About

Timothy C. Zhu, Ph.D., is a Professor of Radiation Oncology at the Hospital of the University of Pennsylvania and serves as the Associate Director of Photodynamic Therapy Physics Research at the University of Pennsylvania. His research focuses on PDT physics, in-vivo dosimetry, and external beam treatment planning. He has developed explicit and implicit dosimetry methods for PDT, light fluence rate calculations, and diode in-vivo dosimetry for real-time radiation dose measurement, including EPID and Cherenkov imaging. Zhu has also contributed to the development of benchmark databases for external beams such as electron, photon, and proton therapies, as well as image co-registration techniques. He has created integrated systems for interstitial PDT light delivery and dosimetry for bulky tumors, including prostate and head & neck cancers, and developed real-time treatment planning systems utilizing IR navigation for intracavitary PDT. As a board-certified physicist in radiation oncology, Zhu is involved in the development of computational treatment planning systems, medical imaging registration, radiation dose calculation, and patient motion monitoring.

Research topics

• Optics
• Materials science
• Medicine
• Physics
• Nuclear medicine

Selected publications

• Evaluation of a time-resolved singlet oxygen detection system for in vivo photodynamic therapy

  Biomedical Optics Express · 2026-03-18

  articleOpen access

  Singlet oxygen ( 1 O 2 ) is the primary cytotoxic agent in Type-II photodynamic therapy (PDT). Single-photon avalanche diode (SPAD)-based time-resolved singlet oxygen luminescence detection (TSOLD) systems enable direct detection of the near-infrared 1 O 2 phosphorescence (∼1270 nm) during PDT, offering a powerful tool for treatment monitoring. However, the efficiency of detection depends strongly on the acquisition parameters. Here, we present a comprehensive evaluation of a TSOLD system with 630 nm and 690 nm nanosecond pulsed diode lasers developed for in vivo PDT monitoring. The influence of acquisition time (1–300 s), SPAD dead time (5-40 µs), and temporal bin width (1–100 ns) on the fidelity of 1 O 2 lifetime measurements and signal-to-noise ratio (SNR) was quantitatively investigated. Measurements were performed using liquid phantoms containing the photosensitizers Photofrin or benzoporphyrin derivative, with acquisition time further validated in vivo in murine tumor models. The results demonstrate that both acquisition time and detector dead time significantly affect the signal vs. time histogram shape and the accuracy of the 1 O 2 and photosensitizer triplet-state lifetime measurements, while an optimal bin width minimizes photon-count noise without compromising temporal resolution. The optimized parameters enable reliable 1 O 2 lifetime extraction within 100 s from the mouse model in vivo . This systematic evaluation establishes quantitative design guidelines for compact TSOLD systems tailored to in vivo applications.

  PublisherDOI

• 3D Reactive Oxygen Species Dosimetry in Pleural Photodynamic Therapy: Integration of Macroscopic Kinetic Modeling and Deformable Registration

  Antioxidants · 2026-05-13

  articleOpen accessSenior author

  Photodynamic therapy (PDT) is a promising treatment for pleural malignancies, yet accurate dosimetry remains challenging due to complex cavity geometries and the need to protect surrounding critical structures. The reactive oxygen species ([ROS]rx) generated during treatment serve as a direct predictor of therapeutic efficacy. We developed a finite element model using COMSOL Multiphysics to simulate macroscopic photophysical kinetics, using clinical data inputs, including light fluence derived from a navigation system and patient-specific photosensitizer concentrations. Crucially, we integrated a deformable image registration framework to align intra-operative navigation data with pre-treatment CT scans, enabling the calculation of [ROS]rx dose accumulation in critical Organs at Risk (OARs), such as the lung, heart, and esophagus. The model successfully reconstructed 3D [ROS]rx distributions for multiple clinical cases. Point-to-point comparison at 32 detector locations across ten patients showed strong agreement between COMSOL-simulated and clinically calculated [ROS]rx (mean percentage difference 0.6 ± 5.8%), while volume-averaged values differed by −6.0%, reflecting the enhanced spatial coverage of the 3D model relative to discrete sampling. The two-stage deformable registration improved CT-to-navigation surface alignment from HD95 = 4.08 mm to 1.78 mm (56.4% reduction) and MSD = 1.77 mm to 0.68 mm (61.5% reduction), enabling the first patient-specific mapping of [ROS]rx onto OAR structures. This study demonstrates the feasibility of a comprehensive 3D dosimetry system for pleural PDT. By integrating kinetic modeling with deformable registration, we provide a robust platform for evaluating treatment efficacy and ensuring OAR safety, paving the way for eventual integration into treatment planning and real-time feedback.

  PublisherDOI

• Optimizing excitation wavelength for enhanced singlet oxygen generation with benzoporphyrin derivatives in photodynamic therapy

  2026-03-05

  article

  Detection of singlet oxygen (¹O₂) generation during photodynamic therapy (PDT) remains a challenge, especially in vivo, due to the extremely weak signal and interference of background emissions. We developed a bifurcated, fiber-based system for time-resolved singlet oxygen luminescence (TSOLD) to detect ¹O₂in vivo. The system integrates a pulsed diode laser, a bifurcated fiber optic, a single-photon avalanche diode (SPAD), customized long and bandpass filters, and time-tagger electronics. The bifurcated system design facilitates the physical separation of detection and excitation channels, thereby minimizing crosstalk and enhancing the signal-to-noise ratio. This configuration allows for the simultaneous collection of both sub-surface and surface signals in small animal models. To ensure the validity of the system, we measured singlet oxygen with benzoporphyrin derivative (BPD) in ethanol with and without sodium azide. Further, we analyse the cumulative ¹O₂generation by BPD in liquid phantoms and C3H mice excited by a pulse diode laser at the following wavelengths: 405, 520, 640, and 690nm. Photon-counting measurements of ¹O₂luminescence at 1270nm reveal that after excitation with a 690nm pulsed laser, BPD can produce significantly higher signals of ¹O₂as compared to other wavelengths in liquid phantoms. In an in vivo study, the 690nm laser demonstrated a capacity to generate 2 to 3 times more singlet oxygen in C3H mice as compared to other excitation wavelengths. This enhanced ¹O₂production is attributable to superior tissue penetration and the effective absorption of benzoporphyrin derivative (BPD) at 690nm excitation wavelength. This bifurcated-fiber TSOLD system represents a significant advancement in ¹O₂detection technology, enabling real-time, minimally invasive monitoring during PDT. It supports preclinical assessments, optimizes PDT light delivery planning, and facilitates the clinical translation of ¹O₂based dosimetry.

  PublisherDOI

• Multispectral singlet oxygen luminescence dosimetry (MSOLD) for direct singlet oxygen monitoring during in-vivo benzoporphyrin derivative (BPD) mediated photodynamic therapy (PDT)

  2026-03-05

  articleSenior author
  PublisherDOI

• Integrated three-dimensional deformable image registration and reactive oxygen species modeling for pleural photodynamic therapy

  2026-03-05

  articleSenior author
  PublisherDOI

• Refining photochemical dose–response modeling in single-fraction Photofrin-PDT using [ROS]X and MSOLD correlation

  2026-03-05

  articleSenior author

  Photodynamic therapy (PDT) efficacy is governed by singlet oxygen generation, which depends on light delivery, photosensitizer concentration, and tissue oxygenation. Conventional fluence-based dosimetry does not explicitly account for these interacting factors and often exhibits variability in treatment response. In this study, we examine the relationship between modeled reacted singlet oxygen dose and long-term tumor control in a murine Photofrin-mediated PDT model under standardized illumination conditions. Tumors were treated using a 630nm continuous-wave laser at a fixed fluence rate of 150mW/cm², with total fluence varied by adjusting treatment time to produce four treatment groups (≈180–337J/cm²). Group-averaged reacted singlet oxygen dose ([ROS]ₓ) was estimated using the ROSED photochemical model incorporating measured photosensitizer concentration and tumor oxygenation. Local control rate (LCR) was assessed using Kaplan–Meier analysis. In a subset of animals, multispectral singlet oxygen luminescence detection (MSOLD) was performed to directly measure singlet oxygen emission during PDT. A monotonic increase in LCR was observed with increasing group-averaged [ROS]ₓ, while fluence alone showed greater variability. MSOLD measurements confirmed singlet oxygen generation across all treatment groups. Although instantaneous MSOLD signals exhibited substantial temporal variability, cumulative MSOLD signals increased approximately linearly with illumination time and showed group-dependent differences consistent with modeled photochemical dose. These results support the use of photochemical dose metrics incorporating physiological parameters as a more biologically relevant descriptor of PDT response than fluence alone and establish a refined single-fraction baseline for future PDT dosimetry studies.

  PublisherDOI

• Light dosimetry on biological tissue

  2026-03-05

  article1st authorCorresponding

  Light dosimetry is essential for Photobiomodulation (PBM). This review highlights key aspects of light dosimetry, such as fundamental quantities, the instrumentation used, tissue optical properties, and their influence on light distribution within turbid media.

  PublisherDOI

• Monte Carlo analysis of light fluence rate distribution in pleural photodynamic therapy: a study of geometric and optical property effects on treatment delivery

  Journal of Biomedical Optics · 2026-01-05 · 1 citations

  articleOpen accessSenior authorCorresponding

  SignificancePleural photodynamic therapy (PDT) faces significant dosimetry challenges due to complex light distribution patterns within the pleural cavity, where integrating sphere effects dominate light propagation. Accurate prediction of light fluence rate distributions is essential for optimizing treatment protocols and improving therapeutic outcomes in this emerging clinical application.AimThe aim is to quantitatively analyze light fluence rate distributions in pleural PDT using Monte Carlo (MC) simulations in various cavity geometries and tissue optical properties, providing essential data for treatment planning.ApproachGraphics processing unit-accelerated MC simulations (108 photons) using MCmatlab analyzed light distribution in spherical cavities (radii 0.2 to 10 cm) and anatomically realistic lung cavity models (volume = 2 L) with point sources. Simulations include a range of tissue optical properties (μa: 0.1 to 1.0 cm−1; μs′: 5 to 40 cm−1) for a flat-cut fiber source inside a realistic three-dimensional (3D) lung geometry, including realistic thoracotomy access openings and different fill media (air versus saline). Experimental validation is made using isotropic detectors in the same 3D-printed lung phantom with varying optical properties.ResultsMC statistical uncertainties averaged 1.9% across all voxels. Spherical cavities (r=4 cm) demonstrated highly uniform scattered light distribution along cavity–tissue boundaries (distribution uniformity 4.9%), whereas anatomically realistic lung phantoms showed greater heterogeneity (49.9%). Scattered light fluence rate per source power (ϕs/S) strongly correlated with tissue optical properties, particularly scattering coefficients. Source position minimally affected scattered light patterns, though direct components remained position-dependent. Side openings reduced scatter fluence near access points, with saline-filled cavities showing slightly higher fluence rates than air-filled cavities.ConclusionsWe demonstrate that patient-specific factors including cavity geometry, tissue optical properties, and surgical access considerations significantly influence light distribution in pleural PDT. The quantitative relationships established between these parameters and fluence patterns provide essential data for developing personalized treatment planning protocols to optimize therapeutic light delivery.

  PublisherOA PDFDOI

• In Vivo Assessment of Benzoporphyrin Uptake and Singlet Oxygen Generation in Mice for Photodynamic Therapy Monitoring

  ACS Photonics · 2026-01-08 · 1 citations

  articleOpen access

  The efficacy of photodynamic therapy (PDT) is strongly influenced by the biodistribution of the photosensitizer and the local generation of 1O2 within tumor tissue. However, real-time in vivo monitoring of these critical parameters for clinically approved photosensitizers remain a major challenge in translational photodynamic research. We report a novel portable bifurcated fiber-coupled time-resolved singlet oxygen luminescence detection instrument combining an integrating pulsed 690 nm diode laser system. Using this instrument, 1O2 signal is estimated corresponding to the uptake kinetics of the clinical photosensitizer benzoporphyrin derivative (BPD) in tumor-bearing mice up to 3 h post injection along with pre- and post-PDT 1O2 luminescence were measured in the same mice. The measured 1O2 counts correlate with the increase in BPD accumulation in the tumor region from 15 min to 2 h post injection and then remain constant in the 2–3 h measurement period. A strong positive correlation was observed between local BPD uptake and singlet oxygen signal. The estimated lifetime of 1O2 in vivo was 0.25–0.35 μs. The TSOLD system provided consistent, noninvasive readouts of 1O2 generation in real time with minimal background interference. Control experiments using BPD-free conditions confirmed the specificity of the detected signal. This study demonstrates a novel, noninvasive optical approach for simultaneous murine in vivo quantification of photosensitizer uptake and singlet oxygen production during PDT. This portable TSOLD instrument enables dynamic monitoring of therapeutic conditions in preclinical cancer models and has potential for future adaptation to clinical settings, supporting more precise and personalized PDT planning and dosimetry.

  PublisherDOI

• Monte Carlo simulation of light propagation in oral tissues for photobiomodulation therapy

  2026-03-05

  articleSenior author

  Photobiomodulation (PBM) has emerged as a non-invasive approach for managing oral conditions such as oral mucositis, periodontal disease, and post-surgical wound healing. Despite encouraging clinical outcomes, no consensus exists regarding optimal PBM treatment protocols, particularly with respect to laser wavelength, power, and exposure time. A key barrier is the limited understanding of how light propagates through the heterogeneous and complex structures of the oral cavity. We utilize Monte Carlo (MC) simulations to model light propagation in oral tissues to better understand PBM dose distribution for dental and oral disease applications. Monte Carlo simulations were performed using both a simplified cubic geometry and a human head phantom. Our results demonstrate a significant angular dependence for 810nm light transport. Furthermore, the limited penetration depth—restricted to only a few millimeters of cortical tissue—suggests that transdermal delivery is insufficient for targeting the intraoral cavity, necessitating an internal light source for effective treatment. The results provide mechanistic insights into how light scattering and absorption govern therapeutic dose delivery in the oral cavity. These findings will contribute to the rational design of PBM protocols for oral diseases, supporting the establishment of standardized, evidence-based treatment parameters. Ultimately, this work aims to bridge the gap between clinical practice and biophysical modeling, enabling safer and more effective PBM therapy in dentistry.

  PublisherDOI

Recent grants

• Real-Time PDT Dosimetry with Feedback Light Delivery

  NIH · $1.2M · 2005–2010

• Optimizing singlet oxygen dosimetry for photodynamic therapy (PDT)

  NIH · $2.4M · 2022–2027

• NIH Grant P01CA087971

  NIH · $28.4M · 2022

• In situ PEDSy and light delivery platform for Intracavitory Photodynamic Therapy

  NIH · $2.2M · 2020–2025

• Development of Novel Fast GPU Monte Carlo and Active Photonics Simulation Software for Predicting PDT Efficacy

  NIH · $1.5M · 2014–2019

Frequent coauthors

• Volker Budach

  124 shared

• Jarod C. Finlay

  107 shared

• Theresa M. Busch

  81 shared

• Andreea Dimofte

  California University of Pennsylvania

  80 shared

• David E. Wazer

  68 shared

• Michele M. Kim

  University of Pennsylvania

  67 shared

• Tony S. Quang

  Tibor Rubin VA Medical Center

  66 shared

• Anthony E. Dragun

  62 shared

Education

• Postdoctoral fellow, Radiation Medicine

  Brown University

  1994

• PhD, Physics

  Brown University

  1991