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Professor Dayong Jin

Biography

ARC Future Fellow, in biophotonics, nanotechnology & medical biotechnology

Director, ARC Research Hub for Integrated Device for End-user Analysis at Low-levels (IDEAL Hub), 2016–2021

Director, Institute for Biomedical Materials & Devices (IBMD), School of Mathematical and Physical Sciences, Faculty of Science, University of Technology, Sydney (UTS)

Qualifications

PhD, 2003 July – 2007 May, Macquarie University, Supervisor Prof Jim Piper, a well-respected laser physicist. During his PhD research, Professor Jin invented “time-gated fluorescence flow cytometry” (US patent, US2010/0032584, WO/2008/019448, PCT/AU2007/001168).

BSc 1998–2002, Liaoning Normal University, Dalian, followed by postgraduate study,
2002–2003, in optoelectronics at shanghai institute of fine mechanics and optics, the Chinese Academy of Sciences, Shanghai, China.

Employment summary: In 2015, Prof Jin joined UTS as a chair professor to lead its research strength in Materials and Technology and to establish an integrated research Institute for Biomedical Materials & Devices with a $7m budget.  By transforming advances in photonics and materials into revolutionary biomedical technologies, his institute will leverage multi-disciplinary sciences in instrumental physics, materials science, photonics, nanotechnology, molecular biology and engineering to develop a range of research capabilities, and new technology solutions in the areas of cancer, neuron, pathogen, data storage (security), displays, wearable devices, and implantable biomaterials and devices.

Since his shift to UTS for the last 26 months, Prof Jin has established a new team of 20 PhD students, 8 postdoc researchers and 5 visiting research fellows. He developed a new research consortium of four UTS based research groups, four research groups from the University of South Australia, and six Australian biotechnology companies, and successfully secured funding of $6.8 m ($3.7 from ARC) to build the ARC Research Hub for Integrated Device for End-user Analysis at Low-levels (IDEAL Hub).

Prof Jin was previously at Macquarie University where, after his PhD, he had established the Advanced Cytometry Laboratories, engaging a network of collaborators from 14 world-leading research institutions and six companies in Australia, the USA, China, Singapore, France and Germany. He had been promoted to Lecturer in 2010, Senior Lecturer in 2013, Associate Professor in 2014 and Professorial Fellow in 2015.

Professor Jin is a lead inventor on five active international patents (three in national phase, two filed in 2015):

·      Jin D, Lu Y, Piper J, "Two-dimensional scanning for luminescence microscopy" PCT/AU2013/000559 – describing the invention of a high-speed scanning detection device for detection of rare cells.

·      Jin D, Lu Y, Zhao J, "Multiplex suspension assay/array using lifetime coding" PCT/AU2013/000672 – disclosing the “τ-Dots” technology for high speed bio-assays and anti-counterfeiting applications.

·      Jin D, Zhao J, "Enhancing upconversion luminescence in rare earth doped particles" PCT/AU2013/001055 – covering the discovery of the brightest known nanocrystals, the SuperDot® (Trademark # 1582355) technology.

·      Jin D, Xi P, "Mirror enhanced axial narrowing super-resolution microscopy" Australian Provisional Patent Application No. 2015902932, discovering a simple way to convert fluorescence microscopy for super resolution nanoscopy based on growing cells on a tiny mirror.

·      Jin D, Liu D, Xu X, "Controlled growth of three-dimensional heterogeneous nanocrystals" Australian Provisional Patent Application No. 2015902932, disclosing Hyper Dots technology for programmable and precise engineering of multi-functional nanocrystals for bio-imaging, diagnostics and nanomedicine.  

Professional

Major Awards and Honours

2017    the Australian nominee for the APEC Science Prize for Innovation, Research and Education 2017 (by The Minister for Industry, Innovation and Science Senator the Hon. Arthur Sinodinos AO and the Australian Academ of Science)

2017    John Booker Medallist (by the Australian Academy of Science). The John Booker Medal in engineering science is awarded annually by the Australian Academy of Science to recognise outstanding research in the sciences that underpin chemical, civil, electrical, mechanica or materials engineering, and their associated discipines.             

2016   Listed by the Knowledge Society and the Office of the Chief Scientist in conjunction with The Australian newspaper as one of Australia's "Knowledge Nation 100", described as "visionaries, intellects, founders and game changers building the industries and institutions that will underwrite the nation’s future prosperity"

2015  led the SuperDots team, along with Prof. Tanya Monro from the University of South Australia and Prof Bradley Walsh from Minomic International Ltd, and won the UNSW Australian Museum Eureka Prize for Excellence in Interdisciplinary Scientific Research - one of Australia’s most prestigious science awards. http://australianmuseum.net.au/media/2015-eureka-interdisciplinary-scientific-research

           The diverse impact of Super Dots technologies - from non-invasive cancer diagnosis and rapid pathogen detection to invisible coding for authentication of pharmaceuticals, passports and banknotes - is based on advances in diverse fields: material chemistry, optical physics, nanotechnology, biotechnology, computational modelling and instrumentation engineering.

2014   Outcomes profiled in the ARC Annual report – “Nanoparticles revolutionizing health care diagnostics”

2014   Outcomes highlighted in Macquarie University’s 50 years anniversary book

2014   Shortlisted for the Prime Minister’s McIntosh Prize for Physical Scientist of the Year

2014   Appointed a guest professor with the National Natural Science Foundation of China to build a satellite research lab at Peking University focusing on super resolution optical nanoscopy technology and applications in cell biology and materials characterizations

2013   Awarded an “Excellence in Research – Science & Engineering Award” at the Macquarie University Research Award Ceremony for his invention of Super Dots technology

2012   Became the youngest recipient of a Macquarie University Vice-Chancellor’s Innovation Fellowship targeting transformational research, commercialization and industry partnerships

2010  Awarded Early Career Researcher of the Year at the Macquarie University Research Award Ceremony (sole recipient)

2010   Awarded the Asia Nano Forum 2010 Best Presentation Award (sole winner; Oct 2010, Singapore, at Asia Nanotech Camp, 50 selected representatives from 14 countries)

2007   Became the first Australian recipient of the five-year ISAC Scholar Award from the International Society for Analytical Cytology, as one of the Emerging Young Scientists in the field of cell biology methods

2006   Awarded the Macquarie University Postgraduate Award and Innovation Award for his invention of a “low-cost, accurate and portable flow cytometer” device (sole recipient)

2006   Poster Award by International Imaging and Flow Cytometry Association (Pittsburgh, USA);

Milestone Journal Publications: Since his PhD in 2007, Prof Jin has published over 80 peer-reviewed publications across the disciplines of photonics engineering, nanotechnology and cell biology methods, including his six milestone papers in Nature journals (as principal inventor, research project leader and corresponding author).

2017 January - JIN's lab in Australian and Xi's lab in China, after 6 years of experments, has demonstrated a low-power upconversion super-resolution nanoscopy and discovered a new route to alleviate the square root law in super resolution. This work was published by Nature;

– Liu Y, Lu Y, Yang X, Zheng X, Wen S, Wang F, Vidal X, Zhao, Liu D, Zhou Z, Ma C, Zhou J, Piper J, Xi P, Jin D+, “Amplified stimulated emission in upconversion nanoparticles for super resolution nanoscopy”, accepted on 9th Jan 2017, DOI: 10.1038/nature21366 

2016 January – JIN’s lab led the frontier in nanomaterials engineering by realising controlled fabrication of rare-earth-doped nanomaterials with designed size, shape, surface and composition placements, towards building hybrid nanocrystals with integrated multiple functionalities. This work was published by Nature Communications;

– Liu D, Xu X, Du Y, Qin X, Zhang Y, Ma C, Wen S, Ren W, Goldys E, Piper J, Dou S, Liu X, Jin D, “Three-dimensional controlled growth of monodisperse sub-50 nm heterogeneous nanocrystals”, 7, 10254. [over 12,000 downloads since its publication on 8 Jan 2016]

2015 November – As a world leader in upconversion nanotechnology, JIN was invited by Nature Nanotechnology to publish this review paper with his collaborator Prof Xiaogang Liu at National University of Singapore.

– Zhou B, Shi B, Jin D, and Liu X, “Controlling upconversion nanocrystals for emerging applications”, 10, 924-936. [invited review]

2014 May – JIN’s pioneering work on high-speed lifetime decoding technology for rapid pathogen detection was published by Nature Communications;

– Lu Y, Lu J, Zhao J, Cusido J, Raymo F, Yuan J, Yang S, Leif R, Huo Y, Piper J, Robinson J, Goldys E, Jin D “On-the-fly decoding luminescence lifetimes in the microsecond region for lanthanide-encoded suspension arrays”, 5, 3741, IF = 11; [40 citations]

2014 Jan. – JIN’s pioneering work on time-domain nanophotonics sensing was published by Nature Photonics; (press release by ABC Science “Nanocrystals could help prevent forgery” 16 Dec 2013; Australian Pharmacist Feb. 2014 “Biotech offers rapid diagnostics and antidrug counterfeiting”).

– Lu Y, Zhao J, Zhang R, Liu Y, Liu D, Goldys E, Yang X, Xi P, Sunna A, Lu J, Shi Y, Leif R, Huo Y, Shen J, Piper J, Robinson J,  Jin D “Tunable lifetime multiplexing using luminescent nanocrystals”, 8, 32-36. IF = 32; [150 citations]

2013 Sep. – JIN’s breakthrough work on creating the brightest nanoparticles, the SuperDots®, was published by Nature Nanotechnology; (press release by the Statesman newspaper “turning the light up” on 4 Sep 2013; Nature highlights ¾ “Super-bright nanocrystals” Nature 501, 8).

– Zhao J, Jin D, Schartner E, Lu Y, Liu Y, Zhang L, Zvyagin A, Dawes J, Xi P, Piper J, Goldys E, Monro T “Single nanocrystal sensitivity achieved by enhanced upconversion luminescence”, 8, 729-734; IF = 34; [170 citations]

Research funding income:

Since his PhD in 2007, Prof Jin has attracted competitive research funding of over $40 m ($10 m as lead or sole Chief Investigator, including four consecutive research fellowship awards).

2016   An ARC Research Hub for Integrated Device for End-user Analysis at Low-levels (IDEAL Hub, as Director; $3.7m from ARC; $1.1m from five Australian Biotechnology industry partners; $2m from UTS and University of South Australia)

2015   A major ARC LIEF grant ($0.8m; as lead Chief Investigator) to build a National Live Cell Scanning Platform for Nanoparticle Tracking

2014   An ARC Linkage grant (as lead Chief Investigator; $480k) with Sydney-based AusDiagnostics to explore new photonic and biochemistry approaches to DNA recognition for rapid pathogen detection

2013   An ARC Centre of Excellence grant for Nanoscale Bio Photonics ($23m as Chief Investigator). Prof Jin attracted cash contributions from two of his partners: $0.3m from Olympus and $0.5m from Peking University. Prof Jin co-leads the “Illuminate” Science Theme to develop strategic research direction on advanced functional/optical materials, and oversee the progress of Centre programs to deliver a library of efficient nanoscale light sources.

2014   A Commercialisation Australia Entrepreneur grant to support the Super Dots business plan, targeting potential markets in diagnostics, medicine, lighting and security

2013   An ARC Future Fellowship to develop highly sensitive, nanophotonics luminescent probes for more accurate detection and diagnosis of cancer and infection

2013   An ARC Linkage grant (as the Lead Chief Investigator, $617k) with Sydney-based Minomic International Ltd and Melbourne-based Patrys Ltd to develop rapid detection of rare-event cancer cells by Super Dots

2009   An ARC International Collaboration Award to establish the Advanced Cytometry Laboratories at Macquarie

2009   An ARC Postdoctoral Fellowship (APD) to develop cytometry, functional nano-/micro- particles for high-throughput biomolecular discovery

2008   A Macquarie University Research Fellowship (success rate 6%) for biosensors underpinning analytical cytology

Media coverage: Prof Jin’s research has gained over 100 media mentions, including on:

·      AustraliaUnlimited (“Harnessing light for a healthcare revolution” 9 Aug 2016)

·      ABC Radio (interview, “Nanotechnology offering cancer treatment, diagnosis and surgery solutions” 11 Jan 2016)

·      4BC news talk (live interview, “Prize winning nano torch to help fight disease” 31 Aug 2015)

·      ABC Science (“Nanocrystals could help prevent forgery” 16 Dec 2013)

·      The Statesman newspaper (“Turning the light up” 4 Sep 2013 and “Taking turns in the spotlight” 12 Feb 2014)

·      ScienceNewsline (“Timing is everything in new nanotechnology for medicine, security and research” 16 Dec 2013)

·      Australian Pharmacist (“Biotech offers rapid diagnostics and antidrug counterfeiting” Feb 2014)

Invited Speaker and Invitations: Keynote and invited talks at international conferences include the International Conference on Nanoscience and Nanotechnology (2014, 2016); Asia-Pacific Conference on Near-field Optics and Nanophotonics (2013, 2015); 15th Asian Chemical Congress (2013); and the Light, Energy and the Environment Congress (2014). Prof Jin has been invited to present a plenary speech at the Association of Regulatory and Clinical Scientists Australian Congress (May 2016), and keynote talks at the following in 2016: 1st Conference and Spring School on Properties, Design and Applications of Upconverting Nanomaterials; International Symposium on Luminescence, Spectroscopy and Applications; and 9th Singapore International Chemical Conference.

Since 2011 − Grant assessor for Australian Research Council, Netherlands Organisation for Health Research and Development, Austrian Science Fund, and the Belgium FWO Research Foundation; Since 2011 − International Advisory Committee of Asia-Pacific Near-field Optics, and Strategic planning committee of International Society for Advancement of Cytometry;  Journal referee for more than 30 multi-disciplinary journals and societies including regular reviewer for the top ranked journals of Nature Nanotechnology, Nature Photonics, Nature Communications, Advanced Materials, Cytometry A, NanoScale, Scientific Report (editorial board),  Applied Physics Letters, Optics Letters, Small, and Analytical Chemistry

Image of Dayong Jin
Distinguished Professor, School of Mathematical and Physical Sciences
Physics, Biophotonics
 

Research Interests

In 2015, Professor Jin accepted an offer to join UTS as a full professor to lead its research strength in Materials and Technology at School of Physical Sciences and grow the research Institute of Biomedical Materials & Devices (IBMD) with a $2 m seeding budget plus ten research fellowship and a dozen of PhD scholarship positions. Prof. Jin will maintain his relationship with Macquarie University through an Adjunct Professor role, to continue his numerous research projects and supervision of PhD students and postdocs at the ARC Centre of Excellence for Nanoscale BioPhotonics. IBMD will further develop the next-generation technologies for multi-functional hybrid biomaterials, rapid diagnostics, point-of-care sensing, targeted delivery systems and biomedical device engineering. By 2020, IBMD aims to become a transformational research hub to incubate 10 mid-career leaders, train 50 skilled PhD students, fill gaps between physics, chemistry, biology, medicine and engineering, network with 30 leading international research institutes, and build 10 industry partnerships to transform leading-edge and cost-effective technologies. 

News: 

http://www.australiaunlimited.com/science/harnessing-light-for-a-healthcare-revolution

http://www.abc.net.au/news/2016-01-11/nanocrystals-could-change-the-way-cancer-is-treated/7079958

http://www.4bc.com.au/news/fighting-disease--counterfeitfree-passports-a-reality-thanks-to-nano-torch-20150831-gjbd5r.html

http://newsroom.uts.edu.au/news/2016/11/uts-researchers-honoured-excellence-engineering-science-and-physics

http://www.uts.edu.au/about/faculty-science/news/new-collaborative-science-expert-put-ibmd-world-stage

http://www.uts.edu.au/about/faculty-science/news/uts-researchers-named-among-100-australian-visionaries

http://www.uts.edu.au/about/faculty-science/news/uts-claims-double-eureka

https://www.uts.edu.au/about/faculty-science/news/uts-science-lead-australia%E2%80%99s-first-biomedical-devices-hub

http://newsroom.uts.edu.au/news/2016/05/uts-industry-collaborations-receive-55m-boost

http://www.abc.net.au/science/articles/2013/12/16/3910603.htm?site=science/tricks&topic=latest

http://www.purdue.edu/newsroom/releases/2014/Q2/luminescent-nanocrystal-tags-and-high-speed-scanner-enable-rapid-detection-of-multiple-pathogens-in-a-single-test.html

http://www.mq.edu.au/researchawards/winners/winners-2013.html#exc-sci-eng

http://www.mq.edu.au/newsroom/2013/12/23/australian-research-council-funds-23-million-research-centre-with-macquarie-as-one-of-three-core-participants/

http://www.mq.edu.au/newsroom/2013/09/02/breakthrough-in-sensing-at-the-nanoscale/

http://www.mq.edu.au/newsroom/2013/12/16/new-biotechnology-offers-rapid-diagnostics-and-anti-drug-counterfeiting/

http://mq.edu.au/newsroom/2014/05/07/high-speed-scanning-of-tau-dots-enables-rapid-pathogen-detection-and-personalised-medicine/

https://www.youtube.com/watch?v=UYQ8OXxOzCA

https://www.youtube.com/watch?v=F7Zyy1kfaRA

https://www.youtube.com/watch?v=VXjx8yDHgVE

https://www.youtube.com/watch?v=h4ZJ8i7l5W0

Can supervise: Yes

Mentorship/Supervision:  Prof Jin currently mentors nine early-/mid-career researchers. In 2015, four of his postdocs received prestigious fellowship: a Marie Curie fellowship, an NHMRC-ARC Career Development Fellowship, an ARC Future Fellowship and an ARC DECRA Fellowship. He also supervises eight PhD students at UTS and two at Macquarie. Of his six PhDs completions to date, one was awarded an ARC DECRA fellowship in 2012; another was awarded a five year International Society for Analytical Cytology (ISAC) scholar award; a third was awarded the 2013 Royal Society of New South Wales Award; a fourth was awarded a top 5% PhD thesis award in 2015 and is starting an entrepreneurial R&D company in China; and a fifth works with Olympus as a product engineer. 

Chapters

Bradac, C., Gaebel, T., Rabeau, J.R. & Barnard, A.S. 2011, 'Nitrogen-vacancy colour centres in diamond: Theory, characterisation, and applications' in Nanotechnology in Australia: Showcase of Early Career Research, pp. 113-149.
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Jin, D., Yuan, J. & Piper, J. 2011, 'Long-lifetime luminescent nanobioprobes for advanced cytometry biosensing' in Nanotechnology in Australia: Showcase of Early Career Research, pp. 317-345.
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Jin, D. 2011, 'Background-free cytometry using rare earth complex bioprobes.' in Recent Advances in Cytometry, Part A — Instrumentation, Methods, Elsevier, The Netherlands, pp. 479-513.
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In the analytical fields of microbiology, disease diagnosis, and antibioterrorism, there are increasing demands for rapid yet inexpensive quantification of rare cells. This has proven to be challenging by the conventional spectral discrimination of using traditional fluorescent probes, since the strong autofluorescence from background cells or particles overlaps spectrally with the probe fluorescence. This is particularly true when the target cell occurs at very low frequency (one in more than 100,000 background cells) representing a needle-in-a-haystack problem. This chapter describes a low-cost solution to overcome this problem by employing a novel detection technology, namely the use of rare-earth (lanthanide) complex bioprobes with luminescence lifetimes in the hundreds of microseconds. Due to this long persistence in lifetime, microsecond duration luminescence can be detected under conditions where fluorescent backgrounds would overwhelm the emission of conventional fluorochromes. The nanosecond duration autofluorescence associated with cells can be suppressed by time-gated detection, allowing detection of long lifetime lanthanide-based bioprobes with minimal background interference. This technology is applicable to a broad range of detection technologies in both cytometry and imaging. In this chapter, we highlight a typical application in the monitoring of the rare microbial pathogens Cryptosporidium parvum and Giardia lamblia against the complex background of concentrated drinking water. We also describe recent nanotechnological developments in the production of rare-earth nanoparticle bioprobes required for this technology. Other applications of rare-earth bioprobes and time-gated flow cytometry will also be discussed.

Conferences

Wen, S., Li, D., Liu, D., Xu, X., Du, Y., Mitchell, D.R.G., Shi, B., Shi, X. & Jin, D. 2016, 'Seed mediated one-pot growth of versatile heterogeneous upconversion nanocrystals for multimodal bioimaging', Proceedings of SPIE - The International Society for Optical Engineering, International Society for Optical Engineering, SPIE Digital Library, Adelaide, South Australia, Australia.
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© 2016 SPIE.The rapid development of a variety of molecular contrast agents makes the multimodality bioimaging highly attractive towards higher resolution, more sensitive, informative diagnosis. The key lies in the development of facile material synthesis that allows the integration of multiple contrast agents, ideally in a way that each of the components should be logically assembled to maximize their performances. Here, we report the one-pot programmable growth of multifunctional heterogeneous nanocrystal with tunable size, shape, composition, and properties. We demonstrated a facile one-pot hot-injection method to enable the highly selectively controlled growth of different sodium lanthanide fluoride nanomaterials in either longitudinal or transversal directions with atomic scale precision. This technique allows the upconversion luminescence signal, MRI signal and x-ray signal logically integrated and optimized within one single versatile nanoplatform for multimode bioimaging. These findings suggest that the facile strategy developed here have the promising to get the desired heterogeneous nanocrystals as an all-in-one contrast agent for integrated and self-correlative multimodal bioimaging.
Zhao, J., Zheng, X., Schartner, E.P., Ionescu, P., Zhang, R., Nguyen, T.L., Jin, D. & Ebendorff-Heidepriem, H. 2016, 'Upconversion nanocrystals doped glass: A new paradigm for integrated optical glass', Optics InfoBase Conference Papers.
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Jin, D., Li, D. & Shi, X. 2016, 'Polydopamine-coated gold nanostars for CT imaging and enhanced photothermal therapy of tumors', Proceedings of SPIE - The International Society for Optical Engineering, The International Society for Optical Engineering, SPIE, Adelaide.
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The advancement of biocompatible nanoplatforms with dual functionalities of diagnosis and therapeutics is strongly demanded in biomedicine in recent years. In this work, we report the synthesis and characterization of polydopamine (pD)-coated gold nanostars (Au NSs) for computed tomography (CT) imaging and enhanced photothermal therapy (PTT) of tumors. Au NSs were firstly formed via a seed-mediated growth method and then stabilized with thiolated polyethyleneimine (PEI-SH), followed by deposition of pD on their surface. The formed pD-coated Au NSs (Au-PEI@pD NSs) were well characterized. We show that the Au-PEI@pD NSs are able to convert the absorbed near-infrared laser light into heat, and have strong X-ray attenuation property. Due to the co-existence of Au NSs and the pD, the light to heat conversion efficiency of the NSs can be significantly enhanced. These very interesting properties allow their uses as a powerful theranostic nanoplatform for efficient CT imaging and enhanced phtotothermal therapy of cancer cells in vitro and the xenografted tumor model in vivo. With the easy functionalization nature enabled by the coated pD shell, the developed pD-coated Au NSs may be developed as a versatile nanoplatform for targeted CT imaging and PTT of different types of cancer. © (2016) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE). Downloading of the abstract is permitted for personal use only.
Jin, D. 2014, 'Upconversion SuperDots', Optical Instrumentation for Energy and Environmental Applications, E2 2014.
Zhao, J., Lu, Z., Yin, Y., Zhang, L., McKay, A., McRae, C., Piper, J.A., Jin, D., Goldys, E.M. & Dawes, J.M. 2013, 'Characterisation of upconversion nanoparticles for imaging', Asia Communications and Photonics Conference, ACP, Optical Society of America.
By controlling the size of Yb,Er, doped upconversion nanoparticles, we obtain varying emission lifetimes and emission ratios of green and red light, which we explain by modelling of excited state decay mechanisms. © OSA 2013.
Xie, H., Ding, Y., Liu, Y., Zhang, L., Jin, D., Santangelo, P.J., Ren, Q. & Xi, P. 2013, 'Sted3D: Point spread function simulation for high numerical aperture objective and resolution evaluation', Optical Trapping Applications, OTA 2013.
Lu, Y., Lu, J., Piper, J.A., Xi, P. & Jin, D. 2013, 'Orthogonal scanning automated microscopy speeds up time-gated luminescence detection', Optical Trapping Applications, OTA 2013.
Xi, P., Xie, H., Liu, Y. & Jin, D. 2013, 'Stimulated emission depletion point spread function generation with vector solution', Nanophotonics, Nanoelectronics and Nanosensor, N3 2013.
Lu, Y., Lu, J., Piper, J.A., Xi, P. & Jin, D. 2013, 'Orthogonal scanning automated microscopy speeds up time-gated luminescence detection', Optical Molecular Probes, Imaging and Drug Delivery, OMP 2013.
Xie, H., Ding, Y., Liu, Y., Zhang, L., Jin, D., Santangelo, P.J., Ren, Q. & Xi, P. 2013, 'Sted3d: Point spread function simulation for high numerical aperture objective and resolution evaluation', Optical Molecular Probes, Imaging and Drug Delivery, OMP 2013.
Xie, H., Ding, Y., Liu, Y., Zhang, L., Jin, D., Santangelo, P.J., Ren, Q. & Xi, P. 2013, 'STED3D: Point spread function simulation for high numerical aperture objective and resolution evaluation', Bio-Optics: Design and Application, BODA 2013.
Lu, Y., Lu, J., Piper, J.A., Xi, P. & Jin, D. 2013, 'Orthogonal scanning automated microscopy (OSAM) speeds up time-gated luminescence detection', Bio-Optics: Design and Application, BODA 2013.
Schartner, E.P., Jin, D., Zhao, J. & Monro, T.M. 2013, 'Sensitive detection of NaYF4: Yb/Tm nanoparticles using suspended core microstructured optical fibers', Progress in Biomedical Optics and Imaging - Proceedings of SPIE.
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Zhao, J., Lu, Z., Yin, Y., Zhang, L., McKay, A., McRae, C., Piper, J.A., Jin, D., Goldys, E.M. & Dawes, J.M. 2013, 'Characterisation of upconversion nanoparticles for imaging', Asia Communications and Photonics Conference, ACP.
Peng, T., Xie, H., Ding, Y., Wang, W., Li, Z., Jin, D., Tang, Y., Ren, Q. & Xi, P. 2012, 'Confocal reflectance/auto-fluorescence tomograpy (CRAFT) for early skin cancer diagnosis', Biomedical Optics, BIOMED 2012.
Liu, Y., Xie, H., Alonas, E., Santangelo, P.J., Jin, D. & Xi, P. 2012, 'CW STED nanoscopy with a Ti:Sapphire oscillator', Progress in Biomedical Optics and Imaging - Proceedings of SPIE.
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Peng, T., Xie, H., Ding, Y., Lu, Y., Jin, D. & Xi, P. 2012, 'LOSOM: Phase Relief Imaging Can Be Achieved with Confocal System', OPTICS IN HEALTH CARE AND BIOMEDICAL OPTICS V.
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Leif, R.C., Yang, S., Lu, Y., Jin, D. & Chambers, S. 2012, 'A cost-effective analog method to produce time-gated luminescence images', Progress in Biomedical Optics and Imaging - Proceedings of SPIE.
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Schartner, E.P., Jin, D., Ebendorff-Heidepriem, H., Piper, J.A. & Monro, T.M. 2012, 'Lanthanide upconversion nanocrystals within microstructured optical fibres; A sensitive platform for biosensing and a new tool for nanocrystal characterisation', Proceedings of SPIE - The International Society for Optical Engineering.
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Lu, Y., Piper, J.A., Huo, Y. & Jin, D. 2011, 'Cytometric investigation of rare-events featuring time-gated detection and high-speed stage scanning', Optics InfoBase Conference Papers, pp. 2011-2013.
Zhao, J., Piper, J.A., Dawes, J.M., Jin, D. & Goldys, E.M. 2011, 'Mechanisms of size-dependent lifetime quenching in luminescent upconverting colloidal NaYF4: Yb, Er nanocrystals', Optics InfoBase Conference Papers, pp. 384-386.
Jin, D., Lu, Y., Zhao, J., Deng, W., Lu, J. & Piper, J.A. 2011, 'Advances in lanthanide bioprobes and high-throughput background-free biophotonics sensing', Optics InfoBase Conference Papers, pp. 80-82.
Jin, D., Lu, Y., Zhao, J., Deng, W., Lu, J. & Piper, J.A. 2011, 'Advances in lanthanide bioprobes and high-throughput background-free biophotonics sensing', 2011 Int. Quantum Electron. Conf., IQEC 2011 and Conf. Lasers and Electro-Optics, CLEO Pacific Rim 2011 Incorporating the Australasian Conf. Optics, Lasers and Spectroscopy and the Australian Conf., pp. 80-82.
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Lu, Y., Piper, J.A., Huo, Y. & Jin, D. 2011, 'Cytometric investigation of rare-events featuring time-gated detection and high-speed stage scanning', 2011 Int. Quantum Electron. Conf., IQEC 2011 and Conf. Lasers and Electro-Optics, CLEO Pacific Rim 2011 Incorporating the Australasian Conf. Optics, Lasers and Spectroscopy and the Australian Conf., pp. 2011-2013.
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Zhao, J., Piper, J.A., Dawes, J.M., Jin, D. & Goldys, E.M. 2011, 'Mechanisms of size-dependent lifetime quenching in luminescent upconverting colloidal NaYF 4:Yb, Er nanocrystals', 2011 Int. Quantum Electron. Conf., IQEC 2011 and Conf. Lasers and Electro-Optics, CLEO Pacific Rim 2011 Incorporating the Australasian Conf. Optics, Lasers and Spectroscopy and the Australian Conf., pp. 384-386.
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Goldys, E.M., Deng, W., Calander, N.P., Drozdowicz-Tomsia, K. & Jin, D. 2011, 'Nanoscale plasmonic resonators with high Purcell factor: Spontaneous and stimulated emission', Progress in Biomedical Optics and Imaging - Proceedings of SPIE.
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Deng, W., Jin, D., Drozdowicz-Tomsia, K., Yuan, J., Wu, J. & Goldys, E.M. 2011, 'Plasmonic Ag/SiO2 composite nanoparticles doped with europium chelate and their metal enhanced fluorescence', Progress in Biomedical Optics and Imaging - Proceedings of SPIE.
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Jin, D., Piper, J., Yuan, J. & Leif, R. 2010, 'Time-gated real-time bioimaging system using multicolor microsecond-lifetime silica nanoparticles', Progress in Biomedical Optics and Imaging - Proceedings of SPIE.
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Deng, W., Drozdowicz-Tomsia, K., Jin, D. & Goldys, E.M. 2010, 'Silver nanostructure coated beads enhance fluorescence for sensitive immunoassays and bioimaging', ICONN 2010 - Proceedings of the 2010 International Conference on Nanoscience and Nanotechnology, pp. 108-111.
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Leif, R.C., Jin, D., Piper, J., Vallarino, L.M., Williams, J.W., Yang, S. & Zucker, R.M. 2008, 'Calibration beads containing luminescent lanthanide ion complexes', Progress in Biomedical Optics and Imaging - Proceedings of SPIE.
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Jin, D., Ferrari, B., Leif, R.C., Yang, S., Vallarino, L.M., Williams, J. & Piper, J. 2008, 'UV LED excited time-gated luminescence flow cytometry: Evaluation for rare-event particle counting', Progress in Biomedical Optics and Imaging - Proceedings of SPIE.
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Dayong, J., Connally, R. & Piper, J. 2006, 'UV LED excited time-gated luminescence flow cytometry: Concepts and experimental evaluation', Proceedings of SPIE - The International Society for Optical Engineering.
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Piper, J.A., Connally, R.E. & Jin, D.Y. 2005, 'High-contrast detection of target organisms in highly autofluorescent backgrounds using time-resolved techniques', Conference Proceedings - Lasers and Electro-Optics Society Annual Meeting-LEOS, pp. 159-160.
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Jin, D., Connally, R. & Piper, J. 2005, 'Investigation of UV LED luminescence properties for time-resolved fluorescence biomedical applications', Conference Proceedings - Lasers and Electro-Optics Society Annual Meeting-LEOS, pp. 161-162.
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Connally, R., Jin, D. & Piper, J. 2005, 'BHHST: An improved lanthanide chelate for time-resolved fluorescence applications', Progress in Biomedical Optics and Imaging - Proceedings of SPIE, pp. 93-104.
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Jin, D., Connally, R. & Piper, J. 2005, 'Ultra-sensitive time-resolved nanoliter volume fluorometry based on UV LEDs and a channel photomultiplier tube', Progress in Biomedical Optics and Imaging - Proceedings of SPIE, pp. 237-245.
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Journal articles

Teng, B., Ma, P., Yu, C., Zhang, X., Feng, Q., Wen, L., Li, C., Cheng, Z., Jin, D. & Lin, J. 2017, 'Upconversion nanoparticles loaded with eIF4E siRNA and platinum(IV) prodrug to sensitize platinum based chemotherapy for laryngeal cancer and bioimaging', Journal of Materials Chemistry B, vol. 5, no. 2, pp. 307-317.
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Zou, R., Huang, J., Shi, J., Huang, L., Zhang, X., Wong, K.L., Zhang, H., Jin, D., Wang, J. & Su, Q. 2017, 'Silica shell-assisted synthetic route for mono-disperse persistent nanophosphors with enhanced in vivo recharged near-infrared persistent luminescence', Nano Research, vol. 10, no. 6, pp. 2070-2082.
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Liu, Y., Lu, Y., Yang, X., Zheng, X., Wen, S., Wang, F., Vidal, X., Zhao, J., Liu, D., Zhou, Z., Ma, C., Zhou, J., Piper, J.A., Xi, P. & Jin, D. 2017, 'Amplified stimulated emission in upconversion nanoparticles for super-resolution nanoscopy', Nature, vol. 543, no. 7644, pp. 229-233.
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Ma, C., Xu, X., Wang, F., Zhou, Z., Liu, D., Zhao, J., Guan, M., Lang, C.I. & Jin, D. 2017, 'Optimal Sensitizer Concentration in Single Upconversion Nanocrystals.', Nano Lett, vol. 17, no. 5, pp. 2858-2864.
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Each single upconversion nanocrystal (UCNC) usually contains thousands of photon sensitizers and hundreds of photon activators to up-convert near-infrared photons into visible and ultraviolet emissions. Though in principle further increasing the sensitizers' concentration will enhance the absorption efficiency to produce brighter nanocrystals, typically 20% of Yb(3+) ions has been used to avoid the so-called "concentration quenching" effect. Here we report that the concentration quenching effect does not limit the sensitizer concentration and NaYbF4 is the most bright host matrix. Surface quenching and the large size of NaYbF4 nanocrystals are the only factors limiting this optimal concentration. Therefore, we further designed sandwich nanostructures of NaYbF4 between a small template core to allow an epitaxial growth of the size-tunable NaYbF4 shell enclosed by an inert shell to minimize surface quenching. As a result, the suspension containing 25.2 nm sandwich structure UCNCs is 1.85 times brighter than the homogeneously doped ones, and the brightness of each single 25.2 nm heterogeneous UCNC is enhanced by nearly 3 times compared to the NaYF4: 20% Yb(3+), 4% Tm(3+) UCNCs in similar sizes. Particularly, the blue emission intensities of the UCNCs with the sandwich structure in the size of 13.6 and 25.2 nm are 1.36 times and 3.78 times higher than that of the monolithic UCNCs in the similar sizes. Maximizing the sensitizer concentration will accelerate the development of brighter and smaller UCNCs as more efficient biomolecule probes or photon energy converters.
Xu, X., Clarke, C., Ma, C., Casillas, G., Das, M., Guan, M., Liu, D., Wang, L., Tadich, A., Du, Y., Ton-That, C. & Jin, D. 2017, 'Depth-profiling of Yb(3+) sensitizer ions in NaYF4 upconversion nanoparticles.', Nanoscale, vol. 9, no. 23, pp. 7719-7726.
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Enhancing the efficiency of upconversion nanoparticles (UCNPs) and therefore their brightness is the critical goal for this emerging material to meet growing demands in many potential applications including sensing, imaging, solar energy conversion and photonics. The distribution of the photon sensitizer and activator ions that form a network of energy transfer systems within each single UCNP is vital for understanding and optimizing their optical properties. Here we employ synchrotron-based X-ray Photoelectron Spectroscopy (XPS) to characterize the depth distribution of Yb(3+) sensitizer ions in host NaYF4 nanoparticles and systematically correlate the structure with the optical properties for a range of UCNPs with different sizes and doping concentrations. We find a radial gradient distribution of Yb(3+) from the core to the surface of the NaYF4 nanoparticles, regardless of their size or the sensitizer's concentration. Energy dispersive X-ray Spectroscopy (EDX) was also used to further confirm the distribution of the sensitizer ions in the host matrix. These results have profound implications for the upconversion optical property variations.
Marciniak, L., Pilch, A., Arabasz, S., Jin, D. & Bednarkiewicz, A. 2017, 'Heterogeneously Nd(3+) doped single nanoparticles for NIR-induced heat conversion, luminescence, and thermometry.', Nanoscale, vol. 9, no. 24, pp. 8288-8297.
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The current frontier in nanomaterials engineering is to intentionally design and fabricate heterogeneous nanoparticles with desirable morphology and composition, and to integrate multiple functionalities through highly controlled epitaxial growth. Here we show that heterogeneous doping of Nd(3+) ions following a core-shell design already allows three optical functions, namely efficient ( > 72%) light-to-heat conversion, bright NIR emission, and sensitive (SR > 0.1% K(-1)) localized temperature quantification, to be built within a single ca. 25 nm nanoparticle. Importantly, all these optical functions operate within the transparent biological window of the NIR spectral region (exc 800 nm, emi 860 nm), in which light scattering and absorption by tissues and water are minimal. We find NaNdF4 as a core is efficient in absorbing and converting 808 nm light to heat, while NaYF4:1%Nd(3+) as a shell is a temperature sensor based on the ratio-metric luminescence reading but an intermediate inert spacer shell, e.g. NaYF4, is necessary to insulate the heat convertor and thermometer by preventing the possible Nd-Nd energy relaxation. Moreover, we notice that while temperature sensitivity and luminescence intensity are optically stable, increased excitation intensity to generate heat above room temperature may saturate the sensing capacity of temperature feedback. We therefore propose a dual beam photoexcitation scheme as a solution for possible light-induced hyperthermia treatment.
Wu, R., Zhou, J., Lei, L., Zhang, S., Xiao, Z., Zhang, J. & Xu, S. 2017, '-NaYF4:Yb3+-Tm3+@CaF2 nanocrystals for NIR-to-NIR temperature sensing', Chemical Physics Letters, vol. 667, pp. 206-210.
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Wu, R., Zhou, J., Lei, L., Zhang, S., Xiao, Z., Zhang, J. & Xu, S. 2017, '-NaYF4:Yb3+-Tm3+@CaF2 nanocrystals for NIR-to-NIR temperature sensing', Chemical Physics Letters, vol. 667, pp. 206-210.
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Liu, B., Zhang, X., Li, C., He, F., Chen, Y., Huang, S., Jin, D., Yang, P., Cheng, Z. & Lin, J. 2016, 'Magnetically targeted delivery of DOX loaded Cu9S5@mSiO2@Fe3O4-PEG nanocomposites for combined MR imaging and chemo/photothermal synergistic therapy.', Nanoscale.
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The combination of multi-theranostic modes in a controlled fashion has received tremendous attention for the construction of cooperative therapeutic systems in nanomedicine. Herein, we have synthesized a smart magnetically targeted nanocarrier system, Cu9S5@mSiO2@Fe3O4-PEG (labelled as CMF), which integrates NIR triggered photothermal therapy, pH/NIR-responsive chemotherapy and MR imaging into one nanoplatform to enhance the therapeutic efficacy. This new multifunctional paradigm has a uniform and monodisperse sesame ball-like structure by decorating tiny Fe3O4 nanoparticles on the surface of Cu9S5@mSiO2 before a further PEG modification to improve its hydrophilicity and biocompatibility. With doxorubicin (DOX) payload, the as-obtained CMF-DOX composites can simultaneously provide an intense heating effect and enhanced DOX release upon 980 nm NIR light exposure, achieving a combined chemo/photothermal therapy. Under the influence of an external magnetic field, the magnetically targeted synergistic therapeutic effect of CMF-DOX can lead to highly superior inhibition of animal H22 tumor in vivo when compared to any of the single approaches alone. The results revealed that this Cu9S5 based magnetically targeted chemo/photothermal synergistic nanocarrier system has great promise in future MR imaging assisted tumor targeted therapy of cancer.
He, F., Li, C., Zhang, X., Chen, Y., Deng, X., Liu, B., Hou, Z., Huang, S., Jin, D. & Lin, J. 2016, 'Optimization of upconversion luminescence of Nd(3+)-sensitized BaGdF5-based nanostructures and their application in dual-modality imaging and drug delivery.', Dalton transactions (Cambridge, England : 2003), vol. 45, no. 4, pp. 1708-1716.
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808 nm excited upconversion nanoparticles (UCNPs) have received extensive attention in the biomedical areas. However, one of the limitations of UCNPs is their lower luminescence efficiency. Aimed at this problem, a series of BaGdF5-based UCNPs were prepared by a layer-by-layer procedure. And UC luminescence properties are optimized by varying the doping concentration of rare earth ions, amount and types of shells. It is found that if the amount of core BaGdF5:20%Yb(3+)/2%Er(3+) was fixed at 0.5 mmol, the optimized conditions of three shell layers are 0.3 mmol of BaGdF5:10%Yb(3+), 0.5 mmol of BaNdF5 and 0.5 mmol of BaGdF5. Thus the UC luminescence intensity of the resultant nanoparticles BaGdF5:20%Yb(3+)/2%Er(3+)@BaGdF5:10%Yb(3+)@BaNdF5@BaGdF5 (Er@Yb@Nd@Gd) is enhanced more than four times compared with that of BaGdF5:20%Yb(3+)/2%Er(3+)@BaGdF5:10%Yb(3+)@BaNdF5 (Er@Yb@Nd). To further improve the biocompatibility and applications in the biological field, carboxymethyl chitosan (CMC), a type of biocompatible water-transfer agent, was used as a capping ligand to modify the surface of Er@Yb@Nd@Gd. An antitumor drug doxorubicin (DOX) was loaded to the CMC-modified Er@Yb@Nd@Gd nanocarriers by electrostatic interactions. The DOX can be selectively released in an acidic environment, which shows a pH-triggered drug release behavior. On the other hand, Er@Yb@Nd@Gd nanoparticles have excellent magnetic properties due to the presence of Gd components. T1-weighted magnetic resonance imaging (MRI) reveals the concentration-dependent brightening effect with longitudinal relaxivity (r1) as high as 43.77 s(-1) (mM)(-1), much higher than that of previous Gd(3+)-based counterparts. The results indicate that this multifunctional drug delivery system is expected to be a promising platform for simultaneous cancer therapy and bioimaging.
Zheng, X., Lu, Y., Zhao, J., Zhang, Y., Ren, W., Liu, D., Lu, J., Piper, J.A., Leif, R.C., Liu, X. & Jin, D. 2016, 'High-Precision Pinpointing of Luminescent Targets in Encoder-Assisted Scanning Microscopy Allowing High-Speed Quantitative Analysis.', Analytical chemistry, vol. 88, no. 2, pp. 1312-1319.
Compared with routine microscopy imaging of a few analytes at a time, rapid scanning through the whole sample area of a microscope slide to locate every single target object offers many advantages in terms of simplicity, speed, throughput, and potential for robust quantitative analysis. Existing techniques that accommodate solid-phase samples incorporating individual micrometer-sized targets generally rely on digital microscopy and image analysis, with intrinsically low throughput and reliability. Here, we report an advanced on-the-fly stage scanning method to achieve high-precision target location across the whole slide. By integrating X- and Y-axis linear encoders to a motorized stage as the virtual "grids" that provide real-time positional references, we demonstrate an orthogonal scanning automated microscopy (OSAM) technique which can search a coverslip area of 50 24 mm(2) in just 5.3 min and locate individual 15 m lanthanide luminescent microspheres with standard deviations of 1.38 and 1.75 m in X and Y directions. Alongside implementation of an autofocus unit that compensates the tilt of a slide in the Z-axis in real time, we increase the luminescence detection efficiency by 35% with an improved coefficient of variation. We demonstrate the capability of advanced OSAM for robust quantification of luminescence intensities and lifetimes for a variety of micrometer-scale luminescent targets, specifically single down-shifting and upconversion microspheres, crystalline microplates, and color-barcoded microrods, as well as quantitative suspension array assays of biotinylated-DNA functionalized upconversion nanoparticles.
Liu, D., Xu, X., Du, Y., Qin, X., Zhang, Y., Ma, C., Wen, S., Ren, W., Goldys, E.M., Piper, J.A., Dou, S., Liu, X. & Jin, D. 2016, 'Three-dimensional controlled growth of monodisperse sub-50 nm heterogeneous nanocrystals', Nature Communications, vol. 7.
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Cong, Y., Shi, B., Lu, Y., Wen, S., Chung, R. & Jin, D. 2016, 'One-step Conjugation of Glycyrrhetinic Acid to Cationic Polymers for High-performance Gene Delivery to Cultured Liver Cell.', Scientific reports, vol. 6, p. 21891.
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Gene therapies represent a promising therapeutic route for liver cancers, but major challenges remain in the design of safe and efficient gene-targeting delivery systems. For example, cationic polymers show good transfection efficiency as gene carriers, but are hindered by cytotoxicity and non-specific targeting. Here we report a versatile method of one-step conjugation of glycyrrhetinic acid (GA) to reduce cytotoxicity and improve the cultured liver cell -targeting capability of cationic polymers. We have explored a series of cationic polymer derivatives by coupling different ratios of GA to polypropylenimine (PPI) dendrimer. These new gene carriers (GA-PPI dendrimer) were systematically characterized by UV-vis,(1)H NMR titration, electron microscopy, zeta potential, dynamic light-scattering, gel electrophoresis, confocal microscopy and flow cytometry. We demonstrate that GA-PPI dendrimers can efficiently load and protect pDNA, via formation of nanostructured GA-PPI/pDNA polyplexes. With optimal GA substitution degree (6.31%), GA-PPI dendrimers deliver higher liver cell transfection efficiency (43.5% vs 22.3%) and lower cytotoxicity (94.3% vs 62.5%, cell viability) than the commercial bench-mark DNA carrier bPEI (25 kDa) with cultured liver model cells (HepG2). There results suggest that our new GA-PPI dendrimer are a promising candidate gene carrier for targeted liver cancer therapy.
Zheng, X., Zhu, X., Lu, Y., Zhao, J., Feng, W., Jia, G., Wang, F., Li, F. & Jin, D. 2016, 'High-Contrast Visualization of Upconversion Luminescence in Mice Using Time-Gating Approach.', Analytical chemistry, vol. 88, no. 7, pp. 3449-3454.
Optical imaging through the near-infrared (NIR) window provides deep penetration of light up to several centimeters into biological tissues. Capable of emitting 800 nm luminescence under 980 nm illumination, the recently developed upconversion nanoparticles (UCNPs) suggest a promising optical contrast agent for in vivo bioimaging. However, presently they require high-power lasers to excite when applied to small animals, leading to significant scattering background that limits the detection sensitivity as well as a detrimental thermal effect. In this work, we show that the time-gating approach implementing pulsed illumination from a NIR diode laser and time-delayed imaging synchronized via an optical chopper offers detection sensitivity more than 1 order of magnitude higher than the conventional approach using optical band-pass filters (S/N, 47321/6353 vs 5339/58), when imaging UCNPs injected into Kunming mice. The pulsed laser illumination (70 s ON in 200 s period) also reduces the overall thermal accumulation to 35% of that under the continuous-wave mode. Technical details are given on setting up the time-gating unit comprising an optical chopper, a pinhole, and a microscopy eyepiece. Being generally compatible with any camera, this provides a convenient and low cost solution to NIR animal imaging using UCNPs as well as other luminescent probes.
Deng, X., Chen, Y., Cheng, Z., Deng, K., Ma, P., Hou, Z., Liu, B., Huang, S., Jin, D. & Lin, J. 2016, 'Rational design of a comprehensive cancer therapy platform using temperature-sensitive polymer grafted hollow gold nanospheres: simultaneous chemo/photothermal/photodynamic therapy triggered by a 650 nm laser with enhanced anti-tumor efficacy.', Nanoscale, vol. 8, no. 12, pp. 6837-6850.
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Combining multi-model treatments within one single system has attracted great interest for the purpose of synergistic therapy. In this paper, hollow gold nanospheres (HAuNs) coated with a temperature-sensitive polymer, poly(oligo(ethylene oxide) methacrylate-co-2-(2-methoxyethoxy)ethyl methacrylate) (p(OEGMA-co-MEMA)), co-loaded with DOX and a photosensitizer Chlorin e6 (Ce6) were successfully synthesized. As high as 58% DOX and 6% Ce6 by weight could be loaded onto the HAuNs-p(OEGMA-co-MEMA) nanocomposites. The grafting polymer brushes outside the HAuNs play the role of "gate molecules" for controlled drug release by 650 nm laser radiation owing to the temperature-sensitive property of the polymer and the photothermal effect of HAuNs. The HAuNs-p(OEGMA-co-MEMA)-Ce6-DOX nanocomposites with 650 nm laser radiation show effective inhibition of cancer cells in vitro and enhanced anti-tumor efficacy in vivo. In contrast, control groups without laser radiation show little cytotoxicity. The nanocomposite demonstrates a way of "killing three birds with one stone", that is, chemotherapy, photothermal and photodynamic therapy are triggered simultaneously by the 650 nm laser stimulation. Therefore, the nanocomposites show the great advantages of multi-modal synergistic effects for cancer therapy by a remote-controlled laser stimulus.
Zhao, J., Zheng, X., Schartner, E.P., Ionescu, P., Zhang, R., Nguyen, T.L., Jin, D. & Ebendorff-Heidepriem, H. 2016, 'Upconversion Nanocrystal-Doped Glass: A New Paradigm for Photonic Materials', Advanced Optical Materials, vol. 4, no. 10, pp. 1507-1517.
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The integration of novel luminescent nanomaterials into glassy matrix can lead to new hybrid materials and photonic devices with promising material performance and device functions. Lanthanide-containing upconversion nanocrystals have become unique candidates for sensing, bioimaging, photon energy management, volumetric displays, and other photonic applications. Here, a versatile direct-doping approach is developed to integrate bright upconversion nanocrystals in tellurite glass with tailored nanoscale properties. Following our two-temperature glass-melting technique, the doping temperature window of 550-625 °C and a 5 min dwell time at 577 °C are determined as the key to success, which balances the survival and dispersion of upconversion nanocrystals in glass. It is identified that the fine spectra of upconversion emissions can be used to diagnose the survival and dissolution fraction of doped nanocrystals in the glass. Moreover, 3D dispersion of nanocrystals in the glass is visualized by upconversion scanning confocal microscopy. It is further demonstrated that a low-loss fiber, drawn from the highly transparent nanocrystals-doped glass retains the distinct optical properties of upconversion nanocrystals. These results suggest a robust strategy for fabrication of high-quality upconversion nanocrystal-doped glasses. The new class of hybrid glasses allows for fiber-based devices to be developed for photonic applications or as a useful tool for tailoring light-nanoparticles interactions study.
Hou, Z., Deng, K., Li, C., Deng, X., Lian, H., Cheng, Z., Jin, D. & Lin, J. 2016, '808 nm Light-triggered and hyaluronic acid-targeted dual-photosensitizers nanoplatform by fully utilizing Nd3+-sensitized upconversion emission with enhanced anti-tumor efficacy', Biomaterials, vol. 101, pp. 32-46.
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© 2016 Elsevier Ltd.The current near-infrared (NIR) light-induced photodynamic therapy (PDT) can enhance the tissue penetration depth to trigger photosensitizers (PSs) far from the surface. NIR-mediated PDT is still challenged by overheating effect on normal tissues, limited tumor selectivity and low reactive oxygen species (ROS) yields. Here we construct a dual-agent photosensitizing nanoplatform by combining UV-blue upconversion emitting NaYF4:Yb/Tm@NaYF4:Yb@NaNdF4:Yb@NaYF4 (labeled as UCNPs) multi-shell nanocrystals with titanium dioxide (TiO2, UV-light-excited PS) and hypocrellin A (HA, blue-light-excited PS), which can induce cancer cell apoptosis by 808 nm light-triggered and hyaluronic acid (Hyal)-targeted PDT. In this construction strategy, the crystallized TiO2 shells on the surface of UCNPs can play dual roles as UV-light excited PS and conjugation site for Hyal, and then Hyal is served as targeting-ligand as well as the carrier of HA simultaneously. The step-by-step reactive mode of loading PSs and modifying targeting-ligands is a controllable and ordered design based on the use of one intermediate product as the reaction site for the next component. The Nd3+-sensitized UCNPs with quenching reduction layer can efficiently convert 808 nm NIR light to UV-blue emission for simultaneous activation of two PSs with enhanced intracellular ROS generation. Through the in vitro and in vivo experiment results, the dual-photosensitizers nanoplatform presents enhanced anti-tumor efficacy by effective targeting cellular uptake and taking full advantage of upconversion emission, which may make a major step toward next generation of NIR-mediated PDT.
Yang, X., Xie, H., Alonas, E., Liu, Y., Chen, X., Santangelo, P.J., Ren, Q., Xi, P. & Jin, D. 2016, 'Mirror-enhanced super-resolution microscopy.', Light, science & applications, vol. 5.
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Axial excitation confinement beyond the diffraction limit is crucial to the development of next-generation, super-resolution microscopy. STimulated Emission Depletion (STED) nanoscopy offers lateral super-resolution using a donut-beam depletion, but its axial resolution is still over 500 nm. Total internal reflection fluorescence microscopy is widely used for single-molecule localization, but its ability to detect molecules is limited to within the evanescent field of ~ 100 nm from the cell attachment surface. We find here that the axial thickness of the point spread function (PSF) during confocal excitation can be easily improved to 110 nm by replacing the microscopy slide with a mirror. The interference of the local electromagnetic field confined the confocal PSF to a 110-nm spot axially, which enables axial super-resolution with all laser-scanning microscopes. Axial sectioning can be obtained with wavelength modulation or by controlling the spacer between the mirror and the specimen. With no additional complexity, the mirror-assisted excitation confinement enhanced the axial resolution six-fold and the lateral resolution two-fold for STED, which together achieved 19-nm resolution to resolve the inner rim of a nuclear pore complex and to discriminate the contents of 120 nm viral filaments. The ability to increase the lateral resolution and decrease the thickness of an axial section using mirror-enhanced STED without increasing the laser power is of great importance for imaging biological specimens, which cannot tolerate high laser power.
Liu, B., Li, C., Xie, Z., Hou, Z., Cheng, Z., Jin, D. & Lin, J. 2016, '808 nm photocontrolled UCL imaging guided chemo/photothermal synergistic therapy with single UCNPs-CuS@PAA nanocomposite.', Dalton transactions (Cambridge, England : 2003), vol. 45, no. 33, pp. 13061-13069.
Recently, incorporating multiple components into one nanostructured matrix to construct a multifunctional nanomedical platform has attracted more and more attention for simultaneous anticancer diagnosis and therapy. Herein, a novel anti-cancer nanoplatform has been successfully developed by coating a uniform shell of poly(acrylic acid) (PAA) on the surface of CuS-decorated upconversion nanoparticles (UCNPs). Benefiting from the enhanced 808 nm-excited UCL intensity of the multilayer UCNPs, the unique photothermal properties of CuS and the pH-responsive drug release capacity of the PAA shell, such a nanoplatform design of UCNPs-CuS@PAA (labeled UCP) offers a new route to achieve 808 nm-excited UCL imaging guided chemo/photothermal combination therapy. We have found that the combined chemo/photothermal therapy can significantly improve the therapeutic efficacy compared with chemotherapy or photothermal therapy (PTT) alone. Moreover, the pH/NIR-dependent drug delivery properties, 808 nm-excited UCL imaging, as well as in vitro/in vivo biocompatibility tests were also investigated in detail. These results show promising applications of UCP nanoparticles as a novel theranostic agent for the detection and treatment of tumors.
Ma, C., Xu, X., Wang, F., Zhou, Z., Wen, S., Liu, D., Fang, J., Lang, C.I. & Jin, D. 2016, 'Probing the Interior Crystal Quality in the Development of More Efficient and Smaller Upconversion Nanoparticles', Journal of Physical Chemistry Letters, vol. 7, pp. 3252-3258.
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Sayyadi, N., Justiniano, I., Connally, R.E., Zhang, R., Shi, B., Kautto, L., Everest-Dass, A.V., Yuan, J., Walsh, B.J., Jin, D., Willows, R.D., Piper, J.A. & Packer, N.H. 2016, 'Sensitive Time-Gated Immunoluminescence Detection of Prostate Cancer Cells Using a TEGylated Europium Ligand.', Analytical chemistry.
We describe the application of a synthetically developed tetradentate -diketonate-europium chelate with high quantum yield (39%), for sensitive immunodetection of prostate cancer cells (DU145). MIL38 antibody, a mouse monoclonal antibody against Glypican 1, conjugated directly to the chelate via lysine residues, resulted in soluble (hydrophilic) and stable immunoconjugates. Indirect labeling of the antibody by a europium chelated secondary polyclonal antibody and a streptavidin/biotin pair was also performed. All of these bright luminescent conjugates were used to stain DU145 cells, a prostate cancer cell line, using time gated luminescence microscopy for imaging, and their performances were compared to conventional FITC labeling. For all prepared conjugates, the europium chelate in conjunction with a gated autosynchronous luminescence detector (GALD) completely suppressed the cellular autofluorescence background to allow capture of vivid, high contrast images of immune-stained cancer cells.
Jin, D. 2016, 'View from. UPCON 2016: Bright future for upconversion', Nature Photonics, vol. 10, no. 9, pp. 567-569.
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Yang, X., Zhanghao, K., Wang, H., Liu, Y., Wang, F., Zhang, X., Shi, K., Gao, J., Jin, D. & Xi, P. 2016, 'Versatile Application of Fluorescent Quantum Dot Labels in Super-resolution Fluorescence Microscopy', ACS Photonics, vol. 3, no. 9, pp. 1611-1618.
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Liu, D., Xu, X., Wang, F., Zhou, J., Mi, C., Zhang, L., Lu, Y., Ma, C., Goldys, E., Lin, J. & Jin, D. 2016, 'Emission stability and reversibility of upconversion nanocrystals', Journal of Materials Chemistry C, vol. 4, pp. 9227-9234.
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Shi, Y., Shi, B., Dass, A.V.E., Lu, Y., Sayyadi, N., Kautto, L., Willows, R.D., Chung, R., Piper, J., Nevalainen, H., Walsh, B., Jin, D. & Packer, N.H. 2016, 'Stable Upconversion Nanohybrid Particles for Specific Prostate Cancer Cell Immunodetection.', Sci Rep, vol. 6, p. 37533.
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Prostate cancer is one of the male killing diseases and early detection of prostate cancer is the key for better treatment and lower cost. However, the number of prostate cancer cells is low at the early stage, so it is very challenging to detect. In this study, we successfully designed and developed upconversion immune-nanohybrids (UINBs) with sustainable stability in a physiological environment, stable optical properties and highly specific targeting capability for early-stage prostate cancer cell detection. The developed UINBs were characterized by transmission electron microscopy (TEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), dynamic light scattering (DLS) and luminescence spectroscopy. The targeting function of the biotinylated antibody nanohybrids were confirmed by immunofluorescence assay and western blot analysis. The UINB system is able to specifically detect prostate cancer cells with stable and background-free luminescent signals for highly sensitive prostate cancer cell detection. This work demonstrates a versatile strategy to develop UCNPs based sustainably stable UINBs for sensitive diseased cell detection.
Zhanghao, K., Chen, L., Yang, X.-.S., Wang, M.-.Y., Jing, Z.-.L., Han, H.-.B., Zhang, M.Q., Jin, D., Gao, J.-.T. & Xi, P. 2016, 'Super-resolution dipole orientation mapping via polarization demodulation', Light: Science & Applications, vol. 5, no. 10, pp. e16166-e16166.
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Liu, D., Xu, X., Wang, F., Zhou, J., Mi, C., Zhang, L., Lu, Y., Ma, C., Goldys, E., Lin, J. & Jin, D. 2016, 'Emission stability and reversibility of upconversion nanocrystals', Journal of Materials Chemistry C, vol. 4, no. 39, pp. 9227-9234.
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Yao, Q., Li, W., Yu, S., Ma, L., Jin, D., Boccaccini, A.R. & Liu, Y. 2015, 'Multifunctional chitosan/polyvinyl pyrrolidone/45S5 Bioglass® scaffolds for MC3T3-E1 cell stimulation and drug release.', Materials science & engineering. C, Materials for biological applications, vol. 56, pp. 473-480.
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Novel chitosan-polyvinyl pyrrolidone/45S5 Bioglass® (CS-PVP/BG) scaffolds were prepared via foam replication and chemical cross-linking techniques. The pristine BG, CS-PVP coated BG and genipin cross-linked CS-PVP/BG (G-CS-PVP/BG) scaffolds were synthesized and characterized in terms of chemical composition, physical structure and morphology respectively. Resistance to enzymatic degradation of the scaffold is improved significantly with the use of genipin cross-linked CS-PVP. The bio-effects of scaffolds on MC3T3-E1 osteoblast-like cells were evaluated by studying cell viability, adhesion and proliferation. The CCK-8 assay shows that cell viability on the resulting G-CS-PVP/BG scaffold is improved obviously after cross-linking of genipin. Cell skeleton images exhibit that well-stretched F-actin bundles are obtained on the G-CS-PVP/BG scaffold. SEM results present significant improvement on the cell adhesion and proliferation for cells cultured on the G-CS-PVP/BG scaffold. The drug release performance on the as-synthesized scaffold was studied in a phosphate buffered saline (PBS) solution. Vancomycin is found to be released in burst fashion within 24h from the pristine BG scaffold, however, the release period from the G-CS-PVP/BG scaffold is enhanced to 7days, indicating improved drug release properties of the G-CS-PVP/BG scaffold. Our results suggest that the G-CS-PVP/BG scaffolds possess promising physicochemical properties, sustained drug release capability and good biocompatibility for MC3T3-E1 cells' proliferation and adhesion, suggesting their potential applications in areas such as MC3T3-E1 cell stimulation and bone tissue engineering.
Yang, M., Liang, Y., Gui, Q., Zhao, B., Jin, D., Lin, M., Yan, L., You, H., Dai, L. & Liu, Y. 2015, 'Multifunctional luminescent nanomaterials from NaLa(MoO4)2:Eu(3+)/Tb(3+) with tunable decay lifetimes, emission colors, and enhanced cell viability.', Scientific reports, vol. 5, p. 11844.
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A facile, but effective, method has been developed for large-scale preparation of NaLa(MoO4)2 nanorods and microflowers co-doped with Eu(3+) and Tb(3+) ions (abbreviated as: NLM:Ln(3+)). The as-synthesized nanomaterials possess a pure tetragonal phase with variable morphologies from shuttle-like nanorods to microflowers by controlling the reaction temperature and the amount of ethylene glycol used. Consequently, the resulting nanomaterials exhibit superb luminescent emissions over the visible region from red through yellow to green by simply changing the relative doping ratios of Eu(3+) to Tb(3+) ions. Biocompatibility study indicates that the addition of NLM:Ln(3+) nanomaterials can stimulate the growth of normal human retinal pigment epithelium (ARPE-19) cells. Therefore, the newly-developed NaLa(MoO4)2 nanomaterials hold potentials for a wide range of multifunctional applications, including bioimaging, security protection, optical display, optoelectronics for information storage, and cell stimulation.
Lu, J., Chen, Y., Liu, D., Ren, W., Lu, Y., Shi, Y., Piper, J.A., Paulsen, I.T. & Jin, D. 2015, 'One-step Protein Conjugation to Upconversion Nanoparticles', Analytical Chemistry, vol. 87, no. 20, pp. 10406-10413.
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The emerging upconversion nanoparticles offer a fascinating library of ultrasensitive luminescent probes for a range of biotechnology applications from biomarker discovery to single molecule tracking, early disease diagnosis, deep tissue imaging, and drug delivery and therapies. The effective bioconjugation of inorganic nanoparticles to the molecule-specific proteins, free of agglomeration, nonspecific binding, or biomolecule deactivation, is crucial for molecular recognition of target molecules or cells. The current available protocols require multiple steps which can lead to low probe stability, specificity, and reproducibility. Here we report a simple and rapid protein bioconjugation method based on a one-step ligand exchange using the DNAs as the linker. Our method benefits from the robust DNA–protein conjugates as well as from multiple ions binding capability. Protein can be preconjugated via an amino group at the 3 end of a synthetic DNA molecule, so that the 5 end phosphoric acid group and multiple phosphate oxygen atoms in the phosphodiester bonds are exposed to replace the oleic acid ligands on the surface of upconversion nanoparticles due to their stronger chelating capability to lanthanides. We demonstrated that our method can efficiently pull out the upconversion nanoparticles from organic solvent into an aqueous phase. The upconversion nanoparticles then become hydrophilic, stable, and specific biomolecules recognition. This allows us to successfully functionalize the upconversion nanoparticles with horseradish peroxidise (HRP) for catalytic colorimetric assay and for streptavidin (SA)–biotin immunoassays.
Shi, B. & Jin, D. 2015, 'Rapid detection of rare-event cell by SUPER Dots based diagnostics nano-platform.', Journal of controlled release : official journal of the Controlled Release Society, vol. 213, pp. e11-e12.
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Song, B., Ye, Z., Yang, Y., Ma, H., Zheng, X., Jin, D. & Yuan, J. 2015, 'Background-free in-vivo Imaging of Vitamin C using Time-gateable Responsive Probe.', Scientific reports, vol. 5, p. 14194.
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Sensitive optical imaging of active biomolecules in the living organism requires both a molecular probe specifically responsive to the target and a high-contrast approach to remove the background interference from autofluorescence and light scatterings. Here, a responsive probe for ascorbic acid (vitamin C) has been developed by conjugating two nitroxide radicals with a long-lived luminescent europium complex. The nitroxide radical withholds the probe on its "off" state (barely luminescent), until the presence of vitamin C will switch on the probe by forming its hydroxylamine derivative. The probe showed a linear response to vitamin C concentration with a detection limit of 9.1 nM, two orders of magnitude lower than that achieved using electrochemical methods. Time-gated luminescence microscopy (TGLM) method has further enabled real-time, specific and background-free monitoring of cellular uptake or endogenous production of vitamin C, and mapping of vitamin C in living Daphnia magna. This work suggests a rational design of lanthanide complexes for background-free small animal imaging of biologically functional molecules.
Zhou, B., Shi, B., Jin, D. & Liu, X. 2015, 'Controlling upconversion nanocrystals for emerging applications.', Nature nanotechnology, vol. 10, no. 11, pp. 924-936.
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Lanthanide-doped upconversion nanocrystals enable anti-Stokes emission with pump intensities several orders of magnitude lower than required by conventional nonlinear optical techniques. Their exceptional properties, namely large anti-Stokes shifts, sharp emission spectra and long excited-state lifetimes, have led to a diversity of applications. Here, we review upconversion nanocrystals from the perspective of fundamental concepts and examine the technical challenges in relation to emission colour tuning and luminescence enhancement. In particular, we highlight the advances in functionalization strategies that enable the broad utility of upconversion nanocrystals for multimodal imaging, cancer therapy, volumetric displays and photonics.
Cheng, R., Ou, S., Bu, Y., Li, X., Liu, X., Wang, Y., Guo, R., Shi, B., Jin, D. & Liu, Y. 2015, 'Starch-borate-graphene oxide nanocomposites as highly efficient targeted antitumor drugs', RSC Advances, vol. 5, no. 115, pp. 94855-94858.
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Jin, D., Lu, Y., Leif, R.C., Yang, S., Rajendran, M. & Miller, L.W. 2014, 'How to build a time-gated luminescence microscope.', Current protocols in cytometry / editorial board, J. Paul Robinson, managing editor ... [et al.], vol. 67, pp. Unit-2.22..
The sensitivity of filter-based fluorescence microscopy techniques is limited by autofluorescence background. Time-gated detection is a practical way to suppress autofluorescence, enabling higher contrast and improved sensitivity. In the past few years, three groups of authors have demonstrated independent approaches to build robust versions of time-gated luminescence microscopes. Three detailed, step-by-step protocols are provided here for modifying standard fluorescent microscopes to permit imaging time-gated luminescence.
Ye, Z., Zhang, R., Song, B., Dai, Z., Jin, D., Goldys, E.M. & Yuan, J. 2014, 'Development of a functional ruthenium(II) complex for probing hypochlorous acid in living cells.', Dalton transactions (Cambridge, England : 2003), vol. 43, no. 22, pp. 8414-8420.
A functional ruthenium(ii) complex, [Ru(bpy)2(AN-bpy)](PF6)2 (bpy: 2,2'-bipyridine, AN-bpy: 4-methyl-4'-(4-amino-3-nitro-phenoxy-methylene)-2,2'-bipyridine), has been designed and synthesized as a turn-on luminescent probe for the imaging of hypochlorous acid (HOCl) in living cells. Due to the intramolecular photoinduced electron transfer (PET), the ruthenium(ii) complex itself is almost non-luminescent. However, it can specifically and rapidly react with HOCl in aqueous media to afford a highly luminescent derivative, [Ru(bpy)2(HM-bpy)](PF6)2 (HM-bpy: 4-hydroxymethyl-4'-methyl-2,2'-bipyridine), accompanied by a 110-fold luminescence enhancement. Taking advantage of high specificity and sensitivity, and excellent photophysical properties of the ruthenium(ii) complex probe, [Ru(bpy)2(AN-bpy)](PF6)2 was successfully applied to the luminescence imaging of the exogenous HOCl in living HeLa cells and the endogenous HOCl in porcine neutrophils. The results corroborate that indeed [Ru(bpy)2(AN-bpy)](PF6)2 is a useful luminescent probe for the monitoring of HOCl in biological systems.
Lu, Y., Lu, J., Zhao, J., Cusido, J., Raymo, F.M., Yuan, J., Yang, S., Leif, R.C., Huo, Y., Piper, J.A., Paul Robinson, J., Goldys, E.M. & Jin, D. 2014, 'On-the-fly decoding luminescence lifetimes in the microsecond region for lanthanide-encoded suspension arrays.', Nature communications, vol. 5, p. 3741.
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Significant multiplexing capacity of optical time-domain coding has been recently demonstrated by tuning luminescence lifetimes of the upconversion nanoparticles called '-Dots'. It provides a large dynamic range of lifetimes from microseconds to milliseconds, which allows creating large libraries of nanotags/microcarriers. However, a robust approach is required to rapidly and accurately measure the luminescence lifetimes from the relatively slow-decaying signals. Here we show a fast algorithm suitable for the microsecond region with precision closely approaching the theoretical limit and compatible with the rapid scanning cytometry technique. We exploit this approach to further extend optical time-domain multiplexing to the downconversion luminescence, using luminescence microspheres wherein lifetimes are tuned through luminescence resonance energy transfer. We demonstrate real-time discrimination of these microspheres in the rapid scanning cytometry, and apply them to the multiplexed probing of pathogen DNA strands. Our results indicate that tunable luminescence lifetimes have considerable potential in high-throughput analytical sciences.
Zhang, Y., Zhang, L., Deng, R., Tian, J., Zong, Y., Jin, D. & Liu, X. 2014, 'Multicolor barcoding in a single upconversion crystal.', Journal of the American Chemical Society, vol. 136, no. 13, pp. 4893-4896.
We report the synthesis of luminescent crystals based on hexagonal-phase NaYF4 upconversion microrods. The synthetic procedure involves an epitaxial end-on growth of upconversion nanocrystals comprising different lanthanide activators onto the NaYF4 microrods. This bottom-up method readily affords multicolor-banded crystals in gram quantity by varying the composition of the activators. Importantly, the end-on growth method using one-dimensional microrods as the template enables facile multicolor tuning in a single crystal, which is inaccessible in conventional upconversion nanoparticles. We demonstrate that these novel materials offer opportunities as optical barcodes for anticounterfeiting and multiplexed labeling applications.
Xie, H., Jin, D., Yu, J., Peng, T., Ding, Y., Zhou, C. & Xi, P. 2014, 'Schlieren confocal microscopy for phase-relief imaging', OPTICS LETTERS, vol. 39, no. 5, pp. 1238-1241.
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Lu, Y., Zhao, J., Zhang, R., Liu, Y., Liu, D., Goldys, E.M., Yang, X., Xi, P., Sunna, A., Lu, J., Shi, Y., Leif, R.C., Huo, Y., Shen, J., Piper, J.A., Robinson, J.P. & Jin, D. 2014, 'Tunable lifetime multiplexing using luminescent nanocrystals', Nature Photonics, vol. 8, no. 1, pp. 32-36.
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Zhang, L., Zheng, X., Deng, W., Lu, Y., Lechevallier, S., Ye, Z., Goldys, E.M., Dawes, J.M., Piper, J.A., Yuan, J., Verelst, M. & Jin, D. 2014, 'Practical implementation, characterization and applications of a multi-colour time-gated luminescence microscope.', Scientific reports, vol. 4, p. 6597.
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Time-gated luminescence microscopy using long-lifetime molecular probes can effectively eliminate autofluorescence to enable high contrast imaging. Here we investigate a new strategy of time-gated imaging for simultaneous visualisation of multiple species of microorganisms stained with long-lived complexes under low-background conditions. This is realized by imaging two pathogenic organisms (Giardia lamblia stained with a red europium probe and Cryptosporidium parvum with a green terbium probe) at UV wavelengths (320-400nm) through synchronization of a flash lamp with high repetition rate (1kHz) to a robust time-gating detection unit. This approach provides four times enhancement in signal-to-background ratio over non-time-gated imaging, while the average signal intensity also increases six-fold compared with that under UV LED excitation. The high sensitivity is further confirmed by imaging the single europium-doped YOS nanocrystals (150nm). We report technical details regarding the time-gating detection unit and demonstrate its compatibility with commercial epi-fluorescence microscopes, providing a valuable and convenient addition to standard laboratory equipment.
Jin, D., Lu, Y., Leif, R.C., Yang, S., Rajendran, M. & Miller, L.W. 2014, 'How to build a time-gated luminescence microscope.', Current protocols in cytometry / editorial board, J. Paul Robinson, managing editor ... [et al.], vol. 67, pp. Unit-2.22..
The sensitivity of filter-based fluorescence microscopy techniques is limited by autofluorescence background. Time-gated detection is a practical way to suppress autofluorescence, enabling higher contrast and improved sensitivity. In the past few years, three groups of authors have demonstrated independent approaches to build robust versions of time-gated luminescence microscopes. Three detailed, step-by-step protocols are provided here for modifying standard fluorescent microscopes to permit imaging time-gated luminescence. Copyright © 2014 John Wiley & Sons, Inc.
Zhao, J., Jin, D., Schartner, E.P., Lu, Y., Liu, Y., Zvyagin, A.V., Zhang, L., Dawes, J.M., Xi, P., Piper, J.A., Goldys, E.M. & Monro, T.M. 2013, 'Single-nanocrystal sensitivity achieved by enhanced upconversion luminescence.', Nature nanotechnology, vol. 8, no. 10, pp. 729-734.
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Upconversion nanocrystals convert infrared radiation to visible luminescence, and are promising for applications in biodetection, bioimaging, solar cells and three-dimensional display technologies. Although the design of suitable nanocrystals has improved the performance of upconversion nanocrystals, their emission brightness is limited by the low doping concentration of activator ions needed to avoid the luminescence quenching that occurs at high concentrations. Here, we demonstrate that high excitation irradiance can alleviate concentration quenching in upconversion luminescence when combined with higher activator concentration, which can be increased from 0.5 mol% to 8 mol% Tm(3+) in NaYF. This leads to significantly enhanced luminescence signals, by up to a factor of 70. By using such bright nanocrystals, we demonstrate remote tracking of a single nanocrystal with a microstructured optical-fibre dip sensor. This represents a sensitivity improvement of three orders of magnitude over benchmark nanocrystals such as quantum dots.
Zhang, L., McKay, A. & Jin, D. 2013, 'High-throughput 3-dimensional time-resolved spectroscopy: Simultaneous characterisation of luminescence properties in spectral and temporal domains', RSC Advances, vol. 3, no. 23, pp. 8670-8673.
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Lu, J., Paulsen, I.T. & Jin, D. 2013, 'Application of exonuclease III-aided target recycling in flow cytometry: DNA detection sensitivity enhanced by orders of magnitude.', Analytical chemistry, vol. 85, no. 17, pp. 8240-8245.
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DNA-functionalized microspheres in conjugation with flow cytometry detection are widely used for high-throughput nucleic acid assays. Although such assays are rapid and capable of simultaneous analysis of multiple nucleic acid analytes in a single test, the intrinsic limitation in sensitivity remains challenging. Here we report a simple, highly sensitive, and reproducible method based on Exonuclease III-aided target recycling technique applied for DNA quantification in flow cytometry. By loading a high density of Cy5-labeled probe DNA on microspheres (15 m), we achieved hitherto unreported DNA detection limit of 3.2 pM in flow cytometry bead assay, enhancing the sensitivity by a factor of over 56.8 compared to the conventional direct hybridization bead assay. Furthermore, we evaluated multiplexing capability by simultaneous detections of two target DNAs with FAM and Cy5 reporter conjugated probes. Therefore, the novel Exonuclease III-amplified flow cytometry bead assay has great potential for the rapid, sensitive, and accurate detection and quantification of nucleic acids in clinical diagnosis and biomedical research.
Xie, H., Liu, Y., Jin, D., Santangelo, P.J. & Xi, P. 2013, 'Analytical description of high-aperture STED resolution with 0-2 vortex phase modulation.', Journal of the Optical Society of America. A, Optics, image science, and vision, vol. 30, no. 8, pp. 1640-1645.
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Stimulated emission depletion (STED) can achieve optical superresolution, with the optical diffraction limit broken by the suppression on the periphery of the fluorescent focal spot. Previously, it is generally experimentally accepted that there exists an inverse square root relationship with the STED power and the resolution, but with arbitrary coefficients in expression. In this paper, we have removed the arbitrary coefficients by exploring the relationship between the STED power and the achievable resolution from vector optical theory for the widely used 0-2 vortex phase modulation. Electromagnetic fields of the focal region of a high numerical aperture objective are calculated and approximated into polynomials of radius in the focal plane, and analytical expression of resolution as a function of the STED intensity has been derived. As a result, the resolution can be estimated directly from the measurement of the saturation power of the dye and the STED power applied in the region of high STED power.
Ding, Y., Zhang, Y., Peng, T., Lu, Y., Jin, D., Ren, Q., Liu, Y., Han, J. & Xi, P. 2013, 'Observation of mesenteric microcirculatory disturbance in rat by laser oblique scanning optical microscopy', SCIENTIFIC REPORTS, vol. 3.
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Song, Z., Anissimov, Y.G., Zhao, J., Nechaev, A.V., Nadort, A., Jin, D., Prow, T.W., Roberts, M.S. & Zvyagin, A.V. 2013, 'Background free imaging of upconversion nanoparticle distribution in human skin.', Journal of biomedical optics, vol. 18, no. 6, p. 061215.
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Widespread applications of nanotechnology materials have raised safety concerns due to their possible penetration through skin and concomitant uptake in the organism. This calls for systematic study of nanoparticle transport kinetics in skin, where high-resolution optical imaging approaches are often preferred. We report on application of emerging luminescence nanomaterial, called upconversion nanoparticles (UCNPs), to optical imaging in skin that results in complete suppression of background due to the excitation light back-scattering and biological tissue autofluorescence. Freshly excised intact and microneedle-treated human skin samples were topically coated with oil formulation of UCNPs and optically imaged. In the first case, 8- and 32-nm UCNPs stayed at the topmost layer of the intact skin, stratum corneum. In the second case, 8-nm nanoparticles were found localized at indentations made by the microneedle spreading in dermis very slowly (estimated diffusion coefficient, D(np) = 3-7 10(-12) cm(2) s(-1)). The maximum possible UCNP-imaging contrast was attained by suppressing the background level to that of the electronic noise, which was estimated to be superior in comparison with the existing optical labels.
Zhao, J., Lu, Z., Yin, Y., McRae, C., Piper, J.A., Dawes, J.M., Jin, D. & Goldys, E.M. 2013, 'Upconversion luminescence with tunable lifetime in NaYF4:Yb,Er nanocrystals: role of nanocrystal size.', Nanoscale, vol. 5, no. 3, pp. 944-952.
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Despite recent achievements to reduce surface quenching in NaYF(4):Yb,Er nanocrystals, a complete understanding of how the nanocrystal size affects the brightness of upconversion luminescence is still incomplete. Here we investigated upconversion luminescence of Yb,Er-doped nanocrystals in a broad range of sizes from 6 nm to 45 nm (cubic or hexagonal phases), displaying an increasing red-to-green luminescence intensity ratio and reduced luminescence lifetimes with decreasing size. By analyzing the upconversion process with a set of rate equations, we found that their asymptotic analytic solutions explain lower decay rates of red compared to green upconversion luminescence. Furthermore, we quantified the effect of the surface on luminescence lifetime in a model where nanocrystal emitters are divided between the near-surface and inside regions of each nanocrystal. We clarify the influence of the four nonradiative recombination mechanisms (intrinsic phonon modes, vibration energy of surface ligands, solvent-mediated quenching, and surface defects) on the decay rates for different-size nanocrystals, and find that the defect density dominates decay rates for small (below 15 nm) nanocrystals. Our results indicate that a defect-reduction strategy is a key step in producing small upconversion nanocrystals with increased brightness for a variety of bioimaging and biosensing applications.
Schartner, E.P., Jin, D., Ebendorff-Heidepriem, H., Piper, J.A., Lu, Z. & Monro, T.M. 2012, 'Lanthanide upconversion within microstructured optical fibers: Improved detection limits for sensing and the demonstration of a new tool for nanocrystal characterization', Nanoscale, vol. 4, no. 23, pp. 7448-7451.
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Lu, J., Martin, J., Lu, Y., Zhao, J., Yuan, J., Ostrowski, M., Paulsen, I., Piper, J.A. & Jin, D. 2012, 'Resolving low-expression cell surface antigens by time-gated orthogonal scanning automated microscopy.', Analytical chemistry, vol. 84, no. 22, pp. 9674-9678.
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We report a highly sensitive method for rapid identification and quantification of rare-event cells carrying low-abundance surface biomarkers. The method applies lanthanide bioprobes and time-gated detection to effectively eliminate both nontarget organisms and background noise and utilizes the europium containing nanoparticles to further amplify the signal strength by a factor of 20. Of interest is that these nanoparticles did not correspondingly enhance the intensity of nonspecific binding. Thus, the dramatically improved signal-to-background ratio enables the low-expression surface antigens on single cells to be quantified. Furthermore, we applied an orthogonal scanning automated microscopy (OSAM) technique to rapidly process a large population of target-only cells on microscopy slides, leading to quantitative statistical data with high certainty. Thus, the techniques together resolved nearly all false-negative events from the interfering crowd including many false-positive events.
Lu, Y., Xi, P., Piper, J.A., Huo, Y. & Jin, D. 2012, 'Time-gated orthogonal scanning automated microscopy (OSAM) for high-speed cell detection and analysis.', Scientific reports, vol. 2, p. 837.
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We report a new development of orthogonal scanning automated microscopy (OSAM) incorporating time-gated detection to locate rare-event organisms regardless of autofluorescent background. The necessity of using long-lifetime (hundreds of microseconds) luminescent biolabels for time-gated detection implies long integration (dwell) time, resulting in slow scan speed. However, here we achieve high scan speed using a new 2-step orthogonal scanning strategy to realise on-the-fly time-gated detection and precise location of 1-m lanthanide-doped microspheres with signal-to-background ratio of 8.9. This enables analysis of a 15 mm 15 mm slide area in only 3.3 minutes. We demonstrate that detection of only a few hundred photoelectrons within 100 s is sufficient to distinguish a target event in a prototype system using ultraviolet LED excitation. Cytometric analysis of lanthanide labelled Giardia cysts achieved a signal-to-background ratio of two orders of magnitude. Results suggest that time-gated OSAM represents a new opportunity for high-throughput background-free biosensing applications.
Everest-Dass, A.V., Jin, D., Thaysen-Andersen, M., Nevalainen, H., Kolarich, D. & Packer, N.H. 2012, 'Comparative structural analysis of the glycosylation of salivary and buccal cell proteins: innate protection against infection by Candida albicans.', Glycobiology, vol. 22, no. 11, pp. 1465-1479.
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Mucosal epithelial surfaces, such as line the oral cavity, are common sites of microbial colonization by bacteria, yeast and fungi. The microbial interactions involve adherence between the glycans on the host cells and the carbohydrate-binding proteins of the pathogen. Saliva constantly bathes the buccal cells of the epithelial surface of the mouth and we postulate that the sugars on the salivary glycoproteins provide an innate host immune mechanism against infection by competitively inhibiting pathogen binding to the cell membranes. The structures of the N- and O-linked oligosaccharides on the glycoproteins of saliva and buccal cell membranes were analyzed using capillary carbon liquid chromatography-electrospray ionization MS/MS. The 190 glycan structures that were characterized were qualitatively similar, but differed quantitatively, between saliva and epithelial buccal cell membrane proteins. The similar relative abundance of the terminal glycan epitope structures (e.g. ABO(H) blood group, sialylation and Lewis-type antigens) on saliva and buccal cell membrane glycoproteins indicated that the terminal N- and O-linked glycan substructures in saliva could be acting as decoy-binding receptors to competitively inhibit the attachment of pathogens to the surface of the oral mucosa. A flow cytometry-based binding assay quantified the interaction between buccal cells and the commensal oral pathogen Candida albicans. Whole saliva and released glycans from salivary proteins inhibited the interaction of C. albicans with buccal epithelial cells, confirming the protective role of the glycans on salivary glycoproteins against pathogen infection.
Zhang, W., Zhang, R., Zhang, J., Ye, Z., Jin, D. & Yuan, J. 2012, 'Photoluminescent and electrochemiluminescent dual-signaling probe for bio-thiols based on a ruthenium(II) complex.', Analytica chimica acta, vol. 740, pp. 80-87.
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Photoluminescence (PL) and electrochemiluminescence (ECL) detection techniques are highly sensitive and widely used methods for clinical diagnostics and analytical biotechnology. In this work, a unique ruthenium(II) complex, [Ru(bpy)(2)(DNBSO-bpy)](PF(6))(2) (bpy: 2,2'-bipyridine; DNBSO-bpy: 2,4-dinitrobenzenesulfonate of 4-(4-hydroxyphenyl)-2,2'-bipyridine), has been designed and synthesized as a highly sensitive and selective PL and ECL dual-signaling probe for the recognition and detection of bio-thiols in aqueous media. As a thiol-responsive probe, the complex can specifically and rapidly react with bio-thiols in aqueous solutions to yield a bipyridine-Ru(II) complex derivative, [Ru(bpy)(2)(HP-bpy)](2+) (HP-bpy: 4-(4-hydroxyphenyl)-2,2'-bipyridine), accompanied by the remarkable PL and ECL enhancements. The complex was used as a probe for the PL and ECL detections of cysteine (Cys) and glutathione (GSH) in aqueous solutions. The dose-dependent PL and ECL enhancements showed good linear relationships against the Cys/GSH concentrations with the detection limits at nano-molar concentration level. Moreover, the complex-loaded HeLa cells were prepared for PL imaging of the endogenous intracellular thiols. The results demonstrated the practical utility of the complex as a cell-membrane permeable probe for PL imaging detection of bio-thiols in living cells.
Ding, Y., Xie, H., Peng, T., Lu, Y., Jin, D., Teng, J., Ren, Q. & Xi, P. 2012, 'Laser oblique scanning optical microscopy (LOSOM) for phase relief imaging', OPTICS EXPRESS, vol. 20, no. 13, pp. 14100-14108.
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Liu, Y., Ding, Y., Alonas, E., Zhao, W., Santangelo, P.J., Jin, D., Piper, J.A., Teng, J., Ren, Q. & Xi, P. 2012, 'Achieving /10 resolution CW STED nanoscopy with a Ti:Sapphire oscillator.', PloS one, vol. 7, no. 6, p. e40003.
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In this report, a Ti:Sapphire oscillator was utilized to realize synchronization-free stimulated emission depletion (STED) microscopy. With pump power of 4.6 W and sample irradiance of 310 mW, we achieved super-resolution as high as 71 nm. With synchronization-free STED, we imaged 200 nm nanospheres as well as all three cytoskeletal elements (microtubules, intermediate filaments, and actin filaments), clearly demonstrating the resolving power of synchronization-free STED over conventional diffraction limited imaging. It also allowed us to discover that, Dylight 650, exhibits improved performance over ATTO647N, a fluorophore frequently used in STED. Furthermore, we applied synchronization-free STED to image fluorescently-labeled intracellular viral RNA granules, which otherwise cannot be differentiated by confocal microscopy. Thanks to the widely available Ti:Sapphire oscillators in multiphoton imaging system, this work suggests easier access to setup super-resolution microscope via the synchronization-free STED.
Zhang, L., Wang, Y., Ye, Z., Jin, D. & Yuan, J. 2012, 'New class of tetradentate -diketonate-europium complexes that can be covalently bound to proteins for time-gated fluorometric application.', Bioconjugate chemistry, vol. 23, no. 6, pp. 1244-1251.
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Luminescent lanthanide complexes that can be covalently bound to proteins have shown great utility as biolabels for highly sensitive time-gated luminescence bioassays in clinical diagnostics and biotechnology discoveries. In this work, three new tetradentate -diketonate-europium complexes that can be covalently bound to proteins to display strong and long-lived Eu(3+) luminescence, 1,2-bis[4'-(1",1",1",2",2",3",3"-heptafluoro-4",6"-hexanedion-6"-yl)-benzyl]-4-chlorosulfobenzene-Eu(3+) (BHHBCB-Eu(3+)), 1,2-bis[4'-(1",1",1",2",2"-pentafluoro-3",5"-pentanedion-5"-yl)-benzyl]-4-chlorosulfobenzene-Eu(3+) (BPPBCB-Eu(3+)), and 1,2-bis[4'-(1",1",1"-trifluoro-2",4"-butanedion-4"-yl)-benzyl]-4-chlorosulfobenzene-Eu(3+) (BTBBCB-Eu(3+)), have been designed and synthesized as biolabels for time-gated luminescence bioassay applications. The luminescence spectroscopy characterizations of the aqueous solutions of three complex-bound bovine serum albumin reveal that BHHBCB-Eu(3+) has the strongest luminescence with the largest quantum yield (40%) and longest luminescence lifetime (0.52 ms) among the complexes, which is superior to the other currently available europium biolabels. The BHHBCB-Eu(3+)-labeled streptavidin was prepared and used for both the time-gated luminescence immunoassay of human prostate specific antigen and the time-gated luminescence microscopy imaging of a pathogenic microorganism Cryptosporidium muris . The results demonstrated the practical utility of the new Eu(3+) complex-based biolabel for time-gated luminescence bioassay applications.
Tian, L., Dai, Z., Zhang, L., Zhang, R., Ye, Z., Wu, J., Jin, D. & Yuan, J. 2012, 'Preparation and time-gated luminescence bioimaging applications of long wavelength-excited silica-encapsulated europium nanoparticles.', Nanoscale, vol. 4, no. 11, pp. 3551-3557.
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Silica-encapsulated luminescent lanthanide nanoparticles have shown great potential as biolabels for various time-gated luminescence bio-detections in recent years. The main problem of these nano-biolabels is their short excitation wavelengths within the UV region. In this work, a new type of silica-encapsulated luminescent europium nanoparticle, with a wide excitation range from UV to visible light in aqueous solutions, has been prepared using a conjugate of (3-isocyanatopropyl)triethoxysilane bound to a visible light-excited Eu(3+) complex, 2,6-bis(1',1',1',2',2',3',3'-heptafluoro-4',6'-hexanedion-6'-yl)-dibenzothiophene-Eu(3+)-2-(N,N-diethylanilin-4-yl)-4,6-bis(pyrazol-1-yl)-1,3,5-triazine (IPTES-BHHD-Eu(3+)-BPT conjugate), as a functionalized precursor. The nanoparticles, which are prepared by the copolymerization of the IPTES-BHHD-Eu(3+)-BPT conjugate, tetraethyl orthosilicate and (3-aminopropyl)triethoxysilane in a water-in-oil reverse microemulsion consisting of Triton X-100, n-octanol, cyclohexane and water in the presence of aqueous ammonia, are monodisperse, spherical and uniform in size. Their diameter is 42 ± 3 nm and they are strongly luminescent with a wide excitation range from UV to 475 nm and a long luminescence lifetime of 346 s. The nanoparticles were successfully used for streptavidin labeling and the time-gated luminescence imaging detection of two environmental pathogens, cryptosporidium muris and cryptosporidium parvium, in water samples. The results demonstrated the practical utility of the new nanoparticles as visible light-excited biolabels for time-gated luminescence bioassay applications.
Peng, T., Xie, H., Ding, Y., Wang, W., Li, Z., Jin, D., Tang, Y., Ren, Q. & Xi, P. 2012, 'CRAFT: Multimodality confocal skin imaging for early cancer diagnosis', JOURNAL OF BIOPHOTONICS, vol. 5, no. 5-6, pp. 469-476.
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Zhang, R., Ye, Z., Yin, Y., Wang, G., Jin, D., Yuan, J. & Piper, J.A. 2012, 'Developing red-emissive ruthenium(II) complex-based luminescent probes for cellular imaging.', Bioconjugate chemistry, vol. 23, no. 4, pp. 725-733.
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Ruthenium(II) complexes have rich photophysical attributes, which enable novel design of responsive luminescence probes to selectively quantify biochemical analytes. In this work, we developed a systematic series of Ru(II)-bipyrindine complex derivatives, [Ru(bpy)(3-n)(DNP-bpy)(n)](PF(6))(2) (n = 1, 2, 3; bpy, 2,2'-bipyridine; DNP-bpy, 4-(4-(2,4-dinitrophenoxy)phenyl)-2,2'-bipyridine), as luminescent probes for highly selective and sensitive detection of thiophenol in aqueous solutions. The specific reaction between the probes and thiophenol triggers the cleavage of the electron acceptor group, 2,4-dinitrophenyl, eliminating the photoinduced electron transfer (PET) process, so that the luminescence of on-state complexes, [Ru(bpy)(3-n)(HP-bpy)(n)](2+) (n = 1, 2, 3; HP-bpy, 4-(4-hydroxyphenyl)-2,2'-bipyridine), is turned on. We found that the complex [Ru(bpy)(DNP-bpy)(2)](2+) remarkably enhanced the on-to-off contrast ratio compared to the other two (37.8 compared to 21 and 18.7). This reveals a new strategy to obtain the best Ru(II) complex luminescence probe via the most asymmetric structure. Moreover, we demonstrated the practical utility of the complex as a cell-membrane permeable probe for quantitative luminescence imaging of the dynamic intracellular process of thiophenol in living cells. The results suggest that the new probe could be a very useful tool for luminescence imaging analysis of the toxic thiophenol in intact cells.
Calander, N., Jin, D. & Goldys, E.M. 2012, 'Taking plasmonic core-shell nanoparticles toward laser threshold', Journal of Physical Chemistry C, vol. 116, no. 13, pp. 7546-7551.
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Deng, W., Jin, D., Drozdowicz-Tomsia, K., Yuan, J., Wu, J. & Goldys, E.M. 2011, 'Ultrabright Eu-doped plasmonic Ag@SiO2 nanostructures: time-gated bioprobes with single particle sensitivity and negligible background.', Advanced materials (Deerfield Beach, Fla.), vol. 23, no. 40, pp. 4649-4654.
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Deng, W., Sudheendra, L., Zhao, J., Fu, J., Jin, D., Kennedy, I.M. & Goldys, E.M. 2011, 'Upconversion in NaYF(4):Yb, Er nanoparticles amplified by metal nanostructures.', Nanotechnology, vol. 22, no. 32, p. 325604.
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Upconversion (UC) fluorescence in NaYF(4):Yb, Er nanoparticles amplified by metal nanostructures was compared in two nanostructure geometries: gold nanoshells surrounding nanoparticles and silver nanostructures adjacent to the nanoparticles, both placed on a dielectric silica surface. Enhanced UC luminescence signals and modified lifetimes induced by these two metals were observed in our study. The UC luminescence intensities of green and red emissions were enhanced by Ag nanostructures by a factor of approximately 4.4 and 3.5, respectively. The corresponding UC lifetimes were reduced 1.7-fold and 2.4-fold. In NaYF(4):Yb, Er nanoparticles encapsulated in gold nanoshells, higher luminescence enhancement factors were obtained (9.1-fold for the green emission and 6.7-fold for the red emission). However, the Au shell coating extended the red emission by a factor of 1.5 and did not obviously change the lifetime of green emission. The responsible mechanisms such as plasmonic enhancement and surface effects are discussed.
Jin, D. 2011, 'Demonstration of true-color high-contrast microorganism imaging for terbium bioprobes.', Cytometry. Part A : the journal of the International Society for Analytical Cytology, vol. 79, no. 5, pp. 392-397.
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Lanthanide bioprobes offer a number of novel advantages for advanced cytometry, including the microsecond luminescence lifetime, sharp spectral emission, and large stokes shift. However, to date, only the europium-based bioprobes have been broadly studied for time-gated luminescence cell imaging, though a wide range of efficient terbium bioprobes have been synthesized and some of them are commercially available. We analyze that the bottleneck problem was due to the lack of an efficient microscope with pulsed excitation at wavelengths of 300-330 nm. We investigate a recently available 315 nm ultraviolet (UV) light emitting diode to excite an epifluorescence microscope. Substituting a commercial UV objective (40), the 315 nm light efficiently delivered the excitation light onto the uncovered specimen. A novel pinhole-assisted optical chopper unit was attached behind the eyepiece for direct lifetime-gating to permit visual inspection of background-free images. We demonstrate the use of a commercial terbium complex for high-contrast imaging of an environmental pathogenic microorganism, Cryptosporidium parvum. As a result of effective autofluorescence suppression by a factor of 61.85 in the time domain, we achieved an enhanced signal-to-background ratio of 14.43. This type of time-gating optics is easily adaptable to the use of routine epifluorescence microscopes, which provides an opportunity for high-contrast imaging using multiplexed lanthanide bioprobes.
Jin, D. & Piper, J.A. 2011, 'Time-gated luminescence microscopy allowing direct visual inspection of lanthanide-stained microorganisms in background-free condition.', Analytical chemistry, vol. 83, no. 6, pp. 2294-2300.
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Application of standard immuno-fluorescence microscopy techniques for detection of rare-event microorganisms in dirty samples is severely limited by autofluorescence of nontarget organisms or other debris. Time-gated detection using gateable array detectors in combination with microsecond-lifetime luminescent bioprobes (usually lanthanide-based) is highly effective in suppression of (nanosecond-lifetime) autofluorescence background; however, the complexity and cost of the instrumentation is a major barrier to application of these techniques to routine diagnostics. We report a practical, low-cost implementation of time-gated luminescence detection in a standard epifluorescence microscope which has been modified to include a high-power pulsed UV light-emitting diode (LED) illumination source and a standard fast chopper inserted in the focal plane behind a microscope eyepiece. Synchronization of the pulsed illumination/gated detection cycle is driven from the clock signal from the chopper. To achieve time-gated luminescence intensities sufficient for direct visual observation, we use high cycle rates, up to 2.5 kHz, taking advantage of the fast switching capabilities of the LED source. We have demonstrated real-time direct-visual inspection of europium-labeled Giardia lamblia cysts in dirty samples and Cryptosporidium parvum oocysts in fruit juice concentrate. The signal-to-background ratio has been enhanced by a factor of 18 in time-gated mode. The availability of low-cost, robust time-gated microscopes will aid development of long-lifetime luminescence bioprobes and accelerate their application in routine laboratory diagnostics.
Lu, Y., Jin, D., Leif, R.C., Deng, W., Piper, J.A., Yuan, J., Duan, Y. & Huo, Y. 2011, 'Automated detection of rare-event pathogens through time-gated luminescence scanning microscopy.', Cytometry. Part A : the journal of the International Society for Analytical Cytology, vol. 79, no. 5, pp. 349-355.
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Many microorganisms have a very low threshold (<10 cells) to trigger infectious diseases, and, in these cases, it is important to determine the absolute cell count in a low-cost and speedy fashion. Fluorescent microscopy is a routine method; however, one fundamental problem has been associated with the existence in the sample of large numbers of nontarget particles, which are naturally autofluorescent, thereby obscuring the visibility of target organisms. This severely affects both direct visual inspection and the automated microscopy based on computer pattern recognition. We report a novel strategy of time-gated luminescent scanning for accurate counting of rare-event cells, which exploits the large difference in luminescence lifetimes between the lanthanide biolabels, >100 s, and the autofluorescence backgrounds, <0.1 s, to render background autofluorescence invisible to the detector. Rather than having to resort to sophisticated imaging analysis, the background-free feature allows a single-element photomultiplier to locate rare-event cells, so that requirements for data storage and analysis are minimized to the level of image confirmation only at the final step. We have evaluated this concept in a prototype instrument using a 2D scanning stage and applied it to rare-event Giardia detection labeled by a europium complex. For a slide area of 225 mm(2) , the time-gated scanning method easily reduced the original 40,000 adjacent elements (0.075 mm 0.075 mm) down to a few "elements of interest" containing the Giardia cysts. We achieved an averaged signal-to-background ratio of 41.2 (minimum ratio of 12.1). Such high contrasts ensured the accurate mapping of all the potential Giardia cysts free of false positives or negatives. This was confirmed by the automatic retrieving and time-gated luminescence bioimaging of these Giardia cysts. Such automated microscopy based on time-gated scanning can provide novel solutions for quantitative diagnostics in advanced biolo...
Jiang, L., Wu, J., Wang, G., Ye, Z., Zhang, W., Jin, D., Yuan, J. & Piper, J. 2010, 'Development of a visible-light-sensitized europium complex for time-resolved fluorometric application.', Analytical chemistry, vol. 82, no. 6, pp. 2529-2535.
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The time-resolved luminescence bioassay technique using luminescent lanthanide complexes as labels is a highly sensitive and widely used bioassay method for clinical diagnostics and biotechnology. A major drawback of the current technique is that the luminescent lanthanide labels require UV excitation (typically less than 360 nm), which can damage living biological systems and is holding back further development of time-resolved luminescence instruments. Herein we describe two approaches for preparing a visible-light-sensitized Eu(3+) complex in aqueous media for time-resolved fluorometric applications: a dissociation enhancement aqueous solution that can be excited by visible light for ethylenediaminetetraacetate (EDTA)-Eu(3+) detection and a visible-light-sensitized water-soluble Eu(3+) complex conjugated bovine serum albumin (BSA) for biolabeling and time-resolved luminescence bioimaging. In the first approach, a weakly acidic aqueous solution consisting of 4,4'-bis(1'',1'',1'',2'',2'',3'',3''-heptafluoro-4'',6''-hexanedion-6''-yl)-o-terphenyl (BHHT), 2-(N,N-diethylanilin-4-yl)-4,6-bis(3,5-dimethylpyrazol-1-yl)-1,3,5-triazine (DPBT), and Triton X-100 was prepared. This solution shows a strong luminescence enhancement effect for EDTA-Eu(3+) with a wide excitation wavelength range from UV to visible light (a maximum at 387 nm) and a long luminescence lifetime (520 micros), to provide a novel dissociation enhancement solution for time-resolved luminescence detection of EDTA-Eu(3+). In the second approach, a ternary Eu(3+) complex, 4,4'-bis(1'',1'',1'',2'',2'',3'',3''-heptafluoro-4'',6''-hexanedion-6''-yl)-chlorosulfo-o-terphenyl (BHHCT)-Eu(3+)-DPBT, was covalently bound to BSA to form a water-soluble BSA-BHHCT-Eu(3+)-DPBT conjugate. This biocompatible conjugate is of the visible-light excitable feature in aqueous media with a wide excitation wavelength range from UV to visible light (a maximum at 387 nm), a long luminescence lifetime (460 micros), and a higher qu...
Deng, W., Jin, D., Drozdowicz-Tomsia, K., Yuan, J. & Goldys, E.M. 2010, 'Europium chelate (BHHCT-Eu3+) and its metal nanostructure enhanced luminescence applied to bioassays and time-gated bioimaging.', Langmuir : the ACS journal of surfaces and colloids, vol. 26, no. 12, pp. 10036-10043.
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We report the use of europium chelate, 4,4'-bis(1'',1'',1'',2'',2'',3'',3''-heptafluoro-4'',6''-hexanedion-6''-yl)chlorosulfo-o-terphenyl-Eu(3+) (BHHCT-Eu(3+)), in silver nanostructure-enhanced luminescence and its application to bioassays and bioimaging. The highest luminescence intensity enhancement factor of BHHCT-Eu(3+) achieved in this study was about 11 times, while the simultaneously measured luminescence lifetime was reduced 2-fold. The luminophore photostability was also improved by a factor of 3. On the basis of these experimental results, we estimated the impact of silver nanostructures on the excitation and emission enhancement factors. Luminescence enhancement was demonstrated in two geometries: on planar glass substrates and on silica beads. In the biotin-modified IgG antibody assay the bead geometry provided slightly higher enhancement factor and greater sensitivity. Subsequently, we applied such bead substrates to time-gated luminescence imaging of Giardia lamblia cells stained by BHHCT-Eu(3+) where we observed improved brightness by a factor of 2. Such improved photostability and brightness of BHHCT-Eu(3+) in the presence of metal nanostructures are highly desirable for ultrasensitive bioassays and bioimaging, especially with time gating.
Jiang, H., Wang, G., Zhang, W., Liu, X., Ye, Z., Jin, D., Yuan, J. & Liu, Z. 2010, 'Preparation and time-resolved luminescence bioassay application of multicolor luminescent lanthanide nanoparticles.', Journal of fluorescence, vol. 20, no. 1, pp. 321-328.
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Because highly luminescent lanthanide compounds are limited to Eu(3+) and Tb(3+) compounds with red (Eu, approximately 615 nm) and green (Tb, approximately 545 nm) emission colors, the development and application of time-resolved luminescence bioassay technique using lanthanide-based multicolor luminescent biolabels have rarely been investigated. In this work, a series of lanthanide complexes covalently bound silica nanoparticles with an excitation maximum wavelength at 335 nm and red, orange, yellow and green emission colors has been prepared by co-binding different molar ratios of luminescent Eu(3+)-Tb(3+) complexes with a ligand N,N,N(1),N(1)-(4'-phenyl-2,2':6',2''-terpyridine-6,6''-diyl)bis(methylenenitrilo) tetrakis (acetic acid) inside the silica nanoparticles. The nanoparticles characterized by transmission electron microscopy and luminescence spectroscopy methods were used for streptavidin labeling, and time-resolved fluoroimmunoassay (TR-FIA) of human prostate-specific antigen (PSA) as well as time-resolved luminescence imaging detection of an environmental pathogen, Giardia lamblia. The results demonstrated the utility of the new multicolor luminescent lanthanide nanoparticles for time-resolved luminescence bioassays.
Deng, W., Drozdowicz-Tomsia, K., Jin, D. & Goldys, E.M. 2009, 'Enhanced flow cytometry-based bead immunoassays using metal nanostructures.', Analytical chemistry, vol. 81, no. 17, pp. 7248-7255.
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While the principle of fluorescence enhancement of metal nanostructures is well-known, the utility of this effect in practical methodologies used in analytical laboratories remains to be established. In this work, we explore the advantage of fluorescence enhancement for flow cytometry. We report the observation of metal-enhanced fluorescence emission of fluorophores located on the surface of silica beads coated with nanostructured silver, suitable for flow cytometry detection. The fluorescence enhancement was investigated using a model AlexaFluor 430 IgG immunoassay and AlexaFluor 430 labeling. Approximately 8.5-fold and 10.1-fold higher fluorescence intensities at 430 nm excitation were, respectively, observed from silvered approximately 400 nm and 5 microm silica beads deposited on glass as compared to the control sample. The 400 nm and 5 microm beads were compatible with the flow cytometry readout, although lower enhancement factors of 3.0 and 3.7 were obtained. We show that such values are consistent with less favorable overlap of the plasmon resonance in silver nanostructures with 488 nm excitation wavelength used in the flow cytometry experiment. We, thus, demonstrated that the silvered silica beads are able to provide intensified fluorescence signals in flow cytometry which can improve the sensitivity of flow cytometry-based bioassay systems.
Jin, D., Piper, J.A., Leif, R.C., Yang, S., Ferrari, B.C., Yuan, J., Wang, G., Vallarino, L.M. & Williams, J.W. 2009, 'Time-gated flow cytometry: an ultra-high selectivity method to recover ultra-rare-event mu-targets in high-background biosamples.', Journal of biomedical optics, vol. 14, no. 2, p. 024023.
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A fundamental problem for rare-event cell analysis is auto-fluorescence from nontarget particles and cells. Time-gated flow cytometry is based on the temporal-domain discrimination of long-lifetime (>1 micros) luminescence-stained cells and can render invisible all nontarget cell and particles. We aim to further evaluate the technique, focusing on detection of ultra-rare-event 5-microm calibration beads in environmental water dirt samples. Europium-labeled 5-microm calibration beads with improved luminescence homogeneity and reduced aggregation were evaluated using the prototype UV LED excited time-gated luminescence (TGL) flow cytometer (FCM). A BD FACSAria flow cytometer was used to sort accurately a very low number of beads (<100 events), which were then spiked into concentrated samples of environmental water. The use of europium-labeled beads permitted the demonstration of specific detection rates of 100%+/-30% and 91%+/-3% with 10 and 100 target beads, respectively, that were mixed with over one million nontarget autofluorescent background particles. Under the same conditions, a conventional FCM was unable to recover rare-event fluorescein isothiocyanate (FITC) calibration beads. Preliminary results on Giardia detection are also reported. We have demonstrated the scientific value of lanthanide-complex biolabels in flow cytometry. This approach may augment the current method that uses multifluorescence-channel flow cytometry gating.
Wu, J., Ye, Z., Wang, G., Jin, D., Yuan, J., Guan, Y. & Piper, J. 2009, 'Visible-light-sensitized highly luminescent europium nanoparticles: Preparation and application for time-gated luminescence bioimaging', Journal of Materials Chemistry, vol. 19, no. 9, pp. 1258-1264.
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Leif, R.C., Yang, S., Jin, D., Piper, J., Vallarino, L.M., Williams, J.W. & Zucker, R.M. 2009, 'Calibration beads containing luminescent lanthanide ion complexes.', Journal of biomedical optics, vol. 14, no. 2, p. 024022.
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The reliability of lanthanide luminescence measurements, by both flow cytometry and digital microscopy, would be enhanced by the availability of narrowband emitting, UV excited lanthanide calibration beads. 0.5-, 3-, and 5-microm beads containing a luminescent europium-complex are manufactured. The luminescence distribution of the 5-microm beads is measured with a time-delayed light-scatter-gated luminescence flow cytometer to have a 7.0% coefficient of variation (CV) The spacial distribution of the europium-complex in individual beads is determined to be homogeneous by confocal microscopy. Emission peaks are found at 592, 616 (width 9.9 nm), and 685 nm with a PARISS spectrophotometer. The kinetics of the luminescence bleaching caused by UV irradiation of the 0.5- and 5-microm beads measured under LED excitation with a fluorescence microscope indicate that bleaching does not interfere with their imaging. The luminescence lifetimes in water and air were 340 and 460 micros, respectively. Thus, these 5-microm beads can be used for spectral calibration of microscopes equipped with a spectrograph, as test particles for time-delayed luminescence flow cytometers, and possibly as labels for macromolecules and cells.
Song, C., Ye, Z., Wang, G., Jin, D., Yuan, J., Guan, Y. & Piper, J. 2009, 'Preparation and time-gated luminescence bioimaging application of ruthenium complex covalently bound silica nanoparticles.', Talanta, vol. 79, no. 1, pp. 103-108.
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Luminescent ruthenium(II) complex covalently bound silica nanoparticles have been prepared and used as a probe for time-gated luminescence bioimaging. The new nanoparticles were prepared by copolymerization of a luminescent Ru(II) complex tris(5-amino-1,10-phenanthroline)ruthenium(II) conjugated with 3-aminopropyl(triethoxy)silane (APS-Ru conjugate), free (3-aminopropyl)triethoxysilane (APS) and tetraethyl orthosilicate (TEOS) in a water-in-oil reverse microemulsion consisting of Triton X-100, n-octanol, cyclohexane and water in the presence of aqueous ammonia. Characterization by transmission electron microscopy indicates that the nanoparticles are monodisperse, spherical and uniform in size, 64+/-4 nm in diameter. Compared with the dye-doping nanoparticles, dye leakage of the new nanoparticles was remarkably decreased. In addition, it was found that the Ru(II) complex luminescence could be effectively enhanced with a longer luminescence lifetime (approximately 2.3 micros) after forming the nanoparticles, which enables the nanoparticles to be suitable as a bioprobe for time-gated luminescence bioimaging applications. The nanoparticle-labeled streptavidin was prepared and successfully used for time-gated luminescence imaging detection of an environmental pathogen, Giardia lamblia, with high specificity and sensitivity.
Wu, J., Wang, G., Jin, D., Yuan, J., Guan, Y. & Piper, J. 2008, 'Luminescent europium nanoparticles with a wide excitation range from UV to visible light for biolabeling and time-gated luminescence bioimaging.', Chemical communications (Cambridge, England), no. 3, pp. 365-367.
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Silica-encapsulated highly luminescent europium nanoparticles with a wide excitation range from UV to visible light (200-450 nm) have been prepared and used for streptavidin labeling and time-gated luminescence imaging of an environmental pathogen, Giardia lamblia.
Jin, D., Connally, R. & Piper, J. 2007, 'Practical time-gated luminescence flow cytometry. I: concepts.', Cytometry. Part A : the journal of the International Society for Analytical Cytology, vol. 71, no. 10, pp. 783-796.
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The method of time-gated detection of long-lifetime (1-2,000 micros) luminescence-labeled microorganisms following rapid excitation pulses has proved highly efficient in suppressing nontarget autofluorescence (<0.1 micros), scatterings, and other prompt stray light (Hemmila and Mukkala, Crit Rev Clin Lab Sci 2001;38:441-519). The application of such techniques to flow cytometry is highly attractive but there are significant challenges in implementing pulsed operation mode to rapid continuous flowing sample to achieve high cell analysis rates (Leif R, Vallarino L, Rare-earth chelates as fluorescent markers in cell separation and analysis, In: Cell Separation Science and Technology, ACS Symposium Series 464, American Chemical Society, 1991, pp 41-58; Condrau et al., Cytometry 1994;16:187-194; Condrau et al., Cytometry 1994;16:195-205; Shapiro HM, Improving signals from labels: Amplification and other techniques, In: Practical Flow Cytometry, 4th ed., Wiley, New York, 2002, p 345). We present here practical approaches for achieving high cell analysis rates at 100% detection efficiency, using time-gated luminescence (TGL) flow cytometry. In particular, we report that new-generation UV LEDs are practical sources in TGL flow cytometry. Spatial effects of long-lived luminescence from the target fluorophore in a fast-flowing sample stream have been investigated; excitation and detection requirements in TGL flow cytometry were theoretically analyzed; two practical approaches, a triggered model and a continuous flow-section model, were considered as a function of flow speed, sizes and relative positions of the excitation/detection spots, label lifetime, excitation pulse duration/intensity, and detection duration. A particular configuration using LED excitation to detect europium dye-labeled targets in such a system has been modeled in detail. In the triggered model, TGL mode is confined to a low repetition rate (<1 kHz) and engaged only while a target particle is present i...
Jin, D., Connally, R. & Piper, J. 2007, 'Practical time-gated luminescence flow cytometry. II: experimental evaluation using UV LED excitation.', Cytometry. Part A : the journal of the International Society for Analytical Cytology, vol. 71, no. 10, pp. 797-808.
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In the previous article [Part 1 (8)], we have modelled alternative approaches to design of practical time-gated luminescence (TGL) flow cytometry and examined the feasibility of employing a UV LED as the excitation source for the gated detection of europium dye labelled target in rapid flow stream. The continuous flow-section approach is well suited for rare-event cell counting in applications with a large number of nontarget autofluorescent particles. This article presents details of construction, operation and evaluation of a TGL flow cytometer using a UV LED excitation and a gated high-gain channel photomultiplier tube (CPMT) for detection. The compact prototype TGL flow cytometer was constructed and optimised to operate at a TGL cycle rate of 6 kHz, with each cycle consisting of 100 micros LED pulsed excitation and approximately 60 micros delay-gated detection. The performance of the TGL flow cytometer was evaluated by enumerating 5.7 microm Eu(3+) luminescence beads (having comparable intensity to europium-chelate-labeled Giardia cysts) in both autofluorescence-rich environmental water concentrates and Sulforhodamine 101 (S101) solutions (broadband red fluorescence covering the spectral band of target signals), respectively. The prototype TGL flow cytometer was able to distinguish the target beads, and a maximum signal to background ratio of 38:1 was observed. Neither the environmental water concentrates nor S101 solution contributed to the background in the TGL detection phase. The counting efficiency of the TGL flow cytometer was typically >93% of values determined using conventional counting methods.
Connally, R., Jin, D. & Piper, J. 2006, 'High intensity solid-state UV source for time-gated luminescence microscopy.', Cytometry. Part A : the journal of the International Society for Analytical Cytology, vol. 69, no. 9, pp. 1020-1027.
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BACKGROUND: The unique discriminative ability of immunofluorescent probes can be severely compromised when probe emission competes against naturally occurring, intrinsically fluorescent substances (autofluorophores). Luminescence microscopes that operate in the time-domain can selectively resolve probes with long fluorescence lifetimes (tau > 100 micros) against short-lived fluorescence to deliver greatly improved signal-to-noise ratio (SNR). A novel time-gated luminescence microscope design is reported that employs an ultraviolet (UV) light emitting diode (LED) to excite fluorescence from a europium chelate immunoconjugate with a long fluorescence lifetime. METHODS: A commercial Zeiss epifluorescence microscope was adapted for TGL operation by fitting with a time-gated image-intensified CCD camera and a high-power (100 mW) UV LED. Capture of the luminescence was delayed for a precise interval following excitation so that autofluorescence was suppressed. Giardia cysts were labeled in situ with antibody conjugated to a europium chelate (BHHST) with a fluorescence lifetime >500 micros. RESULTS: BHHST-labeled Giardia cysts emit at 617 nm when excited in the UV and were difficult to locate within the matrix of fluorescent algae using conventional fluorescence microscopy, and the SNR of probe to autofluorescent background was 0.51:1. However in time-gated luminescence mode with a gate-delay of 5 mus, the SNR was improved to 12.8:1, a 25-fold improvement. CONCLUSION: In comparison to xenon flashlamps, UV LEDs are inexpensive, easily powered, and extinguish quickly. Furthermore, the spiked emission of the LED enabled removal of spectral filters from the microscope to significantly improve efficiency of fluorescence excitation and capture.
Jin, D., Connally, R. & Piper, J. 2006, 'Long-lived visible luminescence of UV LEDs and impact on LED excited time-resolved fluorescence applications', Journal of Physics D: Applied Physics, vol. 39, no. 3, pp. 461-465.
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Research funding income: Since his PhD in 2007, Prof Jin has attracted competitive research funding of over $40 m ($10 m as lead or sole Chief Investigator, including four consecutive research fellowship awards). 

ARC Industry Transformational Research Hub for Integrated Device for End-user Analysis at Low-levels (IDEAL) as the Director. ($3.7 million requested from ARC), with University of Technology  Sydney, University of South Australia, PERKINELMER PTY LTD, MINOMIC INTERNATIONAL LTD, SURGICAL DIAGNOSTICS PTY LIMITED, PREG TECH PTY LTD, ALCOLIZER TECHNOLOGY By transforming Australian advances in biomolecular science, nanotechnology and device engineering into highvalue products, the Hub aims to radically improve sensitivity, selectivity, speed and cost for detection of biological materials. The mission is to build a portable device for rapid, time-critical detection of low abundance molecular and cellular analytes. The resulting technologies will be designed for use on the production line, at the clinic, bedside, roadside and transport points to identify tiny levels of targeted molecules. The initial focus is early diagnosis of disease and point-of-care drug testing for humans and animals, but the technology platform could be used to sample food and environmental toxins, for example.

ARC (LIEF 150100177), $440,000.00 from ARC + $370 k from collaboration institutions, Macquarie University, the University of Sydney, RMIT University, and the University of Adelaide, (Lead Chief Investigator) "National live cell scanning platform for nanoparticle tracking" Chief Investigators: Jin, A/Prof Dayong; Monro, Prof Tanya M; Braet, A/Prof Filip C; Gibson, Dr Brant C; Paulsen, Prof Ian T; Traini, A/Prof Daniela; Hutchinson, A/Prof Mark R; Greentree, A/Prof Andrew D; Chung, Prof Roger; Young, A/Prof Paul M; Willows, A/Prof Robert D; Lu, Dr Yiqing; project summary: The aim of the project is to establish a multi-disciplinary, multi-user, self-correlated scanning facility to reach a new level of temporal and spatial precision for real-time tracking and quantification of biomolecules and nanoparticles within large populations of living cells. The facility will consist of a live-cell spinning-disc confocal microscope, a correlated biological atomic force microscope, and remote access facilities. It is expected that with superior optical characterisation and mechanical manipulation, the automated orthogonal scanning facility will open new avenues to reveal unprecedented information from biological and pathological processes. The collaborative facility will support world-class researchers in the multi-disciplinary areas of physical, material and life sciences, placing Australia at the forefront of nanoscale biophotonics.

ARC Industry Linkage Project 2014 -2017 (LP140100462), $370,000.00 from ARC + $ 110k cash & $341 k in-kind from industry, (Lead Chief Investigator) “Rapid Pathogen Detection using Super-Sensitive Multiplexing Nanophotonic Probes”; Project Summary: Responding to an urgent need to advance rapid molecular diagnostics, this project aims to explore new photonics and biochemistry approaches to DNA recognition. It is anchored on proprietary light-emitting nanodots which have single- molecule sensitivity in conjunction with tunable optical identities. The project aims to develop a multiplexing reagent library of DNA probes to sense trace DNA molecules and to recognise multiple pathogens in a single assay. This innovation aims to create a hybrid-Polymerase Chain Reaction (PCR) technology platform for current industry-standard pathogen detection tests.

ARC Future Fellowship 2013 -2017, $753,270.00 from ARC + $200,000.00 from Macquarie University (Sole Chief Investigator) “Beyond Spectral Detection: Engineering SUPER Dot Probes for High-Throughput Discovery”

ARC Centre of Excellence – Nanoscale Biophotonics, 2014 – 2020, $23,000,000.00 funded from the Australian Research Council (Centre Director, Prof. Tanya Monro). I am one of the ten Chief Investigators spanning the University of Adelaide, Macquarie University and RMIT University, and co-leading the “Illuminate” Science Theme to develop strategic research direction on advanced functional/optical materials, and oversee the progress of Centre programs to deliver a library of efficient nanoscale light sources.

ARC Industry Linkage Project 2013 - 2016, $427,510.00 from ARC + $190,000.00 cash & $570,000.00 in-kind from industry, (Lead Chief Investigator) "Rapid detection of rare-event cells by strong UP-conversion encoded nano-radiators (SUPER Dots): finding a needle in a haystack" Project Summary: Current diagnostic tests are not sensitive enough to detect cancer in its very early stages or early recurrence following treatment. The new technologies developed by this project will be able to find single cancer cells in blood and urine samples heralding a new era in medical diagnostics.

ARC Australian Research Council Linkage Infrastructure, Equipment and Facilities 2014, $300,000.00 (Co CI) " CyTOF platform for the Advanced Cytometry Facility: overcoming fluorescence spectral barriers to truly multiparametric cytometry by mass spectrometry"

Macquarie University Research Development Grant 2013 –2014, $ 30, 000 (sole Chief Investigator) “Pass the barriers: new opportunities to investigate the nanoscale drug delivery”

MQ safety net fund, 2013, $25,000.00 (co-CI) “Lanthanide Dyes for Super Resolution: Achieving Stimulated Emission Depletion at Sub-milliwatt Powers (DP140104227: Piper & Jin)”

Research Infrastructure Block Grants (RIBG) 2014, $ 100,000.00 (First Lead CI) “Automated Scanning Cytometry for Rapid Detection, Quantification and Localization of Pathogens, Cells, and Photonics Nanomaterials” Research Infrastructure Block Grants (RIBG) 2012, $ 98,784.00 (Co CI) “An in vivo platform for background-free luminescence imaging of small animals”

Macquarie University Vice-Chancellor's Innovation Fellowship Scheme 2013, $250,000.00, (Sole CI) " Biophotonics: Powering Next-generation Molecular Diagnostics"

Research Infrastructure Block Grants (RIBG) 2012, $ 98,000.00 (First Lead CI) “Flow cytometry platform promoting multidisciplinary research excellence” Research Infrastructure Block Grants (RIBG) 2012, $ 85,650.00 (Co CI) “Broadly tunable UV-visible-IR pulsed light source for spectroscopy and nanophotonics”

Australian Research Council Linkage Infrastructure, Equipment and Facilities 2012, $654,000.00 (Co CI) "Single cell genomics"

Macquarie University Linkage Projects Seeding Grants 2010 Stage 1, $ 10, 000 (Sole Chief Investigator) "Medical Demonstration of Background-free Cytometry on Rare Earth" collaborating with BD Biosciences, San Jose, CA, USA

Macquarie University Linkage Projects Seeding Grants 2010 Stage 1, $10, 000 (Sole Chief Investigator) "Handheld flow cytometer for point-of-need microbiological testing of water" collaborating with Palo Alto Research Centre (PARC), CA, USA

Research Infrastructure Block Grants (RIBG) 2011, $ 60, 000 (Lead Chief Investigator) “High-throughput Simultaneous Photon-Sensing Platform” Research Infrastructure Block Grants (RIBG) 2011, $ 40, 000 (Co-Chief Investigator) “Multi-color imaging facility”

MQ Research Centre Scheme 2011, MQ Biofocus Research Centre (Co-Chief Investigator) $50,000

Macquarie University Research Development Grant 2010 –2012, $ 50, 000 (sole Chief Investigator) “Developing nanolasers as bio-nano-probes for ultra-sensitive biomolecular detection”

Australian Research Council Discovery Project DP1095465, 2010-2012, $ 335,125.00 (Chief Investigators Prof. J.A. Piper, Dr. D. Jin)“Novel coding and decoding in suspension arrays for accelerated biomolecular discovery and personalised medicine”

Macquarie University Research Fellowship Scheme, 2008-2011, $49,940.00 Project fund (Chief Investigator) “Background-free 100 kHz time-gated luminescence techniques for high-throughput screening of microorganisms” and $250,000.00 Salary fund

IPCMC commercialisation/Access MQ project fund, 2008, $18,331.00 (sole CI) “time-gated fluorescence flow cytometry”

MQSNS, safety net fund, 2008, $16,800.00 (sole CI) “High-speed time-gated flow cytometry with ultrabright microsecond nano-probes”

Support Scheme for Emerging Research Projects, 2006” from the FABLS network for $9,109.00 (Chief Investigator) “Time-gated Luminescence flow cytometry counting method for HIV monitoring in resource poor settings”

Support Scheme for Emerging Research Projects, 2007” from the FABLS network for $6,135.00 (Chief Investigator) “Background-free imaging flow cytometry”.