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Kirigami-inspired stents for sustained local delivery of therapeutics

Abstract

Implantable drug depots have the capacity to locally meet therapeutic requirements by maximizing local drug efficacy and minimizing potential systemic side effects. Tubular organs including the gastrointestinal tract, respiratory tract and vasculature all manifest with endoluminal disease. The anatomic distribution of localized drug delivery for these organs using existing therapeutic modalities is limited. Application of local depots in a circumferential and extended longitudinal fashion could transform our capacity to offer effective treatment across a range of conditions. Here we report the development and application of a kirigami-based stent platform to achieve this. The stents comprise a stretchable snake-skin-inspired kirigami shell integrated with a fluidically driven linear soft actuator. They have the capacity to deposit drug depots circumferentially and longitudinally in the tubular mucosa of the gastrointestinal tract across millimetre to multi-centimetre length scales, as well as in the vasculature and large airways. We characterize the mechanics of kirigami stents for injection, and their capacity to engage tissue in a controlled manner and deposit degradable microparticles loaded with therapeutics by evaluating these systems ex vivo and in vivo in swine. We anticipate such systems could be applied for a range of endoluminal diseases by simplifying dosing regimens while maximizing drug on-target effects through the sustained release of therapeutics and minimizing systemic side effects.

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Fig. 1: Overview and numerical characterization of injectable kirigami-based stents.
Fig. 2: Stent fabrication and mechanical characterization of the oesophageal stent prototypes.
Fig. 3: Ex vivo and in vivo evaluation of controlled penetration of the stent needles to the oesophageal tissue.
Fig. 4: In vivo extended drug release through deposition of drug-loaded polymeric particles.

Data availability

All the data supporting the results in this study are available within the paper and its Supplementary Information. Source data are provided with this paper.

Code availability

Abaqus scripts used for the numerical analyses are available from the corresponding author upon request.

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Acknowledgements

We thank R. Langer for helpful discussion and support. We thank V. Spanoudaki and W. Huang for help with the micro-CT and histology images, A. Rafsanjani for productive discussions and all colleagues of the Langer and Traverso Laboratories for fruitful discussions. This work was funded in part by the Karl van Tassel (1925) Career Development Professorship and the Department of Mechanical Engineering, Massachusetts Institute of Technology.

Author information

Affiliations

Authors

Contributions

S.B., Y.S. and G.T. conceived and designed the research. S.B. and Y.S. performed the design, FE simulations, manufacturing, mechanical characterization and in vitro testing of the stent prototypes. S.T., J.E.C., K.I., A.M.H., M.A., S.B. and Y.S. performed the in vivo pig experiments. S.A. performed particle synthesis and characterization. K.H. and A.L. performed the biochemistry analysis. S.B., Y.S., S.A., M.W., M.A. and G.T. discussed and analysed the results and wrote the manuscript. All authors reviewed the manuscript and provided active and valuable feedback.

Corresponding author

Correspondence to Giovanni Traverso.

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Competing interests

S.B., Y.S., S.A., M.A. and G.T. are co-inventors on provisional patent application 63/041154 describing the technologies presented in this paper. Complete details of all relationships for profit and not for profit for G.T. can be found at the following link: https://www.dropbox.com/sh/szi7vnr4a2ajb56/AABs5N5i0q9AfT1IqIJAE-T5a?dl=0. The other authors declare no competing interests.

Additional information

Peer review Information Nature Materials thanks Edith Mathiowitz and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–13, Methods and captions for Videos 1–9.

Reporting Summary

Supplementary Video 1

Deformation of the kirigami-based stent obtained using FE simulations.

Supplementary Video 2

Effect of the size of kirigami needles on deformation of the kirigami-based stents using FE simulations.

Supplementary Video 3

Effect of kirigami shell thickness on deformation of the kirigami-based stents using FE simulations.

Supplementary Video 4

Fluid-powered soft linear actuator.

Supplementary Video 5

Effect of kirigami surface thickness on deformation of the kirigami stents using experiments and FE simulations.

Supplementary Video 6

Effect of the size of kirigami needles on deformation of the kirigami stents using experiments and FE simulations.

Supplementary Video 7

Characterization of the fabricated oesophageal kirigami stent.

Supplementary Video 8

Spray coating of the kirigami stent.

Supplementary Video 9

Endoscopic evaluation of oesophagus after in vivo deployment of the kirigami stents in pigs.

Source data

Source Data Fig. 1

Source data for numerical characterization of kirigami-based stents.

Source Data Fig. 2

Source data for experimental characterization of the oesophageal stent prototypes.

Source Data Fig. 3

Source data for evaluation of controlled penetration of the stent needles.

Source Data Fig. 4

Source data for extended drug release.

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Babaee, S., Shi, Y., Abbasalizadeh, S. et al. Kirigami-inspired stents for sustained local delivery of therapeutics. Nat. Mater. 20, 1085–1092 (2021). https://doi.org/10.1038/s41563-021-01031-1

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