Magnetic Ion Channel Activation (MICA)-Enabled Screening Assay: A Dynamic Platform for Remote Activation of Mechanosensitive Ion Channels.

This study reports results of a mechanical platform-based screening assay (MICA) to evaluate the remote activation of mechanosensitive ion channels. Here, we studied ERK pathway activation and the elevation in intracellular Ca2+ levels in response to the MICA application using the Luciferase assay and Fluo-8AM assay, respectively. Functionalised magnetic nanoparticles (MNPs) targeting membrane-bound integrins and mechanosensitive TREK1 ion channels were studied with HEK293 cell lines under MICA application. The study demonstrated that active targeting of mechanosensitive integrins via RGD (Arginylglycylaspartic acid) motifs or TREK1 (KCNK2, potassium channel subfamily K member 2) ion channels can stimulate the ERK pathway and intracellular calcium levels compared to non-MICA controls. This screening assay offers a powerful tool, which aligns with existing high-throughput drug screening platforms for use in the assessment of drugs that interact with ion channels and influence ion channel-modulated diseases.

Hexa-functional tumour-seeking nano voyagers and annihilators for synergistic cancer theranostic applications.

In order to meet the unmet medical needs for effective cancer treatment, multifunctional nanocarriers based on iron oxide nanoparticles hold tremendous promise. Here we report a superparamagnetic iron oxide nanoparticles based hexa-functional nanosystem for synergistic cancer theranostic applications by offering active tumour targeting, accumulation and complementary imaging capability by combining magnetic resonance imaging as well as near-infrared fluorescence, magnetophotothermia and chemotherapy. The uniquely designed nanosystem exhibited a paramount increase in the antitumour efficacy through the simultaneous application of multiple thermal effects called magnetophotothermia, which outweighed the therapeutic efficacy of the current thermo-chemo therapies or stand-alone therapies. The active tumour-seeking property with prolonged tumour accumulation and complementary imaging capability with improved sensitivity and resolution also augments the therapeutic efficacy of the proposed nanosystem. Additionally, the work proposes a deep-learning-based tumour cell nuclei detection technique from H&E stained images in anticipation of providing much inspiration for the future of precision histology.

Strategic Design and Fabrication of Biomimetic 3D Scaffolds: Unique Architectures of Extracellular Matrices for Enhanced Adipogenesis and Soft Tissue Reconstruction.

The higher rate of soft tissue impairment due to lumpectomy or other trauma greatly requires the restoration of the irreversibly lost subcutaneous adipose tissues. The nanofibers fabricated by conventional electrospinning provide only a superficial porous structure due to its sheet like 2D structure and thereby hinder the cell infiltration and differentiation throughout the scaffolds. Thus we developed a novel electrospun 3D membrane using the zwitterionic poly (carboxybetaine-co-methyl methacrylate) co-polymer (CMMA) through electrostatic repulsion based electrospinning for soft tissue engineering. The inherent charges in the CMMA will aid the nanofiber to directly transform into a semiconductor and thereby transfer the immense static electricity from the grounded collector and will impart greater fluffiness to the scaffolds. The results suggest that the fabricated 3D nanofiber (CMMA 3NF) scaffolds possess nanofibers with larger inter connected pores and less dense structure compared to the conventional 2D scaffolds. The CMMA 3NF exhibits significant cues of soft tissue engineering such as enhanced biocompatibility as well as the faster regeneration of cells. Moreover the fabricated 3D scaffolds greatly assist the cells to develop into its stereoscopic topographies with an enhanced adipogenic property.

Electromagnetic manipulation enabled calcium alginate Janus microsphere for targeted delivery of mesenchymal stem cells.

We prepared Janus microspheres based on sodium alginate for the encapsulation of mesenchymal stem cells (MSC) in one compartment and iron oxide nanoparticles (IONP) or a drug in the second compartment. 4% percent sodium alginate solution was allowed to pass through a septum-theta capillary device and react with 2.5% calcium chloride to allow crosslinking to occur in the solution, forming calcium alginate Janus microspheres. Physico-chemical characterization of microspheres was done by FTIR, TGA, and XRD after loading of stem cells and IONP/drug. The mechanical integrity of microspheres was tested at different time points, which showed that 4% alginate microspheres were mechanically stable for a long period of time. Live/dead staining of MSCs alone and the MTS assay of MSCs and DMSO co-loaded were performed, which showed less toxicity to MSC in the Janus configuration. IONP/MSC-loaded Janus microspheres were tested by magnetic manipulation for targeted MSC delivery for cartilage repair using an electromagnetic manipulation (EMM) device. Janus microspheres can be used for targeted stem cell/drug delivery using EMM for cartilage repair in the near future.

Nature derived scaffolds for tissue engineering applications: Design and fabrication of a composite scaffold incorporating chitosan-g-d,l-lactic acid and cellulose nanocrystals from Lactuca sativa L. cv green leaf.

Through exhaustive extraction via successive alkali and bleaching treatments cellulose was isolated from lettuce. The isolated cellulose was hydrolyzed using 64wt% H2SO4 at 55°C under constant stirring for 1h to obtain cellulose nanocrystals (CNCs). Characterizations such as SEM, TEM, FTIR, TGA and XRD were done in order to determine differences in the physico-chemical characteristics of cellulose after each treatment step. The isolated CNCs have mean dimensions of 237±26, 33±12 and 32±7nm in length, thickness and height, respectively. These nanocrystals were incorporated to the formulations that were used to fabricate different chitosan-g-d,l-lactic acid (CgLA) scaffolds. Amide linkage formation between chitosan and lactic acid and further removal of water was facilitated by oven-drying under vacuum at 80°C. Results show that an increase in the concentration of CNCs added, increase in porosity, degradability, drug release property and cell viability were observed from the fabricated composite scaffolds. These results can provide information on how nanofillers such as CNCs can alter the properties of tissue scaffolds through the chemical properties and interactions they provide. Moreover, these characteristics can give new properties that are necessary for certain tissue engineering applications.

Optimization of Electropolishing on NiTi Alloy Stents and Its Influence on Corrosion Behavior.

Nitinol or NiTi alloys are well-known as an attractive biomedical material due to their unique properties such as the shape memory effect, super-elasticity and biocompatibility. These characteristics enable them to be best candidates for implant materials such as stent. One of the major factors that strongly affect the performance of nitinol stent is its unique surface properties. In this study, the influence of electropolishing on nitinol stents and its corrosion behavior were observed. Electropolishing is an effective method for surface treatment, which not only controls the surface state but also helps to produce uniform surface layers. Therefore, to improve the surface quality of nitinol stents, we conducted an electropolishing under various conditions from 30­40 V and 10­30 s as a post heat treatment for nitinol stent manufacturing process. In order to find the optimal surface state of NiTi stents, various electropolished samples were explored using various characterization techniques. Furthermore, the potentiodynamic polarization tests were also performed to determine the corrosion resistance. The electropolished nitinol stents under the condition of 40 V for 10 s exhibited the best corrosion performance as well as surface quality.

Bimodal fibrous structures for tissue engineering: Fabrication, characterization and in vitro biocompatibility.

We report for the first time a polycaprolactone-human serum albumin (PCL-HSA) membrane with bimodal structures comprised of spider-web-like nano-nets and conventional fibers via facile electro-spinning/netting (ESN) technique. Such unique controllable morphology was developed by electrospinning the blend solution of PCL (8wt% in HFIP 1,1,1,3,3,3,-Hexafluoro-2-propanol) and HSA (10wt% deionized water). The phase separation during electrospinning caused the formation of bimodal structure. Various processing factors such as applied voltage, feeding rate, and distance between nozzle tip and collector were found responsible for the formation and distribution of the nano-nets throughout the nanofibrous mesh. Field emission electron microscopy (FE-SEM) confirmed that the nano-nets were composed of interlinked nanowires with an ultrathin diameter (10-30nm). When compared with a pure PCL membrane, the membrane containing nano-nets was shown to have better support for cellular activities as determined by cell viability and attachment assays. These results revealed that the blending of albumin, a hydrophilic biomolecule, with PCL, a hydrophobic polymer, proves to be an outstanding approach to developing membranes with controlled spider-web-like nano-nets for tissue engineering.

Multifunctional Nanocarpets for Cancer Theranostics: Remotely Controlled Graphene Nanoheaters for Thermo-Chemosensitisation and Magnetic Resonance Imaging.

A new paradigm in cancer theranostics is enabled by safe multifunctional nanoplatform that can be applied for therapeutic functions together with imaging capabilities. Herein, we develop a multifunctional nanocomposite consisting of Graphene Oxide-Iron Oxide -Doxorubicin (GO-IO-DOX) as a theranostic cancer platform. The smart magnetic nanoplatform acts both as a hyperthermic agent that delivers heat when an alternating magnetic field is applied and a chemotherapeutic agent in a cancer environment by providing a pH-dependent drug release to administer a synergistic anticancer treatment with an enhanced T2 contrast for MRI. The novel GO-IO-DOX nanocomposites were tested in vitro and were observed to exhibit an enhanced tumoricidal effect through both hyperthermia and cancer cell-specific DOX release along with an excellent MRI performance, enabling a versatile theranostic platform for cancer. Moreover the localized antitumor effects of GO-IO-DOX increased substantially as a result of the drug sensitization through repeated application of hyperthermia.

An implantable smart magnetic nanofiber device for endoscopic hyperthermia treatment and tumor-triggered controlled drug release.

The study describes the design and synthesis of an implantable smart magnetic nanofiber device for endoscopic hyperthermia treatment and tumor-triggered controlled drug release. This device is achieved using a two-component smart nanofiber matrix from monodisperse iron oxide nanoparticles (IONPs) as well as bortezomib (BTZ), a chemotherapeutic drug. The IONP-incorporated nanofiber matrix was developed by electrospinning a biocompatible and bioresorbable polymer, poly (d,l-lactide-co-glycolide) (PLGA), and tumor-triggered anticancer drug delivery is realized by exploiting mussel-inspired surface functionalization using 2-(3,4-dihydroxyphenyl)ethylamine (dopamine) to conjugate the borate-containing BTZ anticancer drug through a catechol metal binding in a pH-sensitive manner. Thus, an implantable smart magnetic nanofiber device can be exploited to both apply hyperthermia with an alternating magnetic field (AMF) and to achieve cancer cell-specific drug release to enable synergistic cancer therapy. These results confirm that the BTZ-loaded mussel-inspired magnetic nanofiber matrix (BTZ-MMNF) is highly beneficial not only due to the higher therapeutic efficacy and low toxicity towards normal cells but also, as a result of the availability of magnetic nanoparticles for repeated hyperthermia application and tumor-triggered controlled drug release. STATEMENT OF SIGNIFICANCE: The current work report on the design and development of a smart nanoplatform responsive to a magnetic field to administer both hyperthermia and pH-dependent anticancer drug release for the synergistic anticancer treatment. The iron oxide nanoparticles (IONPs) incorporated nanofiber matrix was developed by electrospinning a biocompatible polymer, poly (d,l-lactide-co-glycolide) (PLGA), and tumor-triggered anticancer drug delivery is realized by surface functionalization using 2-(3,4-dihydroxyphenyl)ethylamine (dopamine) to conjugate the boratecontaining anticancer drug bortezomib through a catechol metal binding in a pH-sensitive manner. This implantable magnetic nanofiber device can be exploited to apply hyperthermia with an alternating magnetic field and to achieve cancer cell-specific drug release to enable synergistic cancer therapy, which results in an improvement in both quality of life and patient compliance.

Design and application of a smart nanodevice by combining cationic drug delivery and hyperthermia for cancer apoptosis.

Multifunctional magnetic nanoparticles have gained ample attention in the field of nanomedicine in recent years. Here, novel superparamagnetic core-shell manganese ferrite nanoparticles (MFNP)-encapsulated mesoporous silica nanoparticles (MSMFNPs) loaded with anticancer drug doxorubicin (DOX) for the combined application of hyperthermia and chemotherapy were developed and tested in vitro. Our results indicate that DOX-MSMFNPs achieved a favorable hyperthermic response in an alternating magnetic field in addition to cancer cell-specific cationic DOX release due to the cleavage of amide bonds under acidic pH, and synergistically contributed towards an enhanced tumoricidal effect.

A smart magnetic nanoplatform for synergistic anticancer therapy: manoeuvring mussel-inspired functional magnetic nanoparticles for pH responsive anticancer drug delivery and hyperthermia.

We report the versatile design of a smart nanoplatform for thermo-chemotherapy treatment of cancer. For the first time in the literature, our design takes advantage of the outstanding properties of mussel-inspired multiple catecholic groups - presenting a unique copolymer poly(2-hydroxyethyl methacrylate-co-dopamine methacrylamide) p(HEMA-co-DMA) to surface functionalize the superparamagnetic iron oxide nanoparticles as well as to conjugate borate containing anticancer drug bortezomib (BTZ) in a pH-dependent manner for the synergistic anticancer treatment. The unique multiple anchoring groups can be used to substantially improve the affinity of the ligands to the surfaces of the nanoparticles to form ultrastable iron oxide nanoparticles with control over their hydrodynamic diameter and interfacial chemistry. Thus the BTZ-incorporated-bio-inspired-smart magnetic nanoplatform will act as a hyperthermic agent that delivers heat when an alternating magnetic field is applied while the BTZ-bound catechol moieties act as chemotherapeutic agents in a cancer environment by providing pH-dependent drug release for the synergistic thermo-chemotherapy application. The anticancer efficacy of these bio-inspired multifunctional smart magnetic nanoparticles was tested both in vitro and in vivo and found that these unique magnetic nanoplatforms can be established to endow for the next generation of nanomedicine for efficient and safe cancer therapy.

Fabrication and characterization of electrospun zein/Ag nanocomposite mats for wound dressing applications.

Wound dressing is a very important factor in the process of wound healing as proper wound care can accelerate the recovery of the wound. In this study, zein nanofibrous mats with fiber diameters around 350-500 nm were prepared by electrospinning and silver (Ag) nanoparticles around 20 nm were concurrently synthesized in situ into the mats. The electrospun nanofibers were characterized by Field Emission-Scanning Electron Microscopy (FE-SEM), Transmission Electron Microscopy (TEM), Fourier Transform Infrared Spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS) analysis. Cell viability and activity of fibroblasts cells in zein/Ag mats were also evaluated and results demonstrated good cytocompatibility and attachment of cells on the composite nanofibers. Also, the bactericidal activity of the fabricated mats against gram-positive Staphylococcus aureus (S. aureus) and gram-negative Escherichia coli (E. coli) was investigated via zone of inhibition test and results showed high anti-bacterial performance.

Creation of a functional graded nanobiomembrane using a new electrospinning system for drug release control and an in vitro validation of drug release behavior of the coating membrane.

Functional graded nanobiomembranes (FGMs) with multiple layers were created by a single process using a novel electrospinning system equipped with a generator and a PCI type motion board as a controller in order to control the drug release rate. By varying physical apparatus-related parameters such as nozzle-to-collector distance via a robot and the collector moving velocity the FGMs were formed. For the membrane base layer, poly-(ε-caprolactone) (PCL) with paclitaxel (PTX) was dissolved in a solvent (dichloromethane, N,N-dimethylformamide) and electrospun. For the top layers, the PCL solution was electrospun according to the distance and FGM system parameters, which can move the collector location at a constant ratio. It was observed that pore size, porosity, and permeability were higher when the membrane was spun at the far distance. The top surface of FGM is more porous, rougher, more permeable, and more hydrophilic so as to be active to the surrounding tissue cells. Meanwhile, the porous inside membrane was as low as the membrane spun at a close distance. Thus it induced a slow drug release due to the internal structure of FGM, which is considered to be very effective for slow drug release as well as bioactivity and bioconductivity.

Electrospun polyurethane-dextran nanofiber mats loaded with Estradiol for post-menopausal wound dressing.

Post-menopausal wound care management is a substantial burden on health services, since there are an increased number of elderly populations linked with age-related delayed wound healing. The controlled estrogen replacement can accelerate healing of acute cutaneous wounds, linked to its potent anti-inflammatory activity. The electrospinning technique can be used to introduce the desired therapeutic agents to the nanofiber matrix. So here we introduce a new material for wound tissue dressing, in which a polyurethane-dextran composite nanofibrous wound dressing material loaded with ß-estradiol was obtained through electrospinning. Dextran can promote neovascularization and skin regeneration in chronic wounds. This study involves the characterization of these nanofibers and analysis of cell growth and proliferation to determine the efficiency of tissue regeneration on these biocomposite polymer nanofibrous scaffolds and to study the possibility of using it as a potential wound dressing material in the in vivo models.

Electrospun polyurethane/Eudragit ® L100-55 composite mats for the pH dependent release of paclitaxel on duodenal stent cover application.

A nanofiber composite mat of PU and Eudragit(®) L100-55 was created using electrospinning process. The pH dependent release of paclitaxel was successfully done with the use of PU/EL100-55 nanocomposite mats as the controlling platform. The morphology of the nanofiber composites was surveyed using FESEM and ratios of the polymers affects the diameter of the nanofiber. Characterization of the nanofiber composite mat was done using FTIR, DSC-TGA method. The release rate of paclitaxel was determined and analyzed by in vitro drug release method. In order to mimic the condition of a human duodenum, the fibers were submersed on PBS of different pH levels (4.0, 6.0,) respectively, and then analyzed using high performance liquid chromatography (HPLC). Composite mats submersed in PBS with pH 4.0 showed lesser release profile compared to mats submersed in PBS with pH of 6.0. The composite mat has adequate mechanical properties and in vitro cell biocompatibility indicating that the material can be used for drug eluting stent cover application.

Electrospun antibacterial polyurethane-cellulose acetate-zein composite mats for wound dressing.

In this study, an antibacterial electrospun nanofibrous scaffolds with diameters around 400-700 nm were prepared by physically blending polyurethane (PU) with two biopolymers such as cellulose acetate (CA) and zein. Here, PU was used as the foundation polymer, was blended with CA and zein to achieve desirable properties such as better hydrophilicity, excellent cell attachment, proliferation and blood clotting ability. To prevent common clinical infections, an antimicrobial agent, streptomycin sulfate was incorporated into the electrospun fibers and its antimicrobial ability against the gram negative and gram positive bacteria were examined. The interaction between fibroblasts and the PU-CA and PU-CA-zein-drug scaffolds such as viability, proliferation, and attachment were characterized. PU-CA-zein-drug composite nanoscaffold showed enhanced blood clotting ability in comparison with pristine PU nanofibers. The presence of CA and zein in the nanofiber membrane improved its hydrophilicity, bioactivity and created a moist environment for the wound, which can accelerate wound recovery.