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Creating Living Cellular Machines

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Abstract

Development of increasingly complex integrated cellular systems will be a major challenge for the next decade and beyond, as we apply the knowledge gained from the sub-disciplines of regenerative medicine, synthetic biology, micro-fabrication and nanotechnology, systems biology, and developmental biology. In this prospective, we describe the current state-of-the-art in the assembly of source cells, derived from pluripotent cells, into populations of a single cell type to produce the components or building blocks of higher order systems and finally, combining multiple cell types, possibly in combination with scaffolds possessing specific physical or chemical properties, to produce higher level functionality. We also introduce the issue, questions and ample research opportunities to be explored by others in the field. As these “living machines” increase in capabilities, exhibit emergent behavior and potentially reveal the ability for self-assembly, self-repair, and even self-replication, questions arise regarding the ethical implications of this work. Future prospects as well as ways of addressing these complex ethical questions will be discussed.

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References

  1. Allen, J. W., and S. N. Bhatia. Engineering liver therapies for the future. Tissue Eng. 8:725–737, 2002.

    Article  CAS  PubMed  Google Scholar 

  2. Andrianantoandro, E., S. Basu, D. K. Karig, and R. Weiss. Synthetic biology: new engineering rules for an emerging discipline. Mol. Syst. Biol. 2:2006.0028, 2006.

    Google Scholar 

  3. Atala, A., S. B. Bauer, S. Soker, J. J. Yoo, and A. B. Retik. Tissue-engineered autologous bladders for patients needing cystoplasty. Lancet 367:1241–1246, 2006.

    Article  PubMed  Google Scholar 

  4. Basu, S., Y. Gerchman, C. H. Collins, F. H. Arnold, and R. Weiss. A synthetic multicellular system for programmed pattern formation. Nature 434:1130–1134, 2005.

    Article  CAS  PubMed  Google Scholar 

  5. Beane, W. S., J. Morokuma, J. M. Lemire, and M. Levin. Bioelectric signaling regulates head and organ size during planarian regeneration. Development (Cambridge, England) 140:313–322, 2013.

    Google Scholar 

  6. Berthiaume, F., T. J. Maguire, and M. L. Yarmush. Tissue engineering and regenerative medicine: history, progress, and challenges. Annu. Rev. Chem. Biomol. Eng. 2:403–430, 2011.

    Article  PubMed  Google Scholar 

  7. Beyer, E. C., D. L. Paul, and D. A. Goodenough. Connexin43: a protein from rat heart homologous to a gap junction protein from liver. J. Cell. Biol. 105:2621–2629, 1987.

    Article  CAS  PubMed  Google Scholar 

  8. Booth, R., and H. Kim. Characterization of a microfluidic in vitro model of the blood-brain barrier (μBBB). Lab. Chip 12:1784–1792, 2012.

    Article  CAS  PubMed  Google Scholar 

  9. Chan, V., K. Park, M. B. Collens, H. Kong, T. A. Saif, and R. Bashir. Development of miniaturized walking biological machines. Sci. Rep. 2:857, 2012.

    Article  PubMed Central  PubMed  Google Scholar 

  10. Chan, J. M., I. K. Zervantonakis, T. Rimchala, W. J. Polacheck, J. Whisler, and R. D. Kamm. Engineering of in vitro 3D capillary beds by self-directed angiogenic sprouting. PLoS ONE 7:e50582, 2012.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Chan, V., P. Zorlutuna, J. H. Jeong, H. Kong, and R. Bashir. Three-dimensional photopatterning of hydrogels using stereolithography for long-term cell encapsulation. Lab. Chip 10:2062–2070, 2010.

    Article  CAS  PubMed  Google Scholar 

  12. Chuang, H.-Y., M. Hofree, and T. Ideker. A decade of systems biology. Annu. Rev. Cell Dev. Biol. 26:721–744, 2010.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Davidson, E., and M. Levin. Gene regulatory networks. Proc. Natl Acad. Sci. U.S.A. 102:4935, 2005.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Dodla, M. C., J. Mumaw, and S. L. Stice. Role of astrocytes, soluble factors, cells adhesion molecules and neurotrophins in functional synapse formation: implications for human embryonic stem cell derived neurons. Curr. Stem Cell Res. Ther. 5:251–260, 2010.

    Article  CAS  PubMed  Google Scholar 

  15. Domansky, K., W. Inman, J. Serdy, A. Dash, M. H. M. Lim, and L. G. Griffith. Perfused multiwell plate for 3D liver tissue engineering. Lab. Chip 10:51–58, 2010.

    Article  CAS  PubMed  Google Scholar 

  16. Eckert, P., and K. Schnackerz. Ischemic tolerance of human skeletal muscle. Ann. Plast. Surg. 26:77–84, 1991.

    Article  CAS  PubMed  Google Scholar 

  17. Feinberg, A. W., A. Feigel, S. S. Shevkoplyas, S. Sheehy, G. M. Whitesides, and K. K. Parker. Muscular thin films for building actuators and powering devices. Science (New York, N.Y.) 317:1366–1370, 2007.

  18. Fidkowski, C., M. R. Kaazempur-Mofrad, J. Borenstein, J. P. Vacanti, R. Langer, and Y. Wang. Endothelialized microvasculature based on a biodegradable elastomer. Tissue Eng. 11:302–309, 2005.

    Article  CAS  PubMed  Google Scholar 

  19. Grosberg, A., P. W. Alford, M. L. McCain, and K. K. Parker. Ensembles of engineered cardiac tissues for physiological and pharmacological study: heart on a chip. Lab. Chip 11:4165–4173, 2011.

    Article  CAS  PubMed  Google Scholar 

  20. Grunwald, D. J., and J. S. Eisen. Headwaters of the zebrafish—emergence of a new model vertebrate. Nat. Rev. Genet. 3:717–724, 2002.

    Article  CAS  PubMed  Google Scholar 

  21. Gutman, A., and J. Wagner. NEW DIRECTIONS: Ethics of Synthetic Biology and Emerging Technologies, 2010.

  22. Hansen, A., A. Eder, M. Bönstrup, M. Flato, M. Mewe, S. Schaaf, B. Aksehirlioglu, A. P. Schwoerer, A. Schwörer, J. Uebeler, and T. Eschenhagen. Development of a drug screening platform based on engineered heart tissue. Circ. Res. 107:35–44, 2010.

    Article  CAS  PubMed  Google Scholar 

  23. Hasslacher, B., and M. Tilden. Living machines. Robotics Auton. Syst. 15:143–169, 1995.

    Article  Google Scholar 

  24. Heikkilä, T. J., L. Ylä-Outinen, J. M. A. Tanskanen, R. S. Lappalainen, H. Skottman, R. Suuronen, J. E. Mikkonen, J. A. K. Hyttinen, and S. Narkilahti. Human embryonic stem cell-derived neuronal cells form spontaneously active neuronal networks in vitro. Exp. Neurol. 218:109–116, 2009.

    Article  PubMed  Google Scholar 

  25. Hinds, S., W. Bian, R. G. Dennis, and N. Bursac. The role of extracellular matrix composition in structure and function of bioengineered skeletal muscle. Biomaterials 32:3575–3583, 2011.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Huh, D., D. C. Leslie, B. D. Matthews, J. P. Fraser, S. Jurek, G. A. Hamilton, K. S. Thorneloe, M. A. McAlexander, and D. E. Ingber. A human disease model of drug toxicity-induced pulmonary edema in a lung-on-a-chip microdevice. Sci. Trans. Med. 4:159ra147, 2012.

    Google Scholar 

  27. Kim, J., J. Park, S. Yang, J. Baek, B. Kim, S. H. Lee, E.-S. Yoon, K. Chun, and S. Park. Establishment of a fabrication method for a long-term actuated hybrid cell robot. Lab. Chip 7:1504–1508, 2007.

    Article  CAS  PubMed  Google Scholar 

  28. Kim, S., H. Lee, M. Chung, and N. L. Jeon. Engineering of functional, perfusable 3D microvascular networks on a chip. Lab. Chip. 13:1489–1500, 2013.

    Google Scholar 

  29. Kim, T.-i., J. G. McCall, Y. H. Jung, X. Huang, E. R. Siuda, Y. Li, J. Song, Y. M. Song, H. A. Pao, R.-H. Kim, C. Lu, S. D. Lee, I.-S. Song, G. Shin, R. Al-Hasani, S. Kim, M. P. Tan, Y. Huang, F. G. Omenetto, J. A. Rogers, and M. R. Bruchas. Injectable, cellular-scale optoelectronics with applications for wireless optogenetics. Science 340:211–216, 2013.

    Google Scholar 

  30. Lam, M. T., Y.-C. Huang, R. K. Birla, and S. Takayama. Microfeature guided skeletal muscle tissue engineering for highly organized 3-dimensional free-standing constructs. Biomaterials 30:1150–1155, 2009.

    Article  CAS  PubMed  Google Scholar 

  31. Larkin, L. M., J. H. Van der Meulen, R. G. Dennis, and J. B. Kennedy. Functional evaluation of nerve-skeletal muscle constructs engineered in vitro. In Vitro Cell. Dev. Biol. Animal 42:75–82, 2006.

    Google Scholar 

  32. Lauffenburger, D. A. The multiple dimensions of integrative biology. Integr. Biol. 4:9, 2012.

    Google Scholar 

  33. LeDuc, P. R., W. C. Messner, and J. P. Wikswo. How do control-based approaches enter into biology? Annu. Rev. Biomed. Eng. 13:369–396, 2011.

    Article  CAS  PubMed  Google Scholar 

  34. Lee, S. H., O. S. Kwon, H. S. Song, S. J. Park, J. H. Sung, J. Jang, and T. H. Park. Mimicking the human smell sensing mechanism with an artificial nose platform. Biomaterials 33:1722–1729, 2012.

    Article  CAS  PubMed  Google Scholar 

  35. Leung, A. D., K. H. K. Wong, and J. Tien. Plasma expanders stabilize human microvessels in microfluidic scaffolds. J. Biomed. Mater. Res. Part A 100:1815–1822, 2012.

    Article  Google Scholar 

  36. Lysy, P. A., G. C. Weir, and S. Bonner-Weir. Concise review: pancreas regeneration: recent advances and perspectives. Stem Cells Trans. Med. 1:150–159, 2012.

    Article  CAS  Google Scholar 

  37. MacCalman, C. D., N. Bardeesy, P. C. Holland, and O. W. Blaschuk. Noncoordinate developmental regulation of N-cadherin, N-CAM, integrin, and fibronectin mRNA levels during myoblast terminal differentiation. Dev. Dyn. 195:127–132, 1992.

    Article  CAS  PubMed  Google Scholar 

  38. Miller, J. S., K. R. Stevens, M. T. Yang, B. M. Baker, D.-H. T. Nguyen, D. M. Cohen, E. Toro, A. A. Chen, P. A. Galie, X. Yu, R. Chaturvedi, S. N. Bhatia, and C. S. Chen. Rapid casting of patterned vascular networks for perfusable engineered three-dimensional tissues. Nat. Mater. 11:768–774, 2012.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Moon, S., S. K. Hasan, Y. S. Song, F. Xu, H. O. Keles, F. Manzur, S. Mikkilineni, J. W. Hong, J. Nagatomi, E. Haeggstrom, A. Khademhosseini, and U. Demirci. Layer by layer three-dimensional tissue epitaxy by cell-laden hydrogel droplets. Tissue Eng. Part C 16:157–166, 2010.

    Google Scholar 

  40. Morey, K. J., M. S. Antunes, K. D. Albrecht, T. A. Bowen, J. F. Troupe, K. L. Havens, and J. I. Medford. Developing a synthetic signal transduction system in plants. Methods Enzymol. 497:581–602, 2011.

    Article  CAS  PubMed  Google Scholar 

  41. Morimoto, Y., H. Onoe, S. Takeuchi. Muscle fibers actuated by neural signals. 2012.

  42. Moya, M. L., Y. Hsu, A. P. Lee, C. C. W. Hughes, and S. C. George. In vitro perfused human capillary networks. Tissue Eng. Part C 19:730–737, 2013.

    Google Scholar 

  43. Nakagaki, T. Smart behavior of true slime mold in a labyrinth. Res. Microbiol. 152:767–770, 2001.

    Article  CAS  PubMed  Google Scholar 

  44. National Research Council. A New Biology for the 21st Century. Washington, DC: National Academies Press, 2009.

  45. Nawroth, J. C., H. Lee, A. W. Feinberg, C. M. Ripplinger, M. L. McCain, A. Grosberg, J. O. Dabiri, and K. K. Parker. A tissue-engineered jellyfish with biomimetic propulsion. Nat. Biotechnol. 30:792–797, 2012.

    Article  CAS  PubMed  Google Scholar 

  46. Park, K., L. J. Millet, N. Kim, H. Li, X. Jin, G. Popescu, N. R. Aluru, K. J. Hsia, and R. Bashir. Measurement of adherent cell mass and growth. Proc. Natl Acad. Sci. U.S.A. 107:20691–20696, 2010.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Pimashkin, A., A. Gladkov, I. Mukhina, and V. Kazantsev. Adaptive enhancement of learning protocol in hippocampal cultured networks grown on multielectrode arrays. Frontiers Neural Circuits 7:87, 2013.

    Article  Google Scholar 

  48. Reinecke, H., G. H. MacDonald, S. D. Hauschka, and C. E. Murry. Electromechanical coupling between skeletal and cardiac muscle. Implications for infarct repair. J. Cell Biol. 149:731–740, 2000.

    Article  CAS  PubMed  Google Scholar 

  49. Sakar, M. S., D. Neal, T. Boudou, M. A. Borochin, Y. Li, R. Weiss, R. D. Kamm, C. S. Chen, and H. H. Asada. Formation and optogenetic control of engineered 3D skeletal muscle bioactuators. Lab. Chip. 12:4976–4985, 2012.

    Google Scholar 

  50. Sanger, J. M., B. Mittal, M. B. Pochapin, and J. W. Sanger. Myofibrillogenesis in living cells microinjected with fluorescently labeled alpha-actinin. J. Cell Biol. 102:2053–2066, 1986.

    Article  CAS  PubMed  Google Scholar 

  51. Sanger, J. W., B. Mittal, and J. M. Sanger. Formation of myofibrils in spreading chick cardiac myocytes. Cell Motil. 4:405–416, 1984.

    Article  CAS  PubMed  Google Scholar 

  52. Shahaf, G., and S. Marom. Learning in networks of cortical neurons. J. Neurosci. 21:8782–8788, 2001.

    CAS  PubMed  Google Scholar 

  53. Shimizu, T., M. Yamato, A. Kikuchi, and T. Okano. Cell sheet engineering for myocardial tissue reconstruction. Biomaterials 24:2309–2316, 2003.

    Article  CAS  PubMed  Google Scholar 

  54. Song, J. W., and L. L. Munn. Fluid forces control endothelial sprouting. Proc. Natl Acad. Sci. U.S.A. 108:15342–15347, 2011.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  55. Sudo, R., S. Chung, I. K. Zervantonakis, V. Vickerman, Y. Toshimitsu, L. G. Griffith, and R. D. Kamm. Transport-mediated angiogenesis in 3D epithelial coculture. FASEB J. 23:2155–2164, 2009.

    Article  CAS  PubMed  Google Scholar 

  56. Sung, J. H., M. B. Esch, J.-M. Prot, C. J. Long, A. Smith, J. J. Hickman, and M. L. Shuler. Microfabricated mammalian organ systems and their integration into models of whole animals and humans. Lab. Chip. 13:1201–1212, 2013.

    Google Scholar 

  57. Sung, J. H., J. Yu, D. Luo, M. L. Shuler, and J. C. March. Microscale 3-D hydrogel scaffold for biomimetic gastrointestinal (GI) tract model. Lab. Chip 11:389–392, 2011.

    Article  CAS  PubMed  Google Scholar 

  58. Tanaka, Y., K. Morishima, T. Shimizu, A. Kikuchi, M. Yamato, T. Okano, and T. Kitamori. An actuated pump on-chip powered by cultured cardiomyocytes. Lab. Chip 6:362–368, 2006.

    Article  CAS  PubMed  Google Scholar 

  59. Tanaka, Y., K. Sato, T. Shimizu, M. Yamato, T. Okano, and T. Kitamori. A micro-spherical heart pump powered by cultured cardiomyocytes. Lab. Chip 7:207–212, 2007.

    Article  CAS  PubMed  Google Scholar 

  60. Umbach, J. A., K. L. Adams, C. B. Gundersen, and B. G. Novitch. Functional neuromuscular junctions formed by embryonic stem cell-derived motor neurons. PloS One 7:e36049, 2012.

    Google Scholar 

  61. Vacanti, C., L. Cima, D. Rodkowski, and J. Upton. Tissue engineering of new cartilage in the shape of a human ear using specially configured polymers seeded with chondrocytes. In: MRS Proceedings, Vol. 252, 1992.

  62. Vandenburgh, H. High-content drug screening with engineered musculoskeletal tissues. Tissue Eng. Part B 16:55–64, 2010.

    Google Scholar 

  63. Vickerman, V., and R. D. Kamm. Mechanism of a flow-gated angiogenesis switch: early signaling events at cell-matrix and cell-cell junctions. Integr. Biol. 4:863–874, 2012.

    Article  CAS  Google Scholar 

  64. Volk, T., and B. Geiger. A 135-kd membrane protein of intercellular adherens junctions. EMBO J. 3:2249–2260, 1984.

    CAS  PubMed  Google Scholar 

  65. Volkov, A. G., H. Carrell, T. Adesina, V. S. Markin, and E. Jovanov. Plant electrical memory. Signal. Behav. 3:490–492, 2008.

    Article  Google Scholar 

  66. Wang, S. M., M. L. Greaser, E. Schultz, J. C. Bulinski, J. J. Lin, and J. L. Lessard. Studies on cardiac myofibrillogenesis with antibodies to titin, actin, tropomyosin, and myosin. J Cell Biol. 107:1075–1083, 1988.

    Article  CAS  PubMed  Google Scholar 

  67. Watkins, N., D. Irimia, M. Toner, and R. Bashir. On a chip. IEEE Pulse 2:19–27, 2011.

    Article  PubMed  Google Scholar 

  68. Wheeler, B. C., and G. J. Brewer. Designing neural networks in culture: experiments are described for controlled growth, of nerve cells taken from rats, in predesigned geometrical patterns on laboratory culture dishes. Proc. IEEE 98:398–406, 2010.

    Google Scholar 

  69. Xi, J., J. J. Schmidt, and C. D. Montemagno. Self-assembled microdevices driven by muscle. Nat. Mater. 4:180–184, 2005.

    Article  CAS  PubMed  Google Scholar 

  70. Yannas, I. V, J. F. Burke, D. P. Orgill, and E. M. Skrabut. Wound tissue can utilize a polymeric template to synthesize a functional extension of skin. Science (New York, N.Y.) 215:174–176, 1982.

  71. Yeon, J. H., H. R. Ryu, M. Chung, Q. P. Hu, and N. L. Jeon. In vitro formation and characterization of a perfusable three-dimensional tubular capillary network in microfluidic devices. Lab. Chip 12:2815–2822, 2012.

    Article  CAS  PubMed  Google Scholar 

  72. Zoghi, M. Cardiac memory: do the heart and the brain remember the same? J. Interv. Cardiac Electrophysiol. 11:177–182, 2004.

    Article  Google Scholar 

  73. Zorlutuna, P., J. H. Jeong, H. Kong, and R. Bashir. Stereolithography-based hydrogel microenvironments to examine cellular interactions. Adv. Funct. Mater. 21:3642–3651, 2011.

    Article  CAS  Google Scholar 

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Acknowledgments

The authors acknowledge support from the National Science Foundation (NSF) Science and Technology Center (STC) Emergent Behaviors of Integrated Cellular Systems (EBICS) Grant CBET-0939511, as well as valuable discussions with Robert Nerem, Todd McDevitt, Ron Weiss, Linda Griffith, Hyunjoon Kong, Taher Saif, K. Jimmy Hsia, and many other colleagues from the EBICS STC. The authors have no conflicts of interest to claim in association with this publication.

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Correspondence to Roger D. Kamm.

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Associate Editor Gang Bao oversaw the review of this article.

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Kamm, R.D., Bashir, R. Creating Living Cellular Machines. Ann Biomed Eng 42, 445–459 (2014). https://doi.org/10.1007/s10439-013-0902-7

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