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1. In Vitro Generation of Haploid Germ Cells from Human XY and XXY Immature Testes in a 3D Organoid System.

Author

Galdon, Guillermo, Zarandi, Nima, Deebel, Nicholas, Zhang, Sue, Cornett, Olivia, Lyalin, Dmitry, Pettenati, Mark, Lue, YanHe, Wang, Christina, Swerdloff, Ronald, Shupe, Thomas, Bishop, Colin, Stogner, Kimberly, Kogan, Stanley, Howards, Stuart, Atala, Anthony, and Sadri-Ardekani, Hooman

Subjects
Klinefelter syndrome, cancer survivors, fertility preservation, in vitro, male infertility, organoid, spermatogenesis 3D culture, spermatogonia, spermatogonia stem cells
Abstract

Increasing survival rates of children following cancer treatment have resulted in a significant population of adult survivors with the common side effect of infertility. Additionally, the availability of genetic testing has identified Klinefelter syndrome (classic 47,XXY) as the cause of future male infertility for a significant number of prepubertal patients. This study explores new spermatogonia stem cell (SSC)-based fertility therapies to meet the needs of these patients. Testicular cells were isolated from cryopreserved human testes tissue stored from XY and XXY prepubertal patients and propagated in a two-dimensional culture. Cells were then incorporated into a 3D human testicular organoid (HTO) system. During a 3-week culture period, HTOs maintained their structure, viability, and metabolic activity. Cell-specific PCR and flow cytometry markers identified undifferentiated spermatogonia, Sertoli, Leydig, and peritubular cells within the HTOs. Testosterone was produced by the HTOs both with and without hCG stimulation. Upregulation of postmeiotic germ cell markers was detected after 23 days in culture. Fluorescence in situ hybridization (FISH) of chromosomes X, Y, and 18 identified haploid cells in the in vitro differentiated HTOs. Thus, 3D HTOs were successfully generated from isolated immature human testicular cells from both euploid (XY) and Klinefelter (XXY) patients, supporting androgen production and germ cell differentiation in vitro.

Published
2024

3. Multi-tissue interactions in an integrated three-tissue organ-on-a-chip platform.

Author

Skardal, Aleksander, Murphy, Sean V, Devarasetty, Mahesh, Mead, Ivy, Kang, Hyun-Wook, Seol, Young-Joon, Shrike Zhang, Yu, Shin, Su-Ryon, Zhao, Liang, Aleman, Julio, Hall, Adam R, Shupe, Thomas D, Kleensang, Andre, Dokmeci, Mehmet R, Jin Lee, Sang, Jackson, John D, Yoo, James J, Hartung, Thomas, Khademhosseini, Ali, Soker, Shay, Bishop, Colin E, and Atala, Anthony

Subjects
Liver, Lung, Heart, Organoids, Humans, Tissue Array Analysis, Equipment Design, Microfluidics, Drug Discovery, Lab-On-A-Chip Devices
Abstract

Many drugs have progressed through preclinical and clinical trials and have been available - for years in some cases - before being recalled by the FDA for unanticipated toxicity in humans. One reason for such poor translation from drug candidate to successful use is a lack of model systems that accurately recapitulate normal tissue function of human organs and their response to drug compounds. Moreover, tissues in the body do not exist in isolation, but reside in a highly integrated and dynamically interactive environment, in which actions in one tissue can affect other downstream tissues. Few engineered model systems, including the growing variety of organoid and organ-on-a-chip platforms, have so far reflected the interactive nature of the human body. To address this challenge, we have developed an assortment of bioengineered tissue organoids and tissue constructs that are integrated in a closed circulatory perfusion system, facilitating inter-organ responses. We describe a three-tissue organ-on-a-chip system, comprised of liver, heart, and lung, and highlight examples of inter-organ responses to drug administration. We observe drug responses that depend on inter-tissue interaction, illustrating the value of multiple tissue integration for in vitro study of both the efficacy of and side effects associated with candidate drugs.

Published
2017

5. A liver-on-a-chip platform with bioprinted hepatic spheroids.

Author

Bhise, Nupura S, Manoharan, Vijayan, Massa, Solange, Tamayol, Ali, Ghaderi, Masoumeh, Miscuglio, Mario, Lang, Qi, Shrike Zhang, Yu, Shin, Su Ryon, Calzone, Giovanni, Annabi, Nasim, Shupe, Thomas D, Bishop, Colin E, Atala, Anthony, Dokmeci, Mehmet R, and Khademhosseini, Ali

Subjects
Spheroids, Cellular, Humans, Biological Assay, Organ Culture Techniques, Equipment Design, Equipment Failure Analysis, Toxicity Tests, Liver, Artificial, Lab-On-A-Chip Devices, Hep G2 Cells, Printing, Three-Dimensional, Chemical and Drug Induced Liver Injury, bioprinting, bioreactor, liver, drug toxicity, 3D culture, hepatocytes, Spheroids, Cellular, Liver, Artificial, Printing, Three-Dimensional, Liver Disease, Patient Safety, Bioengineering, Digestive Diseases, Chronic Liver Disease and Cirrhosis, Biotechnology, Oral and Gastrointestinal, Medical Biotechnology, Other Technology, Biomedical Engineering
Abstract

The inadequacy of animal models in correctly predicting drug and biothreat agent toxicity in humans has resulted in a pressing need for in vitro models that can recreate the in vivo scenario. One of the most important organs in the assessment of drug toxicity is liver. Here, we report the development of a liver-on-a-chip platform for long-term culture of three-dimensional (3D) human HepG2/C3A spheroids for drug toxicity assessment. The bioreactor design allowed for in situ monitoring of the culture environment by enabling direct access to the hepatic construct during the experiment without compromising the platform operation. The engineered bioreactor could be interfaced with a bioprinter to fabricate 3D hepatic constructs of spheroids encapsulated within photocrosslinkable gelatin methacryloyl (GelMA) hydrogel. The engineered hepatic construct remained functional during the 30 days culture period as assessed by monitoring the secretion rates of albumin, alpha-1 antitrypsin, transferrin, and ceruloplasmin, as well as immunostaining for the hepatocyte markers, cytokeratin 18, MRP2 bile canalicular protein and tight junction protein ZO-1. Treatment with 15 mM acetaminophen induced a toxic response in the hepatic construct that was similar to published studies on animal and other in vitro models, thus providing a proof-of-concept demonstration of the utility of this liver-on-a-chip platform for toxicity assessment.

Published
2016

6. 3D Bioprinted Liver-on-a-chip for Drug Cytotoxicity Screening

Author

Huh, Jun Tae, primary, Parra, Joao, additional, Copus, Joshua, additional, Kang, Hyun-Wook, additional, Bishop, Colin, additional, Soker, Shay, additional, Murphy, Sean, additional, Shupe, Thomas, additional, Yoo, James J, additional, Lee, Sang Jin, additional, and Atala, Anthony, additional

Published
2023
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7. List of contributors

Author

Abe, Masashi, primary, Ahlstrom, Jon D., additional, Albon, Julie, additional, Allickson, Julie, additional, Almeida-Porada, Graça, additional, Altschuler, Richard A., additional, Anderson, Daniel G., additional, Annabi, Nasim, additional, Arcidiacono, Judith, additional, Ashammakhi, Nureddin, additional, Atala, Anthony, additional, Athanasiou, Kyriacos A., additional, Awad, Hani A., additional, Badylak, Stephen F, additional, Balachander, Gowri, additional, Balkan, Wayne, additional, Bara, Jennifer J., additional, Barry, Michael P., additional, Baskaran, Harihara, additional, Bedell, Matthew L., additional, Belcher, Donald Andrew, additional, Berry, David B., additional, Bhat, Hina, additional, Bhat, Zuhaib F., additional, Bhatia, Sangeeta N., additional, Blackburn, Catherine Clare, additional, Blocki, Anna, additional, Blum, Kevin M., additional, Bochenek, Matthew A., additional, Bonassar, Lawrence J., additional, Bonventre, Joseph V., additional, Borrelli, Mimi R., additional, Bowles, Robby D., additional, Bradshaw, Amy D., additional, Bratt-Leal, Andres M., additional, Breuer, Christopher K., additional, Brewster, Luke, additional, Brey, Eric M., additional, Briquez, Priscilla S., additional, Buckwalter, J.A., additional, Burg, Karen J.L., additional, Burg, Timothy C., additional, Byambaa, Batzaya, additional, Chandra, Prafulla K., additional, Chen, Amanda X., additional, Chen, Fa-Ming, additional, Chen, Shaochen, additional, Chesterman, Julian, additional, Chhabra, Arnav, additional, Chong, Seow Khoon, additional, Clark, Richard A.F., additional, Cleary, Muriel A., additional, Coleman, M., additional, Cotsarelis, George, additional, Crystal, Ronald G., additional, Dagnelie, Gislin, additional, Darabi, Mohammad Ali, additional, Davidson, Jeffrey M., additional, Davidson, Joseph, additional, De Coppi, Paolo, additional, Delcassian, Derfogail, additional, de Vos, Paul, additional, Dominijanni, Anthony, additional, Donahue, Ryan, additional, Drain, Allison P., additional, Duvall, Craig L., additional, Dziki, Jenna L., additional, Elgalad, Abdelmotagaly, additional, Eng, George, additional, Falanga, Vincent, additional, Farhang, Niloofar, additional, Ferreira, Lino, additional, Fink, Donald W., additional, Fleming, Heather E., additional, Fong, Peter, additional, Frey, Mark R., additional, Gay, Denise, additional, Gerecht, Sharon, additional, Gersbach, Charles A., additional, Gibbs, D.M.R., additional, Gidwani, Simran, additional, González Morales, Shaimar R., additional, Goyal, Ritu, additional, Grant, Maria B., additional, Gray, Andrea, additional, Greisler, Howard P., additional, Grikscheit, Tracy C., additional, Grosh, Karl, additional, Guilak, Farshid, additional, Guo, Jason L., additional, Han, Yingli, additional, Hare, Joshua M., additional, Hassanbhai, Ammar Mansoor, additional, Hatzistergos, Konstantinos, additional, Hay, David C., additional, He, Xiao-Tao, additional, Henderson, Timothy, additional, Hickerson, Darren, additional, Hickerson, Darren H.M., additional, Hmadcha, Abdelkrim, additional, Hochman-Mendez, Camila, additional, Huang, Chao, additional, Hubbell, Jeffrey A., additional, Huelsmann, Joern, additional, Huh, Jun Tae, additional, Hunsberger, Joshua G., additional, Iannucci, Leanne E., additional, Inoue, Haruhisa, additional, Jackson, John, additional, Jiang, Yangzi, additional, Kalinichenko, Vladimir V., additional, Kanczler, J.M., additional, Karp, Jeffrey M., additional, Kasper, F. Kurtis, additional, Khademhosseini, Ali, additional, Kim, Ji Hyun, additional, Kimbrel, Erin A., additional, Klimanskaya, Irina, additional, Kohn, Joachim, additional, Kumar, Sunil, additional, Kyriakides, Themis R., additional, Lake, Spencer P., additional, Lam, Johnny, additional, Langer, Robert, additional, Lanza, Robert, additional, Leach, Timothy S., additional, Lee, Benjamin W., additional, Lee, Iris, additional, Lee, Sang Jin, additional, Li, David, additional, Li, Linheng, additional, Liu, Qian, additional, Ljubimov, Alexander V., additional, Lo, Chi, additional, Longaker, Michael T., additional, López-Beas, Javier, additional, Loring, Jeanne F., additional, Luo, Ying, additional, MacArthur, Ben D., additional, Madigan, Nicolas N., additional, Madry, Henning, additional, Magalhaes, Renata S., additional, Manley, Nancy Ruth, additional, Mansbridge, Jonathan, additional, Mao, Jeremy J., additional, Marshall, K.M., additional, Martin, J.A., additional, Martins-Green, M., additional, Maselli, Kathryn M., additional, Maxfield, Mark W., additional, McCracken, Kyle W., additional, Melville, James, additional, Mikos, Antonios G., additional, Millán, José del R., additional, Mirotsou, Maria, additional, Montoro, Daniel T., additional, Murphy, Matthew P., additional, Murphy, Sean V., additional, Musillo, Michael, additional, Muthukumaran, Padmalosini, additional, Navara, Adam M., additional, Nelson, Christopher E., additional, Niklason, Laura E., additional, Nowell, Craig Scott, additional, O’Keefe, Regis J., additional, O’Neill, Kathy E., additional, Oreffo, Richard O.C., additional, Ortiz, Ophir, additional, Palmer, Andre Francis, additional, Perdikis, Serafeim, additional, Petreaca, M., additional, Plikus, Maksim V., additional, Porada, Christopher D., additional, Post, Mark, additional, Prokop, Aleš, additional, Puri, Raj K., additional, Qian, Pengxu, additional, Radisic, Milica, additional, Raredon, Micha Sam Brickman, additional, Richie, Ellen Rothman, additional, Rouse, Paul, additional, Sadri-Ardekani, Hooman, additional, Saltzman, W. Mark, additional, Sampaio, Luiz C., additional, Schlieve, Christopher R., additional, Sha, Su-Hua, additional, Sharpe, Paul T., additional, Shastri, V. Prasad, additional, Shi, Yanhong, additional, Shupe, Thomas, additional, Sirabella, Dario, additional, Skardal, Aleksander, additional, Slack, J.M.W., additional, Sloan, Stephen R., additional, Soker, Shay, additional, Soria, Bernat, additional, Soria-Juan, Bárbara, additional, Stockdale, Frank E., additional, Stover, Josh, additional, Stransky, Thomas, additional, Stronks, H. Christiaan, additional, Stumpf, Patrick S., additional, Sung, Kyung Eun, additional, Swarr, Daniel, additional, Szkolnicka, Dagmara, additional, Takahashi, Jun, additional, Tang, D.K.O., additional, Tang, Winson, additional, Taylor, Doris A., additional, Teng, Yao, additional, Teoh, Swee Hin, additional, Smith, Anthony J., additional, Treffeisen, Elsa, additional, Tuan, Rocky S., additional, Vacanti, Joseph P., additional, van der Weele, Cor, additional, Vincent, Matthew, additional, Vunjak-Novakovic, Gordana, additional, Wahlberg, Lars U., additional, Wan, Derrick C., additional, Wang, Anne, additional, Wang, Dan, additional, Wang, Qiwei, additional, Wang, Yanling, additional, Wang, Yu-li, additional, Wang, Zhanwen, additional, Weaver, Valerie M., additional, Wells, J.A., additional, Welter, Jean F., additional, Wen, Feng, additional, Weston, Jake, additional, Whitsett, Jeffrey A., additional, Williams, James K., additional, Windebank, Anthony J., additional, Wong, Mark Eu-Kien, additional, Worgall, Stefan, additional, Wu, Iwen, additional, Wu, Rui-Xin, additional, Xie, Virginia Y., additional, Xing, Malcolm, additional, Yamada, Kenneth M., additional, Yamanaka, Shinya, additional, Yoo, James J., additional, Young, Simon, additional, Yu, Claire, additional, Yu, Hanry, additional, Yuan, Yifan, additional, Zacharias, William, additional, Zakko, Jason, additional, Zhang, Ai, additional, Zhang, Yuanyuan, additional, Zhang, Zheng, additional, Zhao, Chunfeng, additional, Zhao, Yimu, additional, and Zoloth, Laurie, additional

Published
2020
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8. Multisensor-integrated organs-on-chips platform for automated and continual in situ monitoring of organoid behaviors

Author

Zhang, Yu Shrike, Aleman, Julio, Shin, Su Ryon, Kilic, Tugba, Kim, Duckjin, Shaegh, Seyed Ali Mousavi, Massa, Solange, Riahi, Reza, Chae, Sukyoung, Hu, Ning, Avci, Huseyin, Zhang, Weijia, Silvestri, Antonia, Nezhad, Amir Sanati, Manbohi, Ahmad, De Ferrari, Fabio, Polini, Alessandro, Calzone, Giovanni, Shaikh, Noor, Alerasool, Parissa, Budina, Erica, Kang, Jian, Bhise, Nupura, Ribas, João, Pourmand, Adel, Skardal, Aleksander, Shupe, Thomas, Bishop, Colin E., Dokmeci, Mehmet Remzi, Atala, Anthony, and Khademhosseini, Ali

Published
2017

9. Body-on-a-Chip for Pharmacology and Toxicology

Author

Atala, Anthony, primary, Devarasetty, Mahesh, additional, Forsythe, Steven. D., additional, Dorsey, Russell. M., additional, Salem, Harry, additional, Shupe, Thomas. D., additional, Skardal, Aleksander, additional, and Soker, Shay, additional

Published
2019
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14. Contributors

Author

Agarwal, Rachit, primary, Ahlstrom, Jon D., additional, Ahmad, Rafiq, additional, Alarcon, Emilio I., additional, Almarza, Alejandro J., additional, Almeida-Porada, Graça, additional, Almeida, Manuel, additional, Alvarado-Velez, Melissa, additional, Anderson, James M., additional, Arcidiacono, Judith, additional, Atala, Anthony, additional, Badylak, Stephen F., additional, Balkan, Wayne, additional, Ballios, Brian G., additional, Baptista, Pedro M., additional, Baumann, M. Douglas, additional, Bedi, Supinder S., additional, Bellamkonda, Ravi V., additional, Bergmann, Nicole M., additional, Blau, Helen M., additional, Boerckel, Joel D., additional, Bratt-Leal, Andres M., additional, Brown, James C., additional, Brubaker, Scott, additional, Brunette, Isabelle, additional, Calderon, Gisele A., additional, Caplan, Arnold I., additional, Castner, David G., additional, Chang, Cynthia, additional, Chawla, Aditya, additional, Chen, Xuguang, additional, Cohen, Paul, additional, Cooke, Michael J., additional, Copus, Joshua S., additional, Correlo, Vitor M., additional, Cox, Charles S., additional, Dahl, Abritee, additional, Day, Richard M., additional, De Coppi, Paolo, additional, Dodla, Mahesh C., additional, Elisseeff, Jennifer H., additional, Emamaullee, Juliet A., additional, Esa, Adam, additional, Fang, Yunlan, additional, Faust, Heather J., additional, Fisher, John P., additional, Fisher, Matthew B., additional, Francois, Elvis L., additional, García, Andrés J., additional, Gavrilov, Svetlana, additional, Gazit, Dan, additional, Gazit, Zulma, additional, Gemmiti, Christopher V., additional, Gillispie, Gregory J., additional, Gilpin, Sarah E., additional, Godbey, W.T., additional, Gray, Andrea, additional, Green, Ronald M., additional, Griffith, May, additional, Guldberg, Robert E., additional, Guo, Qiongyu, additional, Gurtner, Geoffrey C., additional, Hacker, Michael C., additional, Hanna, Issa A., additional, Hare, Joshua M., additional, Hatzistergos, Konstantinos E., additional, Herber, Ralf-Peter, additional, Hilborn, Jöns, additional, Humes, H. David, additional, Hunsberger, Joshua G., additional, Iwasa, Kenjiro, additional, Jackson, John D., additional, Jackson, Margaret L., additional, Jang, Hae Lin, additional, Jansen, John A., additional, Johnston, Josephine, additional, Jorns, Carl, additional, Kang, Huijun, additional, Kaplan, David L., additional, Kaplan, David S., additional, Katz, Adam J., additional, Kelley, Matthew W., additional, Kennedy, Kelsey, additional, Khademhosseini, Ali, additional, Khang, Gilson, additional, Kim, Jinho, additional, Klein, Rachel H., additional, Klimanskaya, Irina, additional, Knoepfler, Paul S., additional, Ko, In Kap, additional, Kolambkar, Yash M., additional, Krieghoff, Jan, additional, Kucko, Nathan W., additional, Kumar, Manoj, additional, Kurtzberg, Joanne, additional, Kwilas, Anna, additional, Landry, Donald W., additional, Langhans, Mark T., additional, Lanza, Robert, additional, Lanzoni, Giacomo, additional, Lee, Sang Jin, additional, Leeuwenburgh, Sander C.G., additional, Leong, Kam W., additional, Liang, Rui, additional, Liaudanskaya, Volha, additional, Lin, Hang, additional, Longaker, Michael T., additional, Lorenz, Hermann P., additional, Loring, Jeanne F., additional, Lu, Shi-Jiang, additional, Lue, Alberto, additional, Ma, Peter X., additional, Magalhaes, Renata S., additional, Mandla, Serena, additional, Marshall, Clement D., additional, Martins-Green, Manuela, additional, Mason, Devon E., additional, Mau, Jonquil R., additional, McFarland, Richard, additional, McHale, Melissa K., additional, Melville, James C., additional, Meyers, Jason R., additional, Mikos, Antonios G., additional, Miller, Jordan S., additional, Mittermiller, Paul A., additional, Miyachi, Hideki, additional, Miyamoto, Shinka, additional, Monteiro, Nelson, additional, Moore, Alessandra L., additional, Morini, Sara, additional, Moser, Philipp T., additional, Mukhatyar, Vivek J., additional, Murdock, Mark, additional, Nagiel, Aaron, additional, Naughton, Gail K., additional, Nauta, Allison, additional, Navarro, Javier, additional, Newton, Jared M., additional, Nori, Aparna, additional, Okano, Teruo, additional, Oliveira, Joaquim M., additional, Ott, Harald C., additional, Padmanabhan, Jagannath, additional, Page, Kristin M., additional, Pallickaveedu Rajan Asari, Anil Kumar, additional, Papaioannou, Virginia E., additional, Park, Jihoon, additional, Payne, Samantha L., additional, Pelled, Gadi, additional, Pepper, Andrew, additional, Perumal, Elumalai, additional, Petreaca, Melissa, additional, Pino, Christopher J., additional, Pirosa, Alessandro, additional, Pla-Palacín, Iris, additional, Pokrywczynska, Marta, additional, Porada, Christopher D., additional, Porter, Blaise D., additional, Radisic, Milica, additional, Rambhia, Kunal J., additional, Raquel Maia, F., additional, Ratner, Buddy D., additional, Reddi, A.H., additional, Reis, Rui L., additional, Ricles, Laura, additional, Ricordi, Camillo, additional, Rizwan, Muhammad, additional, Robinson, Rebecca, additional, Rodrigues, Melanie, additional, Rothrauff, Benjamin B., additional, Sadri-Ardekani, Hooman, additional, Sainz-Arnal, Pilar, additional, Sambathkumar, Rangarajan, additional, Sánchez-Romero, Natalia, additional, Scarritt, Michelle, additional, Schneider, Christopher M., additional, Schwartz, Steven D., additional, Selem, Sarah, additional, Serrano-Aulló, Trinidad, additional, Shapiro, A.M. James, additional, Sheyn, Dmitriy, additional, Shimizu, Tatsuya, additional, Shinoka, Toshiharu, additional, Shoichet, Molly S., additional, Shoji, Toshihiro, additional, Shupe, Thomas, additional, Sikora, Andrew G., additional, Simpson, Fiona, additional, Skardal, Aleksander, additional, Skuk, Daniel, additional, Smith, Brandon T., additional, Sohn, Jihee, additional, Soker, Shay, additional, Solanas, Estela, additional, Song, Jeong Eun, additional, Sood, Disha, additional, Stocum, David L., additional, Strom, Stephen C., additional, Sun, Jessica M., additional, Takahashi, Hironobu, additional, Tremblay, Jacques P., additional, Tripathy, Nirmalya, additional, Tse, John W., additional, Tuan, Rocky S., additional, Verfaillie, Catherine M., additional, Vunjak-Novakovic, Gordana, additional, Wagner, William R., additional, Wang, Yanling, additional, Watson, Emma, additional, West, Jennifer L., additional, Williams, David F., additional, Williams, James K., additional, Wong, Mark E., additional, Woo, Savio L-Y., additional, Wood, Fiona M., additional, Xu, Lei, additional, Yakubovich, Doron C., additional, Yang, Yafeng, additional, Yaszemski, Michael J., additional, Yelick, Pamela C., additional, Yim, Evelyn K.F., additional, Yong, Carolyn, additional, Yoo, James J., additional, Young, Simon, additional, Yucel, Nora, additional, Zacharias, Rachel L., additional, Zhang, Yuanyuan, additional, Zhang, Ai, additional, Zhang, Jin, additional, and Zhu, Yang, additional

Published
2018
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22. List of Contributors

Author

Afroze, Syeda H., primary, Alpini, Gianfranco, additional, Anderson, Eric C., additional, Atala, Anthony, additional, Badylak, Stephen F., additional, Baiguera, Silvia, additional, Baiocchi, Leonardo, additional, Baptista, Pedro M., additional, Bejarano-Pineda, Lorena, additional, Benedetti, Enrico, additional, Beraldi, Rosanna, additional, Berdichevski, Alexandra, additional, Bhuyan, Mohammod, additional, Bishop, Alex G., additional, Bitar, Khalil N., additional, Blose, Kory J., additional, Brasile, Lauren, additional, Braza, Faouzi, additional, Breuer, Christopher K., additional, Brouard, Sophie, additional, Brown, Bryan N., additional, Burke, George W., additional, Butler, Peter E., additional, Butler, Colin R., additional, Calderon, Damelys, additional, Cancedda, Ranieri, additional, Cantero Peral, Susana, additional, Carbone, Marco, additional, Castanares-Zapatero, Diego, additional, Castro Santa, Edward, additional, Chatenoud, Lucienne, additional, Chawla, Reema, additional, Chen, Linda, additional, Chiono, Valeria, additional, Ciancio, Gaetano, additional, Ciardelli, Gianluca, additional, Ciccarelli, Olga, additional, Collienne, Christine, additional, Corradini, Francesca, additional, Cortiella, Joaquin, additional, Cravedi, Paolo, additional, Cypel, Marcelo, additional, Da Sacco, Stefano, additional, Date, Hiroshi, additional, Davies, Paige S., additional, De Coppi, Paolo, additional, De Luca, Michele, additional, Dean, Ethan W., additional, Degauque, Nicolas, additional, Domínguez-Bendala, Juan, additional, Dubernard, Jean Michel, additional, ElBackly, Rania M., additional, English, Karen, additional, Fändrich, Fred, additional, Farney, Alan C., additional, Faulk, Denver M., additional, García-Arrarás, José E., additional, Gianello, Pierre, additional, Giangreco, Adam, additional, Glaser, Shannon S., additional, Gobble, Ryan, additional, Goldstein, Aaron S., additional, Grant, Christa N., additional, Grikscheit, Tracy C., additional, Gruessner, Angelika C., additional, Gruessner, Rainer W.G., additional, Guillot, Pascale V., additional, Hamilton, Nicholas, additional, Hantson, Philippe, additional, Hemal, Sij, additional, Hematti, Peiman, additional, Hynds, Robert E., additional, Inverardi, Luca, additional, Jacquet, Luc M., additional, Janes, Sam M., additional, Jell, Gavin, additional, Jensen, Kendal, additional, Jochmans, Ina, additional, Kanai, Nobuo, additional, Katari, Ravi, additional, Keshavjee, Shaf, additional, Kim, Jaehyup, additional, Kim, Yeonhee, additional, King, Nancy M.P., additional, Kobayashi, Eiji, additional, Koshiba, Takaaki, additional, Krawiec, Jeffrey T., additional, Kurobe, Hirotsugu, additional, Lai, Quirino, additional, Lanzoni, Giacomo, additional, Laterre, Pierre-François, additional, Lerut, Jan P., additional, Lerut, Toni, additional, Li, Ou, additional, Macchiarini, Paolo, additional, Maghsoudlou, Panagiotis, additional, Mamode, Nizam, additional, Manzia, Tommaso M., additional, Martinez-Fernandez, Almudena, additional, Martovetsky, Gleb, additional, Mastrogiacomo, Maddalena, additional, Masuda, Shigeo, additional, McQuilling, John P., additional, Mehra, Mandeep R., additional, Menasché, Philippe, additional, Meng, Fanyin, additional, Mironi-Harpaz, Iris, additional, Mirzazadeh, Majid, additional, Moiemen, Naiem S., additional, Moran, Emma, additional, Muiesan, Paolo, additional, Nardo, Tiziana, additional, Nelson, Timothy J, additional, Netti, Paolo A., additional, Neuberger, James M., additional, Nigam, Sanjay K., additional, Ohe, Hidenori, additional, Okano, Teruo, additional, Opara, Emmanuel C., additional, Orgill, Dennis P., additional, Otte, Jean-Bernard, additional, Ozer, Sinan, additional, Pareta, Rajesh A., additional, Patel, Timil, additional, Pellegrini, Graziella, additional, Peloso, Andrea, additional, Perin, Laura, additional, Petruzzo, Palmina, additional, Pinheiro, Rafael S., additional, Pirenne, Jacques, additional, Poindexter, Lauren K., additional, Pucéat, Michel, additional, Pugliese, Alberto, additional, Raghavan, Shreya, additional, Rahal, Kinan, additional, Rama, Paolo, additional, Remuzzi, Andrea, additional, Remuzzi, Giuseppe, additional, Reyna-Soriano, Daniel, additional, Rico Juri, Juan M., additional, Ricordi, Camillo, additional, Roberts, Keith J., additional, Rocco, Kevin A., additional, Rodriguez-Devora, Jorge I., additional, Rogers, Jeffrey, additional, Rudnick, David A., additional, Ruggenenti, Piero, additional, Sageshima, Junichiro, additional, Salvatori, Marcus, additional, Samavedi, Satyavrata, additional, Sannino, Alessandro, additional, Scalera, Irene, additional, Sedaghati, Tina, additional, Sedrakyan, Sargis, additional, Seifalian, Alexander M., additional, Seifalian, Amelia, additional, Seliktar, Dror, additional, Selvaggi, Gennaro, additional, Shapira-Schweitzer, Keren, additional, Shinoka, Toshiharu, additional, Shupe, Thomas, additional, Smith, Nicholas R., additional, Soulillou, Jean-Paul, additional, Spinelli, Valentina, additional, Sutherland, David E.R., additional, Tara, Shuhei, additional, Teratani, Takumi, additional, Terzic, Andre, additional, Thomas, Sunu S., additional, Tisone, Giuseppe, additional, Totonelli, Giorgia, additional, Tzakis, Andreas, additional, Tzvetanov, Ivo G., additional, Udelsman, Brooks V., additional, Uygun, Basak E., additional, Vacanti, Joseph P., additional, Van Caenegem, Olivier, additional, Van Dyke, Mark, additional, Van Raemdonck, Dirk E., additional, Vorp, David A., additional, Vyas, Dipen, additional, Wang, Kun, additional, Weinbaum, Justin S., additional, Wertheim, Jason A., additional, Williams, David F., additional, Wittebole, Xavier, additional, Wong, Melissa H., additional, Wood, Kathryn J., additional, Xu, Tao, additional, Yamato, Masayuki, additional, You, Sylvaine, additional, Yuan, Yuyu, additional, Zambon, Joao Paulo, additional, Zattoni, Michela, additional, and Zhu, Lei, additional

Published
2014
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24. Bioreactor design and validation for manufacturing strategies in tissue engineering

Author

Lim, Diana, primary, Renteria, Eric S., additional, Sime, Drake S., additional, Ju, Young Min, additional, Kim, Ji Hyun, additional, Criswell, Tracy, additional, Shupe, Thomas D., additional, Atala, Anthony, additional, Marini, Frank C., additional, Gurcan, Metin N., additional, Soker, Shay, additional, Hunsberger, Joshua, additional, and Yoo, James J., additional

Published
2021
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30. Drug compound screening in single and integrated multi-organoid body-on-a-chip systems

Author

Skardal, Aleksander, primary, Aleman, Julio, additional, Forsythe, Steven, additional, Rajan, Shiny, additional, Murphy, Sean, additional, Devarasetty, Mahesh, additional, Pourhabibi Zarandi, Nima, additional, Nzou, Goodwell, additional, Wicks, Robert, additional, Sadri-Ardekani, Hooman, additional, Bishop, Colin, additional, Soker, Shay, additional, Hall, Adam, additional, Shupe, Thomas, additional, and Atala, Anthony, additional

Published
2020
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33. Additional file 4: of Urothelium with barrier function differentiated from human urine-derived stem cells for potential use in urinary tract reconstruction

Author

Wan, Qian, Xiong, Geng, Guihua Liu, Shupe, Thomas, Guanghui Wei, Deying Zhang, Liang, Dan, Xiongbing Lu, Atala, Anthony, and Yuanyuan Zhang

Abstract

Table S4. Percentage of USC expressing tight junction markers 2Â weeks after urothelial induction assessed by immunofluorescence. (DOCX 16Â kb)

Published
2018
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34. Therapeutic effects of a small molecule agonist of the relaxin receptor ML290 in liver fibrosis

Author

Kaftanovskaya, Elena M., primary, Ng, Hooi Hooi, additional, Soula, Mariluz, additional, Rivas, Bryan, additional, Myhr, Courtney, additional, Ho, Brian A., additional, Cervantes, Briana A., additional, Shupe, Thomas D., additional, Devarasetty, Mahesh, additional, Hu, Xin, additional, Xu, Xin, additional, Patnaik, Samarjit, additional, Wilson, Kenneth J., additional, Barnaeva, Elena, additional, Ferrer, Marc, additional, Southall, Noel T., additional, Marugan, Juan J., additional, Bishop, Colin E., additional, Agoulnik, Irina U., additional, and Agoulnik, Alexander I., additional

Published
2019
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35. Small molecule allosteric agonist of relaxin receptor ML290 demonstrates antifibrotic properties in liver fibrosis

Author

Kaftanovskaya, Elena, primary, Ng, Hooi Hooi, additional, Soula, Mariluz, additional, Rivas, Bryan, additional, Myhr, Courtney, additional, Ho, Brian, additional, Cervantes, Briana, additional, Bishop, Colin, additional, Shupe, Thomas, additional, Wilson, Kenneth, additional, Barnaeva, Elena, additional, Ferrer, Marc, additional, Southall, Noel, additional, Marugan, Juan, additional, Agoulnik, Irina, additional, and Agoulnik, Alexander, additional

Published
2019
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36. SAT-035 Small Molecule Allosteric Agonist of Relaxin Receptor Ml290 Demonstrates Antifibrotic Properties in Liver Fibrosis

Author

Kaftanovskaya, Elena, primary, Ng, Hooi Hooi, additional, Rivas, Bryan, additional, Myhr, Courtney, additional, Shupe, Thomas, additional, Hu, Xin, additional, Ferrer, Marc, additional, Southall, Noel, additional, Wilson, Kenneth, additional, Marugan, Juan, additional, Bishop, Colin, additional, Agoulnik, Irina, additional, and Agoulnik, Alexander, additional

Published
2019
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39. Multi-tissue interactions in an integrated three-tissue organ-on-a-chip platform

Author

School of Biomedical Engineering and Sciences, Skardal, Aleksander, Murphy, Sean V., Devarasetty, Mahesh, Mead, Ivy, Kang, Hyun-Wook, Seol, Young-Joon, Zhang, Yu Shrike, Shin, Su-Ryon, Zhao, Liang, Aleman, Julio, Hall, Adam R., Shupe, Thomas D., Kleensang, Andre, Dokmeci, Mehmet R., Lee, Sang Jin, Jackson, John D., Yoo, James J., Hartung, Thomas, Khademhosseini, Ali, Soker, Shay, Bishop, Colin E., Atala, Anthony, School of Biomedical Engineering and Sciences, Skardal, Aleksander, Murphy, Sean V., Devarasetty, Mahesh, Mead, Ivy, Kang, Hyun-Wook, Seol, Young-Joon, Zhang, Yu Shrike, Shin, Su-Ryon, Zhao, Liang, Aleman, Julio, Hall, Adam R., Shupe, Thomas D., Kleensang, Andre, Dokmeci, Mehmet R., Lee, Sang Jin, Jackson, John D., Yoo, James J., Hartung, Thomas, Khademhosseini, Ali, Soker, Shay, Bishop, Colin E., and Atala, Anthony

Abstract

Many drugs have progressed through preclinical and clinical trials and have been available - for years in some cases -before being recalled by the FDA for unanticipated toxicity in humans. One reason for such poor translation from drug candidate to successful use is a lack of model systems that accurately recapitulate normal tissue function of human organs and their response to drug compounds. Moreover, tissues in the body do not exist in isolation, but reside in a highly integrated and dynamically interactive environment, in which actions in one tissue can affect other downstream tissues. Few engineered model systems, including the growing variety of organoid and organ-on-a-chip platforms, have so far reflected the interactive nature of the human body. To address this challenge, we have developed an assortment of bioengineered tissue organoids and tissue constructs that are integrated in a closed circulatory perfusion system, facilitating inter-organ responses. We describe a three-tissue organ-on-a-chip system, comprised of liver, heart, and lung, and highlight examples of inter-organ responses to drug administration. We observe drug responses that depend on inter-tissue interaction, illustrating the value of multiple tissue integration for in vitro study of both the efficacy of and side effects associated with candidate drugs.

Published
2017

40. Multisensor-integrated organs-on-chips platform for automated and continual in situ monitoring of organoid behaviors

Author

Harvard University--MIT Division of Health Sciences and Technology, Koch Institute for Integrative Cancer Research at MIT, Zhang, Weijia, Khademhosseini, Alireza, Zhang, Yu Shrike, Aleman, Julio, Shin, Su Ryon, Kilic, Tugba, Kim, Duckjin, Mousavi Shaegh, Seyed Ali, Massa, Solange, Riahi, Reza, Chae, Sukyoung, Hu, Ning, Avci, Huseyin, Silvestri, Antonia, Sanati Nezhad, Amir, Manbohi, Ahmad, De Ferrari, Fabio, Polini, Alessandro, Calzone, Giovanni, Shaikh, Noor, Alerasool, Parissa, Budina, Erica, Kang, Jian, Bhise, Nupura, Ribas, João, Pourmand, Adel, Skardal, Aleksander, Shupe, Thomas, Bishop, Colin E., Dokmeci, Mehmet Remzi, Atala, Anthony, Khademhosseini, Ali, Harvard University--MIT Division of Health Sciences and Technology, Koch Institute for Integrative Cancer Research at MIT, Zhang, Weijia, Khademhosseini, Alireza, Zhang, Yu Shrike, Aleman, Julio, Shin, Su Ryon, Kilic, Tugba, Kim, Duckjin, Mousavi Shaegh, Seyed Ali, Massa, Solange, Riahi, Reza, Chae, Sukyoung, Hu, Ning, Avci, Huseyin, Silvestri, Antonia, Sanati Nezhad, Amir, Manbohi, Ahmad, De Ferrari, Fabio, Polini, Alessandro, Calzone, Giovanni, Shaikh, Noor, Alerasool, Parissa, Budina, Erica, Kang, Jian, Bhise, Nupura, Ribas, João, Pourmand, Adel, Skardal, Aleksander, Shupe, Thomas, Bishop, Colin E., Dokmeci, Mehmet Remzi, Atala, Anthony, and Khademhosseini, Ali

Abstract

Organ-on-a-chip systems areminiaturizedmicrofluidic 3D human tissue and organ models designed to recapitulate the important biological and physiological parameters of their in vivo counterparts. They have recently emerged as a viable platform for personalized medicine and drug screening. These in vitro models, featuring biomimetic compositions, architectures, and functions, are expected to replace the conventional planar, static cell cultures and bridge the gap between the currently used preclinical animal models and the human body. Multiple organoid models may be further connected together through the microfluidics in a similar manner in which they are arranged in vivo, providing the capability to analyze multiorgan interactions. Although a wide variety of human organ-on-a-chip models have been created, there are limited efforts on the integration of multisensor systems. However, in situ continual measuring is critical in precise assessment of the microenvironment parameters and the dynamic responses of the organs to pharmaceutical compounds over extended periods of time. In addition, automated and noninvasive capability is strongly desired for long-term monitoring. Here, we report a fully integrated modular physical, biochemical, and optical sensing platform through a fluidics-routing breadboard, which operates organ-on-a-chip units in a continual, dynamic, and automated manner.We believe that this platform technology has paved a potential avenue to promote the performance of current organ-on-a-chip models in drug screening by integrating a multitude of real-time sensors to achieve automated in situ monitoring of biophysical and biochemical parameters., National Institutes of Health (U.S.) (Grant EB012597), National Institutes of Health (U.S.) (Grant AR057837), National Institutes of Health (U.S.) (Grant DE021468), National Institutes of Health (U.S.) (Grant HL099073), National Institutes of Health (U.S.) (Grant R56AI105024), National Institutes of Health (U.S.) (Grant AR068258), National Institutes of Health (U.S.) (Grant AR066193), National Institutes of Health (U.S.) (Grant EB022403), National Institutes of Health (U.S.) (Grant EB021148)

Published
2017

45. Bioengineered transplantable porcine livers with re-endothelialized vasculature

Author

Ko, In Kap, primary, Peng, Li, additional, Peloso, Andrea, additional, Smith, Charesa J., additional, Dhal, Abritee, additional, Deegan, Daniel B., additional, Zimmerman, Cindy, additional, Clouse, Cara, additional, Zhao, Weixin, additional, Shupe, Thomas D., additional, Soker, Shay, additional, Yoo, James J., additional, and Atala, Anthony, additional

Published
2015
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47. Cell and organ bioengineering technology as applied to gastrointestinal diseases.

Author

UCL - SSS/IREC/CHEX - Pôle de chirgurgie expérimentale et transplantation, UCL - (SLuc) Service de chirurgie et transplantation abdominale, Orlando, Giuseppe, Bendala, Juan Domínguez, Shupe, Thomas, Bergman, Christopher, Bitar, Khalil N, Booth, Christopher, Carbone, Marco, Koch, Kenneth L, Lerut, Jan, Neuberger, James M, Petersen, Bryon, Ricordi, Camillo, Atala, Anthony, Stratta, Robert J, Soker, Shay, UCL - SSS/IREC/CHEX - Pôle de chirgurgie expérimentale et transplantation, UCL - (SLuc) Service de chirurgie et transplantation abdominale, Orlando, Giuseppe, Bendala, Juan Domínguez, Shupe, Thomas, Bergman, Christopher, Bitar, Khalil N, Booth, Christopher, Carbone, Marco, Koch, Kenneth L, Lerut, Jan, Neuberger, James M, Petersen, Bryon, Ricordi, Camillo, Atala, Anthony, Stratta, Robert J, and Soker, Shay

Abstract

This review illustrates promising regenerative medicine technologies that are being developed for the treatment of gastrointestinal diseases. The main strategies under validation to bioengineer or regenerate liver, pancreas, or parts of the digestive tract are twofold: engineering of progenitor cells and seeding of cells on supporting scaffold material. In the first case, stem cells are initially expanded under standard tissue culture conditions. Thereafter, these cells may either be delivered directly to the tissue or organ of interest, or they may be loaded onto a synthetic or natural three-dimensional scaffold that is capable of enhancing cell viability and function. The new construct harbouring the cells usually undergoes a maturation phase within a bioreactor. Within the bioreactor, cells are conditioned to adopt a phenotype similar to that displayed in the native organ. The specific nature of the scaffold within the bioreactor is critical for the development of this high-function phenotype. Efforts to bioengineer or regenerate gastrointestinal tract, liver and pancreas have yielded promising results and have demonstrated the immense potential of regenerative medicine. However, a myriad of technical hurdles must be overcome before transplantable, engineered organs become a reality.

Published
2013

48. Inhibition of Notch signaling affects hepatic oval cell response in rat model of 2AAF-PH

Author

Darwiche,Houda, Oh,Seh-Hoon, Steiger-Luther,Nicole C, Williams,Jennifer M, Pintilie,Dana G, Shupe,Thomas D, Petersen,Bryon E, Darwiche,Houda, Oh,Seh-Hoon, Steiger-Luther,Nicole C, Williams,Jennifer M, Pintilie,Dana G, Shupe,Thomas D, and Petersen,Bryon E

Abstract

Houda Darwiche, Seh-Hoon Oh, Nicole C Steiger-Luther, Jennifer M Williams, Dana G Pintilie, Thomas D Shupe, Bryon E PetersenDepartment of Pathology, Immunology, and Laboratory Medicine, Program in Stem Cell Biology and Regenerative Medicine, College of Medicine, University of Florida, Gainesville, FL, USABackground and aims: Activation of the oval cell compartment occurs in the liver when hepatocytes are functionally compromised and/or unable to divide. Our goal was to investigate the systemic signals responsible for determining the efficiency of oval cell-mediated liver regeneration, focusing on the Notch signaling cascade.Methods: The established oval cell induction protocol of 2-acetylaminofluorine (2-AAF) implantation followed by 70% surgical resection of the liver (partial hepatectomy, PH) was employed in a rat model. This oval cell induction model was further combined with injections of a γ-secretase inhibitor (GSI XX) to examine the effects of Notch inhibition on oval cell-aided regeneration of the liver.Results: Notch signaling was found to be upregulated at the peak of oval cell induction during 2AAF-PH alone. Treatment with GSI XX led to interruption of the Notch signal, as shown by a decrease in expression of Hes1. While there was a robust oval cell response seen at day 11 post-PH, there was a measurable delay in differentiation when Notch was inhibited. This was confirmed morphologically as well as by immunohistochemistry for the oval cell markers, α-fetoprotein, OV-6, and CK19. The hepatocytes seen at day 22 demonstrated an enhanced hepatocellular mitoinhibition index (p21Waf1/Ki67), suggestive of dysregulated proliferation and cell cycle progression. Moreover, these hepatocytes exhibited decreased expression of hepatocyte functional markers, such as cytochrome P450 and glucose-6-phosphatase-α.Conclusion: Taken together, these results identify the Notch signaling pathway as a potent regulator of differentiation and prolifer

Published
2011

49. ag) Isolation and characterization of hepatic stem cells, or 'oval cells,' from rat livers.

Author

Shupe, Thomas D., Piscaglia, Anna Chiara, Oh, Seh Hoon, Gasbarrini, Antonio, Petersen, Bryon E., Gasbarrini, Antonio (ORCID:0000-0002-7278-4823), Shupe, Thomas D., Piscaglia, Anna Chiara, Oh, Seh Hoon, Gasbarrini, Antonio, Petersen, Bryon E., and Gasbarrini, Antonio (ORCID:0000-0002-7278-4823)

Abstract

The pace of research on the potential therapeutic uses of liver stem cells or "oval cells" has accelerated significantly in recent years. Concurrent advancements in techniques for the isolation and characterization of these cells have helped fuel this research. Several models now exist for the induction of oval cell proliferation in rodents. Protocols for the isolation and culture of these cells have evolved to the point that they may be set up in any laboratory equipped for cell culture. The advent of magnetic cell sorting has eliminated reliance on expensive flow cytometric sorting equipment to generate highly enriched populations of oval cells. Our laboratory has had much success in using the oval cell surface marker Thy-1 in combination with magnetic sorting to produce material suitable for testing the influence of a myriad of chemical signaling molecules on the oval cell phenotype. This chapter will describe our basic strategy for oval cell induction and isolation. Additionally, two in vitro procedures are described which the reader may find useful in the early stages of developing an oval cell research project.

Published
2009

50. Stem cells, cancer, liver, and liver cancer stem cells: finding a way out of the labyrinth...

Author

Piscaglia, Anna Chiara, Shupe, Thoma, Petersen, Bryon, Gasbarrini, Antonio, Shupe, Thomas, Gasbarrini, Antonio (ORCID:0000-0002-7278-4823), Piscaglia, Anna Chiara, Shupe, Thoma, Petersen, Bryon, Gasbarrini, Antonio, Shupe, Thomas, and Gasbarrini, Antonio (ORCID:0000-0002-7278-4823)

Abstract

Subsequent to an initiating event, tumor promotion requires sustained cell proliferation to allow for progressive accumulation of pro-oncogenic mutations. The unique characteristics of stem cells would seem to implicate these cells as particularly suitable targets for carcinogens. Several lines of evidence suggest that tumors harbor a small population of cancer stem cells (CSC) which both give rise to the bulk of the tumor and are tumorigenic in experimental models. Mounting evidence suggests that these cells are responsible for re-growth of a tumor following unsuccessful treatment and for the establishment of metastases. The concept of CSC has been demonstrated in several human cancers including leukemia, breast, prostate, lung, and brain tumors. Taken together, the properties of CSC suggest that they are appropriate targets for cancer therapies. Such treatments would require a deep understanding of the CSC origin, molecular profile, and interaction with the local microenvironment. This report will summarize what is currently known regarding CSC, with particular emphasis on hepatic cancers, the cellular origin of liver tumors, and the role of liver stem cells and their niche in hepatocarcinogenesis.

Published
2007

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