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1. Enhanced stability and clinical absorption of a form of encapsulated vitamin A for food fortification

Author

Tang, Wen, Zhuang, Jia, Anselmo, Aaron C., Xu, Xian, Duan, Aranda, Zhang, Ruojie, Sugarman, James L., Zeng, Yingying, Rosenberg, Evan, Graf, Tyler, McHugh, Kevin J., Tzeng, Stephany Y., Behrens, Adam M., Freed, Lisa E., Jing, Lihong, Jayawardena, Surangi, Weinstock, Shelley B., Le, Xiao, Sears, Christopher, Oxley, James, Daristotle, John L., Collins, Joe, Langer, Robert, and Jaklenec, Ana

Published
2022

8. Continuous neural control of a bionic limb restores biomimetic gait after amputation

Author

Song, Hyungeun, Hsieh, Tsung-Han, Yeon, Seong Ho, Shu, Tony, Nawrot, Michael, Landis, Christian F., Friedman, Gabriel N., Israel, Erica A., Gutierrez-Arango, Samantha, Carty, Matthew J., Freed, Lisa E., and Herr, Hugh M.

Abstract

For centuries scientists and technologists have sought artificial leg replacements that fully capture the versatility of their intact biological counterparts. However, biological gait requires coordinated volitional and reflexive motor control by complex afferent and efferent neural interplay, making its neuroprosthetic emulation challenging after limb amputation. Here we hypothesize that continuous neural control of a bionic limb can restore biomimetic gait after below-knee amputation when residual muscle afferents are augmented. To test this hypothesis, we present a neuroprosthetic interface consisting of surgically connected, agonist–antagonist muscles including muscle-sensing electrodes. In a cohort of seven leg amputees, the interface is shown to augment residual muscle afferents by 18% of biologically intact values. Compared with a matched amputee cohort without the afferent augmentation, the maximum neuroprosthetic walking speed is increased by 41%, enabling equivalent peak speeds to persons without leg amputation. Further, this level of afferent augmentation enables biomimetic adaptation to various walking speeds and real-world environments, including slopes, stairs and obstructed pathways. Our results suggest that even a small augmentation of residual muscle afferents restores biomimetic gait under continuous neuromodulation in individuals with leg amputation.

Published
2024
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11. Acquisition of Surface EMG Using Flexible and Low-Profile Electrodes for Lower Extremity Neuroprosthetic Control

Author

Program in Media Arts and Sciences (Massachusetts Institute of Technology), Yeon, Seong Ho, Shu, Tony, Song, Hyungeun, Hsieh, Tsung-Han, Qiao, Junqing, Rogers, Emily A, Gutierrez-Arango, Samantha, Israel, Erica, Freed, Lisa E, Herr, Hugh M, Program in Media Arts and Sciences (Massachusetts Institute of Technology), Yeon, Seong Ho, Shu, Tony, Song, Hyungeun, Hsieh, Tsung-Han, Qiao, Junqing, Rogers, Emily A, Gutierrez-Arango, Samantha, Israel, Erica, Freed, Lisa E, and Herr, Hugh M

Abstract

For persons with lower extremity (LE) amputation, acquisition of surface electromyography (sEMG) from within the prosthetic socket remains a significant challenge due to the dynamic loads experienced during the gait cycle. However, these signals are critical for both understanding the clinical effects of LE amputation and determining the desired control trajectories of active LE prostheses. Current solutions for collecting within-socket sEMG are generally (i) incompatible with a subject's prescribed prosthetic socket and liners, (ii) uncomfortable, and (iii) expensive. This study presents an alternative within-socket sEMG acquisition paradigm using a novel flexible and low-profile electrode. First, the practical performance of this Sub-Liner Interface for Prosthetics (SLIP) electrode is compared to that of commercial Ag/AgCl electrodes within a cohort of subjects without amputation. Then, the corresponding SLIP electrode sEMG acquisition paradigm is implemented in a single subject with unilateral transtibial amputation performing unconstrained movements and walking on level ground. Finally, a quantitative questionnaire characterizes subjective comfort for SLIP electrode and commercial Ag/AgCl electrode instrumentation setups. Quantitative analyses suggest comparable signal qualities between SLIP and Ag/AgCl electrodes while qualitative analyses suggest the feasibility of using the SLIP electrode for real-time sEMG data collection from load-bearing, ambulatory subjects with LE amputation.

Published
2022

12. Agonist-antagonist muscle strain in the residual limb preserves motor control and perception after amputation

Author

Program in Media Arts and Sciences (Massachusetts Institute of Technology), Song, Hyungeun, Israel, Erica A, Gutierrez-Arango, Samantha, Teng, Ashley C, Srinivasan, Shriya S, Freed, Lisa E, Herr, Hugh M, Program in Media Arts and Sciences (Massachusetts Institute of Technology), Song, Hyungeun, Israel, Erica A, Gutierrez-Arango, Samantha, Teng, Ashley C, Srinivasan, Shriya S, Freed, Lisa E, and Herr, Hugh M

Abstract

Abstract Background Elucidating underlying mechanisms in subject-specific motor control and perception after amputation could guide development of advanced surgical and neuroprosthetic technologies. In this study, relationships between preserved agonist-antagonist muscle strain within the residual limb and preserved motor control and perception capacity are investigated. Methods Fourteen persons with unilateral transtibial amputations spanning a range of ages, etiologies, and surgical procedures underwent evaluations involving free-space mirrored motions of their lower limbs. Research has shown that varied motor control in biologically intact limbs is executed by the activation of muscle synergies. Here, we assess the naturalness of phantom joint motor control postamputation based on extracted muscle synergies and their activation profiles. Muscle synergy extraction, degree of agonist-antagonist muscle strain, and perception capacity are estimated from electromyography, ultrasonography, and goniometry, respectively. Results Here, we show significant positive correlations (P < 0.005–0.05) between sensorimotor responses and residual limb agonist-antagonist muscle strain. Identified trends indicate that preserving even 20–26% of agonist-antagonist muscle strain within the residuum compared to a biologically intact limb is effective in preserving natural motor control postamputation, though preserving limb perception capacity requires more (61%) agonist-antagonist muscle strain preservation. Conclusions The results suggest that agonist-antagonist muscle strain is a characteristic, readily ascertainable residual limb structural feature that can help explain variability in amputation out

Published
2022

17. Neural interfacing architecture enables enhanced motor control and residual limb functionality postamputation

Author

Massachusetts Institute of Technology. Center for Extreme Bionics, Harvard University--MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology. Department of Mechanical Engineering, Srinivasan, Shriya S, Gutierrez-Arango, Samantha, Teng, Ashley Chia-En, Israel, Erica, Song, Hyungeun, Bailey, Zachary Keith, Carty, Matthew J, Freed, Lisa E, Herr, Hugh M, Massachusetts Institute of Technology. Center for Extreme Bionics, Harvard University--MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology. Department of Mechanical Engineering, Srinivasan, Shriya S, Gutierrez-Arango, Samantha, Teng, Ashley Chia-En, Israel, Erica, Song, Hyungeun, Bailey, Zachary Keith, Carty, Matthew J, Freed, Lisa E, and Herr, Hugh M

Abstract

Despite advancements in prosthetic technologies, patients with amputation today suffer great diminution in mobility and quality of life. We have developed a modified below-knee amputation (BKA) procedure that incorporates agonist-antagonist myoneural interfaces (AMIs), which surgically preserve and couple agonist-antagonist muscle pairs for the subtalar and ankle joints. AMIs are designed to restore physiological neuromuscular dynamics, enable bidirectional neural signaling, and offer greater neuroprosthetic controllability compared to traditional amputation techniques. In this prospective, nonrandomized, unmasked study design, 15 subjects with AMI below-knee amputation (AB) were matched with 7 subjects who underwent a traditional below-knee amputation (TB). AB subjects demonstrated significantly greater control of their residual limb musculature, production of more differentiable efferent control signals, and greater precision of movement compared to TB subjects (P < 0.008). This may be due to the presence of greater proprioceptive inputs facilitated by the significantly higher fascicle strains resulting from coordinated muscle excursion in AB subjects (P < 0.05). AB subjects reported significantly greater phantom range of motion postamputation (AB: 12.47 ± 2.41, TB: 10.14 ± 1.45 degrees) when compared to TB subjects (P < 0.05). Furthermore, AB subjects also reported less pain (12.25 ± 5.37) than TB subjects (17.29 ± 10.22) and a significant reduction when compared to their preoperative baseline (P < 0.05). Compared with traditional amputation, the construction of AMIs during amputation confers the benefits of enhanced physiological neuromuscular dynamics, proprioception, and phantom limb perception. Subjects' activation of the AMIs produces more differentiable electromyography (EMG) for myoelectric prosthesis control and demonstrates more positive clinical outcomes.

Published
2021

18. Multi-Material Tissue Engineering Scaffold with Hierarchical Pore Architecture

Author

Harvard University--MIT Division of Health Sciences and Technology, Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology. Institute for Medical Engineering & Science, Morgan, Kathy Ye, Sklaviadis, Demetra, Tochka, Zachary L, Fischer, Kristin M, Hearon, Keith, Morgan, Thomas D, Langer, Robert, Freed, Lisa E, Harvard University--MIT Division of Health Sciences and Technology, Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology. Institute for Medical Engineering & Science, Morgan, Kathy Ye, Sklaviadis, Demetra, Tochka, Zachary L, Fischer, Kristin M, Hearon, Keith, Morgan, Thomas D, Langer, Robert, and Freed, Lisa E

Abstract

© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Multi-material polymer scaffolds with multiscale pore architectures are characterized and tested with vascular and heart cells as part of a platform for replacing damaged heart muscle. Vascular and muscle scaffolds are constructed from a new material, poly(limonene thioether) (PLT32i), which meets the design criteria of slow biodegradability, elastomeric mechanical properties, and facile processing. The vascular–parenchymal interface is a poly(glycerol sebacate) (PGS) porous membrane that meets different criteria of rapid biodegradability, high oxygen permeance, and high porosity. A hierarchical architecture of primary (macroscale) and secondary (microscale) pores is created by casting the PLT32i prepolymer onto sintered spheres of poly(methyl methacrylate) (PMMA) within precisely patterned molds followed by photocuring, de-molding, and leaching out the PMMA. Prefabricated polymer templates are cellularized, assembled, and perfused in order to engineer spatially organized, contractile heart tissue. Structural and functional analyses show that the primary pores guide heart cell alignment and enable robust perfusion while the secondary pores increase heart cell retention and reduce polymer volume fraction.

Published
2021

19. Combined Technologies for Microfabricating Elastomeric Cardiac Tissue Engineering Scaffolds

Author

Harvard University--MIT Division of Health Sciences and Technology, Guillemette, Maxime D., Park, Hyoungshin, Hsiao, James C., Jain, Saloni R., Larson, Benjamin L., Langer, Robert S, Freed, Lisa E, Harvard University--MIT Division of Health Sciences and Technology, Guillemette, Maxime D., Park, Hyoungshin, Hsiao, James C., Jain, Saloni R., Larson, Benjamin L., Langer, Robert S, and Freed, Lisa E

Abstract

Polymer scaffolds that direct elongation and orientation of cultured cells can enable tissue engineered muscle to act as a mechanically functional unit. We combined micromolding and microablation technologies to create muscle tissue engineering scaffolds from the biodegradable elastomer poly(glycerol sebacate). These scaffolds exhibited well defined surface patterns and pores and robust elastomeric tensile mechanical properties. Cultured C2C12 muscle cells penetrated the pores to form spatially controlled engineered tissues. Scanning electron and confocal microscopy revealed muscle cell orientation in a preferential direction, parallel to micromolded gratings and long axes of microablated anisotropic pores, with significant individual and interactive effects of gratings and pore design.Micropatterning and microablation technologies were combined in the context of the biodegradable elastomer PGS to create a muscle tissue engineering scaffold. Scaffolds enabled cultured muscle cells to preferentially align in parallel to linear gratings and pore edges, with significant individual and interactive effects of surface topography and anisotropic pore design. Copyright © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim., American Recovery and Reinvestment Act - ARRA (1-R01-HL086521-01A2), NIH (DE013023), NSF (BES-0609182)

Published
2021

21. List of Contributors

Author

Bowles, Robby D., primary, (Tony) Smith, Anthony J., additional, Ahlstrom, Jon D., additional, Albon, Julie, additional, Alexander, Peter G., additional, Altschuler, Richard A., additional, Alvarez, Pedro, additional, Amendola, A., additional, Anatol, Rachael, additional, Annabi, Nasim, additional, Anversa, Piero, additional, Arcidiacono, Judith, additional, Atala, Anthony, additional, Athanasiou, Kyriacos A., additional, Auger, François A., additional, Auguste, Debra T., additional, Awad, Hani A., additional, Badylak, Stephen F., additional, Bailey, Alexander M., additional, Barry, Michael P., additional, Becker, Daniel, additional, Belegu, Visar, additional, Bernhard, Jonathan, additional, Bertram, Timothy, additional, Besnard, Valérie, additional, Bhat, Z.F., additional, Bhat, Hina, additional, Bhatia, Sangeeta N., additional, Bhumiratana, Sarindr, additional, Bianco, Paolo, additional, Blackburn, Catherine Clare, additional, Bollenbach, Thomas, additional, Bonassar, Lawrence A., additional, Boulton, Mike, additional, Bradshaw, Amy D., additional, Breuer, Christopher K., additional, Brewster, Luke, additional, Brey, Eric M., additional, Brittan, Mairi, additional, Brown, Bryan N., additional, Brown, T., additional, Buckwalter, J.A., additional, Buffington, Deborah, additional, Burg, Karen J.L., additional, Burg, Timothy C., additional, Chabaud, Stéphane, additional, Swi Chang, Thomas Ming, additional, Chang, Yunchao, additional, Chapman, Robert G., additional, Chen, Fa-Ming, additional, Chen, Una, additional, Cimetta, Elisa, additional, Clark, Richard A.F., additional, Clark, Karen L., additional, Cleary, Muriel A., additional, Cloutier, Réjean, additional, Colton, Clark K., additional, Cotsarelis, George, additional, Crystal, Ronald G., additional, Dagnelie, Gislin, additional, da Silva Ferreira, Lino, additional, Davidson, Jeffrey M., additional, Deuel, Thomas F., additional, Direkze, Natalie, additional, Dressler, Gregory R., additional, Durfor, Charles N., additional, Duvall, Craig L., additional, Eng, George, additional, Engelmayr, George, additional, Eschenhagen, Thomas, additional, Eu-Kien Wong, Mark, additional, Falanga, Vincent, additional, Faria, Katie, additional, Faustman, Denise L., additional, Fauza, Dario O., additional, Feng, Qiang, additional, Ferreira, Lino, additional, Fink, Donald W., additional, Fissell, William, additional, Freed, Lisa E., additional, Furth, Mark E., additional, Gay, Denise, additional, Gerecht-Nir, Sharon, additional, Germain, Lucie, additional, Gersbach, Charles A., additional, Goulet, Francine, additional, Goyal, Ritu, additional, Grant, Maria B., additional, Greisler, Howard P., additional, Guilak, Farshid, additional, Harley, Brendan A.C., additional, Hart, David A., additional, Hmadcha, Abdelkrim, additional, Hodges, Steve J., additional, Hofer, Heidi R., additional, Hollinger, Jeffrey O., additional, Holobaugh, Patricia, additional, Hubbell, Jeffrey A., additional, Humes, H. David, additional, Ingber, Donald E., additional, Inskeep, Beau, additional, Jiang, Xingyu, additional, Kajstura, Jan, additional, Kane, Ravi S., additional, Karp, Jeffrey M., additional, Kasper, F. Kurtis, additional, Khademhosseini, Ali, additional, Kili, Sven, additional, Kimbrel, Erin A., additional, Klimanskaya, Irina, additional, Kohn, Joachim, additional, Kunisaki, Shaun M., additional, Kyriakides, Themis R., additional, Lagasse, Eric, additional, Lamontagne, Jean, additional, Langer, Robert, additional, Lanza, Robert, additional, Lecht, Shimon, additional, Lee, Benjamin W., additional, Lee, Chang H., additional, Lee, Mark H., additional, Lelkes, Peter I., additional, Leri, Annarosa, additional, Levine, David W., additional, Li, Feng, additional, Longaker, Michael T., additional, López, Javier, additional, Lu, Shi-Jiang, additional, Luo, Ying, additional, MacArthur, Ben D., additional, Manley, Nancy Ruth, additional, Manohar, Rohan, additional, Mansbridge, Jonathan, additional, Mantalaris, Athanasios, additional, Mao, Jeremy J., additional, Marsh, J.L., additional, Martin, David C., additional, Martin, J.A., additional, Martins-Green, M., additional, Masuda, Koichi, additional, Maxfield, Mark W., additional, McCabe, Kathryn L., additional, McDonald, John W., additional, McFarland, Richard, additional, Mikos, Antonios G., additional, Millán, José del R., additional, Miller, Josef M., additional, Mills, Shari, additional, Moffat, Kristen L., additional, Mondrinos, Mark J., additional, Montoro, Daniel T., additional, Moore, Malcolm A.S., additional, Neal, Rebekah A., additional, Nerem, Robert M., additional, Ng, Shengyong, additional, Nowell, Craig Scott, additional, Obokata, Haruko, additional, Olsen, Bjorn Reino, additional, Oreffo, Richard O.C., additional, O’Keefe, Regis J., additional, O’Neill, Kathy, additional, Ortiz, Ophir, additional, Pan, Carolyn K., additional, Pathak, Vikas, additional, Petreaca, M., additional, Pezzolla, Daniela, additional, Plikus, Maksim V., additional, Polak, Julia M., additional, Post, Mark, additional, Preston, Sean, additional, Prokop, Aleš, additional, Radisic, Milica, additional, Ranghini, Egon, additional, Raphael, Yehoash, additional, Reddi, A.H., additional, Reichenspurner, Herrmann, additional, Richie, Ellen, additional, Robey, Pamela Gehron, additional, Robinson, Becky, additional, Rojas, Anabel, additional, Roy, Shuvo, additional, Russell, Alan J., additional, Saigal, Rajiv, additional, Saltzman, W. Mark, additional, Samadikuchaksaraei, Ali, additional, Sambanis, Athanassios, additional, Schacht, Jochen, additional, Schutte, Stacey C., additional, Schutte, Lyndsey, additional, Schwartz, Steven D., additional, Schwartz, Robert E., additional, Setton, Lori A., additional, Sha, Su-Hua, additional, Shan, Jing, additional, Sharpe, Paul T., additional, Shi, Songtao, additional, Shrivats, Arun R., additional, Simon, Franck, additional, Sirabella, Dario, additional, Slack, J.M.W., additional, Soria, Bernat, additional, Spicer, Patrick, additional, Stevens, Kelly R., additional, Stockdale, Frank E., additional, Christiaan Stronks, H., additional, Studer, Lorenz, additional, Takayama, Shuichi, additional, Thomson, James A., additional, Trachtenberg, Jordan E., additional, Treffeisen, Elsa, additional, Tuan, Rocky S., additional, Vacanti, Charles A., 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, Westover, Angela J., additional, Whitesides, George M., additional, Whitsett, Jeffrey A., additional, Winitsky, Steve, additional, Witten, Celia, additional, Worgall, Stefan, additional, Wright, Nicholas A., additional, Yannas, Ioannis V., additional, Young, Simon, additional, Yu, Junying, additional, Zhang, Zheng, additional, Zheng, Wenfu, additional, Zimmermann, Wolfram Hubertus, additional, and Zoloth, Laurie, additional

Published
2014
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22. Functional assembly of engineered myocardium by electrical stimulation of cardiac myocytes cultured on scaffolds

Author

Radisic, Milica, Park, Hyoungshin, Park, Shing, Helen, Consi, Thomas, Schoen, Frederick J., Langer, Robert, Freed, Lisa E., and Vunjak-Novakovic, Gordana

Subjects
Tissue engineering -- Analysis, Heart muscle, Science and technology
Abstract

The major challenge of tissue engineering is directing the cells to establish the physiological structure and function of the tissue being replaced across different hierarchical scales. To engineer myocardium, biophysical regulation of the cells needs to recapitulate multiple signals present in the native heart. We hypothesized that excitation-contraction coupling, critical for the development and function of a normal heart, determines the development and function of engineered myocardium. To induce synchronous contractions of cultured cardiac constructs, we applied electrical signals designed to mimic those in the native heart. Over only 8 days in vitro, electrical field stimulation induced cell alignment and coupling, increased the amplitude of synchronous construct contractions by a factor of 7, and resulted in a remarkable level of ultrastructural organization. Development of conductive and contractile properties of cardiac constructs was concurrent, with strong dependence on the initiation and duration of electrical stimulation. contraction | excitation | tissue engineering | ultrastructure | heart

Published
2004

23. Medium perfusion enables engineering of compact and contractile cardiac tissue

Author

Radisic, Milica, Yang, Liming, Boublik, Jan, Cohen, Richard J., Langer, Robert, Freed, Lisa E., and Vunjak-Novakovic, Gordana

Subjects
Cardiology -- Research, Proteins -- Research, Biological sciences
Abstract

We hypothesized that functional constructs with physiological cell densities can be engineered in vitro by mimicking convective-diffusive oxygen transport normally present in vivo. To test this hypothesis, we designed an in vitro culture system that maintains efficient oxygen supply to the cells at all times during cell seeding and construct cultivation and characterized in detail construct metabolism, structure, and function. Neonatal rat cardiomyocytes suspended in Matrigel were cultured on collagen sponges at a high initial density (1.35 X [10.sup.8] cells/[cm.sup.3]) for 7 days with interstitial flow of medium; constructs cultured in orbitally mixed dishes, neonatal rat ventricles, and freshly isolated cardiomyocytes served as controls. Constructs were assessed at timed intervals with respect to cell number, distribution, viability, metabolic activity, cell cycle, presence of contractile proteins (sarcomeric [alpha]-actin, troponin I, and tropomyosin), and contractile function in response to electrical stimulation [excitation threshold (ET), maximum capture rate (MCR), response to a gap junctional blocker]. Interstitial flow of culture medium through the central 5-mm-diameter x 1.5-mm-thick region resulted in a physiological density of viable and differentiated, aerobically metabolizing cells, whereas dish culture resulted in constructs with only a 100--to 200-[micro]m-thick surface layer containing viable and differentiated but anaerobically metabolizing cells around an acellular interior. Perfusion resulted in significantly higher numbers of live cells, higher cell viability, and significantly more cells in the S phase compared with dish-grown constructs. In response to electrical stimulation, perfused constructs contracted synchronously, had lower ETs, and recovered their baseline function levels of ET and MCR after treatment with a gap junctional blocker; dish-grown constructs exhibited arrhythmic contractile patterns and failed to recover their baseline MCR levels. tissue engineering; cardiac muscle; contractile proteins; contractile function

Published
2004

27. CONTRIBUTORS

Author

Ahlstrom, Jon D., primary, Altschuler, Richard A., additional, Amendola, A., additional, Anderson, David J., additional, Anversa, Piero, additional, Atala, Anthony, additional, Athanasiou, Kyriacos A., additional, Auger, François A., additional, Auguste, Debra T., additional, Bearzi, Claudia, additional, Becker, Daniel, additional, Bedoya, Francisco J., additional, Bell, Eugene, additional, Bertram, Timothy, additional, Besnard, Valérie, additional, Bettinger, Christopher J., additional, Bhatia, Sangeeta N., additional, Bianco, Paolo, additional, Bishop, Anne E., additional, Blackburn, C. Clare, additional, Bohrer, Michael P., additional, Bolli, Roberto, additional, Bonassar, Lawrence J., additional, Borenstein, Jeffrey T., additional, Boulton, Michael E., additional, Bradshaw, Amy D., additional, Brewster, Luke, additional, Brey, Eric M., additional, Brittan, Mairi, additional, Brown, T., additional, Bruder, Scott P., additional, Buckwalter, Joseph A., additional, Cannizzaro, Christopher, additional, Cao, Yilin, additional, Cathey, Lamont, additional, Chang, Thomas M.S., additional, Chang, Yunchao, additional, Chapman, Robert G., additional, Chen, Alice A., additional, Chen, Faye H., additional, Chen, Una, additional, Clark, Richard A.F., additional, Colton, Clark K., additional, Cowin, Stephen C., additional, Crystal, Ronald, additional, Dagnelie, Gislin, additional, Davidson, Jeffrey M., additional, Deuel, Thomas F., additional, Deweerd, Elizabeth, additional, Dressler, Gregory R., additional, Engelmayr, George C., additional, Erickson, Carol A., additional, Eschenhagen, Thomas, additional, Falanga, Vincent, additional, Faria, Katie, additional, Faustman, Denise L., additional, Fauza, Dario O., additional, Ferreira, Lino da Silva, additional, Fong, Hanson K., additional, Fong, Peter, additional, Freed, Lisa E., additional, Freshney, R.I., additional, Furth, Mark E., additional, Geesin, Jeffrey, additional, Gerecht, Sharon, additional, Germain, Lucie, additional, Ghosh, Kaustabh, additional, Giannobile, William V., additional, Goulet, Francine, additional, Grant, Maria B., additional, Grayson, Warren, additional, Greisler, Howard P., additional, Guilak, Farshid, additional, Halberstadt, Craig, additional, Harley, Brendan, additional, Hellman, Kiki B., additional, Hmadcha, Abdelkrim, additional, Hodges, Steve J., additional, Holder, Walter D., additional, Holy, Chantal E., additional, Hosoda, Toru, additional, Hubbell, Jeffrey A., additional, Humes, H. David, additional, Ingber, Donald E., additional, Jaklenec, Ana, additional, Jun, Hee-Sook, additional, Kajstura, Jan, additional, Kane, Ravi S., additional, Karp, Jeffrey M., additional, Kay, John, additional, Khademhosseini, Ali, additional, Khetani, Salman R., additional, Kohn, Joachim, additional, Kunisaki, Shaun M., additional, Kwan, Matthew D., additional, Kyriakides, Themis R., additional, Lagasse, Eric, additional, Langer, Robert, additional, Lauffenburger, Douglas A., additional, Yong Lee, Kuen, additional, Leri, Annarosa, additional, Levine, David W., additional, Lewis, Amy S., additional, Li, Wan-Ju, additional, Liu, Wei, additional, Longaker, Michael T., additional, Luo, Ying, additional, Lysaght, Michael J., additional, Manley, Nancy Ruth, additional, Mansbridge, Jonathan, additional, Marsh, J.L., additional, Martin, David C., additional, Martin, J.A., additional, Martins-Green, Manuela, additional, Masuda, Koichi, additional, Mauck, Robert L., additional, McDonald, John W., additional, Mikos, Antonios G., additional, Miller, Josef M., additional, Mooney, David J., additional, Moore, Malcolm A.S., additional, Murphy, Matthew B., additional, Nerem, Robert M., additional, Nikovits, William, additional, Nowell, Craig Scott, additional, Obradovic, Bojana, additional, Olsen, Bjorn R., additional, Pachence, James M., additional, Park, Hyoungshin, additional, Park, Jason, additional, Petreaca, M., additional, Polak, Julia M., additional, Poole, A. Robin, additional, Potten, Christopher S., additional, Prokop, Ales, additional, Radisic, Milica, additional, Raphael, Yehoash, additional, Reddi, A. Hari, additional, Reichenspurner, Herrmann, additional, Richie, Ellen, additional, Robey, Pamela G., additional, Rota, Marcello, additional, Ruberti, Jeffrey W., additional, Russell, Alan J., additional, Sage, E. Helene, additional, Saigal, Rajiv, additional, Saltzman, W. Mark, additional, Sambanis, Athanassios, additional, Schacht, Jochen, additional, Setton, Lori A., additional, Sharma, Upma, additional, Sharpe, Paul T., additional, Slack, Jonathan M.W., additional, Smith, Anthony J., additional, Somerman, Martha J., additional, Song, Lin, additional, Soria, Bernat, additional, Stockdale, Frank E., additional, Studer, Lorenz, additional, Takayama, Shuichi, additional, Tejedo, Juan R., additional, Trinkaus-Randall, Vickery, additional, Trounson, Alan, additional, Tuan, Rocky S., additional, Underhill, Gregory H., additional, Urbanek, Konrad, additional, Vacanti, Charles A., additional, Vacanti, Joseph, additional, Volenec, F. Jerry, additional, Vunjak-Novakovic, Gordana, additional, Wahlberg, Lars U., additional, Wan, Derrick C., additional, Whitesides, George M., additional, Whitsett, Jeffrey A., additional, Wilson, James W., additional, Worgall, Stefan, additional, Wong, Mark E.K., additional, Wright, Nicholas A., additional, Yannas, Ioannis V., additional, Yoon, Ji-Won, additional, Young, Simon, additional, Zhang, Hai, additional, Zhang, Wenjie, additional, Zielinski, Beth A., additional, Zieske, James D., additional, Zimmermann, Wolfram-Hubertus, additional, and Zoloth, Laurie, additional

Published
2007
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30. Oscillating Cell Culture Bioreactor

Author

Freed, Lisa E, Cheng, Mingyu, and Moretti, Matteo G

Subjects
Man/System Technology And Life Support
Abstract

To better exploit the principles of gas transport and mass transport during the processes of cell seeding of 3D scaffolds and in vitro culture of 3D tissue engineered constructs, the oscillatory cell culture bioreactor provides a flow of cell suspensions and culture media directly through a porous 3D scaffold (during cell seeding) and a 3D construct (during subsequent cultivation) within a highly gas-permeable closed-loop tube. This design is simple, modular, and flexible, and its component parts are easy to assemble and operate, and are inexpensive. Chamber volume can be very low, but can be easily scaled up. This innovation is well suited to work with different biological specimens, particularly with cells having high oxygen requirements and/or shear sensitivity, and different scaffold structures and dimensions. The closed-loop changer is highly gas permeable to allow efficient gas exchange during the cell seeding/culturing process. A porous scaffold, which may be seeded with cells, is fixed by means of a scaffold holder to the chamber wall with scaffold/construct orientation with respect to the chamber determined by the geometry of the scaffold holder. A fluid, with/without biological specimens, is added to the chamber such that all, or most, of the air is displaced (i.e., with or without an enclosed air bubble). Motion is applied to the chamber within a controlled environment (e.g., oscillatory motion within a humidified 37 C incubator). Movement of the chamber induces relative motion of the scaffold/construct with respect to the fluid. In case the fluid is a cell suspension, cells will come into contact with the scaffold and eventually adhere to it. Alternatively, cells can be seeded on scaffolds by gel entrapment prior to bioreactor cultivation. Subsequently, the oscillatory cell culture bioreactor will provide efficient gas exchange (i.e., of oxygen and carbon dioxide, as required for viability of metabolically active cells) and controlled levels of fluid dynamic shear (i.e., as required for viability of shear-sensitive cells) to the developing engineered tissue construct. This bioreactor was recently utilized to show independent and interactive effects of a growth factor (IGF-I) and slow bidirectional perfusion on the survival, differentiation, and contractile performance of 3D tissue engineering cardiac constructs. The main application of this system is within the tissue engineering industry. The ideal final application is within the automated mass production of tissue- engineered constructs. Target industries could be both life sciences companies as well as bioreactor device producing companies.

Published
2010

33. 3D structural patterns in scalable, elastomeric scaffolds guide engineered tissue architecture

Author

Harvard University--MIT Division of Health Sciences and Technology, Kolewe, Martin E., Park, Hyoungshin, Gray, Caprice, Ye, Xiaofeng, Langer, Robert, Freed, Lisa E., Harvard University--MIT Division of Health Sciences and Technology, Kolewe, Martin E., Park, Hyoungshin, Gray, Caprice, Ye, Xiaofeng, Langer, Robert, and Freed, Lisa E.

Abstract

Microfabricated elastomeric scaffolds with 3D structural patterns are created by semiautomated layer-by-layer assembly of planar polymer sheets with through-pores. The mesoscale interconnected pore architectures governed by the relative alignment of layers are shown to direct cell and muscle-like fiber orientation in both skeletal and cardiac muscle, enabling scale up of tissue constructs towards clinically relevant dimensions. ©2013, National Heart, Lung and Blood Institute (award: 1-R01-HL107503)

Published
2020

34. Effects of Bone Morphogenic Proteins on Engineered Cartilage

Author

Gooch, Keith, J, Blunk, Torsten, Courter, Donald L, Sieminski, Alisha, Vunjak-Novakovic, Gordana, and Freed, Lisa E

Subjects
Man/System Technology And Life Support
Abstract

A report describes experiments on the effects of bone morphogenic proteins (BMPs) on engineered cartilage grown in vitro. In the experiments, bovine calf articular chondrocytes were seeded onto biodegradable polyglycolic acid scaffolds and cultured in, variously, a control medium or a medium supplemented with BMP-2, BMP-12, or BMP-13 in various concentrations. Under all conditions investigated, cell-polymer constructs cultivated for 4 weeks macroscopically and histologically resembled native cartilage. At a concentration of 100 ng/mL, BMP-2, BMP-12, or BMP-13 caused (1) total masses of the constructs to exceed those of the controls by 121, 80, or 62 percent, respectively; (2) weight percentages of glycosaminoglycans in the constructs to increase by 27, 18, or 15, respectively; and (3) total collagen contents of the constructs to decrease to 63, 89, or 83 percent of the control values, respectively. BMP-2, but not BMP-12 or BMP-13, promoted chondrocyte hypertrophy. These observations were interpreted as suggesting that the three BMPs increase the growth rates and modulate the compositions of engineered cartilage. It was also concluded that in vitro engineered cartilage is a suitable system for studying effects of BMPs on chondrogenesis in a well-defined environment.

Published
2007

35. CONTRIBUTORS

Author

Aebischer, Patrick, primary, Altschuler, Richard A., additional, Ambrosini, Pascal, additional, Anderson, David J., additional, Atala, Anthony, additional, Auger, François A., additional, Avgoustiniatos, Efstathios S., additional, Barnes, David W., additional, Bell, Eugene, additional, Béné, Marie C., additional, Bishop, John G., additional, Bohrer, T., additional, Bonassar, Lawrence J., additional, Bradshaw, Amy D., additional, Brockbank, Kelvin G.M., additional, Browder, Leon W., additional, Bruder, Scott P., additional, Bunge, Mary Bartlett, additional, Caplan, Arnold I., additional, Chang, Thomas Ming Swi, additional, Chapman, Robert G., additional, Chen, Una, additional, Clark, Richard A.F., additional, Cloutier, Réjean, additional, Colton, Clark K., additional, Cousins, Joanne C., additional, Cowin, Stephen C., additional, Dagnelie, Gislin, additional, Deuel, Thomas F., additional, Durfor, Charles N., additional, Edwards, Brian E., additional, Erickson, Carol A., additional, Faure, Gilbert C., additional, Faustman, Denise, additional, Fauza, Dario O., additional, Fine, Eric G., additional, Fradkin, Lee G., additional, Freed, Lisa E., additional, Gaffey, Claudia, additional, Gearhart, John D., additional, Germain, Lucie, additional, Goulet, Francine, additional, Greisler, Howard P., additional, Grodzinsky, Alan J., additional, Halberstadt, Craig R., additional, Hardin-Young, Janet, additional, Hasse, C., additional, Hebrok, Matthias, additional, Hellman, Kiki B., additional, Holder, Walter D., additional, Hsu, Edward, additional, Hubbell, Jeffrey A., additional, Humayun, Mark S., additional, Humes, H. David, additional, Ingber, Donald E., additional, Jauregui, Hugo O., additional, Kamm, Roger D., additional, Kane, Ravi S., additional, Karlsson, Jens O.M., additional, Kessinger, Anne, additional, Kim, Byung-Soo, additional, Kleitman, Naomi, additional, Kohn, Joachim, additional, Kubota, Hiroshi, additional, Lanza, Robert P., additional, Lauffenburger, Douglas A., additional, Lee, Kuen Yong, additional, Lelkes, Peter I., additional, London, Robert E., additional, Love, Jack W., additional, Luntz, Thomas L., additional, Lysaght, Michael J., additional, Macdonald, Jeffrey M., additional, Martins-Green, Manuela, additional, Massof, Robert W., additional, McPherson, John M., additional, Melton, Douglas A., additional, Mikos, Antonios G., additional, Miller, Josef M., additional, Miller, Neal A., additional, Mooney, David J., additional, Morgan, Jennifer E., additional, Moss, Melvin L., additional, Mullon, Claudy, additional, Muratore, Christopher S., additional, Naughton, Gail K., additional, Nerem, Robert M., additional, Olsen, Björn Reino, additional, Organ, Gregory M., additional, Pachence, James M., additional, Parenteau, Nancy L., additional, Partridge, Terence A., additional, Penaud, Jacques, additional, Poole, A. Robin, additional, Rancourt, Denis, additional, Raphael, Yehoash, additional, Reddi, A.H., additional, Reid, Lola M., additional, Ropp, J. Dezz, additional, Ross, Robert N., additional, Rothmund, M., additional, Rutherford, R. Bruce, additional, Sage, E. Helene, additional, Sagen, Jacqueline, additional, Saltzman, W. Mark, additional, Sato, Gordon H., additional, Schacht, Jochen, additional, Shamblott, Michael J., additional, Sharp, Graham, additional, Shung, Albert K., additional, Singer, Adam J., additional, Solomon, Barry A., additional, Solomon, Ruth R., additional, Sullivan, Susan J., additional, Takayama, Shuichi, additional, Teumer, Jeffrey, additional, Thomson, Robert C., additional, Toner, Mehmet, additional, Trinkaus-Randall, Vickery, additional, Tubo, Ross, additional, Unsworth, Brian R., additional, Vacanti, Charles A., additional, Vacanti, Joseph P., additional, Vacanti, Martin P., additional, Valentini, Robert F., additional, Vunjak-Novakovic, Gordana, additional, Wahlberg, Lars U., additional, Wang, Taylor G., additional, Warner, John F., additional, Whitesides, George M., additional, Wilson, Jay M., additional, Wu, Haiyun, additional, Xu, Arron S.L., additional, Xue, Lian, additional, Yannas, Ioannis V., additional, Yaszemski, Michael J., additional, Zhang, Nan, additional, Zielinski, Beth A., additional, Zielke, A., additional, and Zimmerman, U., additional

Published
2000
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37. Tissue Engineering Using Transfected Growth-Factor Genes

Author

Madry, Henning, Langer, Robert S, Freed, Lisa E, Trippel, Stephen, and Vunjak-Novakovic, Gordana

Subjects
Man/System Technology And Life Support
Abstract

A method of growing bioengineered tissues includes, as a major component, the use of mammalian cells that have been transfected with genes for secretion of regulator and growth-factor substances. In a typical application, one either seeds the cells onto an artificial matrix made of a synthetic or natural biocompatible material, or else one cultures the cells until they secrete a desired amount of an extracellular matrix. If such a bioengineered tissue construct is to be used for surgical replacement of injured tissue, then the cells should preferably be the patient s own cells or, if not, at least cells matched to the patient s cells according to a human-leucocyteantigen (HLA) test. The bioengineered tissue construct is typically implanted in the patient's injured natural tissue, wherein the growth-factor genes enhance metabolic functions that promote the in vitro development of functional tissue constructs and their integration with native tissues. If the matrix is biodegradable, then one of the results of metabolism could be absorption of the matrix and replacement of the matrix with tissue formed at least partly by the transfected cells. The method was developed for articular chondrocytes but can (at least in principle) be extended to a variety of cell types and biocompatible matrix materials, including ones that have been exploited in prior tissue-engineering methods. Examples of cell types include chondrocytes, hepatocytes, islet cells, nerve cells, muscle cells, other organ cells, bone- and cartilage-forming cells, epithelial and endothelial cells, connective- tissue stem cells, mesodermal stem cells, and cells of the liver and the pancreas. Cells can be obtained from cell-line cultures, biopsies, and tissue banks. Genes, molecules, or nucleic acids that secrete factors that influence the growth of cells, the production of extracellular matrix material, and other cell functions can be inserted in cells by any of a variety of standard transfection techniques.

Published
2005

41. Use of fibroblast growth factor 2 for expansion of chondrocytes and tissue engineering

Author

Martin, Ivan, Freed, Lisa E, Langer, Robert, and Vunjak-Novakovic, Gordana

Subjects
Life Sciences (General)
Abstract

The present invention provides an improved method for expanding cells for use in tissue engineering. In particular the method provides specific biochemical factors to supplement cell culture medium during the expansion process in order to reproduce events occurring during embryonic development with the goal of regenerating tissue equivalents that resemble natural tissues both structurally and functionally. These specific biochemical factors improve proliferation of the cells and are capable of de-differentiation mature cells isolated from tissue so that the differentiation potential of the cells is preserved. The bioactive molecules also maintain the responsiveness of the cells to other bioactive molecules. Specifically, the invention provides methods for expanding chondrocytes in the presence of fibroblast growth factor 2 for use in regeneration of cartilage tissue.

Published
2003

42. A heat-stable microparticle platform for oral micronutrient delivery

Author

Anselmo, Aaron C., primary, Xu, Xian, additional, Buerkli, Simone, additional, Zeng, Yingying, additional, Tang, Wen, additional, McHugh, Kevin J., additional, Behrens, Adam M., additional, Rosenberg, Evan, additional, Duan, Aranda R., additional, Sugarman, James L., additional, Zhuang, Jia, additional, Collins, Joe, additional, Lu, Xueguang, additional, Graf, Tyler, additional, Tzeng, Stephany Y., additional, Rose, Sviatlana, additional, Acolatse, Sarah, additional, Nguyen, Thanh D., additional, Le, Xiao, additional, Guerra, Ana Sofia, additional, Freed, Lisa E., additional, Weinstock, Shelley B., additional, Sears, Christopher B., additional, Nikolic, Boris, additional, Wood, Lowell, additional, Welkhoff, Philip A., additional, Oxley, James D., additional, Moretti, Diego, additional, Zimmermann, Michael B., additional, Langer, Robert, additional, and Jaklenec, Ana, additional

Published
2019
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43. Chondrogenic, hypertrophic, and osteochondral differentiation of human mesenchymal stem cells on three‐dimensionally woven scaffolds

Author

Larson, Benjamin L., primary, Yu, Sarah N., additional, Park, Hyoungshin, additional, Estes, Bradley T., additional, Moutos, Franklin T., additional, Bloomquist, Cameron J., additional, Wu, Patrick B., additional, Welter, Jean F., additional, Langer, Robert, additional, Guilak, Farshid, additional, and Freed, Lisa E., additional

Published
2019
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44. A heat-stable microparticle platform for oral micronutrient delivery

Author

Massachusetts Institute of Technology. Department of Biological Engineering, Koch Institute for Integrative Cancer Research at MIT, Anselmo, Aaron C, Xu, Xian, Buerkli, Simone, Zeng, Yingying, Tang, Wen, McHugh, Kevin J, Behrens, Adam M, Rosenberg, Evan, Duan, Aranda R., Sugarman, James L, Zhuang, Jia, Collins, Joseph, Lu, Xueguang, Graf, Tyler, Tzeng, Stephany Y, Rose, Sviatlana, Acolatse, Sarah, Nguyen, Thanh, Le, Xiao, Guerra, Ana Sofia, Freed, Lisa E, Weinstock, Shelley B., Sears, Christopher B., Nikolic, Boris, Wood, Lowell, Welkhoff, Philip A., Oxley, James D., Moretti, Diego, Zimmermann, Michael B., Langer, Robert S, Jaklenec, Ana, Massachusetts Institute of Technology. Department of Biological Engineering, Koch Institute for Integrative Cancer Research at MIT, Anselmo, Aaron C, Xu, Xian, Buerkli, Simone, Zeng, Yingying, Tang, Wen, McHugh, Kevin J, Behrens, Adam M, Rosenberg, Evan, Duan, Aranda R., Sugarman, James L, Zhuang, Jia, Collins, Joseph, Lu, Xueguang, Graf, Tyler, Tzeng, Stephany Y, Rose, Sviatlana, Acolatse, Sarah, Nguyen, Thanh, Le, Xiao, Guerra, Ana Sofia, Freed, Lisa E, Weinstock, Shelley B., Sears, Christopher B., Nikolic, Boris, Wood, Lowell, Welkhoff, Philip A., Oxley, James D., Moretti, Diego, Zimmermann, Michael B., Langer, Robert S, and Jaklenec, Ana

Abstract

Micronutrient deficiencies affect up to 2 billion people and are the leading cause of cognitive and physical disorders in the developing world. Food fortification is effective in treating micronutrient deficiencies; however, its global implementation has been limited by technical challenges in maintaining micronutrient stability during cooking and storage. We hypothesized that polymer-based encapsulation could address this and facilitate micronutrient absorption. We identified poly(butylmethacrylate-co-(2-dimethylaminoethyl)methacrylate-co-methylmethacrylate) (1:2:1) (BMC) as a material with proven safety, offering stability in boiling water, rapid dissolution in gastric acid, and the ability to encapsulate distinct micronutrients. We encapsulated 11 micronutrients (iron; iodine; zinc; and vitamins A, B2, niacin, biotin, folic acid, B12, C, and D) and co-encapsulated up to 4 micronutrients. Encapsulation improved micronutrient stability against heat, light, moisture, and oxidation. Rodent studies confirmed rapid micronutrient release in the stomach and intestinal absorption. Bioavailability of iron from microparticles, compared to free iron, was lower in an initial human study. An organotypic human intestinal model revealed that increased iron loading and decreased polymer content would improve absorption. Using process development approaches capable of kilogram-scale synthesis, we increased iron loading more than 30-fold. Scaled batches tested in a follow-up human study exhibited up to 89% relative iron bioavailability compared to free iron. Collectively, these studies describe a broad approach for clinical translation of a heat-stable ingestible micronutrient delivery platform with the potential to improve micronutrient deficiency in the developing world. These approaches could potentially be applied toward clinical translation of other materials, such as natural polymers, for encapsulation and oral delivery of micronutrients.

Published
2019

45. Cartilaginous and osteochondral tissue formation by human mesenchymal stem cells on three-dimensionally woven scaffolds

Author

Larson, Benjamin L., primary, Yu, Sarah N., additional, Park, Hyoungshin, additional, Estes, Bradley T., additional, Moutos, Franklin T., additional, Bloomquist, Cameron J., additional, Wu, Patrick B., additional, Welter, Jean F., additional, Langer, Robert, additional, Guilak, Farshid, additional, and Freed, Lisa E., additional

Published
2018
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46. Poly(Limonene Thioether) Scaffold for Tissue Engineering

Author

Massachusetts Institute of Technology. Institute for Medical Engineering & Science, Harvard University--MIT Division of Health Sciences and Technology, Koch Institute for Integrative Cancer Research at MIT, Fischer, Kristin McKeon, Morgan, Kathy Ye, Hearon II, Michael Keith, Sklaviadis, Demetra, Tochka, Zachary L, Fenton, Owen S., Anderson, Daniel Griffith, Langer, Robert S, Freed, Lisa E, Fenton, Owen Shea, Massachusetts Institute of Technology. Institute for Medical Engineering & Science, Harvard University--MIT Division of Health Sciences and Technology, Koch Institute for Integrative Cancer Research at MIT, Fischer, Kristin McKeon, Morgan, Kathy Ye, Hearon II, Michael Keith, Sklaviadis, Demetra, Tochka, Zachary L, Fenton, Owen S., Anderson, Daniel Griffith, Langer, Robert S, Freed, Lisa E, and Fenton, Owen Shea

Abstract

A photocurable thiol-ene network polymer, poly(limonene thioether) (PLT32o), is synthesized, characterized, fabricated into tissue engineering scaffolds, and demonstrated in vitro and in vivo. Micromolded PLT32o grids exhibit compliant, elastomeric mechanical behavior similar to grids made of poly(glycerol sebacate) (PGS), an established biomaterial. Multilayered PL32o scaffolds with regular, geometrically defined pore architectures support heart cell seeding and culture in a manner similar to multilayered PGS scaffolds. Subcutaneous implantation of multilayered PLT32o scaffolds with cultured heart cells provides long-term 3D structural support and retains the exogenous cells, whereas PGS scaffolds lose both their structural integrity and the exogenous cells over 31 d in vivo. PLT32o membrane implants retain their dry mass, whereas PGS implants lose 70 percent of their dry mass by day 31. Macrophages are initially recruited to PLT32o and PGS membrane implants but are no longer present by day 31. Facile synthesis and processing in combination with the capability to support heart cells in vitro and in vivo suggest that PLT32o can offer advantages for tissue engineering applications where prolonged in vivo maintenance of 3D structural integrity and elastomeric mechanical behavior are required., United States. National Institutes of Health (R01-HL107503)

Published
2017

50. Scalable Units for Building Cardiac Tissue

Author

Ye, Xiaofeng, primary, Lu, Liang, additional, Kolewe, Martin E., additional, Hearon, Keith, additional, Fischer, Kristin M., additional, Coppeta, Jonathan, additional, and Freed, Lisa E., additional

Published
2014
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