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Injectable and bioresponsive hydrogels for on-demand matrix metalloproteinase inhibition

Nature Materials volume 13, pages 653–661 (2014)Cite this article

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Abstract

Inhibitors of matrix metalloproteinases (MMPs) have been extensively explored to treat pathologies where excessive MMP activity contributes to adverse tissue remodelling. Although MMP inhibition remains a relevant therapeutic target, MMP inhibitors have not translated to clinical application owing to the dose-limiting side effects following systemic administration of the drugs. Here, we describe the synthesis of a polysaccharide-based hydrogel that can be locally injected into tissues and releases a recombinant tissue inhibitor of MMPs (rTIMP-3) in response to MMP activity. Specifically, rTIMP-3 is sequestered in the hydrogels through electrostatic interactions and is released as crosslinks are degraded by active MMPs. Targeted delivery of the hydrogel/rTIMP-3 construct to regions of MMP overexpression following a myocardial infarction significantly reduced MMP activity and attenuated adverse left ventricular remodelling in a porcine model of myocardial infarction. Our findings demonstrate that local, on-demand MMP inhibition is achievable through the use of an injectable and bioresponsive hydrogel.

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Figure 1: The fabrication of injectable and MMP-sensitive hydrogels for therapeutic delivery.
Figure 2: The non-covalent incorporation of rTIMP-3 into hydrogels and on-demand release in response to MMP activity.
Figure 3: The visualization of injected hydrogel distribution and degradation within porcine myocardium.
Figure 4: Hydrogel delivery of rTIMP-3 alters the MMP/TIMP imbalance post MI.
Figure 5: Hydrogel delivery of rTIMP-3 attenuates adverse LV remodelling and improves cardiac function post MI.

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References

  1. Fingleton, B. Matrix metalloproteinases as valid clinical targets. Curr. Pharm. Des. 13, 333–346 (2007).

    Article  CAS  Google Scholar 

  2. Visse, R. & Nagase, H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: Structure, function, and biochemistry. Circ. Res. 92, 827–839 (2003).

    Article  CAS  Google Scholar 

  3. Abbenante, G. & Fairlie, D. P. Protease inhibitors in the clinic. Med. Chem. 1, 71–104 (2005).

    Article  CAS  Google Scholar 

  4. Turk, B. Targeting proteases: Successes, failures and future prospects. Nature Rev. Drug Discov. 5, 785–799 (2006).

    Article  CAS  Google Scholar 

  5. Hao, X. J. et al. Angiogenic effects of sequential release of VEGF-A(165) and PDGF-BB with alginate hydrogels after myocardial infarction. Cardiovasc. Res. 75, 178–185 (2007).

    Article  CAS  Google Scholar 

  6. Ruvinov, E., Leor, J. & Cohen, S. The promotion of myocardial repair by the sequential delivery of IGF-1 and HGF from an injectable alginate biomaterial in a model of acute myocardial infarction. Biomaterials 32, 565–578 (2011).

    Article  CAS  Google Scholar 

  7. Peppas, N. A., Bures, P., Leobandung, W. & Ichikawa, H. Hydrogels in pharmaceutical formulations. Eur. J. Pharm. Biopharm. 50, 27–46 (2000).

    Article  CAS  Google Scholar 

  8. Spinale, F. G., Koval, C. N., Deschamps, A. M., Stroud, R. E. & Ikonomidis, J. S. Dynamic changes in matrix metalloproteinase activity within the human myocardial interstitium during myocardial arrest and reperfusion. Circulation 118, 16–23 (2008).

    Article  Google Scholar 

  9. Webb, C. S. et al. Specific temporal profile of matrix metalloproteinase release occurs in patients after myocardial infarction: Relation to left ventricular remodeling. Circulation 114, 1020–1027 (2006).

    Article  CAS  Google Scholar 

  10. Stuart, M. A. C. et al. Emerging applications of stimuli-responsive polymer materials. Nature Mater. 9, 101–113 (2010).

    Article  Google Scholar 

  11. Lutolf, M. P. et al. Synthetic matrix metalloproteinase-sensitive hydrogels for the conduction of tissue regeneration: Engineering cell-invasion characteristics. Proc. Natl Acad. Sci. USA 100, 5413–5418 (2003).

    Article  CAS  Google Scholar 

  12. Burdick, J. A. & Murphy, W. L. Moving from static to dynamic complexity in hydrogel design. Nature Commun. 3 (2012).

  13. Phelps, E. A., Landazuri, N., Thule, P. M., Taylor, W. R. & Garcia, A. J. Bioartificial matrices for therapeutic vascularization. Proc. Natl Acad. Sci. USA 107, 3323–3328 (2010).

    Article  CAS  Google Scholar 

  14. Kim, S. & Healy, K. E. Synthesis and characterization of injectable poly(N-isopropylacrylamide-co-acrylic acid) hydrogels with proteolytically degradable cross-links. Biomacromolecules 4, 1214–1223 (2003).

    Article  CAS  Google Scholar 

  15. West, J. L. & Hubbell, J. A. Polymeric biomaterials with degradation sites for proteases involved in cell migration. Macromolecules 32, 241–244 (1999).

    Article  CAS  Google Scholar 

  16. Lutolf, M. P. et al. Repair of bone defects using synthetic mimetics of collagenous extracellular matrices. Nature Biotechnol. 21, 513–518 (2003).

    Article  CAS  Google Scholar 

  17. Spinale, F. G. & Zile, M. R. Integrating the myocardial matrix into heart failure recognition and management. Circ. Res. 113, 725–738 (2013).

    Article  CAS  Google Scholar 

  18. Ducharme, A. et al. Targeted deletion of matrix metalloproteinase-9 attenuates left ventricular enlargement and collagen accumulation after experimental myocardial infarction. J. Clin. Invest. 106, 55–62 (2000).

    Article  CAS  Google Scholar 

  19. Rohde, L. E. et al. Matrix metalloproteinase inhibition attenuates early left ventricular enlargement after experimental myocardial infarction in mice. Circulation 99, 3063–3070 (1999).

    Article  CAS  Google Scholar 

  20. Mukherjee, R. et al. Myocardial infarct expansion and matrix metalloproteinase inhibition. Circulation 107, 618–625 (2003).

    Article  CAS  Google Scholar 

  21. King, M. K. et al. Selective matrix metalloproteinase inhibition with developing heart failure: Effects on left ventricular function and structure. Circ. Res. 92, 177–185 (2003).

    Article  CAS  Google Scholar 

  22. Spinale, F. G. et al. Cardiac-restricted overexpression of membrane type-1 matrix metalloproteinase in mice: Effects on myocardial remodeling with aging. Circ. Heart Fail 2, 351–360 (2009).

    Article  CAS  Google Scholar 

  23. Peterson, J. T. The importance of estimating the therapeutic index in the development of matrix metalloproteinase inhibitors. Cardiovasc. Res. 69, 677–687 (2006).

    Article  CAS  Google Scholar 

  24. Overall, C. M. & Kleifeld, O. Tumour microenvironment—opinion: Validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nature Rev. Cancer 6, 227–239 (2006).

    Article  CAS  Google Scholar 

  25. Sahul, Z. H. et al. Targeted imaging of the spatial and temporal variation of matrix metalloproteinase activity in a porcine model of postinfarct remodeling: relationship to myocardial dysfunction. Circ. Cardiovasc. Imaging 4, 381–391 (2011).

    Article  Google Scholar 

  26. Wilson, E. M. et al. Region- and type-specific induction of matrix metalloproteinases in post-myocardial infarction remodeling. Circulation 107, 2857–2863 (2003).

    Article  CAS  Google Scholar 

  27. Brew, K. & Nagase, H. The tissue inhibitors of metalloproteinases (TIMPs): An ancient family with structural and functional diversity. Biochim. Biophys. Acta 1803, 55–71 (2010).

    Article  CAS  Google Scholar 

  28. Fedak, P. W. et al. Matrix remodeling in experimental and human heart failure: A possible regulatory role for TIMP-3. Am. J. Physiol. Heart Circ. Physiol. 284, H626–H634 (2003).

    Article  CAS  Google Scholar 

  29. Fedak, P. W. et al. TIMP-3 deficiency leads to dilated cardiomyopathy. Circulation 110, 2401–2409 (2004).

    Article  CAS  Google Scholar 

  30. Tian, H. et al. TIMP-3 deficiency accelerates cardiac remodeling after myocardial infarction. J. Mol. Cell Cardiol. 43, 733–743 (2007).

    Article  CAS  Google Scholar 

  31. Kassiri, Z. et al. Simultaneous transforming growth factor beta-tumor necrosis factor activation and cross-talk cause aberrant remodeling response and myocardial fibrosis in Timp3-deficient heart. J. Biol. Chem. 284, 29893–29904 (2009).

    Article  CAS  Google Scholar 

  32. Seif-Naraghi, S. B. et al. Safety and efficacy of an injectable extracellular matrix hydrogel for treating myocardial infarction. Sci. Trans. Med. 5 (2013).

  33. Wall, S. T., Yeh, C. C., Tu, R. Y. K., Mann, M. J. & Healy, K. E. Biomimetic matrices for myocardial stabilization and stem cell transplantation. J. Biomed. Mater. Res. Part A 95A, 1055–1066 (2010).

    Article  CAS  Google Scholar 

  34. Ifkovits, J. L. et al. Injectable hydrogel properties influence infarct expansion and extent of postinfarction left ventricular remodeling in an ovine model. Proc. Natl Acad. Sci. USA 107, 11507–11512 (2010).

    Article  CAS  Google Scholar 

  35. Segers, V. F. et al. Local delivery of protease-resistant stromal cell derived factor-1 for stem cell recruitment after myocardial infarction. Circulation 116, 1683–1692 (2007).

    Article  CAS  Google Scholar 

  36. Nelson, D. M., Ma, Z. W., Leeson, C. E. & Wagner, W. R. Extended and sequential delivery of protein from injectable thermoresponsive hydrogels. J. Biomed. Mater. Res. Part A 100A, 776–785 (2012).

    Article  CAS  Google Scholar 

  37. Leco, K. J., Khokha, R., Pavloff, N., Hawkes, S. P. & Edwards, D. R. Tissue inhibitor of metalloproteinases-3 (TIMP-3) is an extracellular matrix-associated protein with a distinctive pattern of expression in mouse cells and tissues. J. Biol. Chem. 269, 9352–9360 (1994).

    CAS  Google Scholar 

  38. Yu, W. H., Yu, S., Meng, Q., Brew, K. & Woessner, J. F. Jr TIMP-3 binds to sulfated glycosaminoglycans of the extracellular matrix. J. Biol. Chem. 275, 31226–31232 (2000).

    Article  CAS  Google Scholar 

  39. Lee, M. H., Atkinson, S. & Murphy, G. Identification of the extracellular matrix (ECM) binding motifs of tissue inhibitor of metalloproteinases (TIMP)-3 and effective transfer to TIMP-1. J. Biol. Chem. 282, 6887–6898 (2007).

    Article  CAS  Google Scholar 

  40. Troeberg, L. et al. Pentosan polysulfate increases affinity between ADAMTS-5 and TIMP-3 through formation of an electrostatically driven trimolecular complex. Biochem. J. 443, 307–315 (2012).

    Article  CAS  Google Scholar 

  41. Burdick, J. A. & Prestwich, G. D. Hyaluronic acid hydrogels for biomedical applications. Adv. Mater. 23, H41–H56 (2011).

    Article  CAS  Google Scholar 

  42. Huang, M., Vitharana, S. N., Peek, L. J., Coop, T. & Berkland, C. Polyelectrolyte complexes stabilize and controllably release vascular endothelial growth factor. Biomacromolecules 8, 1607–1614 (2007).

    Article  CAS  Google Scholar 

  43. Kichula, E. T. et al. Experimental and computational investigation of altered mechanical properties in myocardium after hydrogel injection. Ann. Biomed. Eng. (2013).

  44. Spinale, F. G. et al. A matrix metalloproteinase induction/activation system exists in the human left ventricular myocardium and is upregulated in heart failure. Circulation 102, 1944–1949 (2000).

    Article  CAS  Google Scholar 

  45. Troeberg, L. & Nagase, H. Proteases involved in cartilage matrix degradation in osteoarthritis. Biochim. Biophys. Acta 1824, 133–145 (2012).

    Article  CAS  Google Scholar 

  46. Zeisberg, E. M. et al. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nature Med. 13, 952–961 (2007).

    Article  CAS  Google Scholar 

  47. Tomasek, J. J., Gabbiani, G., Hinz, B., Chaponnier, C. & Brown, R. A. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nature Rev. Mol. Cell Biol. 3, 349–363 (2002).

    Article  CAS  Google Scholar 

  48. Goldsmith, E. C., Bradshaw, A. D. & Spinale, F. G. Cellular mechanisms of tissue fibrosis 2 Contributory pathways leading to myocardial fibrosis: Moving beyond collagen expression. Am. J. Physiol. Cell Physiol. 304, C393–C402 (2012).

    Article  Google Scholar 

  49. Su, W. Y., Chen, Y. C. & Lin, F. H. Injectable oxidized hyaluronic acid/adipic acid dihydrazide hydrogel for nucleus pulposus regeneration. Acta Biomater. 6, 3044–3055 (2010).

    Article  CAS  Google Scholar 

  50. Yushkevich, P. A. et al. User-guided 3D active contour segmentation of anatomical structures: Significantly improved efficiency and reliability. Neuroimage 31, 1116–1128 (2006).

    Article  Google Scholar 

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Acknowledgements

The authors would like to thank T. Lee from Amgen, for supplying the rTIMP-3 peptide used in this study, and W. Liu, S. Pickup and W. Witschey, from Penn Medicine, for MRI technical expertise. This work was financially supported by the National Institutes of Health (R01 HL107938, HL111090, HL095608, T32 HL007954), and a Veterans’ Affairs Health Administration Merit Award (5101BX000168-03) to F.G.S.

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Authors and Affiliations

  1. Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    Brendan P. Purcell, Manoj B. Charati, Shauna M. Dorsey, Ryan J. Wade & Jason A. Burdick

  2. Cardiovascular Translational Research Center, University of South Carolina School of Medicine and the WJB Dorn Veteran Affairs Medical Center, Columbia, South Carolina 29208, USA

    David Lobb, Kia N. Zellars, Heather Doviak, Sara Pettaway, Christina B. Logdon, James A. Shuman, Parker D. Freels & Francis G. Spinale

  3. Department of Surgery, Gorman Cardiovascular Research Laboratory, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    Joseph H. Gorman III & Robert C. Gorman

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Contributions

B.P.P., M.B.C., R.C.G., F.G.S. and J.A.B. conceived the ideas and designed the experiments. B.P.P., D.L., M.B.C., S.M.D., R.J.W., K.N.Z., H.D., S.P., C.B.L., J.A.S. and P.D.F. conducted the experiments and analysed the data. B.P.P., J.H.G., R.C.G, F.G.S. and J.A.B. interpreted the data and wrote the manuscript.

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Correspondence to Jason A. Burdick.

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Purcell, B., Lobb, D., Charati, M. et al. Injectable and bioresponsive hydrogels for on-demand matrix metalloproteinase inhibition. Nature Mater 13, 653–661 (2014). https://doi.org/10.1038/nmat3922

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