Engineered modular biomaterial logic gates for environmentally triggered therapeutic delivery

Abstract

The successful transport of drug- and cell-based therapeutics to diseased sites represents a major barrier in the development of clinical therapies. Targeted delivery can be mediated through degradable biomaterial vehicles that utilize disease biomarkers to trigger payload release. Here, we report a modular chemical framework for imparting hydrogels with precise degradative responsiveness by using multiple environmental cues to trigger reactions that operate user-programmable Boolean logic. By specifying the molecular architecture and connectivity of orthogonal stimuli-labile moieties within material cross-linkers, we show selective control over gel dissolution and therapeutic delivery. To illustrate the versatility of this methodology, we synthesized 17 distinct stimuli-responsive materials that collectively yielded all possible YES/OR/AND logic outputs from input combinations involving enzyme, reductant and light. Using these hydrogels we demonstrate the first sequential and environmentally stimulated release of multiple cell lines in well-defined combinations from a material. We expect these platforms will find utility in several diverse fields including drug delivery, diagnostics and regenerative medicine.

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Figure 1: Rationally designed cross-linker architecture enables logic-based material degradation.
Figure 2: Engineered cross-linkers respond to environmental input combinations on the molecular level.
Figure 3: Logic-gated biomaterials exhibit programmable degradation in response to environmentally presented input combinations.
Figure 4: Logic-based doxorubicin delivery enhances specificity of HeLa cell death in the presence of multiple disease-state hallmarks.
Figure 5: Sequential and spatiotemporally varied delivery of small molecules and cells from gels following logic-based response to environmental cues.

References

  1. 1

    Burdick, J. A. & Murphy, W. L. Moving from static to dynamic complexity in hydrogel design. Nat. Commun. 3, 1269 (2012).

    Article  Google Scholar 

  2. 2

    Hoffman, A. S. Stimuli-responsive polymers: biomedical applications and challenges for clinical translation. Adv. Drug Deliv. Rev. 65, 10–16 (2013).

    CAS  Article  Google Scholar 

  3. 3

    Knipe, J. M. & Peppas, N. A. Multi-responsive hydrogels for drug delivery and tissue engineering applications. Regen. Biomater. 1, 57–65 (2014).

    Article  Google Scholar 

  4. 4

    Mura, S., Nicolas, J. & Couvreur, P. Stimuli-responsive nanocarriers for drug delivery. Nat. Mater. 12, 991–1003 (2013).

    CAS  Article  Google Scholar 

  5. 5

    O'Neill, H. S. et al. Biomaterial-enhanced cell and drug delivery: lessons learned in the cardiac field and future perspectives. Adv. Mater. 28, 5648–5661 (2016).

    CAS  Article  Google Scholar 

  6. 6

    Tibbitt, M. W., Rodell, C. B., Burdick, J. A. & Anseth, K. S. Progress in material design for biomedical applications. Proc. Natl Acad. Sci. USA 112, 14444–14451 (2015).

    CAS  Article  Google Scholar 

  7. 7

    Evans, A. C., Thadani, N. N. & Suh, J. Biocomputing nanoplatforms as therapeutics and diagnostics. J. Control. Rel. 240, 387–393 (2016).

    CAS  Article  Google Scholar 

  8. 8

    Lu, Y., Aimetti, A. A., Langer, R. & Gu, Z. Bioresponsive materials. Nat. Rev. Mater. 2, 16075 (2016).

    Article  Google Scholar 

  9. 9

    DeForest, C. A. & Anseth, K. S. Advances in bioactive hydrogels to probe and direct cell fate. Annu. Rev. Chem. Biomol. Eng. 3, 421–444 (2012).

    CAS  Article  Google Scholar 

  10. 10

    Li, J. & Mooney, D. J. Designing hydrogels for controlled drug delivery. Nat. Rev. Mater. 1, 16071 (2016).

    CAS  Article  Google Scholar 

  11. 11

    McCawley, L. J. & Matrisian, L. M. Matrix metalloproteinases: multifunctional contributors to tumor progression. Mol. Med. Today 6, 149–156 (2000).

    CAS  Article  Google Scholar 

  12. 12

    Chen, X. et al. Dual bioresponsive mesoporous silica nanocarrier as an ‘AND’ logic gate for targeted drug delivery cancer cells. Adv. Funct. Mater. 24, 6999–7006 (2014).

    CAS  Article  Google Scholar 

  13. 13

    Choh, S., Cross, D. & Wang, C. Facile synthesis and characterization of disulfide-cross-linked hyaluronic acid hydrogels for protein delivery and cell encapsulation. Biomacromolecules 12, 1126–1136 (2011).

    CAS  Article  Google Scholar 

  14. 14

    Douglas, S. M., Bachelet, I. & Church, G. M. A logic-gated nanorobot for targeted transport of molecular payloads. Science 335, 831–834 (2012).

    CAS  Article  Google Scholar 

  15. 15

    Ikeda, M. et al. Installing logic-gate responses to a variety of biological substances in supramolecular hydrogel-enzyme hybrids. Nat. Chem. 6, 511–518 (2014).

    CAS  Article  Google Scholar 

  16. 16

    Komatsu, H. et al. Supramolecular hydrogel exhibiting four basic logic gate functions to fine-tune substance release. J. Am. Chem. Soc. 131, 5580–5585 (2009).

    CAS  Article  Google Scholar 

  17. 17

    Liu, G., Ji, W. & Feng, C. Installing logic gates to multiresponsive supramolecular hydrogel co-assembled from phenylalanine amphiphile and bis(pyridinyl) derivative. Langmuir 31, 7122–7128 (2015).

    CAS  Article  Google Scholar 

  18. 18

    Motornov, M. et al. ‘Chemical transformers’ from nanoparticle ensembles operated with logic. Nano Lett. 8, 2993–2997 (2008).

    CAS  Article  Google Scholar 

  19. 19

    Kharkar, P. M., Kiick, K. L. & Kloxin, A. M. Design of thiol- and light-sensitive degradable hydrogels using Michael-type additon reactions. Polym. Chem. 6, 5565–5574 (2015).

    CAS  Article  Google Scholar 

  20. 20

    de Garcia Lux, C. et al. Short soluble coumarin crosslinkers for light-controlled release of cells and proteins from hydrogels. Biomacromolecules 16, 3286–3296 (2015).

    Article  Google Scholar 

  21. 21

    Roche, E. T. et al. Comparison of biomaterial delivery vehicles for improving acute retention of stem cells in the infarcted heart. Biomaterials 35, 6850–6858 (2014).

    CAS  Article  Google Scholar 

  22. 22

    Steinhilber, D. et al. A microgel construction kit for bioorthogonal encapsulation and pH-controlled release of living cells. Angew. Chem. Int. Ed. 52, 13538–13543 (2013).

    CAS  Article  Google Scholar 

  23. 23

    Griffin, D. R. & Kasko, A. M. Photodegradable macromers and hydrogels for live cell encapsulation and release. J. Am. Chem. Soc. 134, 13103–13107 (2012).

    CAS  Article  Google Scholar 

  24. 24

    Nagase, H. & Fields, G. B. Human matrix metalloproteinase specificity studies using collagen sequence-based synthetic peptides. Pept. Sci. 40, 399–416 (1996).

    CAS  Article  Google Scholar 

  25. 25

    Kloxin, A. M., Tibbitt, M. W. & Anseth, K. S. Synthesis of photodegradable hydrogels as dynamically tunable cell culture platforms. Nat. Protoc. 5, 1867–1887 (2010).

    CAS  Article  Google Scholar 

  26. 26

    Agard, N. J., Prescher, J. A. & Bertozzi, C. R. A strain-promoted [3+2] azide–alkyne cycloaddition for covalent modification of biomolecules in living systems. J. Am. Chem. Soc. 126, 15046–15047 (2004).

    CAS  Article  Google Scholar 

  27. 27

    DeForest, C. A. & Anseth, K. S. Cytocompatible click-based hydrogels with dynamically tunable properties through orthogonal photoconjugation and photocleavage reactions. Nat. Chem. 3, 925–931 (2011).

    CAS  Article  Google Scholar 

  28. 28

    DeForest, C. A., Polizzotti, B. D. & Anseth, K. S. Sequential click reactions for synthesizing and patterning three-dimensional cell microenvironments. Nat. Mater. 8, 659–664 (2009).

    CAS  Article  Google Scholar 

  29. 29

    DeForest, C. A. & Tirrell, D. A. A photoreversible protein-patterning approach for guiding stem cell fate in three-dimensional gels. Nat. Mater. 14, 523–531 (2015).

    CAS  Article  Google Scholar 

  30. 30

    Madl, C. M., Katz, L. M. & Heilshorn, S. C. Bio-orthogonally crosslinked, engineered protein hydrogels with tunable mechanics and biochemistry for cell encapsulation. Adv. Funct. Mater. 26, 3612–3620 (2016).

    CAS  Article  Google Scholar 

  31. 31

    Jiang, Y., Chen, J., Deng, C., Suuronen, E. J. & Zhong, Z. Click hydrogels, microgels and nanogels: emerging platforms for drug delivery and tissue engineering. Biomaterials 35, 4969–4985 (2014).

    CAS  Article  Google Scholar 

  32. 32

    Das, R. K., Gocheva, V., Hammink, R., Zouani, O. F. & Rowan, A. E. Stress-stiffening-mediated stem-cell commitment switch in soft responsive hydrogels. Nat. Mater. 15, 318–325 (2016).

    CAS  Article  Google Scholar 

  33. 33

    Hiemenz, P. C. & Lodge, T. P. Polymer Chemistry (CRC Press, 2007).

    Google Scholar 

  34. 34

    Flynn, B. P. et al. Mechanical strain stabilizes reconstituted collagen fibrils against enzymatic degradation by mammalian collagenase matrix metalloproteinase 8 (MMP-8). PLoS ONE 5, e12337 (2010).

    Article  Google Scholar 

  35. 35

    Huo, M., Yuan, J. & Wei, Y. Redox-responsive polymers for drug delivery: from molecular design to applications. Polym. Chem. 5, 1519–1528 (2014).

    CAS  Article  Google Scholar 

  36. 36

    Zhu, C., Ninh, C. & Bettinger, C. J. Photoreconfigurable polymers for biomedical applications: chemistry and macromolecular engineering. Biomacromolecules 15, 3474–3494 (2014).

    CAS  Article  Google Scholar 

  37. 37

    Uhrich, K. E., Cannizzaro, S. M., Langer, R. S. & Shakesheff, K. M. Polymeric systems for controlled drug release. Chem. Rev. 99, 3181–3198 (1999).

    CAS  Article  Google Scholar 

  38. 38

    Arakawa, C. K., Badeau, B. A., Zheng, Y. & DeForest, C. A. Multicellular vascularized engineered tissues through user-programmable biomaterial photodegradation. Adv. Mater. 29, 1703156 (2017).

    Article  Google Scholar 

  39. 39

    Khetan, S. & Burdick, J. A. Patterning network structure to spatially control cellular remodeling and stem cell fate within 3-dimensional hydrogels. Biomaterials 31, 8228–8234 (2010).

    CAS  Article  Google Scholar 

  40. 40

    Khetan, S. et al. Degradation-mediated cellular traction directs stem cell fate in covalently crosslinked three-dimensional hydrogels. Nat. Mater. 12, 458–465 (2013).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

The authors thank B. Hayes and B. Torok-Storb for gifting the hS5 cells, S. Adelmund for synthesizing and supplying BCN-OSu, E. Ruskowitz for useful discussion involving the DOX studies, as well as K. Anseth, D. Tirrell, S. Pun and B. Ratner for constructive comments during the preparation of this manuscript. The authors acknowledge support from S. Edgar at the University of Washington (UW) Mass Spectrometry Center, D. Prunkard at the UW Pathology Flow Cytometry Core Facility, and N. Peters and support from the NIH to the UW W. M. Keck Microscopy Center (S10 OD016240). This work was supported by a University of Washington Faculty Startup Grant (to C.A.D.) and a National Science Foundation CAREER Award (DMR 1652141, to C.A.D.).

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B.A.B. and C.A.D. conceived and designed the experiments. B.A.B., M.P.C., C.K.A. and J.A.S. performed the experiments. B.A.B. and C.A.D. analysed the data and prepared the figures. B.A.B. and C.A.D. wrote the paper.

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Correspondence to Cole A. DeForest.

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Badeau, B., Comerford, M., Arakawa, C. et al. Engineered modular biomaterial logic gates for environmentally triggered therapeutic delivery. Nature Chem 10, 251–258 (2018). https://doi.org/10.1038/nchem.2917

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