THE EUROPEAN UPCONVERSION NETWORK
From the Design of Photon-Upconverting Nanomaterials to Biomedical Applications : COST CM1403
Photoluminescent upconverting nanomaterials (UCNMs) are lanthanide-doped nanocrystals that emit visible light under near-infrared excitation. The unique anti-Stokes emission enables background-free luminescent detection, which is essential for many diagnostic applications, bioimaging and chemical sensing. UCNMs are highly photostable and display narrow line-like emissions that enable long observation times and multiplexed detection. Research on photon-upconversion is highly interdisciplinary, but currently fragmented without synchronised research actions in Europe. Further progress in the field is severely restricted by the lack of unified methods for the synthesis, functionalization and characterisation of UCNMs. Missing reference materials and commercial instrumentation make it impossible to compare the results from different groups and precludes the commercialisation of bioanalytical assays, biosensors and diagnostic tools based on these highly promising materials. Consequently, a European network is required to coordinate basic and applied research on UCNMs, standardise procedures, and to make European scientists as well as the high-tech industry aware of this emerging technology. This Action is based on a broad range of scientific disciplines to identify and solve numerous research problems such as upconversion enhancement, surface (bio)functionalisation, detection instrumentation, bioanalytical and diagnostic applications, as well as (nano)toxicity.
The finantial support from COST Association (under COST Action CM1403) is greatly appreciated.
1 General background
Fluorescence is an invaluable tool for biomedical applications such as clinical diagnostics and bioimaging, and for optical chemical sensing. To improve the sensitivity and reliability of fluorescence-based technologies, it is of key importance to minimise the background fluorescence originating e.g. from surrounding biological materials. An additional challenge, especially in imaging, is the low photostability of fluorescent dyes. These issues can be solved by using anti-Stokes photoluminescence, i.e. photon upconversion which is a unique form of luminescence of certain upconverting nanomaterials (UCNMs).
Upconverting nanomaterials are composed of an optically inactive host material doped with a combination of rare earth ions (e.g. NaYF4 doped with a combination of Yb3+ and Er3+ or Yb3+ and Tm3+) that can convert infrared radiation into visible light via sequential absorption of multiple photons (Angew. Chem. Int. Ed. 2011, 50, 5808–5829). The anti-Stokes emission allows to perform background-free detection, and the infrared excitation is barely absorbed and minimally scattered by biological materials enabling measurements in complex sample matrices, e.g. whole blood, and deep tissue imaging. UCNMs have long luminescence lifetimes, and they are extremely photostable, but do not suffer from blinking such as quantum dots. Their surface can be functionalised with ligands or other kinds of molecular shells yielding hybrid UCNMs as highly promising and target-specific optical reporters. Despite many advantages, the UCNMs have not gained yet as broad interest as quantum dots, because both the upconverting reporters and anti-Stokes photoluminescence detection instrumentation have not been commercially available.
The current Action members are convinced that the unique features of UCNMs offer simplicity, sensitivity and rapid detection for point-of-care diagnostics as well as for bioimaging. There are, however, many challenges that remain to be solved before UCNMs will live up to their full potential in the biomedical field: (1) The upconversion efficiency of UCNMs is still 10 to 20-fold lower compared to the respective bulk materials (Nanoscale, 2010, 2, 1417-1419). (2) A tailor-made surface functionalisation of UCNMs is critical for biospecific detection, biocompatibility and colloidal stability. (3) There are no reference materials and established protocols available for the synthesis, characterisation and biofunctionalisation UCNMs. (4) The sequential multiphoton excitation renders it difficult to measure the quantum yield of UCNMs. (5) Their detection in general is severely limited by the lack of commercial instrumentation for upconversion luminescence. (6) The chemo- and nano-toxicity of UCNMs and their environmental impact have yet to be studied.
Many fragmented research projects on photon upconversion are carried out simultaneously throughout Europe with local grants, infrastructure and researchers. However, these approaches without coordination will not be very effective in pushing the technology forward, especially in comparison to the great progress in China and North America. The lack of harmonised research actions on both UCNMs and instrumentation has severely hindered the development of the technology and its applications in biomedical sciences. Exploitation of the full potential of UCNMs in biology and medicine requires an exceptional amount of multidisciplinary expertise ranging from materials science and bio/photo-physics over optical engineering to biology and biochemistry. This makes cooperation and synchronised research among European scientists essential. This COST Action shall therefore bring together the extensive and cross-disciplinary expertise of European researchers and academic groups. A coordinated platform of research organisations working on UCNMs is required to promote materials and technology transfer between different research groups and industry and to gain essential access to data and protocols. Furthermore, a transnational and transdisciplinary approach of the main European research groups in the field will lead to synergistic results and benefit the European research community as a whole.
2 Current state of knowledge
Research on rare earth doped UCNMs and photon upconversion has drastically evolved during the past years with a focus on materials science, lighting phosphors, lasers and upconversion lasers. Although rapidly maturing, this technology is currently at a stage where quantum dots were a decade ago. The first reports on stable colloidal UCNMs, which were suitable for bio-applications were published in 2003 (Angew. Chem. Int. Ed. 42, 3179-3182). UCNMs have been successfully used for the detection of nucleic acids on microarrays, for the diagnosis of various infectious diseases by lateral flow assays and for various homogeneous bioanalytical assays as well as for optical chemical sensors and bioimaging. These applications greatly benefit from the background-free readout under near infrared (NIR) excitation. In diagnostic assays, the use of UCNMs has led to a much lower detection limit compared to conventional fluorophores, especially when analytes are present in complex biological samples such as blood. The use of UCNMs in bioimaging, on the other hand, has extended the range of conventional fluorescence microscopy to deep tissue imaging and photodynamic therapy (ACS nano 2012, 6, 4054-4062). Monodisperse UCNMs down to 10 nm in diameter with the most efficient upconversion host material known to date (NaYF4) can be prepared via different synthetic routes. The reproducibility of syntheses, however, is insufficient and the upconversion efficiency is not optimal for many applications. The same holds for the surface (bio)functionalisation of UCNMs, which is critical for biospecific detection, biocompatibility and colloidal stability. Several proof-of-concept applications ranging from bioanalytical assays to bioimaging have been developed to demonstrate the high potential of UCNMs but their commercial availability is very limited. All instruments have been custom-made using low-cost components, such as infrared laser diodes as excitation light source, standard long-pass and narrow band-pass filters as excitation and emission filters, and solid-state photo detectors which allow relatively simple and inexpensive detection solutions. However, no commercial instrumentation is available for upconversion imaging or bio-assays. Finally, the toxicity of UCNMs and their environmental impact has not been determined, yet.
China has for long invested strongly into lanthanide-doped nanomaterials research and is also the world’s largest provider of rare earths. North American interest in the photon upconversion technology is also well represented by top scientific papers and numerous patents. In Europe, there are parallel research efforts aiming at solving the challenges of the UCNM technology, but the lack of coordination inevitably results in overlapping activities, delaying the predictable scientific, social and economic achievements and leads to a waste of resources. This Action aims at coordinating European research on photon upconversion to develop optimised UCNMs, novel applications, commercial detection instrumentation, and to increase the awareness of the upconversion technology. The Action is innovative and efficient as it comprehensively addresses issues in both basic and applied research with direct commitment of the private sector.
3 Reasons for the Action
There is an increasing need for rapid and advanced detection methods for both basic research (e.g. in vivo imaging) and different applications (e.g. diagnostics, high-throughput screening). The UCNMs and anti-Stokes photoluminescence detection will generate numerous scientific and technological possibilities, which in turn will have a considerable social and economic impact e.g. on the health care business. However, numerous cross-disciplinary problems have to be solved before UCNMs become a mature technology.
From the companies’ perspective, the following issues have been identified before the UCNMs are ready for commercialisation: (1) The design of a tailor-made surface functionalisation is mandatory for obtaining highly stable dispersions of monomeric UCNMs that have a long shelf-life. (2) An optimized surface functionalization is also required to minimize non-specific binding of UCNMs, which becomes the next limiting factor in assay performance when the luminescence background goes to zero. (3) Standardised reference materials for UCNMs are required to grant batch-to-batch consistency and to scale up the production. (4) Commercial instruments for array readout and in vivo imaging must be available before the upconversion technology can be routinely used e.g. for point-of-care diagnostics or clinical applications. Small companies, however, typically do not have the interdisciplinary expertise and facilities to carry out all the optimisation steps in house.
This Action will build a platform for cooperation and interdisciplinary knowledge exchange between scientists from different COST countries and the private sector, and thus enable Europe to take the initiative in developing UCNMs into an established technology and commercial exploitation. Due to their multiple advantages, UCNMs are foreseen to challenge conventional fluorescent reporters used in biomedical applications. The technology is thus expected to lead to earlier diagnoses and also reduce the costs of European and global healthcare. In addition, the environmental load will be decreased compared to e.g. quantum dots, which usually contain toxic heavy metals.
This Action combines the complementary expertise of physicists, chemists, biologists, biochemists, engineers and the private sector to improve UCNMs, standardise methods for their characterisation, develop new detection instrumentation, evaluate their nanotoxicity and explore their commercialisation. This Action spans from the synthesis and surface chemistry to instrument development, proof-of-principle demonstration of applications and toxicological studies to refine this highly promising reporter technology for presentation to a wider audience.
The future benefits of the COST Action will be the development of new joint research projects and increased national funding for the research on UCNMs. Advances in the innovative photon upconversion technology will also enable the establishment of new spin-off companies leading to new high-tech jobs and strengthening the competitiveness and economical wealth of Europe. This multi-disciplinary collaboration will put Europe at the forefront position in UCNMs research. The methods and interdisciplinary skills related to the photon upconversion technology will be disseminated to young researchers which will strengthen and foster European expertise in the field.
4 Complementarity with other research programmes
Existing partly complementary Actions are not sufficient to fulfil the objectives of this Action but collaboration with them will be suggested as joint symposia and workshops. For example, the European F-Element Network (CM1006) is devoted to research on f-elements in general, whereas this Action focuses on the use of certain lanthanides in inorganic materials suitable for generating upconversion luminescence. The Modelling Nanomaterial Toxicity Action (TD1204) uses a computational modelling technique as an effective alternative to experimental testing of nanostructure toxicity. This modelling approach would also be amenable to study UCNMs. The Rational Design of Hybrid Organic-Inorganic Interfaces Action (MP1202) focuses on the interaction of various types of organic and inorganic materials in the molecular level, and thus this Action could benefit from their knowledge.
The photon upconversion luminescence is currently investigated by four FP7 projects: NANOSPEC aims at increasing solar cell efficiencies via upconversion, UCNANOMAT4IPACT studies the applications of UCNMs in photoactivated chemotherapy, CHROMSENSUC aims at increasing the upconversion through chromophores, and LUNAMED (PEOPLE) investigates the use of UCNMs for diagnostics and therapeutic nanomedicine. The Marie Curie ITNs CHEBANA, LUMINET and Mag(net)icFun cover luminescent materials and/or their bioanalytical applications in general. The existing FP7 projects do not significantly overlap with the Action, which aims to coordinate the research on improved UCNMs and their detection methods for the broad use in different
This Action will coordinate the following research tasks in order to achieve the following objectives :
Chair: dr Hans Gorris (University of Regensburg, Germany)
Vice-Chair: prof.Tero Soukka (University of Turku, Finland)
COST Science Officer: Dr. Lucia Forzi (Bruseels, Belgium)
STSMs Manager: dr hab. Artur Bednarkiewicz (PAS & WCB EIT+, Poland)
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