Faculty Directory

Timothy Muldoon

Timothy Muldoon

Assistant Professor

College of Engineering

(BMEG)-Biomedical Engineering

Phone: 479-575-5324

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Dr. Tim Muldoon is a founding member of the Department of Biomedical Engineering at the University of Arkansas in Fayetteville, AR, joining the faculty as an Assistant Professor in 2012. He received his Ph.D. in Bioengineering at Rice University in Houston, TX in 2009, and was advised by Dr. Rebecca Richards-Kortum. He received an M.D. from Baylor College of Medicine in Houston, TX in 2010. He then served as a postdoctoral research scientist with Dr. Elizabeth Hillman at Columbia University in New York, NY, prior to joining the University of Arkansas. He has authored 18 publications and over 35 conference papers to date. He has served as principal investigator on two National Institutes of Health research grants, including a recently awarded Academic Research Enhancement Award (R15) from the National Cancer Institute for his work on developing multimodal microendoscopy and spectroscopy technologies. 

Cancer of the gastrointestinal epithelium accounts for over 150,000 new cancer cases in the United States each year. Locally advanced (Stage II and III) distal rectal tumors receive neoadjuvant chemoradiotherapy (CRT) prior to surgical resection. Pathologic complete response to neoadjuvant therapy (pCR) is seen in only a minority of cases (<25%), but has been associated with significantly improved clinical outcomes, including disease-free survival. Prediction of which patients will respond to neoadjuvant therapy remains challenging. We are developing optical methods to quantify two potential modes of resistance to neoadjuvant therapy in patients with colorectal tumors: cellular-level resistance to cytotoxic agents and limited perfusion in solid tumors. First, we are studying the use of in vitro patient tumor-derived organoid culture and live-cell metabolic imaging to quantify the heterogeneous drug sensitivity of specific tumors. Secondly, we have developed a hybrid multiscale spectroscopy probe to rapidly assess in vivo intratumoral hemodynamic changes in response to therapy. These methods are currently being validated in preclinical models, and will be deployed in a clinical pilot study following patients with known colorectal tumors receiving neoadjuvant therapy. Our goal is to develop and translate to the clinic novel optical tools which can provide therapeutic guidance tailored to the patient-specific tumor phenotype. These tools will allow physicians to better select cytotoxic agents, rapidly assess response to therapy, and identify potential alternative strategies during neoadjuvant therapy. This new paradigm could increase the likelihood of achieving pCR in patients with locally advanced colorectal tumors.

 

This research encompasses the following areas:

Multimodal microendoscopy

We have designed a multimodal high-resolution microendoscopy to study the link between structural (anatomical) and functional (biochemical) characteristics for healthy and diseased epithelial tissue using a contact-based, fiber-bundle probe. We can potentially use various optical reporters of local vascularization and angiogenesis to non-invasively monitor tumor response to therapy. Additionally, we have employed a traditional microendoscope to develop an automated classification algorithm that utilizes image mosaicking to construct a larger field view of the region of interest to classify colonic diseases.

Multiphoton imaging for gastrointestinal cancer

Using two-photon microscopy and endogenous fluorescence, we are investigating changes in murine (mouse) colorectal tissue, specifically as it progresses from normal to dysplastic. This approach utilizes a myriad of optical markers acquired through label-free two-photon microscopy such as collagen structure, metabolic ratios, and spectral data.

Light sheet confocal microscopy

We have developed a light sheet confocal microscopy system that implements a linear sensor to image cells in suspension, such as whole blood. Considered high throughput image cytometry, this method could aid in rapid imaging of biological fluids on a slide (whole slide scanning) or within a microfluidics chamber (fluid flow). Furthermore, this system is used along with magnetohydrodymanic (MHD) fluid flow to control fluid flow for processing of large volumes of biological fluids.

Whole blood analysis

We are investigating alternative methods to perform a three-part leukocyte differential, which is the count of three subpopulations of cells (lymphocytes, granulocytes, and monocytes). One approach uses the light sheet confocal system for rapid high-throughput imaging of whole blood. The other approach aims to reduce complexity and cost of a device for a point-of-care application. Both methods utilize the fluorescent dye, acridine orange, where the period of time required for overall image acquisition greatly affects the accuracy of the differential due to the instability of the dye and cytotoxicity.

Biomedical Microscopy (BMEG 5504, Fall) is an advanced course covering light microscopy techniques, conjugate image planes, principles of contrast, fluorescence imaging, confocal and multi-photon microscopy, electron microscopy, atomic force microscopy, image reconstruction and digital image processing with supporting units in tissue culture and histology. At the conclusion of the course, students should be able to:

  • Understand the principles of optical imaging, brightfield and fluorescence microscopy, laser scanning microscopy, electron microscopy, and digital image processing
  • Be able to design experiments appropriate for the microscopy method of choice, and understand sample handling, image acquisition parameters, and other techniques necessary to collect quality data
  • Understand good laboratory practices, and appropriate laser safety protocols

Biomedical Instrumentation (BMEG 2904, Spring) is designed for undergraduate biomedical engineering students learning the theoretical and practical considerations behind measurement and instrumentation of biological systems. Topics of the course which will be covered include DC and AC circuits, signal acquisition, analog-to-digital conversion, signal conditioning, and Fourier analysis. The course will extensively use examples drawn from common life science and medical applications, particularly in measuring physiological parameters, such as spirometry and electrocardiograms.

B.S, Biomedical Engineering, Johns Hopkins University, Baltimore MD 2002

Ph.D., Bioengineering, Rice University, Houston TX 2009

M.D., Baylor College of Medicine, Houston TX 2010

Journal Publications

  1. Alhallak, K., Rebello, L., Quinn, K.P., Muldoon, T., Rajaram, N. Optical redox ratio identifies metastatic potential-dependent changes in breast cancer cell metabolism. Biomedical Optics Express, 2016 7(11): 4364-4374 
  2. Lam, N. T., Muldoon, T., Quinn, K.P., Rajaram, N., Balachandran, K. Valve interstitial cell contractile strength and metabolic state are dependent on its shape. Integrative Biology, 2016 8, 1079-1089
  3. Greening, G., James, H., Dierks, M., Vongkittiargorn, N., Osterholm, S., Rajaram, N., Muldoon, T., “Towards monitoring dysplastic progression in the oral cavity using a hybrid fiber-bundle imaging and spectroscopy probe,” Scientific Reports, 2016 6:26734 PMID: 27220821
  4. Greening, G., Rajaram, N., Muldoon, T., “Multimodal imaging and spectroscopy fiber bundle microendoscopy platform for non-invasive in vivo tissue analysis,” Journal of Visualized Experiments, 2016 (116), e54564
  5. Prieto, S., Lai, K., Laryea, J., Mizell, J., Muldoon, T., “Quantitative analysis of ex vivo colorectal epithelium using an automated feature extraction algorithm for microendoscopy image data," Journal of Medical Imaging, 2016 3(2), 024502. PMCID: PMC4891528
  6. Jenkins, S; Meeker, D; Miller, E; Beenken, K; Loughran, A; Powless, A; Muldoon, T; Galanzha, E; Zharov, V; Smeltzer, M S. ; Chen, J. Synergistic Photothermal and Antibiotic Killing of Biofilm-associated Staphylococcus aureus using Targeted, Antibiotic-loaded Gold Nanoconstructs. ACS Infectious Diseases 2016 2(4): 241–250
  7. Greening, G., James, H.M., Powless, A. J., Hutcheson, J. A., Dierks, M.K., Rajaram, N., Muldoon, T. Fiber-bundle microendoscopy with sub-diffuse reflectance spectroscopy and intensity mapping for multimodal optical biopsy of stratified epithelium. Biomedical Optics Express 2016 6(12):4934-50. PMCID: PMC4679267
  8. Hutcheson, J.A., Majid, A.A., Powless, A.J., Muldoon, T. A widefield fluorescence microscope with a linear image sensor for image cytometry of biospecimens: Considerations for image quality optimization. Review of Scientific Instruments, 2015, 86(9), 093709
  9. Prieto, S. P., Powless, A. J., Boice, J.W., Sharma, S.G., Muldoon, T. Proflavine hemisulfate as a rapid-staining, fluorescent cytological dye for qualitative and quantitative analysis. PLOS one 2015 10(5). PMCID: PMC4427403
  10. Greening G, Istfan R, Higgins LM, Balachandran K, Roblyer DM, Pierce MC, Muldoon, T., Characterization of thin poly(dimethylsiloxane)-based tissue simulating phantoms with tunable reduced scattering and absorption coefficients at visible and near-infrared wavelengths. Journal of Biomedical Optics 2014 19 (11), 115002 PMCID: PMC4227531
  11. Muldoon, T., Burgess, S., Chen, B., Ratner, D., Hillman, E.M.C., Analysis of skin lesions using laminar optical tomography. Biomedical Optics Express, 2012 Vol. 3, Issue 7, pp. 1701-1712 PMID: 22808439
  12. Muldoon, T., Roblyer, D., Williams, M.D., Stepanek, V.M.T., Richards-Kortum, R., Gillenwater, A.M. Non-invasive imaging of oral neoplasia with a high-resolution fiber optic microendoscope. Head and Neck. 2012 Vol 34, Issue 3, pp 305-312. PMCID: PMC3078517
  13. Thekkek, N, Muldoon, T, Polydorides, A.D., Maru, D.M., Harpaz, N, Harris M, Hofstettor W, Hiotis S, Kim, S, Ky, A, Anandasabapathy, S, Richards-Kortum, R. Vital-dye enhanced fluorescence imaging of gastrointestinal mucosa: metaplasia, neoplasia, inflammation. Gastrointestinal Endoscopy. 2012 April; 75(4):877-87. PMCID: PMC3336371
  14. Rosbach, K., Shin, D., Muldoon, T., Quraishi, M, Middleton, L., Hunt, K., Meric-Bernstam, F., Yu, T., Richards-Kortum, R., and Yang, W. High-resolution fiber optic microscopy with fluorescent contrast enhancement for the identification of axillary lymph node metastases in breast cancer: a pilot study. Biomedical Optics Express. 2010 Vol. 1, Issue 3, pp. 911-922  PMCID: PMC3018063  
  15. Muldoon, T., Thekkek, N., Roblyer, D., Maru, D., Harpaz, N., Potack, J., Anandasabapathy S., Richards-Kortum, R. Evaluation of quantitative image analysis criteria for the high-resolution micro-endoscopic detection of neoplasia in Barrett’s esophagus. J Biomed Opt. 2010 March–April; 15(2): 026027. PMCID: PMC2874050
  16. Nitin N, Carlson AL, Muldoon T, El-Naggar AK, Gillenwater A, and Richards-Kortum R. Molecular imaging of glucose uptake in oral neoplasia following topical application of fluorescently labeled deoxy-glucose. Int J Cancer. 2009 Jun 1;124(11):2634-42. PMCID: PMC2700039
  17. Muldoon, T., Anandasabapathy, S., Maru, D., and Richards-Kortum, R. High-resolution imaging in Barrett's Esophagus: a novel, low-cost endoscopic microscope. Gastrointest Endosc. 2008 Oct;68(4):737-44. PMCID: PMC2869299
  18. Muldoon, T., Pierce, M., Nida, D., Williams, M., Gillenwater, A. and Richards-Kortum, R. Subcellular-resolution molecular imaging within living tissue by fiber microendoscopy. Optics Express, 2007 Vol. 15, Issue 25, pp. 16413-16423 PMCID: PMC3065245

?Peer-reviewed Conference Proceedings

  1. Prieto, S.P*., Greening, G., Reed, C., Muldoon, T. Quantitative structural markers of colorectal dysplasia progression in a cross sectional study of the APC/min mouse using label-free multiphoton microscopy. Proc. SPIE 9712, Multiphoton Microscopy in the Biomedical Sciences XVI, 97121P, San Francisco, CA 2016
  2. Powless, A.P*., Feekin, L.E., Hutcheson, J.A., Alapat, D.V., Muldoon, T. Low-cost computing and network communication for a point-of-care device to perform a 3-part leukocyte differential. Proc. SPIE 9715, Optical Diagnostics and Sensing XVI: Toward Point-of-Care Diagnostics, 97150A, San Francisco, CA 2016
  3. Hutcheson, J.A*., Powless, A.J., Khan, F.Z., Benson, D., Fritsch, I., Muldoon, T., A light sheet confocal microscope for image cytometry with a variable linear slit detector. Proc. SPIE 9720, High-Speed Biomedical Imaging and Spectroscopy: Toward Big Data Instrumentation and Management, 97200U, San Francisco, CA 2016
  4. Greening, G.*, Rajaram, N., Muldoon, T. In vivo measurement of non-keratinized squamous epithelium using a spectroscopic microendoscope with multiple source-detector separations. Proc. SPIE 9715, Optical Diagnostics and Sensing XVI: Toward Point-of-Care Diagnostics, 97150Z, San Francisco, CA 2016
  5. Senlik, O.*, Greening, G., Muldoon, T., Jokerst, N.M., Spatially Resolved Diffuse Reflectance Spectroscopy of Two-layer Turbid Media Using a Densely Packed Multi-Pixel Photodiode Probe. Proc. SPIE 9700, Design and Quality for Biomedical Technologies IX, 97000O, San Francisco, CA 2016
  6. Powless, A.*, Jenkins, S.V., Chen, J., Muldoon, T. Molecule-specific darkfield imaging using gold nanocages. Reporters, Proc. SPIE 9339, Reporters, Markers, Dyes, Nanoparticles, and Molecular Probes for Biomedical Applications VII, 93390B San Francisco, California 2015
  7. Prieto, S*, Powless, A, Majid, A, Laryea, J, Mizell, J, Muldoon, T. Qualitative and quantitative comparison of colonic microendoscopy image features to histopathology, Proc. SPIE 9328, Imaging, Manipulation, and Analysis of Biomolecules, Cells, and Tissues XIII, 93280B San Francisco, California 2015
  8. Greening, G, Powless, A, Hutcheson, J, Prieto, SP, Majid, AA, Muldoon, T. Design and validation of a diffuse reflectance and spectroscopic microendoscope with poly(dimethylsioxane)-based phantoms. Proc. SPIE 9332, Optical Diagnostics and Sensing XV: Toward Point-of-Care Diagnostics, 93320R, San Francisco, California 2015
  9. Hutcheson, J.*, Claycomb, A., Powless, A., Prieto, S., Majid, A., Fritsch, I., Muldoon, T. High-throughput microfluidic line scan imaging for cytological characterization, Proc. SPIE 9320, Microfluidics, BioMEMS, and Medical Microsystems XIII, 93200Y, San Francisco, California 2015
  10. Pierce, M C*, Schwarz, R A, Rosbach, K, Roblyer, D, Muldoon, T, Williams, M D,  El-Naggar, A K, Gillenwater, A M, Richards-Kortum, R, Proc. SPIE 7548, Photonic Therapeutics and Diagnostics VI, 75481U, San Francisco, California 2010

*Oral presentation

Peer-reviewed Conference Abstracts

  1. Greening, G., Rajaram, N., Muldoon, T., Multimodal diffuse reflectance microendoscopy for clinical guidance in gastrointestinal neoplasia. Gordon Research Conference: Lasers in Medicine and Biology, West Dover, VT 2016
  2. J.A. Hutcheson, Hunter, C.J., Powless, A.J., Muldoon, T. A light sheet microscope with a linear sensor for whole slide imaging: applications for high throughput image cytometry. SPIE Translational Biophotonics, Houston TX 2016
  3. Prieto, S., Lai, K., Laryea, J., Mizell, J., Muldoon, T. Automated quantification and image quality control algorithm for fiber bundle microendoscopy image analysis of ex vivo colorectal epithelium. SPIE Translational Biophotonics, Houston TX 2016
  4. Powless, A.J., Hutcheson, J.A., Feekin, L.E., Muldoon, T. Three-part leukocyte differential using acridine orange and a Raspberry Pi based fluorescence imaging system. SPIE Translational Biophotonics, Houston TX 2016
  5. Wiggins, S.C., Powless, A.J., Muldoon, T. Multiphoton quantification of intra and extracellular receptors in live breast cancer cells as a tool for triple-negative breast cancer diagnostic applications. SPIE Translational Biophotonics, Houston TX 2016
  6. Greening, G., James, H., Dierks, M., Vongkittiargorn, N., Osterholm, S., Rajaram, N., Muldoon, T., Investigating the feasibility of a quantitative hybrid imaging and spectroscopy probe to monitor dysplastic progression in oral mucosa: a pilot and phantom study. SPIE Translational Biophotonics, Houston TX 2016
  7. Khan, F. Z., Jones, B. J., Nash, C. K., Hutcheson, J., Muldoon, T., Fritsch, I. Expanding lab-on-a-chip applications for redox magnetohydrodynamic microfluidics through polymer-modified electrodes and enhanced current-magnet relationships. Pacifichem, Honolulu, HI 2015
  8. Greening, G. J., Prieto, S. P., Dierks, M., James, H.M., Muldoon, T. A Multimodal Sub-diffuse Microendoscopy and Spectroscopy Probe for Detection of Epithelial Dysplasia. Engineering Conferences International Advances in Optics XIV, Vail, CO 2015
  9. Majid, A.A., Hutcheson, J.A., Powless, A.J., Muldoon, T. Fluorescent Imaging on a Microfluidics Chip for Quantification of Leukocyte Count. Engineering Conferences International Advances in Optics XIV, Vail, CO 2015
  10. Nash, C.K., Claycomb, A., Khan, F. Jones, B. J., Hutcheson, J., Muldoon, T., and Fritsch, I. New Advances and Opportunities of Magnetohydrodynamic Microfluidics. 227th Electrochemical Society Meeting, Chicago, IL 2015
  11. Hutcheson, J., Powless, A., Majid, A., Muldoon, T. A mobile health device for high-throughput disease screening. Arkansas Biosciences Institute Fall 2014 Research Symposium, Jonesboro, AR 2014
  12. Powless, A., Prieto, S., Balachandran, K., Muldoon, T. An optofluidics-based, line-scanning imaging system for point-of-care cytology. Gordon Research Conference: Lasers in Medicine and Biology, Holderness, NH 2014
  13. Powless, A, Majid, A, Boice, J, Prieto, S, Pierce, M, Balachandran K, Sharma, S, Muldoon, T. A Fluorescence Imaging Optofluidics Device for Cytologic Morphology Assessment. Optical Society of America Biomedical Optics Conference, Miami, FL 2014
  14. Greening, G, Balachandran, K, Muldoon, T. Thin-film Polydimethylsiloxane-based Optical Phantoms for Epithelial Tissue Simulation. Optical Society of America Biomedical Optics Conference, Miami, FL 2014
  15. Prieto, S, Powless, A, Majid, A, Laryea, J, Mizell, J, Sharma, S, Muldoon, T. Fiber Bundle Microendoscopy for Characterization of Dysplastic Lesions in Colonic Epithelium. Optical Society of America Biomedical Optics Conference, Miami, FL 2014
  16. Muldoon, T, Burgess, S, Ratner, D, Hillman EMC. Analysis of skin lesions using Laminar Optical Tomography. Advances in Optics Conference Poster Session, Naples, Florida 2011
  17. Thekkek, N, Rosbach, K, Muldoon T, Anandasabapathy, S, Richards-Kortum, R. Vital dye enhanced fluorescence imaging of esophageal and colorectal neoplasia. Digestive Diseases Week. Chicago, Illinois 2010
  18. Pierce, M C, Muldoon, T, Kester, R, Gillenwater, A, Anandasabapathy, S, Tkaczyk, T,Richards-Kortum, R, “Integrated optical needle (ION) for cellular and molecular imaging of cancer,” NIH Inter-Institute Workshop on Optical Diagnostic and Biophotonic Methods from Bench to Bedside.  Paper NIH01-32. 2009
  19. Richards-Kortum, R, Pierce, M, Vestewig, L, Muldoon, T, Rahman, M. Global approaches to cancer prevention. SPIE Newsroom. DOI: 10.1117/2.1200812.1437. 2009
  20. Yang, W, Rosbach, K, Muldoon, T, Bedard, N, Middleton, L, Richards-Kortum, R. To Investigate Cellular Alterations in Axillary Lymph Node Metastases in Breast Cancer Patients Using Optical Imaging: A Pilot Study. RSNA 95th Scientific Assembly and Annual Meeting, Chicago, Illinois 2009
  21. Muldoon, T., Roblyer, D, Williams, M, Anandasabapathy, S, Gillenwater, A.M, Richards-Kortum, R High-resolution imaging of esophageal and oral mucosa with a fiber bundle microendoscope. Keystone MSTP Conference, Keystone, Colorado 2009
  22. Muldoon, T., Roblyer, D, Maru, D, Anandasabapathy, S, Richards-Kortum, R. High-resolution microendoscopy and image analysis for early cancer detection in gastrointestinal epithelium. Digestive Diseases Week 2009. Chicago, Illinois 2009
  23. Muldoon, T., Roblyer, D, Williams, M, Anandasabapathy, S, Gillenwater, A.M, Richards-Kortum, R High-resolution imaging of esophageal and oral mucosa with a fiber bundle microendoscope. Baylor College of Medicine Medical Scientist Training Program Annual Symposium, Oral Presentation. Galveston, Texas 2008
  24. Muldoon, T., Williams, M, Anandasabapathy, S, Gillenwater, A.M, Richards-Kortum, R High-Resolution Imaging within Tissue by Fiber Microendoscopy. BIOMED Optical Society of America Conference Oral Presentation, St. Petersburg, Florida 2008
  25. Muldoon, T., Williams, M, Gillenwater, A.M, Richards-Kortum, R. High-Resolution Fiber Microendoscopy. Advances in Optics Conference Poster Session, Naples, Florida 2007
  26. Muldoon, T., Pierce, M, Nida, D., Williams, M, Anandasabapathy, S, Gillenwater, A.M, Richards-Kortum, R. Imaging Deep Tissue Structures with a Coherent Fiber Microscope         NIH Biotechnology Poster Session and Retreat, Rice University, Houston, Texas 2006
  27. Muldoon, T., Pierce, M, Nida, D., Williams, M, Gillenwater, A.M, Richards-Kortum, R. High resolution Imaging of Deep Tissue Structures with a Coherent Fiber Microscope. Society of Molecular Imaging Poster Session, Kona Hawaii 2006

Book Chapters

  1. Jenkins, S.V., Muldoon, T., Chen, J., Plasmonic Nanostructures for Biomedical and Sensing Applications. Metallic Nanostructures, Springer International Publishing Switzerland 2015 ISBN: 9783319113036
  2. Greening, G., H.M. James, Muldoon, T. Optical Phantoms: Diffuse and Sub-diffuse Imaging and Spectroscopy Validation. SPIE Spotlights, SPIE Publications 2015 ISBN: 9781510600324

 

 

Complete List of Published Work in MyBibliography:   http://www.ncbi.nlm.nih.gov/sites/myncbi/timothy.muldoon.1/bibliography/40637141/public/?sort=date&direction=ascending

Invited Talks

  1. Beckman Laser Institute invited seminar, “Towards personalized neoadjuvant therapy in colorectal cancer: optical methods to assess cellular-level and vascular-level resistance to chemoradiotherapy.” University of California at Irvine, Irvine CA 2016
  2.     Breast Cancer Honors Colloquium invited talk, “Basic science and translational applications of microendoscopy and spectroscopy systems” University of Arkansas, Fayetteville, AR 2015
  3.      Department of Biochemistry Seminar invited talk, “Optical imaging and spectroscopy for translational biomedical applications” University of Arkansas, Fayetteville, AR 2015
  4.      Pat Walker Health Center Faculty / Staff invited talk, “Fluorescence imaging for clinical and point-of-care diagnostics” University of Arkansas, Fayetteville, AR  2014
  5.      Department of Chemistry Seminar invited talk, “Principles of fluorescence imaging and fundamentals of biomedical optics” University of Arkansas, Fayetteville, AR 2014
  6.      Cell and Molecular Biology Graduate Seminar, “Microendoscopic imaging for real-time, in vivo histology of epithelial tissues” University of Arkansas, Fayetteville, AR 2013

2016                National Institutes of Health Early Career Reviewer Program Selectee

2016                National Institutes of Health Extramural Clinical Research LRP Award

2015                University of Arkansas Honors College Distinguished Faculty Award

2015                University of Arkansas Department of Biomedical Engineering Outstanding Service Award

2013                University of Arkansas Department of Biomedical Engineering Outstanding Teacher Award

2012                Burroughs Wellcome Fund Collaborative Research Travel Grant

2012                NCI Cancer Research Imaging Camp Participant