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Zhao Y.,University of Alberta | Xing J.,University of Alberta | Xing J.Z.,IntelligentNano Inc. | Xing J.Z.,University of Alberta | And 2 more authors.
Ultrasonics | Year: 2014

Many technologies, such as cell line screening and host cell engineering, culture media optimization and bioprocess optimization, have been proposed to increase monoclonal antibody (mAb) production in Chinese Hamster Ovary (CHO) cells. Unlike the existing biochemical approaches, we investigated stimulation using low-intensity pulsed ultrasound (LIPUS) as a purely physical approach, offering enhanced scalability, contamination control and cost-efficiency, while demonstrating significantly increased cell growth and antibody production. It was found that daily ultrasound treatments at 40 mW/cm2 for 5 min during cell culture increased the production of human anti-IL-8 antibody by more than 30% using 10 or 30 mL shake flasks. Further increasing the ultrasound dosage (either intensities or the treatment duration) did not appreciably increase cell growth or antibody production, however feeding the culture with additional highly-concentrated nutrients, glucose and amino acids (glutamine in this case), did further increase cell growth and antibody titer to 35%. Similar ultrasound treatments (40 mW/cm2, 5 min per day) when scaled up to larger volume wavebags, resulted in a 25% increase in antibody production. Increased antibody production can be attributed to both elevated cell count and the ultrasound stimulation. Theoretical study of underlying mechanisms was performed through the simulations of molecular dynamics using the AMBER software package, with results showing that LIPUS increases cell permeability. The significance of this study is that LIPUS, as a physical-based stimulation approach, can be externally applied to the cell culture without worrying about contamination. By combining with the existing technologies in antibody production, LIPUS can achieve additional mAb yields. Because it can be easily integrated with existing cell culture apparatuses, the technology is expected to be more acceptable by the end users. © 2014 Elsevier B.V. All rights reserved.


Xing J.Z.,University of Alberta | Yang X.,University of Alberta | Xu P.,University of Alberta | Ang W.T.,IntelligentNano Inc. | And 2 more authors.
Ultrasound in Medicine and Biology | Year: 2012

With the rapidly growing demand for monoclonal antibody (mAb)-based products, new technologies are urgently needed to increase mAb production while reducing manufacturing costs. To solve this problem, we report our research findings of using low-intensity pulsed ultrasound (LIPUS) to enhance mAb production. LIPUS with frequency of 1.5 MHz and pulse repetition frequency of 1 kHz, as well as duty cycle of 20%, was used to stimulate hybridoma cells to enhance the production of mAb, anti-CD4 (hybridoma GK1.5). The enzyme-linked immunosorbent assay results show a 60.42 ± 7.63% increase of mAb expression in hybridoma cells. The evidence of structural changes of the cellular outer membrane in both transmission electron microscopy and scanning electron microscopy images and the more than 20% lactate dehydrogenase release indicates that the increased mAb production is related to the increased cell permeability induced by LIPUS. This value-added ultrasound technology provides a potential cost-effective solution for pharmaceutical companies to manufacture mAb-based drugs. The technology, in turn, can reduce the drug manufacturing costs and decrease health care spending. © 2012 World Federation for Ultrasound in Medicine & Biology.


Xing J.,University of Alberta | Choi M.,University of Alberta | Ang W.,IntelligentNano Inc. | Yu X.,University of Alberta | Chen J.,University of Alberta
Ultrasound in Medicine and Biology | Year: 2013

Although the radiation force balance is the gold standard for measuring ultrasound intensity, it cannot be used for real-time monitoring in certain settings, for example, bioreactors or in the clinic to measure ultrasound intensities during treatment. Foreseeing these needs, we propose a close-proximity thermoacoustic sensor. In this article, we describe the design, characterization, testing and implementation of such a sensor. We designed a 20-mm-diameter plexiglass sensor with a 2-mm-long absorber and tested it against low-intensity pulsed ultrasound generated at a 1.5-MHz frequency, 20% duty cycle, 1-kHz pulse repetition frequency and intensities between 30 and 120 mW/cm2. The sensor captures the beam, converts the ultrasound power into heat and indirectly measures the spatial-average time-average ultrasound intensity (Isata) by dividing the calculated power by the beam cross section (or the nominal area of the transducers). A thin copper sheet was attached to the back face of the sensor with thermal paste to increase heat diffusivity 1000-fold, resulting in uniform temperature distribution across the back face. An embedded system design was implemented using an Atmel microcontroller programmed with a least-squares algorithm to fit measured temperature-versus-time data to a model describing the temperature rise averaged across the back side of the sensor in relation to the applied ultrasound intensity. After it was calibrated to the transducer being measured, the thermoacoustic sensor was able to measure ultrasound intensity with an average error of 5.46% compared with readings taken using a radiation force balance. © 2013 World Federation for Ultrasound in Medicine & Biology.


Gul H.,University of Alberta | Gul H.,IntelligentNano Inc. | Lu W.,University of Alberta | Lu W.,IntelligentNano Inc. | And 6 more authors.
Nanotechnology | Year: 2010

Haematopoietic stem and progenitor cell (HSPC) research has significantly contributed to the understanding and harnessing of haematopoiesis for regenerative medicine. However, the methodology for real-time tracking HSPC in vivo is still lacking, which seriously restricts the progress of research. Recently, magnetic carbon nanotubes (mCNT) have generated great excitement because they have been successfully used as vehicles to deliver a lot of biomolecules into various cells. There is, however, no report about mCNT being used for tracking HSPC. In this paper, we investigated the uptake efficiency of fluorescein-isothiocyanate-labelled mCNT (FITC-mCNT) into HSPC and their effect on the cytotoxicity and differentiation of HSPC. We found that cellular uptake of FITC-mCNT was concentration-and time-dependent. The uptake of FITC-mCNT into HSPC reached up to 100% with the highest mean fluorescence (MF). More importantly, efficient FITC-mCNT uptake has no adverse effect on the cell viability, cytotoxicity and differentiation of HSPC as confirmed by colony-forming unit assay (CFU). In conclusion, the results reported here suggest the further tailoring of mCNT for their use in HSPC labelling/tracking in vivo or gene delivery into HSPC. © 2010 IOP Publishing Ltd.


Shaheen M.,University of Alberta | Choi M.,University of Alberta | Ang W.,IntelligentNano Inc. | Zhao Y.,University of Alberta | And 4 more authors.
Renewable Energy | Year: 2013

We explored the application of Low-Intensity Pulsed Ultrasound (LIPUS) technology to improve the metabolic activity of microorganisms. In this study we showed that LIPUS improves bio-ethanol production from lignocellulosic biomass. We determined specific LIPUS conditions to increase the metabolic activity of both the cellulose degrading fungus, Trichoderma reesei Rut C-30 and the ethanol producing yeast, Saccharomyces cerevisiae. LIPUS conditions of 1.5 MHz, 20% duty cycle, 80 mW/cm2 intensity, 5 min exposure and 12 exposures per day were found to improve the activity of the organisms the most. These LIPUS treatment conditions increased cellulase production by T. reesei by 16 ± 6%. The same LIPUS treatment conditions induced a 31 ± 10% increase in ethanol production by S. cerevisiae which implies a cumulative improvement of 52 ± 16% in lignocellulosic bio-ethanol production with LIPUS. This observation shows a new potential for LIPUS in the improvement of lignocellulosic bioethanol production to make it a sustainable energy source. © 2013 Elsevier Ltd.


Patent
IntelligentNano Inc. | Date: 2012-04-05

The invention includes a magnetic nanoparticle molecular delivery vehicle to be used for transfection and delivery of therapeutic molecules across cell membranes and to specific sites in the body, using magnetic forces and ultrasound.


Patent
IntelligentNano Inc. | Date: 2011-09-21

A method of increasing animal cell growth and monoclonal antibody production in an animal cell or cell culture includes the use of ultrasound at a frequency greater than about 1 MHz.


Patent
IntelligentNano Inc. | Date: 2011-09-21

A method of increasing the rate of growth, useful product production, or protein expression of a microorganism includes the step of exposing the microorganism to ultrasound having a frequency greater than about 1 MHz.


Patent
IntelligentNano Inc. and Pharmatech, Inc. | Date: 2010-04-07

The present invention is directed to nanoparticles comprising a cancer therapeutic, pharmaceutical compositions comprising same, and methods for using same for drug delivery and ultrasound or light-based treatment of cancer.


Zhao Y.,University of Alberta | Ang W.T.,IntelligentNano Inc. | Xing J.,IntelligentNano Inc. | Xing J.,University of Alberta | And 2 more authors.
Ultrasound in Medicine and Biology | Year: 2012

Reducing production costs for fermentation-based drugs (e.g., antibiotics) is crucial for the long-term sustainability of healthcare. In this study, we propose a novel low-intensity pulsed ultrasound (LIPUS) stimulation scheme using a nominal frequency of 1.5 MHz with a 20% duty cycle (200 μs ultrasound on and 800 μs ultrasound off) to increase production of fermentation-based drugs. We chose Penicillium brevicompactum as a model system to demonstrate the performance of our LIPUS system. Penicillium brevicompactum can produce mycophenolic acid (MPA), an immunosuppressive agent commonly used to prevent rejection after organ transplantation. We have stimulated Penicillium brevicompactum in 50 mL shake flasks using LIPUS during its fermentation. After a series of screening experiments to optimize ultrasound parameters (e.g., ultrasound intensities, treatment duration and treatment frequency per day), it was concluded that ultrasound stimulation can increase MPA production by as much as 60% when treated eight times a day for 10-min durations at an intensity (spatial peak temporal average) of 200 mW/cm2. These findings elucidate a new approach to reduce the cost of producing fermentation-based drugs. © 2012.

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