Neurophotonics

About

The NeuroPhotonics group is involved in both technology development and conducting experiments to validate the technology in basic and clinically relevant translational models. We are developing A) Laser speckle imaging technology, both for in situ imaging of brain function and a head-mounted imager microscope for imaging brain health and disease in awake-behaving animal, and B) Photoacoustic imaging system for monitoring brain vessels, blood flow and oxygenation at depth and a handheld imager for eventual translation to intraoperative imaging. We use nanoparticles for contrast enhancement, penetrating blood brain barrier, and for drug/oxygen delivery. Our focus is on two applications, A) stroke and B) glioblastoma brain tumor.

Project Description

Nano-Neurophotonics for Stroke and Cancer

We study brain imaging for understanding brain function in stroke and cancer. The student will join a very strong and friendly experimental team to do experiments and help with optical instrumentation and imaging system development. The project is done in a small animal model where either stroke and glioma brain cancer. Our group has develop a photoacoustic imaging system and now a new generation hand-held system is being developed. The student will assist with the design and testing of the hand-held imager (may have uses in the clinic) and experiments on stroke, glioma surgery and analysis of data (for example how to identify tumor, tumor margins and removal using nanoparticle contrast agents). A BME student with interest in imaging, experiments, and brain (stroke, tumor) would find this an exciting hands on, team project.

Projects

Surgical Photoacoustic Nanotechnology (SPAN)

The Surgical PhotoAcoustic Nanotechnology (SPAN), a breakthrough technology is proposed mainly to change the paradigm of brain surgery. To enable a paradigm shift in brain surgery, we propose tumor-resection technology, SPAN, that combines nano neurophotonics with a real-time photoacoustic (PA) imager. This combined approach of cellular level PA image-guided surgery with in-situ photothermal ablation of residual tumor cells will result in a novel paradigm for brain tumor surgery. This goal will be realized through the integration of the first targeted magnetic resonance (MR)-PA-fluorescence (Fl) triple modality contrast agents for glioma tumor with a unique invention of hand-held real-time photoacoustic system (HARP) to yield the SPAN platform, which offers rapid response with tunable imaging depth (0.3-2 cm) and resolution (10-100 µm) for tumor margin/infiltrates identification and real-time imageguided tumor resection. The combination of contrast agents and the HARP system will yield the SPAN platform, offering for the first time the possibility to conduct real-time image-guided surgery with cellular resolution, which will shed light on further translational research to improve the lifespan of cancer patients.

Organic Nanoparticles with Aggregation-Induced Emission for Bone Marrow Stromal Cell Tracking in a Rat PTI Model

Stem cell-based therapy has emerged as a promising alternative therapeutic approach for acute stroke treatment due to its longer therapeutic time window as compared to the gold standard of administration of thrombolytic agent (tissue plasminogen activator). Bone marrow stromal cells (BMSCs) has garnered interest to act as a source of cell for stem cell therapy due to the promising beneficial structural and functional therapeutic outcome from transfusion of BMSCs as stroke treatment. Thus, it is highly desired to label BMSCs for long-term tracking in order to understand the fate of BMSCs after transplantation through reliable imaging technique for therapeutic evaluation. The emerging of fluorogens aggregation-induced emission characteristics (AIEgens), which emits bright fluorescence in aggregation state provides a promising alternative of conventional agents for the long-term cell labelling and tracking. Our group and others have successfully proven that with the help of the organic nanoparticles with bright fluorescence, excellent photostability and good biocompatibility, the nanoparticles (NPs) show good internalization in BMSCs with stable in vitro tracking ability up to 10 days in a rat photothrombotic ischemia (PTI) model. Ex vivo observation on day 7 after transplantation indicates that the BMSCs could migrate to and accumulate at the stroke site which was detected with strong fluorescence signal for the tracking of the BMSCs.

Dual-Modal Optical-based In-Vivo Imaging Using Rare-Earth Doped Nanoprobes

Mesenchymal stem cells (MSCs) were found to be effective in repairing the damaged brain of animals with ischemic brain injury. However, the behavior, distribution and fate of these cells after implantation which gives very important information on cell dynamics and interactions with the host central nervous system is still unknown. Minimally-invasive functional imaging techniques have driven much advancement in medical sciences. One of the challenges in minimally-invasive functional imaging is to achieve both high resolution and SNR. Multi-modal imaging is emerging as a strategy to overcome this challenge by combining two or more imaging modalities. In this project, we seek to combine shortwave infrared (SWIR) and photoacoustic (PA) imaging into one versatile minimally-invasive molecular imaging platform utilizing polymer coated Rare Earth Doped Nanoparticles (REDNs), as imaging probes. Not only do the REDNs enhance SNR and improve resolution, but the REDNs also provide an added analytic ability at the cellular level using the functional relationships between the probes and biological systems.

Preventing Chemotherapy-Induced Peripheral Neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose limiting side effect of several commonly used chemotherapeutic agents, often leading to treatment discontinuation. Up to 20% of patients treated with weekly paclitaxel experience severe CIPN and it is noteworthy that no effective treatment has been established so far. In this study, we assess the effect of hypothermia in preventing CIPN in healthy subjects and then, cancer subjects undergoing adjuvant paclitaxel chemotherapy. This study may contribute to alleviating dose-limitation due to CIPN and increase the likelihood of success of chemotherapy.

Investigation of Cortical Neurovascular Functions and Therapy for Hyperacute Ischemia

This study focuses on investigating the cerebral neurovascular function changes affected by hyperacute ischemic stroke, as well as the progressive changes of the affected cortical regions (i.e., ischemic core and penumbra). Using the developed novel combination of electrocorticography (ECoG) recordings and functional photoacoustic microscopy (fPAM) imaging (i.e., ECoG-fPAM) we investigate cortical functions after photothrombotic ischemia (PTI) in a rat ischemia model. The cortical functions are assessed over a chosen ischemic region via somatosensory-evoked potential (SSEP), resting-state ECoG signals (i.e., alpha-to-delta (ADR) ratio) and evoked hemodynamic responses (i.e., cerebral blood volume (CBV) and hemoglobin oxygen saturation (SO2)). Histological assessment method (2, 3, 5-triphenyl-tetrazolium chloride (TTC) staining) is also used to assess the infarct volume induced by ischemia. In addition, the neuroprotective effect of sensory stimulation as a non-invasive therapeutic intervention for hyperacute ischemia is evaluated in the affected animals.

Laser Speckle Contrast Imaging

Miao P., Li M., Li N., Rege A., Yisheng Z., Thakor N., Tong S., “Detecting cerebral arteries and veins: from large to small,” J. Innovative Optical Health Sci.,Vol. 03 (01), pp. 61-67, 2010.http://dx.doi.org/10.1142/s1793545810000794 .

Rege A*, Senarathna J*, Li N, Thakor N. V., “Anisotropic processing of laser speckle images improves spatiotemporal resolution”, IEEE Trans Biomed Engr vol. 59, no. 5, pp. 1272-128, 2012. (*equal contributions).

Rege A, Seifert AC, Schlattman D, Ouyang Y, Li K, Basaldella L, Brem H, Tyler B and Thakor NV, “Longitudinal in vivo monitoring of rodent glioma models through thinned skull using laser speckle contrast imaging,” J. Biomed. Optics, Vol.17(12), 126017, Dec. 2012. doi:10.1117/1.JBO.17.12.126017.

Rege A, Thakor NV, and Pathak AP, “Optical imaging of microvascular morphology and perfusion,” Current Angiogenesis, Vol. 1, pp. 243-260, 2012

Senarathna J, Rege A, Li N, and Thakor NV, “Laser speckle contrast imaging: theory, instrumentation and applications,” IEEE Rev. Biomed. Eng., Vol. 6, pp. 99-110, Jan 2013. doi: 10.1109/RBME.2013.2243140.

Liao L.-D., Orellana J., Liu Y.-H., Lin Y.-R., Vipin A., Thakor N., Shen K., Wilder-Smith E., "Temperature dependent hemodynamics in rat sciatic nerve,” 12:120, BioMedical Engineering OnLine, 2013.

Miao P., Chao Z., Feng S., Yu H., Ji Y., Li N., Thakor N. V., “Local scattering property scales flow speed estimation in laser speckle contrast imaging,” Laser Physics Letters 12 (7), 075601, 2015.

Yu H., Senarathna J., Tyler B. M., Thakor N. V., Pathak A.P, “Miniaturized optical neuroimaging in unrestrained animals,” Neuroimage, Vol. 113, pp. 397-406, 2015.

Miao P., Zhang L., Li M., Zhang Y., Feng S., Wang Q., and Thakor N. V. “Chronic wide-field imaging of brain hemodynamics in behaving animals,” Optics Express, Vol. 8, Issue 1, pp. 436-445, 2017. https://doi.org/10.1364/BOE.8.000436.

Miao P., Li M., Wang Q., Li Y., Zhang L., Sherman D. L., and Thakor N. V., “Beta oscillation in primary motor cortex couples with the supplying artery’s blood flow activities in freely moving rats,” J. Biophotonics, 2017.

Photo-acoustic Imaging

Tuan Y.,† Wang Z.,‡ Cai P.,# Liu J.,† Liao L.-D.,^ Hong M.,‡ Chen X.,# Thakor N.,^ and Bin L.*,†,§,” Conjugated polymer and drug co-encapsulated nanoparticles for photothermal combined chemotherapy with two-photon regulated fast drug release" Nanoscale, ID: NR-ART-10-2014-006420.

Bandla A., Sundar R., Liao L.-D., Tan S.S.H., Lee S.-C., Thakor N. V., and Wilder-Smith E. P. V., “Hypothermia for preventing chemotherapy-induced neuropathy a pilot study on safety and tolerability in healthy controls,” Acta Oncologica, ISSN: 0284-186X (Print) 1651-226X (Online), 2015. DOI: 10.3109/0284186X.2015.1075664.

Y.-H. Liu, Stacey S. H.Tan, K. Y. Kwon, J. M. Ling, A. Bandla, Y.-Y. I. Shih, E. Tan, W. Li, W. H. Ng, H.-Y. Lai, Y.-Y. Chen, N. V. Thakor, L.-D. Liao “Assessment of neurovascular dynamics during transient ischemic attack by the novel integration of micro-electrocorticography electrode array with functional photoacoustic microscopy, Neurobol. Disease., Vol. 82, pp. 455–465, October 2015. doi:10.1016/j.nbd.2015.06.019.

Sheng Y. Liao, L.-D., Bandla, A., Liu Y.-H.; Thakor N.; Tan M. C. , “"Size and shell effects on the photoacoustic and luminescence properties of dual modal rare-earth doped nanoparticles for infrared photoacoustic imaging" ACS Biomat. Sci. Eng. Manuscript ID: ab-2016-00012p.R1.

Geng+J., Liao+L.-D., Qin W., Tang B., Thakor N., Bin L., "An effective strategy to improve photoacoustic contrast of a fluorophore through introducing molecular rotation,” Accepted, J.Nanosci. Nanotech.,2014.

Y. H. Liu, Y. Xu, L. D. Liao, K. C. Chan, and N. V. Thakor, "A Handheld Real-Time Photoacoustic Imaging System for Animal Neurological Disease Models: From Simulation to Realization," Sensors (Basel), vol. 18, Nov 21 2018.

Y. H. Liu, S. J. Chan, H. C. Pan, A. Bandla, N. K. K. King, P. T. H. Wong, et al., "Integrated treatment modality of cathodal-transcranial direct current stimulation with peripheral sensory stimulation affords neuroprotection in a rat stroke model," Neurophotonics, vol. 4, p. 045002, Oct 2017.

A. Bandla, L. D. Liao, S. J. Chan, J. M. Ling, Y. H. Liu, Y. I. Shih, et al., "Simultaneous functional photoacoustic microscopy and electrocorticography reveal the impact of rtPA on dynamic neurovascular functions after cerebral ischemia," J Cereb Blood Flow Metab, p. 271678X17712399, Jan 01 2017.

Nanoparticles for Photonics and Applications

Li N, Downey J, Bar-Shir A, Gilad A A, Walczak P, Kim H, Joel S E, Pekar J J, Thakor N V and Pelled G., “Optogenetically-guided cortical plasticity following nerve injury,” Proc. Natl. Acad. Sci., Vol. 108(21):8838-43, May 24, 2011. doi: 10.1073/pnas.1100815108. Epub 2011 May 9. PMID: 21555573.

Cai X, Bandla A, Mao D, Feng G, Qin W, Liao LD, Thakor N, Tang BZ, Liu B, “Biocompatible red fluorescent organic nanoparticles with tunable size and aggregation-induced emission for evaluation of blood-brain barrier damage,” Adv Mater. ,2016 Aug 11. doi: 10.1002/adma.201601191. [Epub ahead of print], PMID: 27511643.

Cai X, Liu X, Liao LD, Bandla A, Ling JM, Liu YH, Thakor N, Bazan GC, Liu B., “Encapsulated conjugated oligomer nanoparticles for real-time photoacoustic sentinel lymph node imaging and targeted photothermal therapy,” Small, 2016 Jul 21. doi: 10.1002/smll.201600697. [Epub ahead of print], PMID: 27439884.

Cai X., Bandla,A., Mao D., Feng G., Qin W., Liao L.-D., Thakor N., Tang B. Z. and Liu B., “Biocompatible red Fluorescent organic nanoparticles with tunable size and aggregation-induced emission for evaluation of blood–brain barrier damage,” Adv. Mater., 28: 8760–8765, 2016. doi:10.1002/adma.201601191.

Cai X., Liu X., Liao L.-D., Bandla A., Ling J. M., Liu Y.-H., Thakor N., Bazan G. C. and Liu B., “Encapsulated conjugated oligomer nanoparticles for real-time photoacoustic sentinel lymph node imaging and targeted photothermal therapy,” Small,12: 4873–4880, 2016, doi:10.1002/smll.201600697.

Cai X., Zhang C. J., Wei Lim F. T., Chan S. J., Bandla A., Chuan C. K., Hu F., Xu S., Thakor N. V., Liao L.-D., Liu B., “Cell tracking: organic nanoparticles with aggregation‐induced emission for bone marrow stromal cell tracking in a rat PTI model,” Small, Vol. 12 (47), pp. 6419-6419, 2016.

Shang Y, Liao Lun-De, Thakor N. and Tan M. C., “Rare earth doped particles as dual-modality contrast agent for minimally invasive luminescence and dual wavelength photo-acoustic imaging,” Sci. Reports, Vol. 4: 6562, doi: 10.1038/srep06562, 2014.

Sheng Y., Liao L.-D., Bandla A., Liu Y. H., Thakor N., Tan M. C., “Size and Shell Effects on the Photoacoustic and Luminescence Properties of Dual Modal Rare-Earth-Doped Nanoparticles for Infrared Photoacoustic imaging,” ACS Biomaterials Science & Engineering 2016 2 (5), 809-817.

Sheng Y., Liao L.-D., Bandla A., Liu Y. H., Yuan J., Thakor N., Tan M. C., “Enhanced near-infrared photoacoustic imaging of silica-coated rare-earth doped nanoparticles,” Materials Science and Engineering: C, Vol. 70, pp. 340-346, 2017.

Zhao X., Sheng Y., Liao L.D., Thakor N., Tan M.C., “Rare-earth doped CaF2 nanocrystals for dual-modal short-wavelength infrared fluorescence and photoacoustic imaging,” Nanoscience Nanotechnology Letters, Vol. 9 (4), pp. 481-488, 2017.

Cai X., Liu J., Liew W.H., Duan Y., Thakor N. V., Yao K., Liao L.., Liu B., “Organic molecules with propeller-structures for efficient photoacoustic imaging and photothermal ablation of cancer cells,” Materials Chemistry Frontiers, 2017.

Bandla A., Liao L.-D., Chan S.-C., Ling J. M., Liu Y.-H., Shih I. Y.-Y., Pan H.-C., Peter Tsun- Wong H., Lai H.-Y., King N. K. K., Chen Y.-Y., Ng W. H., and Thakor N. V., “Simultaneous functional photoacoustic microscopy and electrocorticography reveal the impact of rtPA on dynamic neurovascular Functions after cerebral ischemia,” J. Cerebrovasc. Flow Metabolism, 38(6):980-995, 2018. doi: 10.1177/0271678X17712399. Epub 2017 Jul 7.

Hadjiabadi D., Pung L. Zhang J., Ward B., Lim W-T., Kalavar M. Thakor N. Biswal B., Pathak, A., “Brain tumors disrupt the resting state connectome,” Neuroimage Clin. 2018; 18: 279–289.. doi: 10.1016/j.nicl.2018.01.026

Liu J., Cai X., Pan H.-C., Bandla A., Chuan C. K., Wang S., Thakor N., Liao L.-D., Liu B., “Molecular Engineering of photoacoustic Performance by chalcogenide variation in conjugated polymer nanoparticles for brain vascular imaging, Small, 7 February 2018, DOI: 10.1002/smll.201703732.

Duan Y., Xu Y., Mao D., Liw W. H., Guo B., Wang S., Cai X. M., Thakor N., Yao K., Zhabt C.-J., and Liu B., “Photoacoustic and magnetic resonance imaging bimodal contrast agent displaying amplified photoacoustic signal,” Small, https://doi.org/10.1002/smll.201800652, 2018.

Liang L., The D.B. L., Dinh N-D., Cheri W., Chen Q., Wu T. Chowdhury S., Yamanaka A.., Sum T-C., Chen C.-H., Thakor N. V., All A. H. Liu X., “Upconversion amplification through dielectric superlensing modulation,” Nature Comm., Vol. 10, p. 1391, 2019. https://doi.org/10.1038/s41467-019-09345-0.

Zeng X., Chen S., Weitemier A.; Han S., BlasiakA., Prasad A., Zheng K., Yi Z., Luo B.,Yang I.-H., Thakor N., Chai C., Lim K.-L., McHugh T., All A., Liu X., ” Visualization of intra-neuronal motor protein transport through upconversion microscopy" Angewandte Chemie, https://doi.org/10.002/ange.2012904208.

Cai X., Bandla A., Chuan C. K., Magarajah G., Liao L.-D., Teh L., Kennedy B. K., Thakor N., and Liu B., “Identifying glioblastoma margin using dual-targeted organic nanoparticles for efficient in vivo fluorescence image-guided photothermal therapy,” Materials Horizons, Issue 2, 2019.

Zhenghuan Z., Jun Y., Xinyu Z., Bandla A., Thakor N., Tan M. C., “Double-Shelled Rare Earth Doped Nanoparticles for Infrared Imaging and Photothermal Therapy” ACS Biomaterials Science & Engineering, 2019, accepted.

Neurophotonics: Multi-modality Brain Imaging

About

Project Description

Nano-Neurophotonics for Stroke and Cancer

Team

PI: Nitish Thakor

PI: Nitish Thakor

PI: Nitish Thakor

Liu Bin

PI: Nitish Thakor

PI: Nitish Thakor

Tan Mei-Chee

Arvind Pathak

Arvind Pathak

Arvind Pathak

Arvind Pathak

Arvind Pathak

Students and Post-doctoral fellows

Xu Yu

Gayathri Magarajah

Gayathri Magarajah

Gayathri Magarajah

Gayathri Magarajah

Gayathri Magarajah

Yuan Jun

Chan Kim Chuan

Chan Kim Chuan

Chan Kim Chuan

Chan Kim Chuan

Chan Kim Chuan

Alumni

Lun-De Liao

Aishwarya Bandla

Aishwarya Bandla

Aishwarya Bandla

Aishwarya Bandla

Aishwarya Bandla

Yu-Hang Liu

Aishwarya Bandla

Yu-Hang Liu

Projects

Surgical Photoacoustic Nanotechnology (SPAN)

Organic Nanoparticles with Aggregation-Induced Emission for Bone Marrow Stromal Cell Tracking in a Rat PTI Model

Dual-Modal Optical-based In-Vivo Imaging Using Rare-Earth Doped Nanoprobes

Preventing Chemotherapy-Induced Peripheral Neuropathy

Investigation of Cortical Neurovascular Functions and Therapy for Hyperacute Ischemia

Publications

Review

Laser Speckle Contrast Imaging

Photo-acoustic Imaging

Nanoparticles for Photonics and Applications