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Flexible shape-memory scaffold for minimally invasive delivery of functional tissues

Abstract

Despite great progress in engineering functional tissues for organ repair, including the heart, an invasive surgical approach is still required for their implantation. Here, we designed an elastic and microfabricated scaffold using a biodegradable polymer (poly(octamethylene maleate (anhydride) citrate)) for functional tissue delivery via injection. The scaffold’s shape memory was due to the microfabricated lattice design. Scaffolds and cardiac patches (1 cm × 1 cm) were delivered through an orifice as small as 1 mm, recovering their initial shape following injection without affecting cardiomyocyte viability and function. In a subcutaneous syngeneic rat model, injection of cardiac patches was equivalent to open surgery when comparing vascularization, macrophage recruitment and cell survival. The patches significantly improved cardiac function following myocardial infarction in a rat, compared with the untreated controls. Successful minimally invasive delivery of human cell-derived patches to the epicardium, aorta and liver in a large-animal (porcine) model was achieved.

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Figure 1: Scaffold synthesis, fabrication and characterization.
Figure 2: Engineering a functional cardiac tissue on a shape-memory scaffold.
Figure 3: Scaffold and functional cardiac tissue delivery by injection.
Figure 4: Subcutaneously injected rat cardiac tissues exhibit signs of vascularization and cardiomyocyte persistence in a syngeneic rat model.
Figure 5: Cardiac patch surgical implantation improves left ventricular function and gross heart morphology 6 weeks post myocardial infarction.
Figure 6: Minimally invasive delivery of organ-specific engineered tissue patches on the porcine epicardium, liver and aorta.

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Acknowledgements

This work was funded by the Canadian Institutes of Health Research (CIHR) Operating Grant MOP-137107, the National Sciences and Engineering Research Council of Canada (NSERC) Steacie Fellowship to M.R., University of Toronto McLean Award to M.R., NSERC Vanier Scholarship to M.M., Training Program in Organ-on-a-Chip Engineering & Entrepreneurship (TOeP) NSERC CREATE Scholarship to M.M., the CIHR Operating Grant (MOP-126027), the Heart and Stroke Foundation Grant G-16-00012711, NSERC Discovery Grant (RGPIN-2015-05952), Canada Foundation for Innovation Grant (226225) and Ontario Institute for Regenerative Medicine New Ideas Grant (500235). The authors acknowledge the Canada Foundation for Innovation, Project 19119, and the Ontario Research Fund for funding of the Centre for Spectroscopic Investigation of Complex Organic Molecules and Polymers. Some of the equipment used in this study was supported by the 3D (Diet, Digestive Tract and Disease) Centre funded by the Canadian Foundation for Innovation and Ontario Research Fund, project number 19442 and 30961. The assistance in bioluminescence imaging provided by A. Hardy of the CFI 3D facility is highly acknowledged. We thank L. You from the Department of Mechanical and Industrial Engineering at the University of Toronto for offering expertise in reviewing the FEA simulation data, and B. Zhang and A. Korolj in helping review and provide comments on the manuscript.

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Contributions

M.M. and M.R. conceived the idea, designed the experiments and analysed the results. M.M. and S.Ahadian performed the experiments and analysed the results. M.M. and L.D.H. synthesized and characterized the POMAC prepolymer. L.D.H. assisted in animal models. M.L.R., R.D.V. and C.A.C. developed and executed the porcine model and wrote the corresponding method section. R.A.C. assisted in cell culture, porcine experiments and histology sample preparation. L.A.R. assisted in experiments and analysing the results. S.Akbari performed the FEA. A.P. cultured and differentiated human stem cells. J.W. and R.-K.L. performed the functional myocardial infarction study. A.M. performed the surgical placement of scaffolds onto the rat heart in the host response study. M.M., S.Ahadian and M.R. wrote the manuscript. M.R. supervised the entire project. All authors read the manuscript, commented on it and approved its content.

Corresponding author

Correspondence to Milica Radisic.

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The authors declare no competing financial interests.

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Montgomery, M., Ahadian, S., Davenport Huyer, L. et al. Flexible shape-memory scaffold for minimally invasive delivery of functional tissues. Nature Mater 16, 1038–1046 (2017). https://doi.org/10.1038/nmat4956

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