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  • Perspective
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The living interface between synthetic biology and biomaterial design

Abstract

Recent far-reaching advances in synthetic biology have yielded exciting tools for the creation of new materials. Conversely, advances in the fundamental understanding of soft-condensed matter, polymers and biomaterials offer new avenues to extend the reach of synthetic biology. The broad and exciting range of possible applications have substantial implications to address grand challenges in health, biotechnology and sustainability. Despite the potentially transformative impact that lies at the interface of synthetic biology and biomaterials, the two fields have, so far, progressed mostly separately. This Perspective provides a review of recent key advances in these two fields, and a roadmap for collaboration at the interface between the two communities. We highlight the near-term applications of this interface to the development of hierarchically structured biomaterials, from bioinspired building blocks to ‘living’ materials that sense and respond based on the reciprocal interactions between materials and embedded cells.

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Fig. 1: Programmability of synthetic biology.
Fig. 2: The design space for biomaterials.
Fig. 3: Using synthetic biology to fabricate biomaterials with tailored properties toward ‘living’ materials systems.

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References

  1. Meng, F. & Ellis, T. The second decade of synthetic biology: 2010–2020. Nat. Commun. 11, 5174 (2020).

    Article  CAS  Google Scholar 

  2. Sedlmayer, F., Aubel, D. & Fussenegger, M. Synthetic gene circuits for the detection, elimination and prevention of disease. Nat. Biomed. Eng. 2, 399–415 (2018).

    Article  CAS  Google Scholar 

  3. Kolar, K., Knobloch, C., Stork, H., Žnidarič, M. & Weber, W. OptoBase: a web platform for molecular optogenetics. ACS Synth. Biol. 7, 1825–1828 (2018).

    Article  CAS  Google Scholar 

  4. Moon, T. S., Lou, C., Tamsir, A., Stanton, B. C. & Voigt, C. A. Genetic programs constructed from layered logic gates in single cells. Nature 491, 249–253 (2012).

    Article  CAS  Google Scholar 

  5. Gao, X. J., Chong, L. S., Kim, M. S. & Elowitz, M. B. Programmable protein circuits in living cells. Science 361, 1252–1258 (2018).

    Article  CAS  Google Scholar 

  6. Tang, W. & Liu, D. R. Rewritable multi-event analog recording in bacterial and mammalian cells. Science 360, eaap8992 (2018).

    Article  Google Scholar 

  7. Aoki, S. K. et al. A universal biomolecular integral feedback controller for robust perfect adaptation. Nature 570, 533–537 (2019).

    Article  CAS  Google Scholar 

  8. Toda, S., Blauch, L. R., Tang, S. K. Y., Morsut, L. & Lim, W. A. Programming self-organizing multicellular structures with synthetic cell-cell signaling. Science 361, 156–162 (2018).

  9. Smanski, M. J. et al. Synthetic biology to access and expand nature’s chemical diversity. Nat. Rev. Microbiol. 14, 135–149 (2016).

    Article  CAS  Google Scholar 

  10. Noireaux, V. & Liu, A. P. The new age of cell-free biology. Annu. Rev. Biomed. Eng. 22, 51–77 (2020).

    Article  CAS  Google Scholar 

  11. Godino, E. et al. Cell-free biogenesis of bacterial division proto-rings that can constrict liposomes. Commun. Biol. 3, 539 (2020).

    Article  CAS  Google Scholar 

  12. Garenne, D., Libchaber, A. & Noireaux, V. Membrane molecular crowding enhances MreB polymerization to shape synthetic cells from spheres to rods. Proc. Natl Acad. Sci. USA 117, 1902–1909 (2020).

    Article  CAS  Google Scholar 

  13. Saleh, O. A., Jeon, B. J. & Liedl, T. Enzymatic degradation of liquid droplets of DNA is modulated near the phase boundary. Proc. Natl Acad. Sci. USA https://doi.org/10.1073/pnas.2001654117 (2020).

  14. Sokolova, E. et al. Enhanced transcription rates in membrane-free protocells formed by coacervation of cell lysate. Proc. Natl Acad. Sci. USA 110, 11692–11697 (2013).

    Article  CAS  Google Scholar 

  15. Green, L. N. et al. Autonomous dynamic control of DNA nanostructure self-assembly. Nat. Chem. 11, 510–520 (2019).

    Article  CAS  Google Scholar 

  16. Efrat, Y., Tayar, A. M., Daube, S. S., Levy, M. & Bar-Ziv, R. H. Electric-field manipulation of a compartmentalized cell-free gene expression reaction. ACS Synth. Biol. 7, 1829–1833 (2018).

    Article  CAS  Google Scholar 

  17. Dupin, A. & Simmel, F. C. Signalling and differentiation in emulsion-based multi-compartmentalized in vitro gene circuits. Nat. Chem. 11, 32–39 (2019).

  18. Santorelli, M., Lam, C. & Morsut, L. Synthetic development: building mammalian multicellular structures with artificial genetic programs. Curr. Opin. Biotechnol. 59, 130–140 (2019).

    Article  CAS  Google Scholar 

  19. Scheller, L., Strittmatter, T., Fuchs, D., Bojar, D. & Fussenegger, M. Generalized extracellular molecule sensor platform for programming cellular behavior article. Nat. Chem. Biol. 14, 723–729 (2018).

    Article  CAS  Google Scholar 

  20. Rivière, I. & Sadelain, M. Chimeric antigen receptors: a cell and gene therapy perspective. Mol. Ther. 25, 1117–1124 (2017).

    Article  Google Scholar 

  21. Stapornwongkul, K. S., de Gennes, M., Cocconi, L., Salbreux, G. & Vincent, J. P. Patterning and growth control in vivo by an engineered GFP gradient. Science 370, 321–327 (2020).

    Article  CAS  Google Scholar 

  22. Huang, X. et al. DNA scaffolds enable efficient and tunable functionalization of biomaterials for immune cell modulation. Nat. Nanotecnol. 16, 214–223 (2021).

  23. Nielsen, A. A. K. et al. Genetic circuit design automation. Science 352, aac7341 (2016).

    Article  Google Scholar 

  24. Burger, B. et al. A mobile robotic chemist. Nature 583, 237–241 (2020).

    Article  CAS  Google Scholar 

  25. Sanka, R., Lippai, J., Samarasekera, D., Nemsick, S. & Densmore, D. 3DμF—interactive design environment for continuous flow microfluidic devices. Sci. Rep. 9, 9166 (2019).

    Article  Google Scholar 

  26. Zhang, J. et al. Combining mechanistic and machine learning models for predictive engineering and optimization of tryptophan metabolism. Nat. Commun. 11, 4880 (2020).

    Article  Google Scholar 

  27. Waltemath, D. et al. The first 10 years of the international coordination network for standards in systems and synthetic biology (COMBINE). J. Integr. Bioinform. 17, 20200005 (2020).

    Article  Google Scholar 

  28. Huebsch, N. & Mooney, D. J. Inspiration and application in the evolution of biomaterials. Nature 462, 426–432 (2009).

    Article  CAS  Google Scholar 

  29. Dimarco, R. L. & Heilshorn, S. C. Multifunctional materials through modular protein engineering. Adv. Mater. 24, 3923–3940 (2012).

    Article  CAS  Google Scholar 

  30. Chaudhuri, O., Cooper-White, J., Janmey, P. A., Mooney, D. J. & Shenoy, V. B. Effects of extracellular matrix viscoelasticity on cellular behaviour. Nature 584, 535–546 (2020).

    Article  CAS  Google Scholar 

  31. Rodell, C. B. et al. Shear-thinning supramolecular hydrogels with secondary autonomous covalent crosslinking to modulate viscoelastic properties in vivo. Adv. Funct. Mater. 25, 636–644 (2015).

    Article  CAS  Google Scholar 

  32. Baker, B. M. et al. Cell-mediated fibre recruitment drives extracellular matrix mechanosensing in engineered fibrillar microenvironments. Nat. Mater. 14, 1262–1268 (2015).

    Article  CAS  Google Scholar 

  33. Griffin, D. R., Weaver, W. M., Scumpia, P. O., Di Carlo, D. & Segura, T. Accelerated wound healing by injectable microporous gel scaffolds assembled from annealed building blocks. Nat. Mater. 14, 737–744 (2015).

    Article  CAS  Google Scholar 

  34. Skylar-Scott, M. A., Mueller, J., Visser, C. W. & Lewis, J. A. Voxelated soft matter via multimaterial multinozzle 3D printing. Nature 575, 330–335 (2019).

    Article  CAS  Google Scholar 

  35. Guo, Z., Liu, H., Dai, W. & Lei, Y. Responsive principles and applications of smart materials in biosensing. Smart Mater. Med. 1, 54–65 (2020).

    Article  Google Scholar 

  36. Hörner, M. et al. Phytochrome-based extracellular matrix with reversibly tunable mechanical properties. Adv. Mater. 31, e1806727 (2019).

    Article  Google Scholar 

  37. de Almeida, P. et al. Cytoskeletal stiffening in synthetic hydrogels. Nat. Commun. 10, 609 (2019).

    Article  Google Scholar 

  38. Rosales, A. M., Vega, S. L., DelRio, F. W., Burdick, J. A. & Anseth, K. S. Hydrogels with reversible mechanics to probe dynamic cell microenvironments. Angew. Chem. Int. Ed. 56, 12132–12136 (2017).

    Article  CAS  Google Scholar 

  39. Badeau, B. A. & Deforest, C. A. Programming stimuli-responsive behavior into biomaterials. Annu. Rev. Biomed. Eng. 21, 241–265 (2019).

    Article  CAS  Google Scholar 

  40. Chao, Y. & Shum, H. C. Emerging aqueous two-phase systems: from fundamentals of interfaces to biomedical applications. Chem. Soc. Rev. 49, 114–142 (2020).

    Article  CAS  Google Scholar 

  41. Schuster, B. S. et al. Identifying sequence perturbations to an intrinsically disordered protein that determine its phase-separation behavior. Proc. Natl Acad. Sci. USA 117, 11421–11431 (2020).

    Article  CAS  Google Scholar 

  42. Klein, I. A. et al. Partitioning of cancer therapeutics in nuclear condensates. Science 368, 1386–1392 (2020).

    Article  CAS  Google Scholar 

  43. Champeau, M. et al. 4D printing of hydrogels: a review. Adv. Funct. Mater. 30, 1910606 (2020).

    Article  CAS  Google Scholar 

  44. Cangialosi, A. et al. DNA sequence–directed shape change of photopatterned hydrogels via high-degree swelling. Science 357, 1126–1130 (2017).

    Article  CAS  Google Scholar 

  45. Praetorius, F. et al. Biotechnological mass production of DNA origami. Nature 552, 84–87 (2017).

    Article  CAS  Google Scholar 

  46. Barbee, M. H. et al. Protein-mimetic self-assembly with synthetic macromolecules. Macromolecules 54, 3585–3612 (2021).

    Article  CAS  Google Scholar 

  47. Chan, D. et al. Combinatorial polyacrylamide hydrogels for preventing biofouling on implantable biosensors. Preprint at bioRxiv https://doi.org/10.1101/2020.05.25.115675 (2021).

  48. Upadhya, R. et al. Automation and data-driven design of polymer therapeutics. Adv. Drug Deliv. Rev. 171, 1–28 (2021).

    Article  CAS  Google Scholar 

  49. Wu, D. et al. Polymers with controlled assembly and rigidity made with click-functional peptide bundles. Nature 574, 658–662 (2019).

    Article  CAS  Google Scholar 

  50. Seeman, N. C. & Sleiman, H. F. DNA nanotechnology. Nat. Rev. Mater. 3, 17068 (2017).

    Article  Google Scholar 

  51. Buchberger, A., Simmons, C. R., Fahmi, N. E., Freeman, R. & Stephanopoulos, N. Hierarchical assembly of nucleic acid/coiled-coil peptide nanostructures. J. Am. Chem. Soc. 142, 1406–1416 (2020).

    Article  CAS  Google Scholar 

  52. An, B. et al. Programming living glue systems to perform autonomous mechanical repairs. Matter 3, 2080–2092 (2020).

    Article  Google Scholar 

  53. Keeble, A. H. & Howarth, M. Power to the protein: enhancing and combining activities using the Spy toolbox. Chem. Sci. 11, 7281–7291 (2020).

    Article  CAS  Google Scholar 

  54. Nguyen, P. Q., Botyanszki, Z., Tay, P. K. R. & Joshi, N. S. Programmable biofilm-based materials from engineered curli nanofibres. Nat. Commun. 5, 4945 (2014).

    Article  CAS  Google Scholar 

  55. Charrier, M. et al. Engineering the S-layer of Caulobacter crescentus as a foundation for stable, high-density, 2D living materials. ACS Synth. Biol. 8, 181–190 (2019).

    Article  CAS  Google Scholar 

  56. Zhang, G., Johnston, T., Quin, M. B. & Schmidt-Dannert, C. Developing a protein scaffolding system for rapid enzyme immobilization and optimization of enzyme functions for biocatalysis. ACS Synth. Biol. 8, 1867–1876 (2019).

    Article  CAS  Google Scholar 

  57. Shadish, J. A., Strange, A. C. & Deforest, C. A. Genetically encoded photocleavable linkers for patterned protein release from biomaterials. J. Am. Chem. Soc. 141, 15619–15625 (2019).

    Article  CAS  Google Scholar 

  58. Heveran, C. M. et al. Engineered ureolytic microorganisms can tailor the morphology and nanomechanical properties of microbial-precipitated calcium carbonate. Sci. Rep. 9, 14721 (2019).

    Article  Google Scholar 

  59. Heveran, C. M. et al. Biomineralization and successive regeneration of engineered living building materials. Matter 2, 481–494 (2020).

    Article  CAS  Google Scholar 

  60. Nielsen, J. & Keasling, J. D. Engineering cellular metabolism. Cell 164, 1185–1197 (2016).

    Article  CAS  Google Scholar 

  61. Gilbert, C. et al. Living materials with programmable functionalities grown from engineered microbial co-cultures. Nat. Mater. 20, 691–700 (2021).

  62. Duro-Royo, J., Van Zak, J., Tai, Y. J., Ling, A. S. & Oxman, N. in Challenges for Technology Innovation: An Agenda for the Future (eds da Silva, F. M. et al.) Ch. 39 (CRC, 2017).

  63. Sachdeva, G., Garg, A., Godding, D., Way, J. C. & Silver, P. A. In vivo co-localization of enzymes on RNA scaffolds increases metabolic production in a geometrically dependent manner. Nucleic Acids Res. 42, 9493–9503 (2014).

    Article  CAS  Google Scholar 

  64. Park, S. J. et al. Phototactic guidance of a tissue-engineered soft-robotic ray. Science 353, 158–162 (2016).

    Article  CAS  Google Scholar 

  65. Morsut, L. et al. Engineering customized cell sensing and response behaviors using synthetic Notch receptors. Cell 164, 780–791 (2016).

    Article  CAS  Google Scholar 

  66. Schwarz, K. A., Daringer, N. M., Dolberg, T. B. & Leonard, J. N. Rewiring human cellular input–output using modular extracellular sensors. Nat. Chem. Biol. 13, 202–209 (2017).

    Article  CAS  Google Scholar 

  67. Loebel, C., Mauck, R. L. & Burdick, J. A. Local nascent protein deposition and remodelling guide mesenchymal stromal cell mechanosensing and fate in three-dimensional hydrogels. Nat. Mater. 18, 883–891 (2019).

    Article  CAS  Google Scholar 

  68. Ferreira, S. A. et al. Bi-directional cell–pericellular matrix interactions direct stem cell fate. Nat. Commun. 9, 4049 (2018).

    Article  Google Scholar 

  69. Liu, H. et al. Bioenergetic-active materials enhance tissue regeneration by modulating cellular metabolic state. Sci. Adv. 6, 32232154 (2020).

    Google Scholar 

  70. Li, Y. C., Zhang, Y. S., Akpek, A., Shin, S. R. & Khademhosseini, A. 4D bioprinting: the next-generation technology for biofabrication enabled by stimuli-responsive materials. Biofabrication 9, 012001 (2017).

    Article  Google Scholar 

  71. Nam, K. T. et al. Virus-enabled synthesis and assembly of nanowires for lithium ion battery electrodes. Science 312, 885–888 (2006).

    Article  CAS  Google Scholar 

  72. Kan, A. & Joshi, N. S. Towards the directed evolution of protein materials. MRS Commun. 9, 441–455 (2019).

    Article  CAS  Google Scholar 

  73. Green, M. L. et al. Fulfilling the promise of the materials genome initiative with high-throughput experimental methodologies. Appl. Phys. Rev. 4, 011105 (2017).

    Article  Google Scholar 

  74. Algahtani, M. S. et al. High throughput screening for biomaterials discovery. J. Control. Release 190, 115–126 (2014).

    Article  CAS  Google Scholar 

  75. Agresti, J. J. et al. Ultrahigh-throughput screening in drop-based microfluidics for directed evolution. Proc. Natl Acad. Sci. USA 107, 4004–4009 (2010).

    Article  CAS  Google Scholar 

  76. Ma, F. et al. Efficient molecular evolution to generate enantioselective enzymes using a dual-channel microfluidic droplet screening platform. Nat. Commun. 9, 1030 (2018).

    Article  Google Scholar 

  77. Liu, Y. et al. Machine learning in materials genome initiative: a review. J. Mater. Sci. Technol. 57, 113–122 (2020).

    Article  Google Scholar 

  78. Voigt, C. A. Synthetic biology 2020–2030: six commercially-available products that are changing our world. Nat. Commun. 11, 6379 (2020).

    Article  CAS  Google Scholar 

  79. Beal, J. & Rogers, M. Levels of autonomy in synthetic biology engineering. Mol. Syst. Biol. 16, e10019 (2020).

    Article  Google Scholar 

  80. Stowers, R. S. et al. Matrix stiffness induces a tumorigenic phenotype in mammary epithelium through changes in chromatin accessibility. Nat. Biomed. Eng. 3, 1009–1019 (2019).

    Article  Google Scholar 

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Acknowledgements

We thank all the participants of the second Square Table workshop during which the ideas in this Perspective originated. The workshop was funded by the National Science Foundation (NSF) grant BMAT-1939310. We especially acknowledge G. Iannacchione for his stewardship of the Square Table workshops. We also acknowledge support from the National Institutes of Health grants R01 EB030031 (A.P.L.), R35 GM138256 (L.M.), R21 CA232244 (K.H.), NSF grants CMMI 1846367 (O.C.), DMR-BMAT CAREER 1753387 (N.S.), EF-1934496 (V.N.), DMR-2004875 (N.S.J.), DMR-2004937 (M.T.V.), CBET-2033654 (B.M.B.), DMR-2037055 (S.L.V.), MCB-2033387 (S.K.Y.T.), DMR-2004796 (J.M.), DMR-2011824 (A.M.K.), the Human Frontiers in Science Program RGP0045/2018 (S.P.), Department of Energy grants DOE BES DE-SC-0010595 (E.F. and R.S.), DGF grant DFG-EXC-2189 (W.W.), Dutch Ministry of Education, Culture and Science—Gravitation 024.001.035 (P.H.J.K.) and the DARPA Engineered Living Materials Program (P.D.A.).

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Liu, A.P., Appel, E.A., Ashby, P.D. et al. The living interface between synthetic biology and biomaterial design. Nat. Mater. 21, 390–397 (2022). https://doi.org/10.1038/s41563-022-01231-3

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