400 μg mL-1concentration, 84 h of post-exposure, followed by a moderate inhibition by the isotetrone possessingp-hydroxyphenyl substituent. Whereas, the latter isotetrone inhibits the growth of cells at 400 μg mL-1f.c. when monitored for 2 weeks, under PBS starvation condition. Isotetrones also potentiate the inhibition of antibiotic tolerant regrowth of cells by ciprofloxacin antibiotic (0.75 μg mL-1) and thus act as bio-enhancers. The combination is shown to significantly arrest the emergence of ciprofloxacin-resistant genetic mutants. The observations suggest that isotetrones in combination with ciprofloxacin are therapeutically superior when administered together. Systematic molecular dynamics studies show that isotetrone derivative binds to Rel protein more efficiently than vitamin C and the binding is aided by hydrogen bonding, van der Waals and electrostatic interactions at a binding site possessing serine, threonine, lysine and arginine residues. The present study establishes that the identified isotetrone derivatives (i) act as inhibitors ofM. smegmatisbiofilm growth and (ii) arrest the re-emergence of recalcitrant persister cells when administered together with ciprofloxacin antibiotic. Results of this study establish that isotetrones as new chemical entities that interfere with stringent response pathways in a mycobacterium under stress and permit overcoming the multidrug-resistant persister cell emergence in the bacterium.
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