Michael Seungju Yu portrait
  • Adjunct Professor, Molecular Pharmaceutics
  • Professor, Biomedical Engineering
801-587-1264

Publications

  • Xiaojing Li (2023). The Chemistry and Biology of Collagen Hybridization. Journal of the American Chemical Society. Published, 05/09/2023.
  • Nithya Subrahmanyam (2023). Targeting Intratibial Osteosarcoma Using Water-Soluble Copolymers Conjugated to Collagen Hybridizing Peptides. Molecular Pharmaceutics. Published, 02/01/2023.
  • Allen H Lin (2023). Collagen fibrils from both positional and energy-storing tendons exhibit increased amounts of denatured collagen when stretched beyond the yield point. Acta Biomaterialia. Published, 01/01/2023.
  • Nithya Subrahmanyam (2023). HPMA copolymer-collagen hybridizing peptide conjugates targeted to breast tumor extracellular matrix. Journal of Controlled Release. Published, 01/01/2023.
  • KA Smith & AH Lin, AH Stevens, SM Yu, JA Weiss, LH Timmins (2022). Collagen Molecular Damage is a Hallmark of Early Atherosclerosis Development. J. Cardiovasc. Trans. Res. Accepted, 06/17/2022.
  • Y Qi & D. Zhou, JL Kessler, R Qui, SM Yu, G Li, Z Qui, Y. Li (2022). Terminal repeats impact collagen triple-helix stability through hydrogen bonding. Chemical Science. Accepted, 06/15/2022.
  • JL Kessler & G Kang, Z Qin, H Kang, F Whitby, T Cheatham, C Hill, Y Li, and SM Yu (2021). Peptoid residues make diverse hyperstable collagen triple helices. J. Am. Chem. Soc. 10910-10919. Published, 10/01/2021.
  • AG Lin & AN Allan, JL Zitnay, JL Kessler, SM Yu, and JA Weiss (2020). Collagen denaturation is initiated upon tissue yield in both positional and energy-storing tendons. Acta Biomaterialia. Vol. 118, 153. Published, 10/06/2020.
  • JL Zitnay & G Jung, A Lin, Z Qin, SM Yu, MJ Buehler, JA Weiss (2020). Accumulation of Collagen Molecular Unfolding is the Mechanism of Tendon Fatigue Damage and Failure. Science Advances. Vol. 6, eaba2795. Published, 08/15/2020.
  • H. Wahyudi & B.H. San, and S.M. Yu (2020). Targeting disease-related proteins via secondary protein structure-formation. World Scientific Publishing. Published, 08/01/2020.
  • Keith J Arlotta, Boi Hoa San, Hong-Hua Mu, S Michael Yu & Shawn C Owen (2020). Localization of Therapeutic Fab-CHP Conjugates to Sites of Denatured Collagen for the Treatment of Rheumatoid Arthritis. Bioconjugate Chemistry. Vol. 31, 1960-1970. Published, 07/01/2020.
  • Julian L Kessler, Yang Li, Jaime Fornetti, Alana L Welm & S Michael Yu (2020). Enrichment of Collagen Fragments Using Dimeric Collagen Hybridizing Peptide for Urinary Collagenomics. Journal of proteome research. Vol. 19, 2926-2932. Published, 06/05/2020.
  • Yang Li & S. Michael Yu (2019). In Situ Detection of Degraded and Denatured Collagen via Triple Helical Hybridization: New Tool in Histopathology. (pp. 135-144). Humana Press, New York, NY. Published, 07/01/2019.
  • Feinberg TY, Zheng H, Liu R, Wicha MS, Yu SM & Weiss SJ (2018). Divergent Matrix-Remodeling Strategies Distinguish Developmental from Neoplastic Mammary Epithelial Cell Invasion Programs. Developmental cell. Vol. 47, 145-160.e6. Published, 12/01/2018.
  • Allen H. Lin & Jared L. Zitnay, Yang Li, S. Michael Yu, and Jefferey A. Weiss (2018). Microplate Assay for Denatured Collagen using Collagen Hybridizing Peptides. Journal of Orthopedic Research. Vol. 37, 431-438. Published, 11/26/2018.
  • Lucas Bennink & B. J. Kim, B. H. San, I. Shin, D. Yoon, Y. Li and S. M. Yu (2018). Visualizing collagen proteolysis by peptide hybridization: from 3D cell culture to in vivo imaging. Biomaterials. Vol. 183, 67-76. Published, 11/01/2018.
  • S. Michael Yu (2018). Probing Collagen Degradation. Biomaterials. Accepted, 10/01/2018.
  • Hwang J, San BH, Turner NJ, White LJ, Faulk DM, Badylak SF, Li Y & Yu SM (2018). Molecular assessment of collagen denaturation in decellularized tissues using a collagen hybridizing peptide. Acta biomaterialia. Vol. 53, 268-278. Published, 02/01/2018.
  • Converse MI, Walther RG, Ingram JT, Li Y, Yu SM & Monson KL (2018). Detection and characterization of molecular-level collagen damage in overstretched cerebral arteries. Acta biomaterialia. Vol. 67, 307-318. Published, 02/01/2018.
  • San BH, Hwang J, Sampath S, Li Y, Bennink LL & Yu SM (2018). Self-Assembled Water-Soluble Nanofibers Displaying Collagen Hybridizing Peptides. Journal of the American Chemical Society. Vol. 139, 16640-16649. Published, 01/01/2018.
  • Hwang J, Huang Y, Burwell TJ, Peterson NC, Connor J, Weiss SJ, Yu SM & Li Y (2018). In Situ Imaging of Tissue Remodeling with Collagen Hybridizing Peptides. ACS nano. Vol. 11, 9825-9835. Published, 01/01/2018.
  • Bennink LL, Smith DJ, Foss CA, Pomper MG, Li Y & Yu SM (2017). High Serum Stability of Collagen Hybridizing Peptides and Their Fluorophore Conjugates. Molecular pharmaceutics. Vol. 14, 1906-1915. Published, 09/01/2017.
  • Hendra Wahyudi, Amanda A. Reynold, and S. Michael Yu (2016) “Collagen Targeting for Diagnostic Imaging and Therapy” Journal of Controlled Release, 240, 3231. Published, 03/2016.
  • Boi-Hoa San, Yang Li, and S. Michael Yu (2016) “Nanoparticle assembly and gelatin binding mediated by triple helical collagen mimetic peptide” ACS Applied Materials and Interfaces, 8, 19907-15. Published, 03/2016.
  • Chan TR, Stahl PJ, Li Y, and Yu SM (2015) "Collagen-gelatin mixtures as wound model, and substrates for VEGF-mimetic peptide binding and endothelial cell activation" Acta Biomaterialia 15, 164-172. Published, 05/31/2015.
  • Li Y, San BH, Kessler JL, Kim JH, Xu Q, Hanes J, and Yu SM (2015) "Non-covalent photo-patterning of gelatin matrices using caged collagen mimetic peptides" Macromolecular Bioscience 15, 52-62. Published, 03/31/2015.
  • Santos JL, Li Y, Culver HS, Luo H, Yu SM, and Herrera-Alonso M (2014) "Conducting polymer nanoparticles decorated with collagen mimetic peptides for collagen targeting" Chem. Commun. 50, 15045-15048. Published, 11/30/2014.
  • K. Ren, J. E. West, and S. M. Yu, (2014) Planar microphone based on piezoelectric electrospun poly(γ-benzyl-a,L-glutamate) nanofibers. J. Acoust. Soc. Am. 135 (6), EL291. Published, 07/01/2014.
  • P. J. Stahl, T. R. Chan, Y.-I. Shen, G. Sun, S. Gerecht, and S. M. Yu, (2014) Capillary Network-Like Organization of Endothelial Cells in PEGDA Scaffolds Encoded with Angiogenic Signals via Triple Helical Hybridization. Adv. Funct. Mater. 24, 3213–3225. Published, 03/01/2014.
    http://onlinelibrary.wiley.com/doi/10.1002/adfm.20...
  • Y. Li, C. A. Foss, M. G. Pomper, and S. M. Yu (2014) Imaging denatured collagen strands in vivo and ex vivo via photo-triggered hybridization of caged collagen mimetic peptides. J. Vis. Exp. (83), e51052.. Published, 03/01/2014.
    http://www.jove.com/video/51052/imaging-denatured-...
  • "Targeting and mimicking collagens via triple helical peptide assembly," Curr. Opin. Chem. Biol.,17, 1. Published, 12/2013.
    http://www.sciencedirect.com/science/article/pii/S...
  • "Direct detection of collagenous proteins by fluorescently labeled collagen mimetic peptides," Bioconj. Chem. 24, 9. Published, 05/2013.
    http://pubs.acs.org/doi/abs/10.1021/bc3005842

Research Statement

Collagen hybridizing peptide for tissue scaffolds and disease targeting

Collagen as tissue engineering scaffolds: Since the inception of the collagen project, one of our main interests was in spatio-temporal functionalization of collagen for the purpose of engineering structurally organized tissue substitutes. Our earlier work demonstrated that triple helix, the hallmark structural feature seen nearly exclusively in collagen, provides a unique way of functionalizing natural collagens1.

 We discovered that a small collagen mimetic peptide (CMP) of simple (GlyProHyp)X sequence (Hyp: hydroxyproline) with a strong propensity to form triple helix can recognize natural collagen and hybridize to the unstable domains of collagen strands by forming triple helix in a manner similar to primers binding to melted DNA strands during PCR2,3. The binding was observed only when melted single stranded CMP and not folded triple helical CMP was allowed interact with collagen. We studied the binding interaction using pure CMPs, CMP conjugated to nanoparticles4, templated model peptides5, and even model PEG-CMP hydrogels6-8 which provided understanding of the hybridization mechanism in detail. We have developed various CMP derivatives that can be used to functionalize regenerated collagen matrix and control cellular behaviors. PEG-CMP can reduce the cell adhesiveness of collagen substrates,3 and anionically charged CMP can bind to collagen matrix and signal endothelial cells by attracting VEGF within a 3D collagen gel9. Pro-angiogenic peptide was conjugated to the CMP resulting in a new peptide that mimics matrix bound form of VEGF which is considered to be a main challenge in engineering artificial tissues with long-term viability10. Using this peptide, we were able to control areas of peptide immobilization and induce cell morphogenesis in pre-defined areas within wider cell culture. The ability to encode spatially defined morphogenic signals in natural scaffolds is expected to provide new pathways for engineering complex tissues for regenerative medicine. 

Targeting denatured collagens using collagen hybridizing peptide: During the investigation of collagen binding affinity of CMP, we discovered that the CMP binds to denatured collagen strands at orders of magnitude higher level than the fully folded native collagen. This is why supplementing the collagen with gelatin (denatured collagen) increased the loading level and cellular activity of bioactive CMPs11. To our surprise, in contrast to regenerated collagen molecules used in experiments above, CMPs did not bind to collagens in native ex vivo tissues but did so only when the tissue was denatured by heat. This led us to an entirely new research direction (which is currently the major research topic in my lab) that explores collagen mimetic peptide as a molecular probe that specifically targets denatured collagen. We started to use the term collagen hybridizing peptide (CHP) in place of CMP since the peptide no longer mimicked collagen but were used to hybridize to collagen strands via folding into triple helix. In fact, much of our recent efforts have been devoted to developing peptides that do not fold into homo-trimeric triple helix, but able to hybridize to collagen strands. 

As the mostbundant protein in mammals, collagens play a crucial role in tissue development and regeneration, and their structural or metabolic abnormalities are associated with debilitating genetic diseases and various pathologic conditions. Although collagen remodeling occurs during development and normal tissue maintenance, particularly for renewing tissues (e.g. bones), excess remodeling activity is commonly seen in tumors, arthritis, fibrosis, and many other chronic wounds. During collagen remodeling, large portions of collagens are degraded and denatured by proteolytic enzymes (e.g. MMPs) which can be explored for diagnostic and therapeutic purpose. Since denatured collagens (i.e. gelatin) are unstructured and are not ideal targets for rational drug design, library approaches have been employed to develop monoclonal antibody12,13 and peptide probes14that specifically bind to cryptic sites in collagen strands that become exposed when denatured. However, these pro  bes suffer from poor pharmacokinetics 15, and/or low specificity and binding affinity16. We thought that the CHP’s remarkable capacity to hybridize to denatured collagen could be applied to targeting degraded collagens in pathologic tissues.  We developed various strategies to produce single strand CHPs (via heating conventional CHP or photo-triggered activation of caged CHP), and tested their affinity and specificity for denatured collagen from purified collagen and in vitro collagen gels to collagens in animal and human tissue under ex vivo and in vivo conditions. The results confirmed that CHPs can detect denatured collagen associated disease (cancer, osteoarthritis, fibrosis, and others) in histological section17, as well as pericellular collagens digested by invading tumor cells in 3D cell culture (Fig. 2A-C). Most importantly, we learned that CHP has high serum stability18, and when conjugated with near infrared fluorophore and injected in vivo (via tail vein injection), the peptide can highlight areas of high collagen remodeling activity associated with disease. (e.g. high bone remodeling activity of marfan mouse) (Fig. 2D)19. CHP can also be used to gauge the level of matrix denaturation during decellularization of biological scaffolds20. The remarkable success of our work is mainly due to the unique binding process; unlike conventional epitope binding, CHP binds by folding into super-secondary protein structure, made possible by a simple peptide sequence based on GlyHypGly triplet which is non-charged and hydrophilic, and is without any hydrophobic residues. For this reason, CHP has extremely low non-specific affinity and exhibits excellent serum stability ideal for theranostic applications. We are in the process of developing therapeutic molecules which can be delivered to pathologic tissue by CHP mediated binding such as Cathepsin K-CHP conjugates (for osteoporosis) and Fab-CHP conjugates (for rheumatoid arthritis). We are also working on radio-labeled CHPs as diagnostic probes.

Targeting collagens denatured by mechanical damage in load bearing tissues: This has been the most exciting research after moving to the U of U. In collaboration with Jeffrey Weiss at the U of U, we demonstrated that the CHPs is able to detect collagen denatured by not only protease activity but also by mechanical damage21. We used fluorescent CHP to detect damage due to collagen unfolding during subfailure loading for a series of mechanically stretched rat tail tendon fascicles (ex vivo). We demonstrated that the triple helix-mediated hybridization process effectively reports the location and level of molecular damage of the collagens in tendon, which provided ground-breaking insights into the mechanism of mechanical damage to fibrous collagens in load bearing tissues (Fig. 3). This work was expanded to include computational work21 as well as mechanical damage to blood vessels of cerebral arteries22.  Our work elucidated a probable molecular failure mechanism associated with mechanical injuries, and demonstrated the potential of CHP targeting for diagnosis, treatment and monitoring of tissue disease and injury that are associated with mechanical stress. The new NIH R01 which was recently awarded aims to i) develop next generation CHP ideal for this work (hybridization activated fluorescence), and ii) to further understand the mechanism of collagen damage from molecules to fibrils in load bearing tissues including as cartilage.

Research Keywords

  • Medical imaging
  • Histology
  • Fibrosis
  • Extracellular Matrix
  • Drug Delivery Systems
  • Collagen Hybridizing Peptide
  • Collagen

Presentations

  • Gordon Research Conference, Triple Helical Peptoids: from Collagen Mimetics to Collagen Hybridization” . Invited Talk/Keynote, Presented, 01/18/2023.
  • Gordon Research Conference, Collagen Hybridizing Peptides and Peptoids: From Protein Folding To Disease Targeting. Invited Talk/Keynote, Presented, 10/01/2022.
  • Collagen Hybridizing Peptides And Peptoids: From Protein Folding To Disease Targeting, Keynote speaker, Peptoid Summit, UC Berkeley. Invited Talk/Keynote, Accepted, 08/15/2022.
  • Foldamer Workshop, New York University, NY, “Collagen Biology and New Opportunities for Foldamers” . Invited Talk/Keynote, Presented, 07/28/2022.
  • Triple Helical Peptoids: from Collagen Mimetics to Collagen Hybridization” Gordon Research Conference, Peptide Materials, Galveston TX. Invited Talk/Keynote, Accepted, 06/01/2022.
  • Collagen Biology and New Opportunities for Foldamers” Foldamer Workshop, New York University. Invited Talk/Keynote, Accepted, 03/10/2022.
  • Collagen hybridizing peptides and peptoids: from protein folding to nano-assembly and disease targeting, UC Merceds. Invited Talk/Keynote, Accepted, 02/11/2022.
  • Collagen Hybridizing Peptides And Peptoids: From Protein Folding To Disease Targeting” Gordon Research Conference, Chemistry and Biology of Peptides, Ventura CA. Invited Talk/Keynote, Accepted, 01/25/2022.
  • Targeting Damaged Collagens for Diagnostics, Therapeutics, and Regenerative Medicine, Annual Bioscience Symposium, University of Utah. Invited Talk/Keynote, Presented, 09/14/2021.
  • From Research to Startups: Your Roles as PI, Post-Doc, and Graduate Student KSEA-Utah, University of Utah, Salt Lake City,. Invited Talk/Keynote, Presented, 04/01/2021.
  • Collagen: The Myth, Science, and Biotechnology Seoul Forum, Seoul, Korea. This is a global forum organized by one of the major economic newspapers, Seoul Economic Daily, for general public on science technology related to Korean and World economy. Invited Talk/Keynote, Presented, 07/02/2020.
    https://www.youtube.com/watch?v=NclSsxhu63A&t=6s
  • Collagen Hybridizing Peptide: New Molecular Probe for In Vitro and In Vivo Detection of Collagen Fragments, Gordon Research Conference, Metalloproteases. Invited Talk/Keynote, Presented, 05/13/2019.
  • Next Generation Collagen Hybridizing Peptides, American Chemical Society National Meeting, Orlando FL. Invited Talk/Keynote, Presented, 03/01/2019.
  • Tareting Collagen Remodeling Activity by Peptide Hybridization: Prospects for New Diagnostics and Therapeutics Huntsman Cancer Institute, CRR meeting. Invited Talk/Keynote, Presented, 10/22/2018.
  • Collagen Hybridizing Peptide: New Molecular Probe for In Vitro and In Vivo Detection of Degraded and Denatured Collagen American Society of Matrix Biology. Invited Talk/Keynote, Presented, 10/14/2018.
  • In Situ Detection of Degraded Collagen via Triple Helical Hybridization: From Histology to In Vivo Imaging Korean Academy of Science and Technology, Workshop. Invited Talk/Keynote, Presented, 06/19/2018.
  • Targeting Collagen Remodeling Activity by Triple Helical Peptide Hybridization: Prospects for New Diagnostics and Therapeutics” School of Pharmacy, University of Utah, Salt Lake City, March 2016. Invited Talk/Keynote, Presented, 03/2016.
  • Collagen Hybridizing Peptide: Self-Assembly and Denatured Collagen Targeting World Biomaterials Congress, Montreal Canada, 2016. Invited Talk/Keynote, Presented, 03/2016.
  • “Collagen Hybridizing Peptide: Self-Assembly and Denatured Collagen Targeting” Materials Research Society, Phoenix, AZ, March 2016. Invited Talk/Keynote, Presented, 03/2016.
  • “Targeting Collagen Strands by Peptide Hybridization: from Histology to Tissue Engineering and Theranostics” Department of Biomedical Engineering, Hanyang University, Seoul, Korea, November 2015. Invited Talk/Keynote, Presented, 11/2015.
  • “Targeting Collagens Strand by Triple Helical Hybridization” University of Utah, Department of Biochemistry, Salt Lake City, UT. Invited Talk/Keynote, Presented, 01/08/2015.
  • “Targeting Collagens Strand by Triple Helical Hybridization” Materials Research Society Meeting, Boston, MA. Other, Presented, 12/01/2014.
  • “Targeting Collagens Strand by Triple Helical Hybridization” US-Korea Conference, San Francisco, CA. Invited Talk/Keynote, Presented, 08/08/2014.
  • “Targeting Collagens Strand by Triple Helical Hybridization” KIST, Seoul, Korea. Invited Talk/Keynote, Presented, 07/01/2014.
  • "Helical Proteins for Materials Application: from piezoelectric nanofibers to collagen hybridization” SPE ANTEC, Las Vegas, NV. Invited Talk/Keynote, Presented, 04/29/2014.
  • "Targeting Collagens Strand by Triple Helical Hybridization” American Chemical Society National Meeting, Dallas, TX. Invited Talk/Keynote, Presented, 03/20/2014.
  • “Targeting Collagens Strand by Triple Helical Hybridization,” University of Utah, Department of Bioengineering, Salt Lake City UT. Invited Talk/Keynote, Presented, 04/2013.
  • “Targeting Collagens Strand by Triple Helical Hybridization,” SUNY at Buffalo, Department of Biomedical Engineering, Buffalo NY. Invited Talk/Keynote, Presented, 03/2013.
  • “Targeting Collagens Strand by Triple Helical Hybridization,” University of Connecticut, Department of Biomedical Engineering, Storrs CT. Invited Talk/Keynote, Presented, 02/2013.
  • "Targeting Collagens Strand by Triple Helical Hybridization." University of Delaware, Department of Biomedical Engineering, Newark DE. Invited Talk/Keynote, Presented, 01/2013.

Research Groups

  • Christopher Young, Graduate Student. BME. 01/10/2022 - present.
  • Tian Morrison, Graduate Student. BME. 01/10/2022 - present.
  • Erika Petty, Undergraduate Student. BME. 09/01/2021 - 05/01/2022.
  • Trang Duong, Postdoc. 06/07/2021 - 10/15/2021.
  • Evan Tang, Undergraduate Student. 09/01/2020 - 06/01/2021.
  • Isabelle Schlegel, Undergraduate Student. 06/01/2019 - 08/31/2021.
  • Tomas Mikulis, Undergraduate Student. 03/04/2019 - 06/15/2021.
  • Bum Jin Kim, Postdoc. 04/01/2015 - 03/30/2017.
  • Hendra Wahyudi, Postdoc. 03/01/2015 - 03/30/2017.
  • Cameron Leiser, Undergraduate Student. 12/15/2014 - 05/01/2015.
  • Amanda Reynolds, Graduate Student. Bioengineering. 08/20/2014 - 03/30/2018.
  • Jeong Min Hwang, Graduate Student. 04/15/2014 - 06/30/2017.
  • Jin-Hwan Kim, Undergraduate Student. Bioengineering. 12/2013 - 05/01/2016.
  • Soojeong Choi, Undergraduate Student. Bioengineering. 12/2013 - 03/30/2015.
  • Hoa San, Postdoc. Bioengineering. 10/2013 - 05/01/2018.
  • Julian Kessler, Graduate Student. Bioengineering. 09/2013 - present.
  • Yang Li, Postdoc. Bioengineering. 09/2013 - 06/30/2017.

Languages

  • Korean, fluent.

Geographical Regions of Interest

  • Republic of Korea