Deepika Kannan

Abstract: Rapid gelation, low heat generation, biocompatibility, biodegradability, avoiding the use of a small molecular weight gelator and high gel fraction are the essential criteria for the successful biomedical application of an injectable hydrogel We have developed a series of dually crosslinked injectable hydrogels of PEG and poly[2-(dimethylamino)ethyl methacrylate]-b-poly(N-isopropyl acrylamide) through extremely simple chemistry The sequential nucleophilic substitution reaction between PEG containing reactive termini and the copolymer provided chemically crosslinked hydrogels with a gel fraction as high as 96–99% with a gelation time of 1–4 min under physiological conditions The gelation occurred with ca 1 °C rise in temperature per gram of the injectable solution, avoids formation of by-products and can be performed in the temperature range of 20–37 °C The hydrogels undergo hardening at a physiological temperature as confirmed by rheological experiments The gelation time, water swelling, mechanical properties and degradability of the hydrogels depend on the PEG to copolymer ratio in the injectable solution The rheological behaviour of the fully hydrated hydrogels showed desirable mechanical properties for soft tissue regeneration The hydrogels exhibited blood compatibility and retained the viability of HepG2 cells with time Platelet adhesion and aggregation followed by fibrinogen adsorption ability makes these hydrogels suitable for wound healing applications

Abstract: Background Artesunate the most potent antimalarial is widely used for the treatment of multidrug-resistant malaria. The antimalarial cytotoxicity of artesunate has been mainly attributed to its selective, irreversible and iron- radical-mediated damage of parasite biomolecules. In the present research, iron oxide nanoparticle fortified artesunate was tested in P. falciparum and in an experimental malaria mouse model for enhancement in the selectivity and toxicity of artesunate towards parasite. Artesunate was fortified with nontoxic biocompatible surface modified iron oxide nanoparticle which is specially designed and synthesized for the sustained pH-dependent release of Fe2+ within the parasitic food vacuole for enhanced ROS spurt. Methods Antimalarial efficacy of Iron oxide nanoparticle fortified artesunate was evaluated in wild type and artemisinin-resistant Plasmodium falciparum (R539T) grown in O + ve human blood and in Plasmodium berghei ANKA infected swiss albino mice. Internalization of nanoparticles, the pH-dependent release of Fe2+, production of reactive oxygen species and parasite biomolecule damage by iron oxide nanoparticle fortified artesunate was studied using various biochemical, biophysical, ultra-structural and fluorescence microscopy. For determining the efficacy of ATA-IONP+ART on resistant parasite ring survival assay was performed. Results The nanoparticle fortified artesunate was highly efficient in the 1/8th concentration of artesunate IC50 and led to retarded growth of P. falciparum with significant damage to macromolecules mediated via enhanced ROS production. Similarly, preclinical In vivo studies also signified a radical reduction in parasitemia with ~8–10-fold reduced dosage of artesunate when fortified with iron oxide nanoparticles. Importantly, the ATA-IONP combination was efficacious against artemisinin-resistant parasites. Interpretation Surface coated iron-oxide nanoparticle fortified artesunate can be developed into a potent therapeutic agent towards multidrug-resistant and artemisinin-resistant malaria in humans. Fund This study is supported by the Centre for Study of Complex Malaria in India funded by the National Institute of Health, USA.

Abstract: Introduction: Currently, there is no efficient vaccine available against clinical malaria. However, continuous efforts have been committed to develop powerful antimalarial vaccine by discovery of n...

Abstract: Substrate–cell interactions for a bioimplant are driven by substrate’s surface characteristics. In addition, the performance of an implant and resistance to degradation are primarily governed by its surface properties. A bioimplant typically degrades by wear and corrosion in the physiological environment, resulting in metallosis. Surface engineering strategies for limiting degradation of implants and enhancing their performance may reduce or eliminate the need for implant removal surgeries and the associated cost. In the current study, we tailored the surface properties of stainless steel using submerged friction stir processing (FSP), a severe plastic deformation technique. FSP resulted in significant microstructural refinement from 22 μm grain size for the as-received alloy to 0.8 μm grain size for the processed sample with increase in hardness by nearly 1.5 times. The wear and corrosion behavior of the processed alloy was evaluated in simulated body fluid. The processed sample demonstrated remarkable i...

Abstract: Development of new class of anti-malarial drugs is an essential requirement for the elimination of malaria. Bioactive components present in medicinal plants and their chemically modified derivatives could be a way forward towards the discovery of effective anti-malarial drugs. Herein, we describe a new class of compounds, 1,3-benzoxazine derivatives of pharmacologically active phytophenols eugenol (compound 3) and isoeugenol (compound 4) synthesised on the principles of green chemistry, as anti-malarials. Compound 4, showed highest anti-malarial activity with no cytotoxicity towards mammalian cells. Compound 4 induced alterations in the intracellular Na+ levels and mitochondrial depolarisation in intraerythrocytic Plasmodium falciparum leading to cell death. Knowing P-type cation ATPase PfATP4 is a regulator for sodium homeostasis, binding of compound 3, compound 4 and eugenol to PfATP4 was analysed by molecular docking studies. Compounds showed binding to the catalytic pocket of PfATP4, however compound 4 showed stronger binding due to the presence of propylene functionality, which corroborates its higher anti-malarial activity. Furthermore, anti-malarial half maximal effective concentration of compound 4 was reduced to 490 nM from 17.54 µM with nanomaterial graphene oxide. Altogether, this study presents anti-plasmodial potential of benzoxazine derivatives of phytophenols and establishes disruption of parasite sodium homeostasis as their mechanism of action.

Abstract: Here we present a new bifunctional layer-by-layer (LbL) construct made by combining a permanent microbicidal polyelectrolyte multilayered (PEM) base film with a hydrolytically degradable PEM top film that offers controlled and localized delivery of therapeutics. Two degradable film architectures are presented: (1) bolus release of an antibiotic (gentamicin) to eradicate initial infection at the implant site, or (2) sustained delivery of an anti-inflammatory drug (diclofenac) to cope with inflammation at the site of implantation due to tissue injury. Each degradable film was built on top of a permanent base film that imparts the implantable device surface with microbicidal functionality that prevents the formation of biofilms. Controlled-delivery of gentamicin was demonstrated over hours and that of diclofenac over days. Both drugs retained their efficacy upon release. The permanent microbicidal base film was biocompatible with A549 epithelial cancer cells and MC3T3-E1 osteoprogenitor cells, while also pre...

Abstract: Microneedle vaccines mimic several aspects of cutaneous pathogen invasion by targeting antigen to skin-resident dendritic cells and triggering local infl ammatory responses in the skin, which are correlated with enhanced immune responses. Here, we tested whether control over vaccine delivery kinetics can enhance immunity through further mimicry of kinetic profi les present during natural acute infections. An approach for the fabrication of silk/poly(acrylic acid) (PAA) composite microneedles composed of a silk tip supported on a PAA base is reported. On brief application of microneedle patches to skin, the PAA bases rapidly dissolved to deliver a protein subunit vaccine bolus, while also implanting persistent silk hydrogel depots into the skin for a low-level sustained cutaneous vaccine release over 1‐2 weeks. Use of this platform to deliver a model whole-protein vaccine with optimized release kinetics resulted in > 10-fold increases in antigen-specifi c T-cell and humoral immune responses relative to traditional parenteral needle-based immunization. compared with traditional parenteral immunization approaches targeting less immunogenic tissues such as muscle (reviewed elsewhere). [ 1 ] Microneedle vaccination has in many cases also outperformed hypodermic needle-based delivery to the skin, suggesting the importance of factors relating to microneedle delivery itself, such as the infl ammatory state generated by micrometer-scale wounding following microneedle insertion. [ 2 , 3 ] Unrelated studies have begun to reveal the importance of antigen and adjuvant delivery kinetics in the developing immune response, both within the context of vaccination and in natural responses to infection. [ 4‐7 ] For example, the magnitude, functionality, and phenotype of CD8 + T-cell responses can be shaped by immunizations where antigen or adjuvant delivery kinetics are controlled over multi-week periods, with persistent antigenic and infl ammatory signals eliciting stronger responses than transient bolus vaccine exposure. [ 4 , 5 ] These fi ndings are consistent with known differences in the natural immunity generated against transient versus persistent pathogens, indicating specifi c mechanisms of immunity that may be exploited through engineered kinetics to yield greater vaccine effi cacy. We have recently begun to explore the combination of these two approaches for enhancing immunogenicity, through the

Abstract: Increasing demand of lightweight structures with exceptional properties elicits materials processing and manufacturing technologies to tailor blanks in order to achieve or enhance those pre...

Abstract: In this study, a novel Bioglass/albumin composite hydrogel with controllable injectability, good adhesiveness, and bioactivity, is developed by utilizing dual-functional bioactive ions released from Bioglass, which on one side controls the gelling time by creating an alkaline environment to regulate the cross-linking reaction between human serum albumin and succinimidyl succinate modified poly(ethylene glycol), and on the other side stimulates wound healing. The composite hydrogel exhibits adhesive property that is superior to clinically used fibrin and cyanoacrylate glues. The gelation time of the composite hydrogel could be regulated via changing the amounts of Bioglass which endows the hydrogel with good injectability. The in vivo experiment confirms that this composite hydrogel has good bioactivity to stimulate angiogenesis and enhance chronic wound healing. Moreover, for the first time, the concentrations of the bioactive ions released from the composite hydrogel in situ are quantified during wound healing using a microdialysis technique, and a correlation of the in vitro and in vivo concentration of ions released from the hydrogel is determined, which is extremely important for understanding the bioactivity mechanisms of Bioglass/bioceramic-based biomaterials and designing biomaterials for tissue regeneration.

Abstract: Artemisinins are the cornerstone of anti-malarial drugs. Emergence and spread of resistance to them raises risk of wiping out recent gains achieved in reducing worldwide malaria burden and threatens future malaria control and elimination on a global level. Genome-wide association studies (GWAS) have revealed parasite genetic loci associated with artemisinin resistance. However, there is no consensus on biochemical targets of artemisinin. Whether and how these targets interact with genes identified by GWAS, remains unknown. Here we provide biochemical and cellular evidence that artemisinins are potent inhibitors of Plasmodium falciparum phosphatidylinositol-3-kinase (PfPI3K), revealing an unexpected mechanism of action. In resistant clinical strains, increased PfPI3K was associated with the C580Y mutation in P. falciparum Kelch13 (PfKelch13), a primary marker of artemisinin resistance. Polyubiquitination of PfPI3K and its binding to PfKelch13 were reduced by the PfKelch13 mutation, which limited proteolysis of PfPI3K and thus increased levels of the kinase, as well as its lipid product phosphatidylinositol-3-phosphate (PI3P). We find PI3P levels to be predictive of artemisinin resistance in both clinical and engineered laboratory parasites as well as across non-isogenic strains. Elevated PI3P induced artemisinin resistance in absence of PfKelch13 mutations, but remained responsive to regulation by PfKelch13. Evidence is presented for PI3P-dependent signalling in which transgenic expression of an additional kinase confers resistance. Together these data present PI3P as the key mediator of artemisinin resistance and the sole PfPI3K as an important target for malaria elimination.