Charge based intra-cartilage delivery of single dose dexamethasone using Avidin nano-carriers suppresses cytokine-induced catabolism long term

Objective: Avidin exhibits ideal characteristics for targeted intra-cartilage drug delivery: its small size and optimal positive charge enable rapid penetration through full-thickness cartilage and electrostatic binding interactions that give long half-lives in vivo. Here we conjugated Avidin with dexamethasone (DEX) and tested the hypothesis that single-dose Avidin-delivered DEX can ameliorate catabolic effects in cytokine-challenged cartilage relevant to post-traumatic OA. Methods: Avidin was covalently conjugated with DEX using fast (ester) and slow, pH-sensitive release (hydrazone) linkers. DEX release kinetics from these conjugates was characterized using 3H-DEX-Avidin (scintillation counting). Cartilage explants treated with IL-1α were cultured with or without Avidin-DEX conjugates and compared to soluble DEX. Sulfated-glycosaminoglycan (sGAG) loss and biosynthesis rates were measured using DMMB assay and 35S-incorporation, respectively. Chondrocyte viability was measured using fluorescence staining. Results: Ester linker released DEX from Avidin significantly faster than hydrazone under physiological buffer conditions. Single dose Avidin-DEX suppressed cytokine-induced sGAG loss over 3-weeks, rescued IL-1α-induced cell death, and restored sGAG synthesis levels without causing cytotoxicity. The two Avidin-DEX conjugates in 1:1 combination (fast:slow) had the most prominent bioactivity compared to single dose soluble-DEX, which had a shorter-lived effect and thus needed continuous replenishment throughout the culture period to ameliorate catabolic effects. Conclusion: Intra-cartilage drug delivery remains inadequate as drugs rapidly clear from the joint, requiring multiple injections or sustained release of high doses in synovial fluid. A single dose of Avidin-conjugated drug enables rapid uptake and sustained delivery inside cartilage at low intratissue doses, and potentially can minimize unwanted drug exposure to other joint tissues.Deshpande Center for Technological InnovationNational Science Foundation (U.S.). Materials Research Science and Engineering Centers (Program) (Award DMR-1419807

Emergence of THz technologies and design and optimisation low-loss waveguides and devices

THz is an emerging technology with many important applications in imaging and sensing, but due to lack of suitable low-loss waveguides future progress can be limited. A rigorous full-vectorial modal solution approach based on the computationally efficient finite element method is used to find the propagation properties of THz waveguides. Design approaches are presented to reduce the modal loss of such waveguides. Designs of several THz devices, including quantum cascade lasers, power splitters and narrow-band filters are also presented

Low-loss multimode interference couplers for terahertz waves

The terahertz (THz) frequency region of the electromagnetic spectrum is located between the traditional microwave spectrum and the optical frequencies, and offers a significant scientific and technological potential in many fields, such as in sensing, in imaging and in spectroscopy. Waveguiding in this intermediate spectral region is a major challenge. Amongst the various THz waveguides suggested, metal-clad plasmonic waveguides and specifically hollow core structures, coated with insulating material are the most promising low-loss waveguides used in both active and passive devices. Optical power splitters are important components in the design of optoelectronic systems and optical communication networks such as Mach-Zehnder Interferometric switches, polarization splitter and polarization scramblers. Several designs for the implementation of the 3dB power splitters have been proposed in the past, such as the directional coupler-based approach, the Y-junction-based devices and the MMI-based approach. In the present paper a novel MMI-based 3dB THz wave splitter is implemented using Gold/polystyrene (PS) coated hollow glass rectangular waveguides. The H-field FEM based full-vector formulation is used here to calculate the complex propagation characteristics of the waveguide structure and the finite element beam propagation method (FE-BPM) and finite difference time domain (FDTD) approach to demonstrate the performance of the proposed 3dB splitter

A Novel Approach for Integrated Shortest Path Finding Algorithm (ISPSA) Using Mesh Topologies and Networks-on-Chip (NOC)

A novel data dispatching or communication technique based on circulating networks of any network IP is suggested for multi data transmission in multiprocessor systems using Networks-On-Chip (NoC). In wireless communication network management have some negatives have heavy data losses and traffic of data sending data while packet scheduling and low performance in the varied network due to workloads. To overcome the drawbacks, in this method proposed system is Integrated Shortest Path Search Algorithm (ISPSA) using mesh topologies. The message is sent to IP (Internet Protocol) in the network until the specified bus accepts it. Integrated Shortest Path Search Algorithm for communication between two nodes is possible at any one moment. On-chip wireless communications operating at specific frequencies are the most capable option for overcoming metal interconnects multi-hop delay and excessive power consumption in Network-on-Chip (NoC) devices. Each node can be indicated by a pair of coordinates (level, position), where the level is the tree's vertical level and the view point is its horizontal arrangement in the sequence of left to right. The output gateway node's n nodes are linked to two nodes in the following level, with all resource nodes located at the bottommost vertical level and the constraint of this topology is its narrow bisection area. The software Xilinx 14.5 tool by using that overall performance analysis of mesh topology, each method are reduced data losses with better accuracy although the productivity of the delay is decreased by 21 % was evaluated and calculated.

Osteotropic Therapy via Targeted Layer-by-Layer Nanoparticles

Current treatment options for debilitating bone diseases such as osteosarcoma, osteoporosis, and bone metastatic cancer are suboptimal and have low efficacy. New treatment options for these pathologies require targeted therapy that maximizes exposure to the diseased tissue and minimizes off-target side effects. This work investigates an approach for generating functional and targeted drug carriers specifically for treating primary osteosarcoma, a disease in which recurrence is common and the cure rate has remained around 20%. This approach utilizes the modularity of Layer-by-Layer (LbL) assembly to generate tissue-specific drug carriers for systemic administration. This is accomplished via surface modification of drug-loaded nanoparticles with an aqueous polyelectrolyte, poly(acrylic acid) (PAA), side-chain functionalized with alendronate, a potent clinically used bisphosphonate. Nanoparticles coated with PAA-alendronate are observed to bind and internalize rapidly in human osteosarcoma 143B cells. Encapsulation of doxorubicin, a front-line chemotherapeutic, in an LbL-targeted liposome demonstrates potent toxicity in vitro. Active targeting of 143B xenografts in NCR nude mice with the LbL-targeted doxorubicin liposomes promotes enhanced, prolonged tumor accumulation and significantly improved efficacy. This report represents a tunable approach towards the synthesis of drug carriers, in which LbL enables surface modification of nanoparticles for tissue-specific targeting and treatment.National Institutes of Health (U.S.) (P30 CA14051 (NCI))National Institutes of Health (U.S.) (5 U54 CA151884–02 (CCNE))National Institutes of Health (U.S.) (R01 AG029601 (NIA))National Institutes of Health (U.S.) (R01 EB010246 (NIBIB))David H. Koch Institute for Integrative Cancer Research at MIT (Koch Institute Swanson Biotechnology Center)National Science Foundation (U.S.) (Graduate Research Fellowship)National Health and Medical Research Council (Australia)Massachusetts Institute of Technology (David H. Koch (1962) Chair Professorship in Engineering

Adaptive growth factor delivery from a polyelectrolyte coating promotes synergistic bone tissue repair and reconstruction

Traumatic wounds and congenital defects that require large-scale bone tissue repair have few successful clinical therapies, particularly for craniomaxillofacial defects. Although bioactive materials have demonstrated alternative approaches to tissue repair, an optimized materials system for reproducible, safe, and targeted repair remains elusive. We hypothesized that controlled, rapid bone formation in large, critical-size defects could be induced by simultaneously delivering multiple biological growth factors to the site of the wound. Here, we report an approach for bone repair using a polyelectrolye multilayer coating carrying as little as 200 ng of bone morphogenetic protein-2 and platelet-derived growth factor-BB that were eluted over readily adapted time scales to induce rapid bone repair. Based on electrostatic interactions between the polymer multilayers and growth factors alone, we sustained mitogenic and osteogenic signals with these growth factors in an easily tunable and controlled manner to direct endogenous cell function. To prove the role of this adaptive release system, we applied the polyelectrolyte coating on a well-studied biodegradable poly(lactic-co-glycolic acid) support membrane. The released growth factors directed cellular processes to induce bone repair in a critical-size rat calvaria model. The released growth factors promoted local bone formation that bridged a critical-size defect in the calvaria as early as 2 wk after implantation. Mature, mechanically competent bone regenerated the native calvaria form. Such an approach could be clinically useful and has significant benefits as a synthetic, off-the-shelf, cell-free option for bone tissue repair and restoration.National Institutes of Health (U.S.) (Grant R01 AG029601)National Institutes of Health (U.S.) (Grant R01 EB010246)National Institutes of Health (U.S.) (Grant P30 CA014051)Natural Sciences and Engineering Research Council of Canada (Fellowship

RNA-Peptide nanoplexes drug DNA damage pathways in high-grade serous ovarian tumors

DNA damaging chemotherapy is a cornerstone of current front‐line treatments for advanced ovarian cancer (OC). Despite the fact that a majority of these patients initially respond to therapy, most will relapse with chemo‐resistant disease; therefore, adjuvant treatments that synergize with DNA‐damaging chemotherapy could improve treatment outcomes and survival in patients with this deadly disease. Here, we report the development of a nanoscale peptide‐nucleic acid complex that facilitates tumor‐specific RNA interference therapy to chemosensitize advanced ovarian tumors to frontline platinum/taxane therapy. We found that the nanoplex‐mediated silencing of the protein kinase, MK2, profoundly sensitized mouse models of high‐grade serous OC to cytotoxic chemotherapy by blocking p38/MK2‐dependent cell cycle checkpoint maintenance. Combined RNAi therapy improved overall survival by 37% compared with platinum/taxane chemotherapy alone and decreased metastatic spread to the lungs without observable toxic side effects. These findings suggest (a) that peptide nanoplexes can serve as safe and effective delivery vectors for siRNA and (b) that combined inhibition of MK2 could improve treatment outcomes in patients currently receiving frontline chemotherapy for advanced OC.National Institutes of Health (U.S.) (Grant R01-ES015339)National Institute of Biomedical Imaging and Bioengineering (U.S.) (Grant 1F32EB017614)National Science Foundation (U.S.) (Grant GFRP 1122374)National Cancer Institute (U.S.) (Grant P30-CA14051)National Science Foundation (U.S.) (Grant DMR-0819762

PEG–Polypeptide Block Copolymers as pH-Responsive Endosome-Solubilizing Drug Nanocarriers

Herein we report the potential of click chemistry-modified polypeptide-based block copolymers for the facile fabrication of pH-sensitive nanoscale drug delivery systems. PEG–polypeptide copolymers with pendant amine chains were synthesized by combining N-carboxyanhydride-based ring-opening polymerization with post-functionalization using azide–alkyne cycloaddition. The synthesized block copolymers contain a polypeptide block with amine-functional side groups and were found to self-assemble into stable polymersomes and disassemble in a pH-responsive manner under a range of biologically relevant conditions. The self-assembly of these block copolymers yields nanometer-scale vesicular structures that are able to encapsulate hydrophilic cytotoxic agents like doxorubicin at physiological pH but that fall apart spontaneously at endosomal pH levels after cellular uptake. When drug-encapsulated copolymer assemblies were delivered systemically, significant levels of tumor accumulation were achieved, with efficacy against the triple-negative breast cancer cell line, MDA-MB-468, and suppression of tumor growth in an in vivo mouse model.Novartis Institutes of Biomedical ResearchNational Institutes of Health (U.S.) (Centers for Cancer Nanotechnology Excellence Grant P30 CA14051)National Institutes of Health (U.S.) (Centers for Cancer Nanotechnology Excellence Grant 5 U54 CA151884-02)National Science Foundation (U.S.). Graduate Research FellowshipNatural Sciences and Engineering Research Council of Canada (Postdoctoral Fellowship

Microstructure, texture and tensile properties of ultrafine/nano grained magnesium alloy processed by accumulative back extrusion

An AZ31 wrought magnesium alloy was processed by employing multipass accumulative back extrusion process. The obtained microstructure, texture and room temperature tensile properties were characterized and discussed. Ultrafine grained microstructure including nano grains were developed, where the obtained mean grain size was decreased from 8 to 0.5 µm by applying consecutive passes. The frequency of both low angle and high angle boundaries increased after processing. Strength of the experimental alloy was decreased after processing, which was attributed to the obtained texture involving the major component lying inclined to the deformation axis. Both the uniform and post uniform elongations of the processed materials were increased after processing, where a total elongation of 68 pct was obtained after six-pass deformation. The contribution of different twinning and slip mechanism was described by calculating corresponding Schmid factors. The operation of prismatic slip was considered as the major deformation contributor. The significant increase in post uniform deformation of the processed material was discussed relying on the occurrence of grain boundary sliding associated with the operation of prismatic slip.Postprint (author's final draft

RNA‐Peptide nanoplexes drug DNA damage pathways in high‐grade serous ovarian tumors

Abstract DNA damaging chemotherapy is a cornerstone of current front‐line treatments for advanced ovarian cancer (OC). Despite the fact that a majority of these patients initially respond to therapy, most will relapse with chemo‐resistant disease; therefore, adjuvant treatments that synergize with DNA‐damaging chemotherapy could improve treatment outcomes and survival in patients with this deadly disease. Here, we report the development of a nanoscale peptide‐nucleic acid complex that facilitates tumor‐specific RNA interference therapy to chemosensitize advanced ovarian tumors to frontline platinum/taxane therapy. We found that the nanoplex‐mediated silencing of the protein kinase, MK2, profoundly sensitized mouse models of high‐grade serous OC to cytotoxic chemotherapy by blocking p38/MK2‐dependent cell cycle checkpoint maintenance. Combined RNAi therapy improved overall survival by 37% compared with platinum/taxane chemotherapy alone and decreased metastatic spread to the lungs without observable toxic side effects. These findings suggest (a) that peptide nanoplexes can serve as safe and effective delivery vectors for siRNA and (b) that combined inhibition of MK2 could improve treatment outcomes in patients currently receiving frontline chemotherapy for advanced OC