Exploiting the biological windows: current perspectives on fluorescent bioprobes emitting above 1000 nm.

With the goal of developing more accurate, efficient, non-invasive and fast diagnostic tools, the use of near-infrared (NIR) light in the range of the second and third biological windows (NIR-II: 1000-1350 nm, NIR-III: 1550-1870 nm) is growing remarkably as it provides the advantages of deeper penetration depth into biological tissues, better image contrast, reduced phototoxicity and photobleaching. Consequently, NIR-based bioimaging has become a quickly emerging field and manifold new NIR-emitting bioprobes have been reported. Classes of materials suggested as potential probes for NIR-to-NIR bioimaging (using NIR light for the excitation and emission) are quite diverse. These include rare-earth based nanoparticles, Group-IV nanostructures (single-walled carbon nanotubes, carbon nanoparticles and more recently Si- or Ge-based nanostructures) as well as Ag, In and Pb chalcogenide quantum dots. This review summarizes and discusses current trends, material merits, and latest developments in NIR-to-NIR bioimaging taking advantage of the region above 1000 nm (i.e. the second and third biological windows). Further consideration will be given to upcoming probe materials emitting in the NIR-I region (700-950 nm), thus do not possess emissions in these two windows, but have high expectations. Overall, the focus is placed on recent discussions concerning the optimal choice of excitation and emission wavelengths for deep-tissue high-resolution optical bioimaging and on fluorescent bioprobes that have successfully been implemented in in vitro and in vivo applications.

[1]  Aaas News,et al.  Book Reviews , 1893, Buffalo Medical and Surgical Journal.

[2]  Na Li,et al.  Near-infrared fluorescence spectroscopy of single-walled carbon nanotubes and its applications , 2011 .

[3]  F. V. Veggel,et al.  Near-infrared emitting quantum dots: Recent progress on their synthesis and characterization , 2014 .

[4]  S. Dou,et al.  Ultra-small fluorescent inorganic nanoparticles for bioimaging. , 2014, Journal of materials chemistry. B.

[5]  R. Schaller,et al.  Colloidal InSb nanocrystals. , 2012, Journal of the American Chemical Society.

[6]  Shuping Xu,et al.  Near-Infrared Fluorescent Materials for Sensing of Biological Targets , 2008, Sensors.

[7]  Xiaoling Yang,et al.  Graphene quantum dots: emergent nanolights for bioimaging, sensors, catalysis and photovoltaic devices. , 2012, Chemical communications.

[8]  J. Qian,et al.  Biocompatible near-infrared fluorescent nanoparticles for macro and microscopic in vivo functional bioimaging. , 2014, Biomedical optics express.

[9]  M. Falconieri,et al.  Two-photon excitation of luminescence in pyrolytic silicon nanocrystals , 2009 .

[10]  X. Ji,et al.  Fluorescent quantum dots: synthesis, biomedical optical imaging, and biosafety assessment. , 2014, Colloids and surfaces. B, Biointerfaces.

[11]  D. Chiu,et al.  Soft fluorescent nanomaterials for biological and biomedical imaging. , 2015, Chemical Society reviews.

[12]  S. Cotton Lanthanide and Actinide Chemistry: Cotton/Lanthanide and Actinide Chemistry , 2006 .

[13]  Lih-Yuan Lin,et al.  Water-soluble germanium nanoparticles cause necrotic cell death and the damage can be attenuated by blocking the transduction of necrotic signaling pathway. , 2011, Toxicology letters.

[14]  Byung-Ryool Hyun,et al.  Near-infrared fluorescence imaging with water-soluble lead salt quantum dots. , 2007, The journal of physical chemistry. B.

[15]  D. Sardar,et al.  Stokes emission in GdF₃:Nd³⁺ nanoparticles for bioimaging probes. , 2014, Nanoscale.

[16]  Wei Feng,et al.  Cubic sub-20 nm NaLuF(4)-based upconversion nanophosphors for high-contrast bioimaging in different animal species. , 2012, Biomaterials.

[17]  P. Chu,et al.  Group IV nanoparticles: synthesis, properties, and biological applications. , 2010, Small.

[18]  O. Wolfbeis An overview of nanoparticles commonly used in fluorescent bioimaging. , 2015, Chemical Society reviews.

[19]  Ardemis A. Boghossian,et al.  Label-free, single protein detection on a near-infrared fluorescent single-walled carbon nanotube/protein microarray fabricated by cell-free synthesis. , 2011, Nano letters.

[20]  Jean-Claude G. Bünzli,et al.  New Opportunities for Lanthanide Luminescence , 2007 .

[21]  Kohei Soga,et al.  Upconverting and NIR emitting rare earth based nanostructures for NIR-bioimaging. , 2013, Nanoscale.

[22]  A. Benayas,et al.  PbS/CdS/ZnS Quantum Dots: A Multifunctional Platform for In Vivo Near‐Infrared Low‐Dose Fluorescence Imaging , 2015 .

[23]  Heyou Han,et al.  Recent advances in the use of near-infrared quantum dots as optical probes for bioanalytical, imaging and solar cell application , 2014, Microchimica Acta.

[24]  S. Ganesan,et al.  Silicon Quantum Dots for Biological Applications , 2014, Advanced healthcare materials.

[25]  R. C. Benson,et al.  Fluorescence properties of indocyanine green as related to angiography. , 1978, Physics in medicine and biology.

[26]  Neil Genzlinger A. and Q , 2006 .

[27]  A. Albores,et al.  Mechanisms of toxicity by carbon nanotubes , 2013, Toxicology mechanisms and methods.

[28]  M. Foldvari,et al.  Carbon nanotubes as functional excipients for nanomedicines: II. Drug delivery and biocompatibility issues. , 2008, Nanomedicine : nanotechnology, biology, and medicine.

[29]  A. N. Bashkatov,et al.  Optical properties of human skin, subcutaneous and mucous tissues in the wavelength range from 400 to 2000 nm , 2005 .

[30]  S. Bachilo,et al.  Near-infrared fluorescence microscopy of single-walled carbon nanotubes in phagocytic cells. , 2004, Journal of the American Chemical Society.

[31]  Wing-Cheung Law,et al.  Core/shell NaGdF4:Nd(3+)/NaGdF4 nanocrystals with efficient near-infrared to near-infrared downconversion photoluminescence for bioimaging applications. , 2012, ACS nano.

[32]  Zhen Cheng,et al.  Near-infrared fluorescent nanoprobes for cancer molecular imaging: status and challenges. , 2010, Trends in molecular medicine.

[33]  Yan Zhang,et al.  Tracking of Transplanted Human Mesenchymal Stem Cells in Living Mice using Near‐Infrared Ag2S Quantum Dots , 2014 .

[34]  Benoit Dubertret,et al.  Design of new quantum dot materials for deep tissue infrared imaging. , 2013, Advanced drug delivery reviews.

[35]  A. Wan,et al.  Ag2S quantum dots conjugated chitosan nanospheres toward light-triggered nitric oxide release and near-infrared fluorescence imaging. , 2013, Langmuir : the ACS journal of surfaces and colloids.

[36]  John V Frangioni,et al.  Size series of small indium arsenide-zinc selenide core-shell nanocrystals and their application to in vivo imaging. , 2006, Journal of the American Chemical Society.

[37]  Yun Sun,et al.  Dual-modality in vivo imaging using rare-earth nanocrystals with near-infrared to near-infrared (NIR-to-NIR) upconversion luminescence and magnetic resonance properties. , 2010, Biomaterials.

[38]  Nan Ma,et al.  An overview of recent advances in quantum dots for biomedical applications. , 2014, Colloids and surfaces. B, Biointerfaces.

[39]  Chun-Hua Yan,et al.  Bioimaging and toxicity assessments of near-infrared upconversion luminescent NaYF4:Yb,Tm nanocrystals. , 2011, Biomaterials.

[40]  M. Fox Optical Properties of Solids , 2010 .

[41]  M. Tan,et al.  Development of multicolor carbon nanoparticles for cell imaging. , 2013, Talanta.

[42]  A. Yodh,et al.  Diffuse optics for tissue monitoring and tomography , 2010, Reports on progress in physics. Physical Society.

[43]  Bálint Somogyi,et al.  Near-infrared luminescent cubic silicon carbide nanocrystals for in vivo biomarker applications: an ab initio study. , 2012, Nanoscale.

[44]  M. Maeda,et al.  Cancer-targeted near infrared imaging using rare earth ion-doped ceramic nanoparticles. , 2015, Biomaterials science.

[45]  Paras N. Prasad,et al.  Nanophotonics and nanochemistry: controlling the excitation dynamics for frequency up- and down-conversion in lanthanide-doped nanoparticles. , 2013, Accounts of chemical research.

[46]  E. Hemmer,et al.  Lanthanide-based nanostructures for optical bioimaging: Small particles with large promise , 2014, MRS Bulletin.

[47]  Zhuang Liu,et al.  Selective probing and imaging of cells with single walled carbon nanotubes as near-infrared fluorescent molecules. , 2008, Nano letters.

[48]  Kai Yang,et al.  In vivo pharmacokinetics, long-term biodistribution and toxicology study of functionalized upconversion nanoparticles in mice. , 2011, Nanomedicine.

[49]  T. Cheng,et al.  A multifunctional heptamethine near-infrared dye for cancer theranosis. , 2013, Biomaterials.

[50]  L. Lacroix,et al.  New generation of magnetic and luminescent nanoparticles for in vivo real-time imaging , 2013, Interface Focus.

[51]  Christopher B. Murray,et al.  Colloidal synthesis of nanocrystals and nanocrystal superlattices , 2001, IBM J. Res. Dev..

[52]  F. V. Veggel Near-Infrared Quantum Dots and Their Delicate Synthesis, Challenging Characterization, and Exciting Potential Applications , 2014 .

[53]  E. Hemmer,et al.  Er3+ ‐Doped Y2O3 Nanophosphors for Near‐Infrared Fluorescence Bioimaging Applications , 2013 .

[54]  Kevin Welsher,et al.  Deep-tissue anatomical imaging of mice using carbon nanotube fluorophores in the second near-infrared window , 2011, Proceedings of the National Academy of Sciences.

[55]  Role of oxidative stress in carbon nanotube-generated health effects , 2014, Archives of Toxicology.

[56]  Kai Yang,et al.  Carbon materials for drug delivery & cancer therapy , 2011 .

[57]  A. Sasaki,et al.  Recombinant protein (EGFP-Protein G)-coated PbS quantum dots for in vitro and in vivo dual fluorescence (visible and second-NIR) imaging of breast tumors. , 2015, Nanoscale.

[58]  Dongmei Yang,et al.  Current advances in lanthanide ion (Ln(3+))-based upconversion nanomaterials for drug delivery. , 2015, Chemical Society reviews.

[59]  Robert R. Alfano,et al.  Deep optical imaging of tissue using the second and third near-infrared spectral windows , 2014, Journal of biomedical optics.

[60]  Kohei Soga,et al.  In vitro and in vivo investigations of upconversion and NIR emitting Gd2O3:Er3+,Yb3+ nanostructures for biomedical applications , 2012, Journal of Materials Science: Materials in Medicine.

[61]  S. Jacques Optical properties of biological tissues: a review , 2013, Physics in medicine and biology.

[62]  J. C. D. Silva,et al.  Analytical and bioanalytical applications of carbon dots , 2011 .

[63]  Daniel A. Ruddy,et al.  Size and bandgap control in the solution-phase synthesis of near-infrared-emitting germanium nanocrystals. , 2010, ACS nano.

[64]  A. Panariti,et al.  An outlook on the potential of Si nanocrystals as luminescent probes for bioimaging , 2013 .

[65]  Yang Yang,et al.  Long-term in vivo biodistribution imaging and toxicity of polyacrylic acid-coated upconversion nanophosphors. , 2010, Biomaterials.

[66]  J. G. Solé,et al.  Neodymium-doped LaF(3) nanoparticles for fluorescence bioimaging in the second biological window. , 2014, Small.

[67]  Tymish Y. Ohulchanskyy,et al.  High contrast in vitro and in vivo photoluminescence bioimaging using near infrared to near infrared up-conversion in Tm3+ and Yb3+ doped fluoride nanophosphors. , 2008, Nano letters.

[68]  Jun Lin,et al.  Recent progress in rare earth micro/nanocrystals: soft chemical synthesis, luminescent properties, and biomedical applications. , 2014, Chemical reviews.

[69]  E. Hemmer,et al.  Synthesis and toxicity assay of ceramic nanophosphors for bioimaging with near-infrared excitation , 2012 .

[70]  Shuo Diao,et al.  Through-skull fluorescence imaging of the brain in a new near-infrared window , 2014, Nature Photonics.

[71]  H. Dai,et al.  Carbon nanotubes in biology and medicine: In vitro and in vivo detection, imaging and drug delivery , 2009, Nano research.

[72]  S. Cotton Lanthanide and Actinide Chemistry , 1991 .

[73]  Benoit Dubertret,et al.  Cadmium-free CuInS2/ZnS quantum dots for sentinel lymph node imaging with reduced toxicity. , 2010, ACS nano.

[74]  Tomonobu M. Watanabe,et al.  Synthesis and optical properties of emission-tunable PbS/CdS core–shell quantum dots for in vivo fluorescence imaging in the second near-infrared window , 2014 .

[75]  Lina Wu,et al.  Surface Passivation of Carbon Nanoparticles with Branched Macromolecules Influences Near Infrared Bioimaging , 2013, Theranostics.

[76]  Shanyong Zhou,et al.  Lanthanide-doped luminescent nano-bioprobes for the detection of tumor markers. , 2015, Nanoscale.

[77]  T. Sakata,et al.  Aqueous synthesis of glutathione-coated PbS quantum dots with tunable emission for non-invasive fluorescence imaging in the second near-infrared biological window (1000-1400 nm). , 2013, Chemical communications.

[78]  Christoph Abels,et al.  Absorption and Fluorescence Spectroscopic Investigation of Indocyanine Green , 1996 .

[79]  Soojin Lim,et al.  NIR dyes for bioimaging applications. , 2010, Current opinion in chemical biology.

[80]  G. G. Stokes "J." , 1890, The New Yale Book of Quotations.

[81]  R. Schaller,et al.  Colloidal synthesis of infrared-emitting germanium nanocrystals. , 2009, Journal of the American Chemical Society.

[82]  Sanghwa Jeong,et al.  Imaging Depths of Near-Infrared Quantum Dots in First and Second Optical Windows , 2012, Molecular imaging.

[83]  Kohei Soga,et al.  Cytotoxic aspects of gadolinium oxide nanostructures for up-conversion and NIR bioimaging. , 2013, Acta biomaterialia.

[84]  J. G. Solé,et al.  Intratumoral Thermal Reading During Photo‐Thermal Therapy by Multifunctional Fluorescent Nanoparticles , 2015 .

[85]  A. Wan,et al.  Synthesis of near-infrared quantum dots in cultured cancer cells. , 2014, ACS applied materials & interfaces.

[86]  R. Anderson,et al.  The optics of human skin. , 1981, The Journal of investigative dermatology.

[87]  J. Zhao,et al.  Fabrication of highly fluorescent graphene quantum dots using L-glutamic acid for in vitro/in vivo imaging and sensing. , 2013, Journal of materials chemistry. C.

[88]  Xiaoming Li,et al.  Epitaxial seeded growth of rare-earth nanocrystals with efficient 800 nm near-infrared to 1525 nm short-wavelength infrared downconversion photoluminescence for in vivo bioimaging. , 2014, Angewandte Chemie.

[89]  P. Puech,et al.  Synthesis and structure of free-standing germanium quantum dots and their application in live cell imaging , 2015 .

[90]  Freddy T. Nguyen,et al.  Multimodal biomedical imaging with asymmetric single-walled carbon nanotube/iron oxide nanoparticle complexes. , 2007, Nano letters.

[91]  Artur Bednarkiewicz,et al.  Upconverting nanoparticles: assessing the toxicity. , 2015, Chemical Society reviews.

[92]  Miss A.O. Penney (b) , 1974, The New Yale Book of Quotations.

[93]  Benjamin F. P. McVey,et al.  Solution synthesis, optical properties, and bioimaging applications of silicon nanocrystals. , 2014, Accounts of chemical research.

[94]  Kyungsuk Yum,et al.  Single‐walled carbon nanotubes as near‐infrared optical biosensors for life sciences and biomedicine , 2015, Biotechnology journal.

[95]  Shuo Diao,et al.  Ultrafast fluorescence imaging in vivo with conjugated polymer fluorophores in the second near-infrared window , 2014, Nature Communications.

[96]  W. Marsden I and J , 2012 .

[97]  Jie Shen,et al.  Upconversion Nanoparticles: A Versatile Solution to Multiscale Biological Imaging , 2014, Bioconjugate chemistry.

[98]  S. Gambhir,et al.  Quantum Dots for Live Cells, in Vivo Imaging, and Diagnostics , 2005, Science.

[99]  Val Vallyathan,et al.  Single- and Multi-Wall Carbon Nanotubes Versus Asbestos: Are the Carbon Nanotubes a New Health Risk to Humans? , 2010, Journal of toxicology and environmental health. Part A.

[100]  Hongjie Dai,et al.  Ag2S quantum dot: a bright and biocompatible fluorescent nanoprobe in the second near-infrared window. , 2012, ACS nano.

[101]  Michael J Sailor,et al.  Biodegradable luminescent porous silicon nanoparticles for in vivo applications. , 2009, Nature materials.

[102]  Michael C. Kolios,et al.  Hybrid quantum dot-fatty ester stealth nanoparticles: toward clinically relevant in vivo optical imaging of deep tissue. , 2011, ACS nano.

[103]  S. Toyokuni Genotoxicity and carcinogenicity risk of carbon nanotubes. , 2013, Advanced drug delivery reviews.

[104]  Andrew G. Glen,et al.  APPL , 2001 .

[105]  Omar K. Yaghi,et al.  In vivo fluorescence imaging in the second near-infrared window with long circulating carbon nanotubes capable of ultrahigh tumor uptake. , 2012, Journal of the American Chemical Society.

[106]  Y. Song,et al.  Exposure to nanoparticles is related to pleural effusion, pulmonary fibrosis and granuloma , 2009, European Respiratory Journal.

[107]  Rijun Gui,et al.  Water-soluble multidentate polymers compactly coating Ag2S quantum dots with minimized hydrodynamic size and bright emission tunable from red to second near-infrared region. , 2014, Nanoscale.

[108]  C. Allen,et al.  Air-stable near-infrared AgInSe₂ nanocrystals. , 2014, ACS nano.

[109]  V. C. Moore,et al.  Band Gap Fluorescence from Individual Single-Walled Carbon Nanotubes , 2002, Science.

[110]  J. G. Solé,et al.  1.3 μm emitting SrF2:Nd3+ nanoparticles for high contrast in vivo imaging in the second biological window , 2015, Nano Research.

[111]  Weibo Cai,et al.  Are quantum dots ready for in vivo imaging in human subjects? , 2007, Nanoscale research letters.

[112]  M. C. Mancini,et al.  Bioimaging: second window for in vivo imaging. , 2009, Nature nanotechnology.

[113]  B. Bauer,et al.  Length‐Dependent Uptake of DNA‐Wrapped Single‐Walled Carbon Nanotubes , 2007 .

[114]  Kai Yang,et al.  Biodistribution, pharmacokinetics and toxicology of Ag2S near-infrared quantum dots in mice. , 2013, Biomaterials.

[115]  B. Wall,et al.  Rare-earth-doped biological composites as in vivo shortwave infrared reporters , 2013, Nature Communications.

[116]  Rijun Gui,et al.  A facile cation exchange-based aqueous synthesis of highly stable and biocompatible Ag₂S quantum dots emitting in the second near-infrared biological window. , 2014, Dalton transactions.

[117]  Y. Nagasaki,et al.  Near-infrared (1550 nm) in vivo bioimaging based on rare-earth doped ceramic nanophosphors modified with PEG-b-poly(4-vinylbenzylphosphonate). , 2011, Nanoscale.

[118]  Guosong Hong,et al.  Multifunctional in vivo vascular imaging using near-infrared II fluorescence , 2012, Nature Medicine.

[119]  A. Marcelis,et al.  Cytotoxicity of surface-functionalized silicon and germanium nanoparticles: the dominant role of surface charges. , 2013, Nanoscale.

[120]  H. Dai,et al.  Biological imaging without autofluorescence in the second near-infrared region , 2015, Nano Research.

[121]  Gregory D. Scholes,et al.  Colloidal PbS Nanocrystals with Size‐Tunable Near‐Infrared Emission: Observation of Post‐Synthesis Self‐Narrowing of the Particle Size Distribution , 2003 .

[122]  Erlong Zhang,et al.  A review of NIR dyes in cancer targeting and imaging. , 2011, Biomaterials.

[123]  Xiu‐Ping Yan,et al.  Doped quantum dots for chemo/biosensing and bioimaging. , 2013, Chemical Society reviews.

[124]  S. Torti,et al.  Carbon nanotubes in hyperthermia therapy. , 2013, Advanced drug delivery reviews.

[125]  Zhuang Liu,et al.  A route to brightly fluorescent carbon nanotubes for near-infrared imaging in mice. , 2009, Nature nanotechnology.

[126]  Shuo Diao,et al.  Biological imaging using nanoparticles of small organic molecules with fluorescence emission at wavelengths longer than 1000 nm. , 2013, Angewandte Chemie.

[127]  J. Qian,et al.  ‘Green’-synthesized near-infrared PbS quantum dots with silica–PEG dual-layer coating: ultrastable and biocompatible optical probes for in vivo animal imaging , 2012, Nanotechnology.

[128]  Zonghua Wang,et al.  Recent advances in synthetic methods and applications of colloidal silver chalcogenide quantum dots , 2015 .

[129]  Yan Zhang,et al.  In vivo real-time visualization of tissue blood flow and angiogenesis using Ag2S quantum dots in the NIR-II window. , 2014, Biomaterials.

[130]  R. Naccache,et al.  The Fluoride Host: Nucleation, Growth, and Upconversion of Lanthanide‐Doped Nanoparticles , 2015 .

[131]  Kostas Kostarelos,et al.  Hemotoxicity of carbon nanotubes. , 2013, Advanced drug delivery reviews.

[132]  Paul A Schulte,et al.  Occupational nanosafety considerations for carbon nanotubes and carbon nanofibers. , 2013, Accounts of chemical research.

[133]  Yanxia Zhao,et al.  Phase transfer-based synthesis of highly stable, biocompatible and the second near-infrared-emitting silver sulfide quantum dots , 2014 .

[134]  Ravindran Girija Aswathy,et al.  Near-infrared quantum dots for deep tissue imaging , 2010, Analytical and bioanalytical chemistry.

[135]  P. Liu,et al.  Conjugated Polymer-Based Hybrid Nanoparticles with Two-Photon Excitation and Near-Infrared Emission Features for Fluorescence Bioimaging within the Biological Window. , 2015, ACS applied materials & interfaces.

[136]  Uli Lemmer,et al.  Colloidally stable silicon nanocrystals with near-infrared photoluminescence for biological fluorescence imaging. , 2011, Small.

[137]  Y. Duan,et al.  Chemistry, biology, and medicine of fluorescent nanomaterials and related systems: new insights into biosensing, bioimaging, genomics, diagnostics, and therapy. , 2014, Chemical reviews.

[138]  Xiaogang Peng,et al.  Synthesis of Cu-doped InP nanocrystals (d-dots) with ZnSe diffusion barrier as efficient and color-tunable NIR emitters. , 2009, Journal of the American Chemical Society.

[139]  Ken-Tye Yong,et al.  Two- and three-photon absorption and frequency upconverted emission of silicon quantum dots. , 2008, Nano letters.

[140]  M. Ohtsu,et al.  Brightening of excitons in carbon nanotubes on dimensionality modification , 2013, Nature Photonics.

[141]  Scott C. Brown,et al.  Nanoparticles as contrast agents for in-vivo bioimaging: current status and future perspectives , 2011, Analytical and bioanalytical chemistry.

[142]  H. Xiong,et al.  One-pot synthesis of water-dispersible Ag2S quantum dots with bright fluorescent emission in the second near-infrared window , 2013, Nanotechnology.

[143]  Addason F. H. McCaslin,et al.  In vivo optical imaging and dynamic contrast methods for biomedical research , 2011, Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences.

[144]  L. Prodi,et al.  Imaging agents based on lanthanide doped nanoparticles. , 2015, Chemical Society reviews.

[145]  J. G. Solé,et al.  Nd3+ doped LaF3 nanoparticles as self-monitored photo-thermal agents , 2014 .

[146]  Shuo Diao,et al.  In vivo fluorescence imaging with Ag2S quantum dots in the second near-infrared region. , 2012, Angewandte Chemie.

[147]  Shenglin Luo,et al.  A NIR heptamethine dye with intrinsic cancer targeting, imaging and photosensitizing properties. , 2012, Biomaterials.