Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

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.

References

  1. Optimizing the Management of Rotator Cuff Problems (American Academy of Orthopaedic Surgeons Guideline, 2013).

  2. Iannotti, J. P. Full-thickness rotator cuff tears: factors affecting surgical outcome. J. Am. Acad. Orthop. Surg. 2, 87–95 (1994).

    Article  CAS  PubMed  Google Scholar 

  3. Goutallier, D., Postel, J. M., Gleyze, P., Leguilloux, P. & van Driessche, S. Influence of cuff muscle fatty degeneration on anatomic and functional outcomes after simple suture of full-thickness tears. J. Shoulder Elbow Surg. 12, 550–554 (2003).

    Article  PubMed  Google Scholar 

  4. McCarron, J. A. et al. Failure with continuity in rotator cuff repair ‘healing’. Am. J. Sports Med. 41, 134–141 (2013).

    Article  PubMed  Google Scholar 

  5. Rodeo, S. A. Biologic augmentation of rotator cuff tendon repair. J. Shoulder Elbow Surg. 16, S191–S197 (2007).

    Article  PubMed  Google Scholar 

  6. Watts, A. E. et al. MicroRNA29a treatment improves early tendon injury. Mol. Ther. 25, 2415–2426 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Millar, N. L. et al. MicroRNA29a regulates IL-33-mediated tissue remodelling in tendon disease. Nat. Commun. 6, 6774 (2015).

    Article  CAS  PubMed  Google Scholar 

  8. Li, J. et al. Tough composite hydrogels with high loading and local release of biological drugs. Adv. Health. Mater. 7, e1701393 (2018).

    Article  Google Scholar 

  9. Gelberman, R. H. et al. Combined administration of ASCs and BMP-12 promotes an M2 macrophage phenotype and enhances tendon healing. Clin. Orthop. Relat. Res. 475, 2318–2331 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Freedman, B. R. & Mooney, D. J. Biomaterials to mimic and heal connective tissues. Adv. Mater. 31, e1806695 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Murray, M. M. et al. The bridge-enhanced Anterior Cruciate Ligament Repair (BEAR) procedure: an early feasibility cohort study. Orthop. J. Sports Med. 4, 2325967116672176 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Shoaib, A. & Mishra, V. Surgical repair of symptomatic chronic Achilles tendon rupture using synthetic graft augmentation. Foot Ankle Surg. 23, 179–182 (2017).

    Article  PubMed  Google Scholar 

  13. Mitragotri, S., Burke, P. A. & Langer, R. Overcoming the challenges in administering biopharmaceuticals: formulation and delivery strategies. Nat. Rev. Drug Discov. 13, 655–672 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Anselmo, A. C. & Mitragotri, S. Nanoparticles in the clinic: an update. Bioeng. Transl. Med. 4, e10143 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Li, J. & Mooney, D. J. Designing hydrogels for controlled drug delivery. Nat. Rev. Mater. https://doi.org/10.1038/natrevmats.2016.71 (2016).

  16. Bjarnason, I., Hayllar, J., MacPherson, A. J. & Russell, A. S. Side effects of nonsteroidal anti-inflammatory drugs on the small and large intestine in humans. Gastroenterology 104, 1832–1847 (1993).

    Article  CAS  PubMed  Google Scholar 

  17. Svanstrom, H., Lund, M., Melbye, M. & Pasternak, B. Concomitant use of low-dose methotrexate and NSAIDs and the risk of serious adverse events among patients with rheumatoid arthritis. Pharmacoepidemiol. Drug Saf. 27, 885–893 (2018).

    Article  PubMed  Google Scholar 

  18. Blomquist, J., Solheim, E., Liavaag, S., Baste, V. & Havelin, L. I. Do nonsteroidal anti-inflammatory drugs affect the outcome of arthroscopic Bankart repair? Scand. J. Med. Sci. Sports 24, e510–e514 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Soreide, E. et al. The effect of limited perioperative nonsteroidal anti-inflammatory drugs on patients undergoing anterior cruciate ligament reconstruction. Am. J. Sports Med. 44, 3111–3118 (2016).

    Article  PubMed  Google Scholar 

  20. Oh, J. H. et al. Do selective COX-2 inhibitors affect pain control and healing after arthroscopic rotator cuff repair? A preliminary study. Am. J. Sports Med. 46, 679–686 (2018).

    Article  PubMed  Google Scholar 

  21. Kwon, H. H. et al. Synergistic effect of cumulative corticosteroid dose and immunosuppressants on avascular necrosis in patients with systemic lupus erythematosus. Lupus https://doi.org/10.1177/0961203318784648 (2018).

  22. Wang, J. C., Chang, K. V., Wu, W. T., Han, D. S. & Ozcakar, L. Ultrasound-guided standard vs dual-target subacromial corticosteroid injections for shoulder impingement syndrome: a randomized controlled trial. Arch. Phys. Med. Rehabil. 100, 2119–2128 (2019).

    Article  PubMed  Google Scholar 

  23. Hugate, R., Pennypacker, J., Saunders, M. & Juliano, P. The effects of intratendinous and retrocalcaneal intrabursal injections of corticosteroid on the biomechanical properties of rabbit Achilles tendons. J. Bone Joint Surg. Am. 86, 794–801 (2004).

    Article  PubMed  Google Scholar 

  24. Zhang, B., Hu, S. T. & Zhang, Y. Z. Spontaneous rupture of multiple extensor tendons following repeated steroid injections: a case report. Orthop. Surg. 4, 118–121 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Markl, D. & Zeitler, J. A. A review of disintegration mechanisms and measurement techniques. Pharm. Res. 34, 890–917 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Li, J. et al. Tough adhesives for diverse wet surfaces. Science 357, 378–381 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Linderman, S. W. et al. Shear lag sutures: improved suture repair through the use of adhesives. Acta Biomater. 23, 229–239 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Evans, C. E., Lees, G. C. & Trail, I. A. Cytotoxicity of cyanoacrylate adhesives to cultured tendon cells. J. Hand Surg. Br. 24, 658–661 (1999).

    Article  CAS  PubMed  Google Scholar 

  29. Zhao, C. et al. CORR(R) ORS Richard A. Brand Award for outstanding orthopaedic research: engineering flexor tendon repair with lubricant, cells, and cytokines in a canine model. Clin. Orthop. Relat. Res. 472, 2569–2578 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Zhao, C. et al. Surface modification counteracts adverse effects associated with immobilization after flexor tendon repair. J. Orthop. Res. 30, 1940–1944 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Mellstrand-Navarro, C., Pettersson, H. J., Tornqvist, H. & Ponzer, S. The operative treatment of fractures of the distal radius is increasing: results from a nationwide Swedish study. Bone Joint J. 96-B, 963–969 (2014).

    Article  CAS  PubMed  Google Scholar 

  32. Soong, M., Earp, B. E., Bishop, G., Leung, A. & Blazar, P. Volar locking plate implant prominence and flexor tendon rupture. J. Bone Joint Surg. Am. 93, 328–335 (2011).

    Article  PubMed  Google Scholar 

  33. Tang, J. B. Clinical outcomes associated with flexor tendon repair. Hand Clin. 21, 199–210 (2005).

    Article  PubMed  Google Scholar 

  34. Strickland, J. W. Development of flexor tendon surgery: twenty-five years of progress. J. Hand Surg. Am. 25, 214–235 (2000).

    Article  CAS  PubMed  Google Scholar 

  35. May, E. J. & Silfverskiold, K. L. Rate of recovery after flexor tendon repair in zone II. A prospective longitudinal study of 145 digits. Scand. J. Plast. Reconstr. Surg. Hand Surg. 27, 89–94 (1993).

    Article  CAS  PubMed  Google Scholar 

  36. Zhao, X. Multi-scale multi-mechanism design of tough hydrogels: building dissipation into stretchy networks. Soft Matter 10, 672–687 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Sun, J. Y. et al. Highly stretchable and tough hydrogels. Nature 489, 133–136 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Riggin, C. N., Sarver, J. J., Freedman, B. R., Thomas, S. J. & Soslowsky, L. J. Analysis of collagen organization in mouse Achilles tendon using high-frequency ultrasound imaging. J. Biomech. Eng. https://doi.org/10.1115/1.40262851793821 (2013).

  39. Colvin, A. C., Egorova, N., Harrison, A. K., Moskowitz, A. & Flatow, E. L. National trends in rotator cuff repair. J. Bone Joint Surg. Am. 94, 227–233 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Soslowsky, L. J., Carpenter, J. E., DeBano, C. M., Banerji, I. & Moalli, M. R. Development and use of an animal model for investigations on rotator cuff disease. J. Shoulder Elbow Surg. 5, 383–392 (1996).

    Article  CAS  PubMed  Google Scholar 

  41. Kosiyatrakul, A., Loketkrawee, W. & Luenam, S. Different dosages of triamcinolone acetonide injection for the treatment of trigger finger and thumb: a randomized controlled trial. J. Hand Surg. Asian Pac. 23, 163–169 (2018).

    Article  Google Scholar 

  42. Seki, T. et al. Measurement of diffusion coefficients of parabens and steroids in water and 1-octanol. Chem. Pharm. Bull. 51, 734–736 (2003).

    Article  CAS  Google Scholar 

  43. Wang, J. R. et al. Polymorphism of triamcinolone acetonide acetate and its implication for the morphology stability of the finished drug product. Cryst. Growth Des. 17, 9 (2017).

    Article  Google Scholar 

  44. Yang, J., Bai, R., Chen, B. & Zuo, S. Hydrogel adhesion: a supramolecular synergy of chemistry, topology, and mechanics. Adv. Funct. Mater. 27, 1–27 (2019).

    Google Scholar 

  45. He, M. et al. The effect of fibrin glue on tendon healing and adhesion formation in a rabbit model of flexor tendon injury and repair. J. Plast. Surg. Hand Surg. 47, 509–512 (2013).

    PubMed  Google Scholar 

  46. Freedman, B. R., Gordon, J. A. & Soslowsky, L. J. The Achilles tendon: fundamental properties and mechanisms governing healing. Muscles Ligaments Tendons J. 4, 245–255 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Zhang, K. et al. Tendon mineralization is progressive and associated with deterioration of tendon biomechanical properties, and requires BMP-Smad signaling in the mouse Achilles tendon injury model. Matrix Biol. 52–54, 315–324 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Mienaltowski, M. J. et al. Injury response of geriatric mouse patellar tendons. J. Orthop. Res. 34, 1256–1263 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Olsson, N. et al. Major functional deficits persist 2 years after acute Achilles tendon rupture. Knee Surg. Sports Traumatol. Arthrosc. 19, 1385–1393 (2011).

    Article  PubMed  Google Scholar 

  50. Olsson, N. et al. Predictors of clinical outcome after acute Achilles tendon ruptures. Am. J. Sports Med. 42, 1448–1455 (2014).

    Article  PubMed  Google Scholar 

  51. Freedman, B. R. et al. Mechanical, histological, and functional properties remain inferior in conservatively treated Achilles tendons in rodents: long term evaluation. J. Biomech. 56, 55–60 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Freedman, B. R., Sarver, J. J., Buckley, M. R., Voleti, P. B. & Soslowsky, L. J. Biomechanical and structural response of healing Achilles tendon to fatigue loading following acute injury. J. Biomech. 47, 2028–2034 (2014).

    Article  PubMed  Google Scholar 

  53. Langer, R. & Folkman, J. Polymers for the sustained release of proteins and other macromolecules. Nature 263, 797–800 (1976).

    Article  CAS  PubMed  Google Scholar 

  54. Sun, B., Wang, Z., He, Q., Fan, W. & Cai, S. Porous double network gels with high toughness, high stretchability and fast solvent-absorption. Soft Matter 13, 6852–6857 (2017).

    Article  CAS  PubMed  Google Scholar 

  55. Fornasiero, F., Krull, F., Prausnitz, J. M. & Radke, C. J. Steady-state diffusion of water through soft-contact-lens materials. Biomaterials 26, 5704–5716 (2005).

    Article  CAS  PubMed  Google Scholar 

  56. Kapetanos, G. The effect of the local corticosteroids on the healing and biomechanical properties of the partially injured tendon. Clin. Orthop. Relat. Res. 163, 170–179 (1982).

  57. Yang, S. L., Zhang, Y. B., Jiang, Z. T., Li, Z. Z. & Jiang, D. P. Lidocaine potentiates the deleterious effects of triamcinolone acetonide on tenocytes. Med. Sci. Monit. 20, 2478–2483 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Blomgran, P., Hammerman, M. & Aspenberg, P. Systemic corticosteroids improve tendon healing when given after the early inflammatory phase. Sci. Rep. 7, 12468 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Harada, Y. et al. Dose- and time-dependent effects of triamcinolone acetonide on human rotator cuff-derived cells. Bone Joint Res. 3, 328–334 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Wong, M. W., Tang, Y. N., Fu, S. C., Lee, K. M. & Chan, K. M. Triamcinolone suppresses human tenocyte cellular activity and collagen synthesis. Clin. Orthop. Relat. Res. https://doi.org/10.1097/01.blo.0000118184.83983.65 (2004).

  61. Tempfer, H. et al. Effects of crystalline glucocorticoid triamcinolone acetonide on cultered human supraspinatus tendon cells. Acta Orthop. 80, 357–362 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Rudnik-Jansen, I. et al. Local controlled release of corticosteroids extends surgically induced joint instability by inhibiting tissue healing. Br. J. Pharmacol. 176, 4050–4064 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Kazimierczak, P., Koziol, M. & Przekora, A. The chitosan/agarose/nanoHA bone scaffold-induced M2 macrophage polarization and its effect on osteogenic differentiation in vitro. Int. J. Mol. Sci. https://doi.org/10.3390/ijms22031109 (2021).

  64. Ashouri, F. et al. Macrophage polarization in wound healing: role of aloe vera/chitosan nanohydrogel. Drug Deliv. Transl. Res. 9, 1027–1042 (2019).

    Article  CAS  PubMed  Google Scholar 

  65. Papadimitriou, L., Kaliva, M., Vamvakaki, M. & Chatzinikolaidou, M. Immunomodulatory potential of chitosan-graft-poly(ε-caprolactone) copolymers toward the polarization of bone-marrow-derived macrophages. ACS Biomater. Sci. Eng. 3, 1341–1349 (2017).

    Article  PubMed  Google Scholar 

  66. Vasconcelos, D. P. et al. Modulation of the inflammatory response to chitosan through M2 macrophage polarization using pro-resolution mediators. Biomaterials 37, 116–123 (2015).

    Article  CAS  PubMed  Google Scholar 

  67. Vasconcelos, D. P. et al. Macrophage polarization following chitosan implantation. Biomaterials 34, 9952–9959 (2013).

    Article  CAS  PubMed  Google Scholar 

  68. Siebelt, M. et al. Triamcinolone acetonide activates an anti-inflammatory and folate receptor-positive macrophage that prevents osteophytosis in vivo. Arthritis Res. Ther. 17, 352 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Luvanda, M. K. et al. Dexamethasone creates a suppressive microenvironment and promotes Aspergillus fumigatus invasion in a human 3D epithelial/immune respiratory model. J. Fungi https://doi.org/10.3390/jof7030221 (2021).

  70. Bi, Y. et al. Identification of tendon stem/progenitor cells and the role of the extracellular matrix in their niche. Nat. Med. 13, 1219–1227 (2007).

    Article  CAS  PubMed  Google Scholar 

  71. Lee, C. H. et al. Harnessing endogenous stem/progenitor cells for tendon regeneration. J. Clin. Invest. 125, 2690–2701 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Darnell, M. C. et al. Performance and biocompatibility of extremely tough alginate/polyacrylamide hydrogels. Biomaterials 34, 8042–8048 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Blacklow, S. O. et al. Bioinspired mechanically active adhesive dressings to accelerate wound closure. Sci. Adv. 5, eaaw3963 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Smucker, J. D. & Fredericks, D. C. Assessment of Progenix((R)) DBM putty bone substitute in a rabbit posterolateral fusion model. Iowa Orthop. J. 32, 54–60 (2012).

    PubMed  PubMed Central  Google Scholar 

  75. Heijl, L., Heden, G., Svardstrom, G. & Ostgren, A. Enamel matrix derivative (EMDOGAIN) in the treatment of intrabony periodontal defects. J. Clin. Periodontol. 24, 705–714 (1997).

    Article  CAS  PubMed  Google Scholar 

  76. Lee, K. Y. & Mooney, D. J. Alginate: properties and biomedical applications. Prog. Polym. Sci. 37, 106–126 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Lose, G., Mouritsen, L. & Nielsen, J. B. A new bulking agent (polyacrylamide hydrogel) for treating stress urinary incontinence in women. BJU Int. 98, 100–104 (2006).

    Article  CAS  PubMed  Google Scholar 

  78. Kasi, A. D., Pergialiotis, V., Perrea, D. N., Khunda, A. & Doumouchtsis, S. K. Polyacrylamide hydrogel (Bulkamid(R)) for stress urinary incontinence in women: a systematic review of the literature. Int. Urogynecol. J. 27, 367–375 (2016).

    Article  PubMed  Google Scholar 

  79. Qaqish, R. B. & Amiji, M. M. Synthesis of a fluorescent chitosan derivative and its application for the study of chitosan–mucin interactions. Carbohydr. Polym. 38, 8 (1999).

    Article  Google Scholar 

  80. Zelenski, N. A. et al. Flexor pollicis longus tendon wear associated with volar plating: A cadaveric study. J. Hand Surg. Am. 46, 106–113 (2021).

    Article  PubMed  Google Scholar 

  81. Carpenter, A. E. et al. CellProfiler: image analysis software for identifying and quantifying cell phenotypes. Genome Biol. 7, R100 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Shih, T. Y. et al. Injectable, tough alginate cryogels as cancer vaccines. Adv. Health. Mater. 7, e1701469 (2018).

    Article  Google Scholar 

  83. Pardes, A. M. et al. Aging leads to inferior Achilles tendon mechanics and altered ankle function in rodents. J. Biomech. 26, 30–38 (2017).

    Article  Google Scholar 

  84. Mienaltowski, M. J., Adams, S. M. & Birk, D. E. Regional differences in stem cell/progenitor cell populations from the mouse Achilles tendon. Tissue Eng. Part A 19, 199–210 (2013).

    Article  CAS  PubMed  Google Scholar 

  85. Strober, W. Trypan blue exclusion test of cell viability. Curr. Protoc. Immunol. https://doi.org/10.1002/0471142735.ima03bs21 (2001).

  86. Freedman, B. R., Zuskov, A., Sarver, J. J., Buckley, M. R. & Soslowsky, L. J. Evaluating changes in tendon crimp with fatigue loading as an ex vivo structural assessment of tendon damage. J. Orthop. Res. 33, 904–910 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Peltz, C. D. et al. The effect of postoperative passive motion on rotator cuff healing in a rat model. J. Bone Joint Surg. Am. 91, 2421–2429 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Freedman, B. R. et al. Nonsurgical treatment and early return to activity leads to improved Achilles tendon fatigue mechanics and functional outcomes during early healing in an animal model. J. Orthop. Res. 34, 2172–2180 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Verdenius, H. H. & Alma, L. A quantitative study of decalcification methods in histology. J. Clin. Pathol. 11, 229–236 (1958).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Gordon, J. A. et al. Achilles tendons from decorin- and biglycan-null mouse models have inferior mechanical and structural properties predicted by an image-based empirical damage model. J. Biomech. 48, 2110–2115 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Gudnason, K., Sigurdsson, S. & Jonsdottir, F. A numerical framework for diffusive transport in rotational symmetric systems with discontinuous interlayer conditions. IFAC PapersOnLine 51, 5 (2018).

    Article  Google Scholar 

  92. Wilke, C. R. & Chang, P. Correlation of diffusion coefficients in dilute solutions. AlChE J. 1, 7 (1955).

    Article  Google Scholar 

Download references

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

Authors
  1. Benjamin R. Freedman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andreas Kuttler
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nicolau Beckmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sungmin Nam
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Daniel Kent
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael Schuleit
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Farshad Ramazani
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Nathalie Accart
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Anna Rock
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jianyu Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Markus Kurz
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Andreas Fisch
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Thomas Ullrich
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Michael W. Hast
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Yann Tinguely
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Eckhard Weber
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. David J. Mooney
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Ethics declarations

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.

Source data

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.

Source data

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.

Source data

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41551-021-00810-0

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research