Vignesh Muthuvijayan

Biomimicry is becoming deep-rooted as part of bioceramics owing to its numerous functional advantages. Naturally occurring hydroxyapatite (HA) apart from primary nano structures are also characterised by various ionic substitutions. The ease of accommodating such key elements into the HA lattice is known to enhance bone healing properties of bioceramics. In this work, hydroxyapatite synthesized via biomimetic approach was substituted with individual as well as multiple cations for potential applications in bone repair. Ion substitutions of Sr, Mg and Zn was carried out on HA for the first time by using Serratia grown in a defined biomineralization medium. The individual ions of varying concentration substituted in Serratia HA (SHA) (Sr SHA, Mg SHA and Zn SHA) were analysed for crystallinity, functional groups, morphology and crystal size. All three showed decreased crystallinity, phase purity, large agglomerated aggregates and needle-shaped morphologies. Fourier transform infrared spectroscopy (FTIR) spectra indicated increased carbonate content of 5.8% resembling that of natural bone. Additionally, the reduced O-H intensities clearly portrayed disruption of HA lattice and subsequent ion-substitution. The novelty of this study lies primarily in investigating the co-substitution of a combination of 1% Sr, Zn and Mg in SHA and establishing the associated change in bone parameters. Scanning electron microscope (SEM) and transmission electron microscope (TEM) images clearly illustrated uniform nano-sized agglomerates of average dimensions of 20-50 nm length and 8-15 nm width for Sr SHA; 10-40 nm length and 8-10 nm width for both Zn SHA and Mg SHA and 40-70 nm length and 4-10 nm width in the case of 1% Sr, Zn, Mg SHA. In both individual as well as co-substitutions, significant peak shifts were not observed possibly due to the lower concentrations. However, cell volumes increased in both cases due to presence of Sr2+ validating its dominant integration into the SHA lattice. Rich trace ion deposition was presented by energy dispersive X-ray spectroscopy (EDS) and quantified using inductively coupled plasma optical emission spectrometer (ICP-OES). In vitro cytotoxicity studies in three cell lines viz. NIH/3T3 fibroblast cells, MG-63 osteosarcoma cells and RAW 264.7 macrophages showed more than 90% cell viability proving the biocompatible nature of 1% Sr, Zn and Mg in SHA. Microbial biomineralization by Serratia produced nanocrystals of HA that mimicked "bone-like apatite" as evidenced by pure phase, carbonated groups, reduced crystallinity, nano agglomerates, variations in cell parameters, rich ion deposition and non-toxic nature. Therefore ion-substituted and co-substituted biomineralized nano SHA appears to be a suitable candidate for applications in biomedicine addressing bone injuries and aiding regeneration as a result of its characteristics close to that of the human bone.

The authors regret that the following equation, which was used for calculating cell viability in section 2.5.1.1, was inadvertently missed in the final version of the manuscript during proofreading. [Formula presented] The authors would like to apologize for any inconvenience caused.

In this research, biomimetic deposition of “bone-like” apatite by novel Gram-positive bacterium Bacillus tequilensis was investigated. Hydroxyapatite (HA) was produced by Bacillus tequilensis using defined biomineralization media and dried. Calcination was carried out at different temperatures (100 °C–900 °C) and HA nanopowder was analysed for its structural phase composition, crystallinity, crystallite size and functional groups. X-ray diffractometry (XRD) indicated that increasing temperatures increased the crystallinity of HA nanocrystals. The presence of carbonate groups was evidenced by Fourier transform infrared (FTIR) spectrum and the purity of synthesized apatite nanocrystals was validated by absence of secondary peaks in XRD studies. Scanning electron microscopy (SEM) images depicted those uniform spherical agglomerates of HA comprised of nanosized crystallites. Transmission electron microscope (TEM) results identified needle-like crystal morphologies with average dimensions of 30–60 nm length and 3–10 nm width. Rich trace ion deposition was illustrated by energy dispersive x-ray spectroscopy (EDS) and quantified using inductively coupled plasma optical emission spectrometer (ICP-OES). Overall, microbial biomineralization by Bacillus tequilensis produced nanocrystals of HA that mimicked “bone-like apatite” as evidenced by pure phase, B-type carbonated form, poor crystallinity and trace amounts of vital elements (Mg, Na, K, Zn, Sr, Cl). Moreover, in vitro cytotoxicity studies revealed more than 80% cell viability highlighting the biocompatible nature of synthesized nano HA. Thereby, Bacillus tequilensis biomineralized nano HA reflects as a suitable candidate for applications in biomedicine addressing bone injuries and aiding regeneration.

In this study, a pH-induced self-assembly-based method has been developed to form silk fibroin nanoparticles (SFN-2) with a higher drug loading capacity (21.0 ± 2.1%) and cellular uptake than that of silk fibroin particles produced by a conventional desolvation method (SFN-1). Using the self-assembly method, rifampicin-encapsulated silk fibroin nanoparticles (R-SFN-2) were prepared with a size of 165 ± 38 nm at an optimum pH of 3.8. In silico analysis reveals that at acidic pH, the amino acid side chain charge neutralization of acidic residues, especially GLU64, promotes the formation of additional favorable interactions between the silk fibroin and the drug. The SFN-2 also possess a good aerosol property with a mass median aerodynamic diameter of 3.82 ± 0.71 μm and fine particle fraction of 64.0 ± 1.4%. These SFN-2 particles were selectively endocytosed by macrophages through clathrin- and caveolae-mediated endocytosis with a higher uptake efficiency (66.2 ± 2.1%) and were found to exhibit a sustained drug release in the presence of macrophage intracellular lysates. The cytokine and biomarker expression analyses revealed that SFN-2 could exhibit an immunomodulatory effect by polarizing the macrophages to an initial M1 phase and later M2 phase. Further, R-SFN-2 also exhibited an enhanced and sustained intracellular antibacterial activity against Mycobacterium smegmatis-infected macrophages than free rifampicin. Thus, the self-assembled silk fibroin particles with immunomodulatory action combined with a good aerosol and intracellular drug release property can be an attractive choice as a carrier for developing pulmonary drug delivery systems.

Supramolecular micelles are of particular interest in cancer therapy, owing to their capability to enable the on-demand drug release in tumor microenvironments. Nano platforms of supramolecular micelles can be facilely achieved from β-cyclodextrin (β-CD) based polymers. Herein, we developed novel supramolecular micelles of β-CD-(PNVP)4-AD-PLGA produced from β-CD-grafted star poly(N-vinylpyrrolidone) (β-CD-(PNVP)4) and adamantine-terminated linear-poly(lactic-co-glycolide) (AD-PLGA) by host-guest interaction between β-cyclodextrin and adamantine groups. A model anticancer drug, doxorubicin (DOX) was loaded into the supramolecular micelles during self-assembly in aqueous solution. The dissociation of the supramolecular micelles was triggered by acidic environments, which led to the release of DOX more in pH 6.4 compared to pH 7.4. The in vitro toxicity of the drug loaded micelles revealed 87% of cytotoxicity after 72 h against glioblastoma (C6 cells) while β-CD-(PNVP)4-AD-PLGA was biocompatible to HEK 293 cells (non-cancerous). Furthermore, β-CD-(PNVP)4-AD-PLGA and β-CD-(PNVP)4-AD-PLGA/DOX were found to be hemocompatible and more suitable for Intravenous administration. Our results suggest that the developed micelle system can provide a promising robust and sustained anticancer drug delivery system for the future cancer treatment.

The traditional hydrogels are prone to break due to the applied stress. The deformation of the implanted hydrogels would result in the loss of structural integrity, leading to the failure of hydrogel functionalities and tissue regeneration. Self-healing hydrogels (AG-UPy), composed of oxidized alginate and ureidopyrimidinone-functionalized gelatin (G-UPy), were developed to address this challenge. These self-healing hydrogels possess two independent healing mechanisms, viz., Schiff base formation and UPy dimerization. These hydrogels were compared with oxidized alginate-gelatin (AG) hydrogels. AG-UPy hydrogels showed effective self-healing in a short time (about 2 min) after applying 800% strain, wherein recovery was not achieved with the AG hydrogel. However, the shear-Thinning property of UPy made the AG-UPy hydrogel mechanically weaker than the AG hydrogel. To improve the mechanical strength of the AG-UPy hydrogel, we impregnated poly(ethylene glycol)-poly(urethane)/cloisite nanohybrid (PEG-PU/C) to prepare the AG-UPy/PEG-PU/C hydrogel. The incorporation of PEG-PU/C resulted in a 20-fold increase in the compression strength compared to that of the AG-UPy hydrogel. The AG-UPy/PEG-PU/C hydrogels also showed rapid self-healing. Incorporating the nanohybrid improved the cell proliferation by 2-And 1.25-fold compared to that of the AG and AG-UPy hydrogels, respectively. Therefore, PEG-PU/C combined with the UPy-functionalized polymer could be used to modulate mechanical strength and self-healing and enhance cell proliferation.

A design strategy to regulate the physical and chemical cross-linking interactions in double network (DN) hydrogels to improve conductivity, mechanical strength, and self-recovery is described in the present study. One of the challenges in generating robust DN hydrogels is the integration of the desirable toughness with multifunctionality such as good self-healing capability, self-adhesion on irregular surfaces, and high strain sensitivity. This work addresses this challenge through a design approach, which leads to the formation of a conductive, self-healing, and self-adhesive DN hydrogel from chitosan, tetraethylene glycol, and poly(acrylic acid). Three types of DN hydrogels (CTA-1, CTA-2, and CTA-3) are synthesized in the present study, which contain a common chemical cross-linker, and the nature of the second cross-linker is varied among the three hydrogels. The obtained DN hydrogels exhibited tunable mechanical properties that could be conveniently modified in a range of tensile stress (180 to 1170 kPa) and strain (870 to 1175%) values. Further, the hydrogels show self-healing properties with self-healing efficiency as high as 90-95% due to the dynamic cross-linking nature of the polymer networks. The hydrogels are self-adhesive on a variety of materials, which include skin, metal, glass, wood, rubber, coin, copper, plastic, aluminum, and polytetrafluoroethylene, even at underwater conditions, which is ascribed to the abundance of hydroxyl functional groups in the monomers. The results in the present study indicate that the hydrogels can be used as soft human motion sensors in real time.

A rationally designed amphiphilic poly(aryl ether)-based dendrimer self-assembles into nanomicelles and exhibits tunable morphology upon varying the hydrophilic chain length. The 30 nm-sized dendrimer nanomicelles successfully entrapped Doxorubicin, demonstrated the sustained release of Doxorubicin and can successfully penetrate cancer cells through caveolae-dependent endocytosis, compared to the free drug.

The multi-layered skin structure includes the epidermis, dermis and hypodermis, which forms a sophisticated tissue composed of extracellular matrix (ECM). The wound repair is a well-orchestrated process when the skin is injured. However, this natural wound repair will be ineffective for large surface area wounds. Autografts-based treatment is efficient but, additional pain and secondary healing of the patient limits its successful application. Therefore, there is a substantial need for fabricating tissue-engineered skin constructs. The development of a successful skin graft requires a fundamental understanding of the natural skin and its healing process, as well as design criteria for selecting a biopolymer and an appropriate fabrication technique. Further, the fabrication of an appropriate skin graft needs to meet physicochemical, mechanical, and biological properties equivalent to the natural skin. Advanced 3D bioprinting provides spatial control of the placement of functional components, such as biopolymers with living cells, which can satisfy the prerequisites for the preparation of an ideal skin graft. In this view, here we elaborate on the basic design requirements, constraints involved in the fabrication of skin graft and choice of ink, the probable solution by 3D bioprinting technique, as well as their latest advancements, challenges, and prospects.

Cancer is known as the most dangerous disease in the world in terms of mortality and lack of effective treatment. Research on cancer treatment is still active and of great social importance. Since 1930, chemotherapeutics have been used to treat cancer. However, such conventional treatments are associated with pain, side effects, and a lack of targeting. Nanomedicines are an emerging alternative due to their targeting, bioavailability, and low toxicity. Nanoparticles target cancer cells via active and passive mechanisms. Since FDA approval for Doxil®, several nano-therapeutics have been developed, and a few have received approval for use in cancer treatment. Along with liposomes, solid lipid nanoparticles, polymeric nanoparticles, and nanoemulsions, even newer techniques involving extracellular vesicles (EVs) and thermal nanomaterials are now being researched and implemented in practice. This review highlights the evolution and current status of cancer therapy, with a focus on clinical/pre-clinical nanomedicine cancer studies. Insight is also provided into the prospects in this regard.