Tony Hong Wei Chang

All Publications

• Pf bacteriophages hinder sputum antibiotic diffusion via electrostatic binding. Science advances Chen, Q., Cai, P., Chang, T. H., Burgener, E., Kratochvil, M. J., Gupta, A., Hargill, A., Secor, P. R., Nielsen, J. E., Barron, A. E., Milla, C., Heilshorn, S. C., Spakowitz, A., Bollyky, P. L. 2024; 10 (22): eadl5576

  Abstract

  Despite great progress in the field, chronic Pseudomonas aeruginosa (Pa) infections remain a major cause of mortality in patients with cystic fibrosis (pwCF), necessitating treatment with antibiotics. Pf is a filamentous bacteriophage produced by Pa and acts as a structural element in Pa biofilms. Pf presence has been associated with antibiotic resistance and poor outcomes in pwCF, although the underlying mechanisms are unclear. We have investigated how Pf and sputum biopolymers impede antibiotic diffusion using pwCF sputum and fluorescent recovery after photobleaching. We demonstrate that tobramycin interacts with Pf and sputum polymers through electrostatic interactions. We also developed a set of mathematical models to analyze the complex observations. Our analysis suggests that Pf in sputum reduces the diffusion of charged antibiotics due to a greater binding constant associated with organized liquid crystalline structures formed between Pf and sputum polymers. This study provides insights into antibiotic tolerance mechanisms in chronic Pa infections and may offer potential strategies for novel therapeutic approaches.

  View details for DOI 10.1126/sciadv.adl5576

  View details for PubMedID 38820163

  View details for PubMedCentralID PMC11141622

• Hydrogels for Local and Sustained Delivery of Bacteriophages to Treat Multidrug-Resistant Wound Infections. bioRxiv : the preprint server for biology Lin, Y. H., Dharmaraj, T., Chen, Q., Echterhof, A., Manasherob, R., Zheng, L. J., de Leeuw, C., Peterson, N. A., Stannard, W., Li, Z., Hajfathalian, M., Hargil, A., Martinez, H. A., Chang, T. H., Blankenberg, F. B., Amanatullah, D., Chaudhuri, O., Bollyky, P. 2024

  Abstract

  Bacteriophages (phages), viruses that specifically target and kill bacteria, represent a promising strategy to combat multidrug-resistant (MDR) pathogens such as Pseudomonas aeruginosa (Pa). However, delivering sufficient concentrations of active phages directly to the infection site remains challenging, with current methods having variable success. Here we present "HydroPhage", an innovative hydrogel system for the sustained release of high-titer phages to effectively treat infections caused by MDR pathogens. Our injectable hydrogels, featuring dual-crosslinking of hyaluronic acid and PEG-based hydrogels through static covalent thioether bonds and dynamic covalent hemithioacetal crosslinks (DCC), encapsulate phages at concentration up to 1011 PFU/mL, and achieves controlled release of 109 PFU daily over a week, surpassing levels of current clinical dosages, with more than 60% total phage recovery. In a preclinical mouse model of extended wound infection, compared to intravenous treatment, we demonstrate enhanced bacterial clearance by localized, high-dose, and repeated phage dosing despite the emergence of bacterial resistance to phages. This work advances the development of clinically practical wound dressings tailored for resistant infections.

  View details for DOI 10.1101/2024.05.07.593005

  View details for PubMedID 38766200

  View details for PubMedCentralID PMC11100690

• Pf bacteriophages hinder sputum antibiotic diffusion via electrostatic binding. bioRxiv : the preprint server for biology Chen, Q., Cai, P., Chang, T. H., Burgener, E., Kratochvil, M. J., Gupta, A., Hargil, A., Secor, P. R., Nielsen, J. E., Barron, A. E., Milla, C., Heilshorn, S. C., Spakowitz, A., Bollyky, P. L. 2024

  Abstract

  Despite great progress in the field, chronic Pseudomonas aeruginosa (Pa) infections remain a major cause of morbidity and mortality in patients with cystic fibrosis, necessitating treatment with inhaled antibiotics. Pf phage is a filamentous bacteriophage produced by Pa that has been reported to act as a structural element in Pa biofilms. Pf presence has been associated with resistance to antibiotics and poor outcomes in cystic fibrosis, though the underlying mechanisms are unclear. Here, we have investigated how Pf phages and sputum biopolymers impede antibiotic diffusion using human sputum samples and fluorescent recovery after photobleaching. We demonstrate that tobramycin interacts with Pf phages and sputum polymers through electrostatic interactions. We also developed a set of mathematical models to analyze the complex observations. Our analysis suggests that Pf phages in sputum reduce the diffusion of charged antibiotics due to a greater binding constant associated with organized liquid crystalline structures formed between Pf phages and sputum polymers. This study provides insights into antibiotic tolerance mechanisms in chronic Pa infections and may offer potential strategies for novel therapeutic approaches.

  View details for DOI 10.1101/2024.03.10.584330

  View details for PubMedID 38496625

• Rapid assessment of changes in phage bioactivity using dynamic light scattering. PNAS nexus Dharmaraj, T., Kratochvil, M. J., Pourtois, J. D., Chen, Q., Hajfathalian, M., Hargil, A., Lin, Y. H., Evans, Z., Oromí-Bosch, A., Berry, J. D., McBride, R., Haddock, N. L., Holman, D. R., van Belleghem, J. D., Chang, T. H., Barr, J. J., Lavigne, R., Heilshorn, S. C., Blankenberg, F. G., Bollyky, P. L. 2023; 2 (12): pgad406

  Abstract

  Extensive efforts are underway to develop bacteriophages as therapies against antibiotic-resistant bacteria. However, these efforts are confounded by the instability of phage preparations and a lack of suitable tools to assess active phage concentrations over time. In this study, we use dynamic light scattering (DLS) to measure changes in phage physical state in response to environmental factors and time, finding that phages tend to decay and form aggregates and that the degree of aggregation can be used to predict phage bioactivity. We then use DLS to optimize phage storage conditions for phages from human clinical trials, predict bioactivity in 50-y-old archival stocks, and evaluate phage samples for use in a phage therapy/wound infection model. We also provide a web application (Phage-Estimator of Lytic Function) to facilitate DLS studies of phages. We conclude that DLS provides a rapid, convenient, and nondestructive tool for quality control of phage preparations in academic and commercial settings.

  View details for DOI 10.1093/pnasnexus/pgad406

  View details for PubMedID 38111822

  View details for PubMedCentralID PMC10726995

• Rapid assessment of changes in phage bioactivity using dynamic light scattering. bioRxiv : the preprint server for biology Dharmaraj, T., Kratochvil, M. J., Pourtois, J. D., Chen, Q., Hajfathalian, M., Hargil, A., Lin, Y. H., Evans, Z., Oromí-Bosch, A., Berry, J. D., McBride, R., Haddock, N. L., Holman, D. R., van Belleghem, J. D., Chang, T. H., Barr, J. J., Lavigne, R., Heilshorn, S. C., Blankenberg, F. G., Bollyky, P. L. 2023

  Abstract

  Extensive efforts are underway to develop bacteriophages as therapies against antibiotic-resistant bacteria. However, these efforts are confounded by the instability of phage preparations and a lack of suitable tools to assess active phage concentrations over time. Here, we use Dynamic Light Scattering (DLS) to measure changes in phage physical state in response to environmental factors and time, finding that phages tend to decay and form aggregates and that the degree of aggregation can be used to predict phage bioactivity. We then use DLS to optimize phage storage conditions for phages from human clinical trials, predict bioactivity in 50-year-old archival stocks, and evaluate phage samples for use in a phage therapy/wound infection model. We also provide a web-application (Phage-ELF) to facilitate DLS studies of phages. We conclude that DLS provides a rapid, convenient, and non-destructive tool for quality control of phage preparations in academic and commercial settings.

  View details for DOI 10.1101/2023.07.02.547396

  View details for PubMedID 37425882

  View details for PubMedCentralID PMC10327207

• The Environmental Impact of Orthopaedic Surgery. The Journal of bone and joint surgery. American volume Saleh, J. R., Mitchell, A., Kha, S. T., Outterson, R., Choi, A., Allen, L., Chang, T., Ladd, A. L., Goodman, S. B., Fox, P., Chou, L. 2022

  Abstract

  ➤: There are a growing number of opportunities within the field of orthopaedic surgery to address climate change and investigate ways to promote sustainability.➤: Orthopaedic surgeons can take a proactive role in addressing climate change and its impacts within the areas of operating-room waste, carbon emissions from transportation and implant manufacturing, anesthetic gases, and water usage.➤: Future studies are needed to further these initiatives on quantifying and decreasing environmental impact and furthering sustainable use of our resources.

  View details for DOI 10.2106/JBJS.22.00548

  View details for PubMedID 36574633