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  1. Science & Research (Biologics)

Investigating the Effects of Cell-Materials Interactions on the Safety and Effectiveness of Cell-Based Products

 

Dr. Kyung E. Sung

Kyung E. Sung, PhD

Office of Tissues and Advanced Therapies
Division of Cellular and Gene Therapies
Cellular and Tissue Therapy Branch

Kyung.Sung@fda.hhs.gov

Biosketch

Dr. Kyung Sung is a biomedical engineer with expertise in developing functional and practical microphysiological systems for medical and biological applications. Dr. Sung’s main research interests are studying cell-materials interactions and exploring cell behavior in various tissue microenvironmental conditions. Dr. Sung received her PhD in chemical engineering in 2007 at the University of Michigan. She did post-doctoral research in the Department of Biomedical Engineering at the University of Wisconsin-Madison, where she also worked as a principal investigator before joining FDA in 2015. She also worked as a patent examiner in biotechnology at the US Patent and Trademark Office. During her previous research, she used principles from tissue and microsystems engineering to develop tissue-like structures in microphysiological systems to develop new tools for in vitro cancer research. The microphysiological systems provide unique capabilities for studying complex interactions occurring in tissue microenvironments, through precise control of biochemical and biomechanical factors. In addition, small-scale micro-physiological systems enable high-throughput, cell-based assays using small numbers of cells and smaller amounts of expensive reagents. Dr. Sung created innovative techniques and strategies for studies aimed at understanding the role of the tissue microenvironment in regulating cellular functions.

General Overview

Cellular therapies are the infusion of living cells into a patient’s body to treat diseases by repairing or replacing damaged tissue or cellular components.  The field of cellular therapies is growing rapidly due to its potential to fulfill unmet medical needs; however, in order to reach their full potential, cellular therapeutic products (CTPs) must be tested for safety and show clinical efficacy. Although successful translation of CTPs into clinical trials depends on multidisciplinary factors and hurdles, it is critical to have well-controlled manufacturing process and reliable assays for product characterization.

Mounting evidence suggests that cell-biomaterials interactions might play critical roles in controlling CTP’s functional behaviors in vitro and in vivo,by providing specific microenvironmental cues to which cells respond. Accordingly, various biomaterials are being tested for 1) manufacturing CTPs, which include both autologous and allogenic cells and tissue-engineered products that combine cell and biomaterials, and 2) developing reliable in vitro assays. Advances in biomaterials and cell biology have yielded better understanding and guidance as to the optimal biomaterials for manufacturing clinically safe and effective CTPs and developing physiologically relevant, in vitro assays that provide improved predictive values. However, more work is needed to further optimize the conditions of biomaterials for each use because some parameters need to be fine-tuned.

My research program uses multidisciplinary approaches that combine microphysiological systems and biomaterials to study the impact of interactions between living cells and biomaterials used in the manufacture and characterization of CTPs. The primary goals of my laboratory research are to 1) develop 3D micro-physiological systems that reliably measure the functional capacity of multipotent stromal cells (MSCs) and induced pluripotent stem cells (iPSCs)-derived cells in physiologically relevant conditions and 2) understand the functions and behaviors of cellular products in specific microenvironments to predict the safety and efficacy of manufactured CTPs. This will help us see how CTPs should be designed to provide the best method of treatment for patients.

Scientific Overview

Although CTPs come with great promise, due to the complexity of the products and their manufacturing processes there are several manufacturing and regulatory hurdles that must be overcome to successfully move them through clinical trials and on to the clinics. It is now well documented that these cells are inherently heterogeneous and responsive to biomechanical and biochemical factors in their microenvironment. In addition to the inherent heterogeneity of cells, many CTPs use source cells that are cultured in conditions considerably different from those in their native environment. This might also contribute to the functional heterogeneity of CTPs. Since microenvironmental conditions are complex, it is critical to create in vitro experimental platforms that closely mimic key functions and structures of the human tissue microenvironment to reliably predict the function and fate of cellular products after administration. The overall hypothesis of our study is that microphysiological systems that closely mimic certain in vivo microenvironments will 1) yield different insights compared to existing, traditional in vitro approaches and 2) enable the exploration of a larger parameter space than in vivo models or traditional in vitro models. These micro-physiological systems have great potential to become reliable tools for predicting biological functions of various CTPs. By controlling channel geometry, fluid properties, and biomaterials, the systems can be tailored to investigate specific cell-cell interactions, as well as cell-biomaterials interactions. A well-designed microphysiological system will provide a better understanding of cell-biomaterials interactions and how CTPs must be designed to provide the best method of treatment for patients. This research program will also provide physiologically relevant, in vitro test methods using human cells, which will ultimately reduce the use of animal models.

Important Links

Publications

  1. ALTEX 2024 Aug 7 [Epub ahead of print]
    Potential value of animal microphysiological systems.
    Brown PC, Hooberman BH, Skinner BL, Wrzesinski C, Petibone DM, Ford KA, Muldoon-Jacobs K, Sung KE, Valerio LG Jr, Sadrieh NN, Howard PC, Goering PL, Skoog SA, Fitzpatrick SC, Chen T, MacGill TC, Mendrick DL
  2. Trends Biotechnol 2024 May;42(5):526-43
    3D human tissue models and microphysiological systems for HIV and related comorbidities.
    3D Human Tissue Models for HIV Working Group
  3. Lab Chip 2024 Feb 27;24(5):1076-87
    From animal testing to in vitro systems: advancing standardization in microphysiological systems.
    Reyes DR, Esch MB, Ewart L, Nasiri R, Herland A, Sung K, Piergiovanni M, Lucchesi C, Shoemaker JT, Vukasinovic J, Nakae H, Hickman J, Pant K, Taylor A, Heinz N, Ashammakhi N
  4. Lab Chip 2024 Feb 27;24(5):1293-306
    Progress in developing microphysiological systems for biological product assessment.
    Mansouri M, Lam J, Sung KE
  5. Reprod Toxicol 2024 Jan:123:108523
    Evaluation of a microphysiological human placental barrier model for studying placental drug transfer.
    Rahman S, Kwee B, Li M, Chidambaram M, He X, Bryant M, Mehta D, Nakamura N, Phanavanh B, Fisher J, Sung K
  6. Exp Biol Med 2023 Nov;248(22):2001-19
    Modeling immunity in microphysiological systems.
    Kwee BJ, Li X, Nguyen XX, Campagna C, Lam J, Sung KE
  7. Adv Biol 2023 Oct 9 [Epub ahead of print]
    Considerations from an international regulatory and pharmaceutical industry (IQ MPS Affiliate) workshop on the standardization of complex in vitro models in drug development.
    Tomlinson L, Ramsden D, Leite SB, Beken S, Bonzo JA, Brown P, Candarlioglu PL, Chan TS, Chen E, Choi CK, David R, Delrue N, Devine PJ, Ford K, Garcia MI, Gosset JR, Hewitt P, Homan K, Irrechukwu O, Kopec AK, Liras JL, Mandlekar S, Raczynski A, Sadrieh N, Sakatis MZ, Siegel J, Sung K, Sunyovszki I, Van Vleet TR, Ekert JE, Hardwick RN
  8. Adv Biol 2023 Jul 6 [Epub ahead of print]
    Characterizing on-chip angiogenesis induction in a microphysiological system as a functional measure of mesenchymal stromal cell bioactivity.
    Lam J, Yu J, Lee B, Campagna C, Yoo S, Baek K, Jeon NL, Sung KE
  9. Biomaterials 2022 Nov;290:121826
    A microphysiological system-based potency bioassay for the functional quality assessment of mesenchymal stromal cells targeting vasculogenesis.
    Lam J, Lee B, Yu J, Kwee BJ, Kim Y, Kim J, Choi Y, Yoon JS, Kim Y, Baek K, Jeon NL, Sung KE
  10. Oncogenesis 2022 Oct 25;11(1):65
    The SUMO protease SENP1 promotes aggressive behaviors of high HIF2alpha expressing renal cell carcinoma cells.
    Lee MH, Sung K, Beebe D, Huang W, Shapiro D, Miyamoto S, Abel EJ
  11. ALTEX 2022;39(2):297-314
    Perspectives on the evaluation and adoption of complex in vitro models in drug development: workshop with the FDA and the pharmaceutical industry (IQ MPS Affiliate).
    Baran SW, Brown PC, Baudy AR, Fitzpatrick SC, Frantz C, Fullerton A, Gan J, Hardwick RN, Hillgren KM, Kopec AK, Liras JL, Mendrick DL, Nagao R, Proctor WR, Ramsden D, Ribeiro AJS, Stresser D, Sung KE, Sura R, Tetsuka K, Tomlinson L, Van Vleet T, Wagoner MP, Wang Q, Arslan SY, Yoder G, Ekert JE
  12. Curr Opin Chem Eng 2022 Mar;21:100361
    Science-based regulatory considerations for regenerative medicine cellular products.
    Lam J, Sung KE, Oh SS
  13. Adv Exp Med Biol 2022 Jan;247(1):1-75
    Emerging technologies and their impact on regulatory science.
    Anklam E, Bahl MI, Ball R, Beger RD, Cohen J, Fitzpatrick S, Girard P, Halamoda-Kenzaoui B, Hinton D, Hirose A, Hoeveler A, Honma M, Hugas M, Ishida S, Kass GE, Kojima H, Krefting I, Liachenko S, Liu Y, Masters S, Marx U, McCarthy T, Mercer T, Patri A, Pelaez C, Pirmohamed M, Platz S, Ribeiro AJ, Rodricks JV, Rusyn I, Salek RM, Schoonjans R, Silva P, Svendsen CN, Sumner S, Sung K, Tagle D, Tong L, Tong W, Eijnden-van-Raaij JVD, Vary N, Wang T, Waterton J, Wang M, Wen H, Wishart D, Yuan Y, Slikker W Jr
  14. Proc Natl Acad Sci U S A 2021 Aug 31;118(35):e2105972118
    Functional heterogeneity of IFN-gamma-licensed mesenchymal stromal cell immunosuppressive capacity on biomaterials.
    Kwee BJ, Lam J, Akue A, KuKuruga MA, Zhang K, Gu L, Sung KE
  15. Exp Biol Med 2021 Aug;246(16):1845-56
    Engineering microenvironments for manufacturing therapeutic cells.
    Kwee BJ, Sung KE
  16. Acta Biomater 2021 Jul 1;128:120-9
    Bilayered, peptide-biofunctionalized hydrogels for in vivo osteochondral tissue repair.
    Guo JL, Kim YS, Koons GL, Lam J, Navara AM, Barrios S, Xie VY, Watson E, Smith BT, Pearce HA, Orchard EA, van den Beucken JJJP, Jansen JA, Wong ME, Mikos AG
  17. Biomed Microdevices 2021 Apr 14;23(2):25
    Pumpless, modular, microphysiological systems enabling tunable perfusion for long-term cultivation of endothelialized lumens.
    Tronolone JJ, Lam J, Agrawal A, Sung K
  18. Biotechnol Bioeng 2021 Aug;118(8):2958-66
    Evaluation of tissue integration of injectable, cell-laden hydrogels of cocultures of mesenchymal stem cells and articular chondrocytes with an ex vivo cartilage explant model.
    Kim YS, Mehta SM, Guo JL, Pearce HA, Smith BT, Watson E, Koons GL, Navara AM, Lam J, Jane Grande-Allen K, Mikos AG
  19. Sci Adv 2019 Jun 5;5(6):eaaw7396
    Modular, tissue-specific, and biodegradable hydrogel cross-linkers for tissue engineering.
    Guo JL, Kim YS, Xie VY, Smith BT, Watson E, Lam J, Pearce HA, Engel PS, Mikos AG
  20. EBioMedicine 2019 Apr;42:408-19
    Patient-specific organotypic blood vessels as an in vitro model for anti-angiogenic drug response testing in renal cell carcinoma.
    Jimenez-Torres JA, Virumbrales-Munoz M, Sung KE, Lee MH, Abel EJ, Beebe DJ
  21. MAGMA 2019 Feb;32(1):15-23
    Improvement of 19F MR image uniformity in a mouse model of cellular therapy using inductive coupling.
    Park BS, Ma G, Koch WT, Rajan SS, Mastromanolis M, Lam J, Sung K, McCright B
  22. Stem Cells Transl Med 2018 Sep;7(9):664-75
    Functional profiling of chondrogenically induced multipotent stromal cell aggregates reveals transcriptomic and emergent morphological phenotypes predictive of differentiation capacity.
    Lam J, Bellayr IH, Marklein RA, Bauer SR, Puri RK, Sung KE
  23. Trends Biotechnol 2018 Jan;36(1):105-18
    Functionally-relevant morphological profiling: a tool to assess cellular heterogeneity.
    Marklein RA, Lam J, Guvendiren M, Sung KE, Bauer SR
  24. SLAS Technol 2017 Dec;22(6):646-61
    Adaptation of a simple microfluidic platform for high-dimensional quantitative morphological analysis of human mesenchymal stromal cells on polystyrene-based substrates.
    Lam J, Marklein RA, Jimenez-Torres JA, Beebe DJ, Bauer SR, Sung KE
  25. Biomacromolecules 2017 Mar 13;18(3):709-18
    The influence of biomaterials on cytokine production in 3D cultures.
    Regier MC, Montanez-Sauri SI, Schwartz MP, Murphy WL, Beebe DJ, Sung KE
  26. Methods Mol Biol 2016;1458:59-69
    A microfluidic method to mimic luminal structures in the tumor microenvironment.
    Jimenez-Torres JA, Beebe DJ, Sung KE

 

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