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A perfusable, multifunctional epicardial device improves cardiac function and tissue repair

Nature Medicine volume 27, pages 480–490 (2021)Cite this article

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Abstract

Despite advances in technologies for cardiac repair after myocardial infarction (MI), new integrated therapeutic approaches still need to be developed. In this study, we designed a perfusable, multifunctional epicardial device (PerMed) consisting of a biodegradable elastic patch (BEP), permeable hierarchical microchannel networks (PHMs) and a system to enable delivery of therapeutic agents from a subcutaneously implanted pump. After its implantation into the epicardium, the BEP is designed to provide mechanical cues for ventricular remodeling, and the PHMs are designed to facilitate angiogenesis and allow for infiltration of reparative cells. In a rat model of MI, implantation of the PerMed improved ventricular function. When connected to a pump, the PerMed enabled targeted, sustained and stable release of platelet-derived growth factor-BB, amplifying the efficacy of cardiac repair as compared to the device without a pump. We also demonstrated the feasibility of minimally invasive surgical PerMed implantation in pigs, demonstrating its promise for clinical translation to treat heart disease.

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Fig. 1: Design of the PerMed device.
Fig. 2: The PerMed device improved recovery of cardiac function and limited adverse LV remodeling in a rat model of MI.
Fig. 3: Regional assessment of wall stress, radial and circumferential strain and collagen subtype after PerMed implantation.
Fig. 4: The PerMed (PGS/PCL) device improved angiogenesis and cardiac metabolism and reduced cardiomyocyte apoptosis.
Fig. 5: Performance of the targeted delivery system of the PerMed for sustained release of therapeutic reagents.
Fig. 6: Minimally invasive surgical implantation of an advanced PerMed device in pigs.

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Article 01 December 2022

Zixuan Zhao, Xinyi Chen, … Hanry Yu

Data availability

The Gene Ontology annotations were downloaded from the National Center for Biotechnology Information (http://www.ncbi.nlm.nih.gov/), UniProt (http://www.UniProt.org/) and Gene Ontology (http://www.geneontology.org/). The significant pathways of the DEGs were analyzed according to the KEGG database (https://www.genome.jp/kegg/kegg1.html). The data that support the findings of this study are available within the article and its Supplementary Information files. Imaging source data about cMRI, PET and Masson’s trichrome staining are provided in Supplementary Fig. 5a–c. Statistical source data of figures and extended data figures are provided with this paper. The data that support the findings of this study are available from the corresponding author upon reasonable request. Source data are provided with this paper.

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Acknowledgements

We acknowledge financial support by the Natural Science Foundation of China (81671832, 81571826 and 21574019), the Shanghai Municipal Education Commission–Gaofeng Clinical Medicine Grant Support (826158), the Natural Science Foundation of Shanghai (20ZR1402500 and 18ZR1401900), Belt & Road Young Scientist Exchanges Project of Science and Technology Commission Foundation of Shanghai (20520741000), Science and Technology Commission of Shanghai Municipality (20DZ2254900 and 20DZ2270800), the Donghua University International Postdoctoral Program, the Shanghai Belt and Road Joint Laboratory of Advanced Fiber and Low-dimension Materials (Donghua University) (18520750400), the Fundamental Research Funds for the Central Universities and DHU Distinguished Young Professor Program (LZA2019001).

Author information

Author notes

  1. These authors contributed equally: Shixing Huang, Dong Lei.

Authors and Affiliations

  1. Department of Cardiovascular Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

    Shixing Huang, Qi Yang, Chenyu Jiang, Hongpeng Shi, Bei Qian, Qiang Long, Qiang Zhao & Xiaofeng Ye

  2. State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Shanghai Belt and Road Joint Laboratory of Advanced Fiber and Low-dimension Materials (Donghua University), College of Materials Science and Engineering, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, Donghua University, Shanghai, China

    Dong Lei, Wenyi Chen & Zhengwei You

  3. Department of Cardiothoracic Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

    Yang Yang

  4. Department of Cardiology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

    Youming Chen

  5. Department of Radiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

    Lan Zhu, Wenjie Yang & Lan Wang

  6. Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

    Wangxi Hai

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Contributions

S.H. designed the study, performed all experiments, analyzed the data and wrote and edited the manuscript and figures. D.L. designed and fabricated PerMeds, performed SEM characterization and mechanical testing and wrote the manuscript. Q.Y., Y.Y., C.J. and H.S. contributed to the animal experiments. W.C. contributed to mechanical testing. L.W. and W.H. instructed imaging study, including cMRI, micro-CT and PET–CT. Q.Z. designed and supervised the animal experiments and wrote the manuscript. Z.Y. designed and supervised the fabrication of PerMeds and testing of the materials and wrote the manuscript. X.Y. designed and supervised the whole work and wrote the manuscript.

Corresponding authors

Correspondence to Qiang Zhao, Zhengwei You or Xiaofeng Ye.

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Competing interests

The authors declare no competing interests.

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Peer review information Michael Basson was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Extended data

Extended Data Fig. 1 Structure and hydrophilicity of BEPs and PHMs.

a, Gross images of BEPs with different proportions. The arrows indicate the phase separation of the PCL. b, SEM images from the side view (i) and the top view (ii) presenting the structural integrity of the PGS/PCL (9:1) BEP, n = 3 independent experiments. c,d, Contact angle of BEPs at 10 s; n = 6 independent experiments per group. e-h, Morphology and microstructure of PHMs, n = 3 independent experiments per group. i, Contact angle and dynamic contact angle of PHMs; n = 4 independent experiments. The data are expressed as mean ± s.d. NS indicates not significant. The data are expressed as mean ± s.d. ***p<0.001. Data were analysed by one-way ANOVA followed by Bonferroni’s post hoc test.

Source data

Extended Data Fig. 2 Characterization of BEPs and PHMs.

a, Tensile strain-stress curves of BEPs (The bottom black X axis and the left black Y axis correspond to PGS and PGS/PCL(9:1) BEPs. The top red X axis and the right red Y axis correspond to PCL BEP) (i); the tensile modulus of BEPs (ii); the compressive strain-stress curves of BEPs (iii); the compressive modulus of BEPs (iv); n = 4 independent experiments per group. b, SEM images of the sutured PGS/PCL (9:1) BEP (i) and PGS BEP (ii); mechanical testing (iii) and quantitative analysis of the maximum breaking load (N) (iv); n = 4 independent experiments per group. c, Compressive modulus of PHMs; n = 4 independent experiments per group. The data are expressed as mean ± s.d. ***p<0.001. Data in (a (iv)) and (c) were analysed by one-way ANOVA followed by Bonferroni’s post hoc test; data in (a (ii)) and (b) were analysed using a two-tailed Student’s t-test.

Source data

Extended Data Fig. 3 In vitro biocompatibility of PHMs.

a,b, Quantification of ADSCs (a) and CFs (b) viability by CCK-8 assay on days 1, day 3 and day 7; n = 6 independent experiments per group. c, SEM images showing CF attachment to and retention on the interconnected microchannels of the PCL/gelatin (3:1) PHMs; n = 4 independent experiments. Arrow indicates CFs. d, 3D image of CFs on the surface of the PHMs by live/dead staining 7 days after cell seeding, n = 6 independent experiments per group. The data are expressed as mean ± s.d. *p<0.05 and ***p<0.001. Data were analysed by one-way ANOVA followed by Bonferroni’s post hoc test. CFs: cardiac fibroblasts; ADSCs: adipose-derived stem cells.

Source data

Extended Data Fig. 4 In vitro biocompatibility of BEPs.

a,b, Quantification of ADSCs (a) and CFs (b) viability by CCK-8 assay on days 1, 3 and 7; n = 6 independent experiments per group. c, Live/dead staining of ADSCs and CFs (i); immunofluorescence staining of NRCMs (α-actinin, red) and ADSCs (actin, green). d,e, Quantification of the ratio of live cells or dead cells to total cells for ADSCs (d) and CFs (e); n = 6 independent experiments per group. The data are expressed as mean ± s.d. NS indicates not significant. Data were analysed by one-way ANOVA followed by Bonferroni’s post hoc test. CFs: cardiac fibroblasts; ADSCs: adipose-derived stem cells; NRCMs: neonatal rat cardiomyocytes.

Source data

Extended Data Fig. 5 Histological assessment and evaluation of the angiogenic effect of PHMs and BEPs.

a, Representative Masson’s trichrome staining on day 28. b, Quantitative analysis of the wall thickness based on the Masson’s trichrome staining; n = 8 biologically independent samples per group. c, Representative staining in the IZ, BZ and in the BEP/PHMs for α-SMA (green), CD31 (red), and DAPI (blue) to visualize arteries on day 28. d-f, Quantitative analysis of the vessel number in all groups based on immunofluorescent staining for α-SMA (green), CD31 (red), and DAPI (blue); n = 6 biologically independent samples per group. HPF: high-power field; IZ: infarcted zone; BZ: border zone. The data are expressed as mean ± s.d. NS indicates not significant. ***p<0.001 and **p<0.01. Data were analysed by one-way ANOVA followed by Bonferroni’s post hoc test.

Source data

Extended Data Fig. 6 Illustration of cardiomyocyte apoptosis after PerMed implantation.

a, Representative images of cardiomyocyte apoptosis after PerMed implantation. b, Quantification of apoptotic cells in the IZ; n = 5 biologically independent samples per group. The data are expressed as mean ± s.d. IZ: infarcted zone; BZ: border zone.

Source data

Extended Data Fig. 7 Evaluation of capacity of PerMed for liquid distribution.

a, Representative in vivo CT images before and after the injection of contrast medium to assess the distribution of liquid on days 7, 14 and 28 (i); quantitative analysis of the ratio of the CT value after to before the injection of contrast medium (CT valueaft / CT valuebef) (ii); n = 3 biologically independent animals per group. b, Representative in vitro CT images before and after the injection of contrast medium to assess the distribution of liquid within PerMed on days 7, 14 and 28 (i); CT valueaft/CT valuebef was also analysed (ii); n = 3 biologically independent samples per group. c, Representative Masson’s trichrome staining in the IZ (i); assessment of PHMs porosity on days 7, 14 and 28 (ii); n = 7 biologically independent samples for Day 7 group, n = 8 biologically independent samples for Day 14 and 28 group. The data are expressed as mean ± s.d. NS indicates not significant. Data were analysed by one-way ANOVA followed by Bonferroni’ s post hoc test. IZ: infarcted zone.

Source data

Extended Data Fig. 8 Evaluation of the diffusion of a viral vector from the PerMed to the heart.

a, Representative images of immunofluorescence staining for GFP and α-actinin 7 and 28 days after implantation of the PerMed in the BZ. b, Representative images of immunofluorescence staining for GFP and α-SMA 7 and 28 days after implantation of the PerMed in the border zone. c, Quantitative analysis of the expression of GFP by the ratio of the GFP area to the ROI area; n = 5 biologically independent samples per group. The data are expressed as mean ± s.d. NS indicates not significant. Data in (c) were analysed using a two-tailed Student’s t-test. AAV9: adeno-associated virus 9; GFP: green fluorescent protein; ROI: region of interest; BZ: border zone.

Source data

Extended Data Fig. 9 Evaluation of the diffusion of a small molecule from the PerMed to the heart by PET-CT.

a, Representative PET-CT images every hour on the TRA, COR and SAG axis on days 7 and day 28. TRA: transverse; COR: coronal; SAG: sagittal; SUV: standardized uptake value.

Extended Data Fig. 10 Vision for clinical translation of the PerMed.

a, Schematic of the design and components of the PerMed equipped with the claw-shaped fixator. b, Design of the claw-shaped fixators with components of different types and sizes. The claw-shaped fixator consisted of a middle ring and three or four lateral arms with barbs (i, ii). The height of the arms was 4.0, 4.5, 5.0 and 6.0 mm (iii, iv); ‘h’ indicates the length of the arm, ‘w’ indicates the width of the arm, and ‘r’ indicates the diameter of the middle ring. c, Schematic of the clinical application of the PerMed. T1 indicates trocar 1; T2 indicates trocar 2; T3 indicates trocar 3. d, Schematic of the process of minimally invasive surgical implantation of the PerMed under thoracoscopic guidance, including compression of the PerMed (i), delivery of the PerMed through T2, stretching of the PerMed (iii), anchoring of the PerMed onto the surface of the porcine heart (iv, v) and extraction of the outer sheath (vi). Purple rings indicate the location of the PerMed. e, Image of the PerMed used in the porcine heart (3 cm in diameter and 2 mm in thickness). f, Top view of the PerMed anchored onto a porcine heart(i), closure of the pericardium, and conformability of the PerMed to the porcine heart (iii), n = 3 independent experiments.

Supplementary information

Supplementary Information

Supplementary Figs. 1–14, Supplementary Movie legends 1–8 and Supplementary Tables 1–4.

Reporting Summary

Supplementary Movie 1

Live and dead staining of CFs on the PCL/gelatin (3:1) PHMs.

Supplementary Movie 2

Continuous frames of cMRI cine sequence in the MI group.

Supplementary Movie 3

Continuous frames of cMRI cine sequence in the PerMed (PGS/PCL) group.

Supplementary Movie 4

3D reconstruction of the microvasculature within the PHMs (lower layer of the PerMed) 28 d after in vivo implantation.

Supplementary Movie 5

Perfusion of the PerMed with methylene blue liquid in vitro.

Supplementary Movie 6

Minimally invasive surgical implantation of the PerMed on the porcine heart under thoracoscopic guidance.

Supplementary Movie 7

Permanent ligation of the LAD to establish a rat MI model.

Supplementary Movie 8

Implantation of the PerMed onto the epicardial surface of the rat heart.

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Huang, S., Lei, D., Yang, Q. et al. A perfusable, multifunctional epicardial device improves cardiac function and tissue repair. Nat Med 27, 480–490 (2021). https://doi.org/10.1038/s41591-021-01279-9

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