Research

I. Cardiovascular tissue regeneration through engineered ECM-based scaffolds: The extracellular matrix (ECM) serves as a critical scaffold and signaling cue for tissue regeneration. To elucidate the role of ECM in this process, we have pioneered the application of defined, ECM-mimicking biomaterials in conjunction with advanced manufacturing technologies, including Design of Experiments and 3D bioprinting, to accelerate tissue regeneration. Our studies have demonstrated that an optimized combination of ECM-derived polypeptides outperforms fibronectin-coated scaffold surfaces, and that a specific combination of ECM proteins significantly enhances the differentiation of induced pluripotent stem cells into cardiomyocytes capable of handling intracellular calcium transients, exhibiting spontaneous contraction, and expressing sarcomere/gap junction proteins. Furthermore, we have successfully identified ECM profiles from developing and postnatal murine hearts to fabricate 3D tissue scaffolds for myocardial repair without the need for synthetic biomaterials. We are currently harnessing advanced machine learning approaches to further optimize tissue regeneration using ECM proteins and engineered biomaterials.

Relevant publications:

1) Co-assembling Peptides as Defined Matrices for Endothelial Cells. JP Jung, AK Nagaraj, EK Fox, JS Rudra, JM Devgun, JH Collier. Biomaterials. 2009 Apr;30(12):2400-10. doi: 10.1016/j.biomaterials.2009.01.033.

2) Spatial and Temporal Analysis of Extracellular Matrix Proteins in the Developing Murine Heart: a Blueprint for Regeneration. KP Hanson, JP Jung, QA Tran, SP Hsu, R Iida, V Ajeti, PJ Campagnola, KW Eliceiri, JM Squirrell, GE Lyons, BM Ogle. Tissue Eng Part A. 2013 May;19(9-10):1132-43. doi: 10.1089/ten.TEA.2012.0316.

3) An Integrated Statistical Model for Enhanced Murine Cardiomyocyte Differentiation via Optimized Engagement of 3D Extracellular Matrices. JP Jung, D Hu, IJ Domian, BM Ogle. Sci Rep. 2015 Dec 21; 5:18795. doi: 10.1038/srep18705.

4) Myocardial Tissue Engineering with Cells Derived from Human Induced Pluripotent Stem Cells and a Native-like, High-resolution, 3-dimensionally Printed Scaffold. L Gao, ME Kupfer, JP Jung, L Yang, P Zhang, Y Da Sie, QA Tran, V Ajeti, BT FReeman, VG Fast, PJ Campagnola, BM Ogle, J Zhang. Circ Res. 2017 Jan 9 doi: 10.1161/CIRCRESAHA.116.310277

II. Engineering biomaterial platforms for accelerated tissue regeneration: Engineering biomaterial platforms plays a pivotal role in synergistically utilizing extracellular matrix (ECM) proteins and simultaneously instructing cells for enhanced tissue regeneration. We have developed a range of modular biomaterial platforms that can be employed with chemoselective chemistry or molecular self-assembly. Orthogonal, chemoselective native chemical ligation (NCL) enabled us to control the stiffness of endothelial cell scaffolds without compromising the presentation of cell-adhesive ligands to integrins. We leveraged a similar approach to incorporate multiple ECM proteins, facilitating the differentiation of mesenchymal stem cells into myogenic, osteogenic and adipogenic lineages without chemical induction. By mimicking ECM presentation at the dermoepidermal junction, we were able to identify the differential adhesive force of skin layers fabricated with Epidermolysis Bullosa (EB) patient-derived dermal fibroblasts and keratinocytes. We are currently refining chemoselective chemistry to engineer targeted scaffold properties while fully capitalizing on ECM functionality for enhanced tissue regeneration.

Relevant publications:

1) Modulating the Mechanical Properties of Self-assembled Peptide Hydrogels via Native Chemical Ligation. JP Jung, JL Jones, SA Cronier, JH Collier. Biomaterials. 2008 May;29(13):2143-51. doi: 10.1016/j.biomaterials.2008.01.008.

2) ECM-incorporated Hydrogels Cross-linked via Native Chemical Ligation to Engineer Stem Cell Microenvironments. JP Jung, AJ Sprangers, JR Byce, J Su, JM Squirrell, PB Messersmith, KW Eliceiri, BM Ogle. Biomacromolecules. 2013 Sep 9;14(9):3102-11. doi: 10.1021/bm400728e.

3) Heterogeneous Differentiation of Human Mesenchymal Stem Cells in 3D Extracellular Matrix Composites. JP Jung, MK Bache-Wiig, PP Provenzano, BM Ogle. Biores Open Access. 2016 Jan 29; 5:37-48. doi:10.1089/biores.2015.0044.

4) A 3D In Vitro Model of the Dermoepidermal Junction Amenable to Mechanical Testing. JP Jung*, WH Lin, MJ Riddle, J Tolar, BM Ogle. J Biomed Mater Res A. 2018 Jul 30 doi: 10.1002/jbm.a.36519

III. Machine learning-assisted design and analysis for tissue regeneration: Statistical modeling and data analysis provide valuable insights that complement experimental findings. While data mining is not the primary objective of these projects, we have employed RNA-sequencing and NMR-based metabolomics to gain a deeper understanding of cellular responses to our scaffold design and their impact on tissue regeneration. These rich datasets can be further harnessed through machine learning approaches. To this end, we have collaborated with a computer scientist to develop robust machine learning models for protein engineering and 3D bioprinting processes, aiming to enhance cardiomyocyte proliferation for cardiac repair. Specifically, a Gaussian Process-assisted method facilitates directed evolution of a specific ECM domain, while Bayesian Optimization is applied to 3D bioprinting of a cardiac fibrosis model in our lab.

Relevant publications:

1) Single-cell RNA-seq of Bone Marrow-derived Mesenchymal Stem Cells Reveals Unique Profiles of Lineage Priming. BT Freeman, JP Jung, BM Ogle. PLoS One. 2015 Sep 9; 10(9):e0136199. doi: 10.1371/journal.pone.0136199.

2) Single-cell RNA-seq Reveals Activation of Unique Gene Groups as a Consequence of Stem Cell-Parenchymal Cell Fusion. BT Freeman, JP Jung, BM Ogle. Sci Rep. 2016 Mar 21;6:23270. doi: 10.1038/srep23270.

3) Conserved Pathway Activation Following Xenogenic, Heterotypic Fusion. C Yuan, BT Freeman, TJ McArdle, JP Jung, BM Ogle. FASEB J 2019 Feb 26 doi.org/10.1096/fj.201801700R

4) Augmentation of Structure Information to the Sequence-Based Machine Learning-Assisted Directed Protein Evolution. LD Yutzy, KL Nguyen, PA Vallet, J Yu, R He, J Li, Le Yan, J Kim*, JP Jung* (*co-corresponding) (submitted), ChemRxiv|doi:10.26434/chemrxiv-2023-llpnk

IV. Lignin's untapped potential in biomedical applications: Despite its ability to modulate cellular responses, lignin remains underutilized in the biomedical field. Recognizing this untapped potential, our research group, with its expertise in engineering synthetic biomaterials, has delved into the development of lignin-incorporated scaffolds for wound healing and 3D printing applications. To mitigate oxidative damage to stromal cells while maintaining controlled oxygen release to tissue microenvironments, we have employed thiol-ene click chemistry, a chemoselective approach. This innovative strategy enables us to preserve lignin's native anti-oxidant properties while minimizing cytotoxicity and immunogenicity. We are currently designing multi-scale lignin-incorporated tissue scaffolds with the goal of accelerating wound healing.

Relevant publications:

1) Modulating Mechanical Properties of Collagen-Lignin Composites. JA Belgodere, SA Zamin, RM Kalinoski, CE Astete, JC Penrod, KM Hamel, BC Lynn, JS Rudra, J Shi*, Jung JP* (*co-corresponding) ACS Applied Bio Materials 2019 Jul 30 doi:10.1021/acsabm.9b00444

2) Attenuating Fibrotic Markers of Patient-Derived Dermal Fibroblasts by Thiolated Lignin Composites. JA Belgodere, D Son, B Jeon, J Choe, AC Guidry, SA Zamin, AX Bao, UM Parikh, S Balaji, M Kim*, JP Jung* (*co-corresponding) ACS Biomater Sci Eng 2021 May 3 doi:10.1021/acsbiomaterials.1c00427

3) Injectable Antioxidant and Oxygen-Releasing Lignin Composites to Promote Wound Healing. S Balaji*, WD Short, BW Padon, TJ Prajapati, F Farouk, JA Belgodere, SE Jimenez, NT Deoli, AC Guidry, JC Green, A Kaul, D Son, OS Jung, CE Astete, M Kim, JP Jung* (*co-corresponding) ACS Appl Mater Interface 2023 Apr 6| doi: 10.1021/acsami.2c22982

4) Lignin Composites with Sustained Oxygenation and Reactive Oxygen Species-Scavenging Improve Neovascularization and Healing of Diabetic Wounds. BW Padon, O Oluyinka, WD Short, A Kaul, LD Yutzy, F Farouk, OS Jung, P Kogan, L Yu, H Li, JP Jung*, S Balaji*. (*co-corresponding) bioRxiv. doi:10.1101/2022.06.18.496670.