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Enhanced tendon healing by a tough hydrogel with an adhesive side and high drug-loading capacity

Nature Biomedical Engineering volume 6, pages 1167–1179 (2022)Cite this article

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Abstract

Hydrogels that provide mechanical support and sustainably release therapeutics have been used to treat tendon injuries. However, most hydrogels are insufficiently tough, release drugs in bursts, and require cell infiltration or suturing to integrate with surrounding tissue. Here we report that a hydrogel serving as a high-capacity drug depot and combining a dissipative tough matrix on one side and a chitosan adhesive surface on the other side supports tendon gliding and strong adhesion (larger than 1,000 J m−2) to tendon on opposite surfaces of the hydrogel, as we show with porcine and human tendon preparations during cyclic-friction loadings. The hydrogel is biocompatible, strongly adheres to patellar, supraspinatus and Achilles tendons of live rats, boosted healing and reduced scar formation in a rat model of Achilles-tendon rupture, and sustainably released the corticosteroid triamcinolone acetonide in a rat model of patellar tendon injury, reducing inflammation, modulating chemokine secretion, recruiting tendon stem and progenitor cells, and promoting macrophage polarization to the M2 phenotype. Hydrogels with ‘Janus’ surfaces and sustained-drug-release functionality could be designed for a range of biomedical applications.

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Fig. 1: An overview of the vision for the multifunctional performance of the JTAs for tendon.
Fig. 2: JTA adheres strongly to diverse tendon surfaces.
Fig. 3: JTA promotes tendon gliding.
Fig. 4: JTA is biocompatible with tendon and supports healing.
Fig. 5: JTA enables dissolution-controlled release at high drug loadings.
Fig. 6: JTA modulates vascularization and tendon properties in a rat model of patellar tendon injury.
Fig. 7: JTA induces immune modulation in tendon following injury.

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Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. Source data are provided with this paper. All raw and analysed datasets generated during the study are available for research purposes from the corresponding authors on reasonable request.

Code availability

The MATLAB code used to process mechanical data is available on reasonable request, and we will ensure its compatibility with any study-specific datasets generated.

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Acknowledgements

This work was supported by the National Institute on Aging of the NIH (F32AG057135, K99AG065495), Novartis and the Wyss Institute for Biologically Inspired Engineering. Porcine tissues ex vivo were donated by Boston Children’s Hospital. We thank M. Lewandowski and the Harvard Center for Biological Imaging for discussion.

Author information

Authors and Affiliations

  1. John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA

    Benjamin R. Freedman, Sungmin Nam & David J. Mooney

  2. Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA

    Benjamin R. Freedman, Sungmin Nam, Daniel Kent, Anna Rock, Yann Tinguely & David J. Mooney

  3. Novartis Institutes for Biomedical Research, Basel, Switzerland

    Andreas Kuttler, Nicolau Beckmann, Michael Schuleit, Farshad Ramazani, Nathalie Accart, Markus Kurz, Andreas Fisch, Thomas Ullrich & Eckhard Weber

  4. Department of Mechanical Engineering, McGill University, Montreal, Quebec, Canada

    Jianyu Li

  5. Biedermann Lab for Orthopaedic Research, Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA, USA

    Michael W. Hast

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Contributions

All authors contributed to the preparation of this manuscript. B.R.F., A.K., S.N., D.K., A.R., N.B. and E.W. performed the experiments. B.R.F., A.K., N.B. and Y.T. performed data analysis. B.R.F., E.W. and D.J.M. planned experiments.

Corresponding authors

Correspondence to Eckhard Weber or David J. Mooney.

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Competing interests

The authors receive grant support through Novartis. The views and opinions expressed in this article are those of the authors and do not necessarily reflect the position of the Wyss Institute for Biologically Inspired Engineering at Harvard University or Novartis.

Additional information

Peer review information Nature Biomedical Engineering thanks Manuela Gomes, Stavros Thomopoulos and Xuanhe Zhao for their contribution to the peer review of this work. Peer reviewer reports are available.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Effect of CORT releasing JTAs on animal physiology over time.

(a) The JTA dissolution-controlled release system was surrounded by an outer JTA to stabilize it on the rat patellar tendon and enable a depot-based delivery system. (b) Rat body weight was examined over time. Data shown as mean ± s.d., as analyzed by ANOVAs, with post hoc tests with Bonferroni corrections. a: P = 0.0008, b: P = 0.002; c: P = 0.006; d: P = 0.0011. N = 4–6 rats/group. (c) Blood glucose levels were evaluated over time. Data shown as mean ± s.d., as evaluated by a one-way ANOVA, with post hoc Tukey Tests for multiple comparisons. N = 4–6 rats/group. (d) The effect of injury, JTA, and CORT on corticosterone levels 2 days and 14 days post-implantation. Data shown as mean ± s.d., as analyzed by a two-way repeated ANOVA (time and treatment), with post hoc Tukey Tests for multiple comparisons. N = 4–6 samples/group.

Source data

Extended Data Fig. 2 Effect of the JTA and corticosteroid delivery on chemokines.

The effect of injury, JTA, and CORT on (a) GROα and (b) RANTES was evaluated after 2 and 14 days of healing. Data shown as mean ± s.d., as evaluated by a two-way repeated measures ANOVA with post hoc Tukey Tests for multiple comparisons. N = 5–6 samples/group.

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Extended Data Fig. 3 Effect of the JTA and corticosteroid delivery on tendon histological properties.

The effect of injury, JTA, and CORT on (a) nuclear aspect ratio, (b) CD45, (c) CD31, (d) CD146, (e) αSMA, and (f) iNos staining was evaluated after 2-weeks of healing. Data shown as mean ± s.d., as evaluated by a one-way ANOVA with post hoc Tukey Tests for multiple comparisons. N = 4–6 tendons/group.

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Supplementary information

Supplementary Information

Supplementary figures, tables and video captions.

Reporting Summary.

Peer Review File.

Supplementary Video 1

Janus tough adhesive adheres strongly to tendon.

Supplementary Video 2

Tough adhesion maintained after incubation in DMEM.

Supplementary Video 3

Tough adhesion maintained after interaction with blood.

Supplementary Video 4

Tough adhesion to diverse porcine tendon surfaces.

Supplementary Video 5

Tough adhesion to porcine Achilles tendon.

Supplementary Video 6

Janus tough adhesive promotes gliding.

Supplementary Video 7

Janus tough adhesive glides through transverse carpal ligaments.

Supplementary Video 8

Examination of the Janus tough adhesive using HFUS.

Supplementary Video 9

Attachment of the Janus tough adhesive to bone.

Supplementary Video 10

Modelling dissolution-controlled release.

Supplementary Video 11

Ultrasound assessment of tendon and the Janus tough adhesive.

Supplementary Video 12

Doppler ultrasound imaging of tendon and the Janus tough adhesive.

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Freedman, B.R., Kuttler, A., Beckmann, N. et al. Enhanced tendon healing by a tough hydrogel with an adhesive side and high drug-loading capacity. Nat. Biomed. Eng 6, 1167–1179 (2022). https://doi.org/10.1038/s41551-021-00810-0

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