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Zwitterionic hydrogels implanted in mice resist the foreign-body reaction

Abstract

The performance of implantable biomedical devices is impeded by the foreign-body reaction, which results in formation of a dense collagenous capsule that blocks mass transport and/or electric communication between the implant and the body. No known materials or coatings can completely prevent capsule formation. Here we demonstrate that ultra-low-fouling zwitterionic hydrogels can resist the formation of a capsule for at least 3 months after subcutaneous implantation in mice. Zwitterionic hydrogels also promote angiogenesis in surrounding tissue, perhaps owing to the presence of macrophages exhibiting phenotypes associated with anti-inflammatory, pro-healing functions. Thus, zwitterionic hydrogels may be useful in a broad range of applications, including generation of biocompatible implantable medical devices and tissue scaffolds.

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Figure 1: Components of PCBMA and PHEMA hydrogels and H&E stain images of samples implanted subcutaneously in mice for one week.
Figure 2: Collagen and blood vessel formation in tissues near subcutaneously implanted PCBMA and PHEMA hydrogels.
Figure 3: Phenotypes of macrophages in the tissue surrounding the hydrogels.

References

  1. Anderson, J.M., Rodriguez, A. & Chang, D.T. Foreign body reaction to biomaterials. Semin. Immunol. 20, 86–100 (2008).

    CAS  Article  Google Scholar 

  2. Langer, R. Perspectives and challenges in tissue engineering and regenerative medicine. Adv. Mater. 21, 3235–3236 (2009).

    CAS  Article  Google Scholar 

  3. Langer, R. & Tirrell, D.A. Designing materials for biology and medicine. Nature 428, 487–492 (2004).

    CAS  Article  Google Scholar 

  4. Ratner, B.D., Hoffman, A.S., Schoen, F.J. & Lemons, J.E. Biomaterials Science (Edn. 3) (Elsevier, Amsterdam, 2012).

  5. Williams, D.F. On the mechanisms of biocompatibility. Biomaterials 29, 2941–2953 (2008).

    CAS  Article  Google Scholar 

  6. Williams, D.F. On the nature of biomaterials. Biomaterials 30, 5897–5909 (2009).

    CAS  Article  Google Scholar 

  7. Peppas, N.A. & Langer, R. New challenges in biomaterials. Science 263, 1715–1720 (1994).

    CAS  Article  Google Scholar 

  8. Ratner, B.D. Reducing capsular thickness and enhancing angiogenesis around implant drug release systems. J. Control. Release 78, 211–218 (2002).

    CAS  Article  Google Scholar 

  9. Hetrick, E.M., Prichard, H.L., Klitzman, B. & Schoenfisch, M.H. Reduced foreign body response at nitric oxide-releasing subcutaneous implants. Biomaterials 28, 4571–4580 (2007).

    CAS  Article  Google Scholar 

  10. Ward, W.K. A review of the foreign-body response to subcutaneously-implanted devices: the role of macrophages and cytokines in biofouling and fibrosis. J. Diabetes Sci. Technol. 2, 768–777 (2008).

    Article  Google Scholar 

  11. Ostuni, E., Chapman, R.G., Holmlin, R.E., Takayama, S. & Whitesides, G.M. A survey of structure-property relationships of surfaces that resist the adsorption of protein. Langmuir 17, 5605–5620 (2001).

    CAS  Article  Google Scholar 

  12. Jiang, S.Y. & Cao, Z.Q. Ultralow-fouling, functionalizable, and hydrolyzable zwitterionic materials and their derivatives for biological applications. Adv. Mater. 22, 920–932 (2010).

    CAS  Article  Google Scholar 

  13. Lynn, A.D., Kyriakides, T.R. & Bryant, S.J. Characterization of the in vitro macrophage response and in vivo host response to poly(ethylene glycol)-based hydrogels. J. Biomed. Mater. Res. A 93, 941–953 (2010).

    PubMed  Google Scholar 

  14. Campioni, E.G., Nobrega, J.N. & Sefton, M.V. HEMA/MMMA microcapsule implants in hemiparkinsonian rat brain: biocompatibility assessment using [H-3] PK11195 as a marker for gliosis. Biomaterials 19, 829–837 (1998).

    CAS  Article  Google Scholar 

  15. Shen, M.C. et al. PEO-like plasma polymerized tetraglyme surface interactions with leukocytes and proteins: in vitro and in vivo studies. J. Biomater. Sci. Polym. Ed. 13, 367–390 (2002).

    CAS  Article  Google Scholar 

  16. Ward, W.K., Slobodzian, E.P., Tiekotter, K.L. & Wood, M.D. The effect of microgeometry, implant thickness and polyurethane chemistry on the foreign body response to subcutaneous implants. Biomaterials 23, 4185–4192 (2002).

    CAS  Article  Google Scholar 

  17. Hayward, J.A. & Chapman, D. Biomembrane surfaces as models for polymer design: the potential for haemocompatibility. Biomaterials 5, 135–142 (1984).

    CAS  Article  Google Scholar 

  18. Ishihara, K., Ziats, N.P., Tierney, B.P., Nakabayashi, N. & Anderson, J.M. Protein adsorption from human plasma is reduced on phospholipid polymers. J. Biomed. Mater. Res. 25, 1397–1407 (1991).

    CAS  Article  Google Scholar 

  19. Smith, R.S. et al. Vascular catheters with a nonleaching poly-sulfobetaine surface modification reduce thrombus formation and microbial attachment. Sci. Transl. Med. 4, 153ra132 (2012).

    Google Scholar 

  20. Ladd, J., Zhang, Z., Chen, S., Hower, J.C. & Jiang, S. Zwitterionic polymers exhibiting high resistance to nonspecific protein adsorption from human serum and plasma. Biomacromolecules 9, 1357–1361 (2008).

    CAS  Article  Google Scholar 

  21. Ueland, P.M., Holm, P.I. & Hustad, S. Betaine: a key modulator of one-carbon metabolism and homocysteine status. Clin. Chem. Lab. Med. 43, 1069–1075 (2005).

    CAS  Article  Google Scholar 

  22. Carr, L.R., Cheng, G., Xue, H. & Jiang, S. Engineering the polymer backbone to strengthen nonfouling sulfobetaine hydrogels. Langmuir 26, 14793–14798 (2010).

    CAS  Article  Google Scholar 

  23. Carr, L.R., Xue, H. & Jiang, S.Y. Functionalizable and nonfouling zwitterionic carboxybetaine hydrogels with a carboxybetaine dimethacrylate crosslinker. Biomaterials 32, 961–968 (2011).

    CAS  Article  Google Scholar 

  24. Carr, L.R., Zhou, Y.B., Krause, J.E., Xue, H. & Jiang, S.Y. Uniform zwitterionic polymer hydrogels with a nonfouling and functionalizable crosslinker using photopolymerization. Biomaterials 32, 6893–6899 (2011).

    CAS  Article  Google Scholar 

  25. Madden, L.R. et al. Proangiogenic scaffolds as functional templates for cardiac tissue engineering. Proc. Natl. Acad. Sci. USA 107, 15211–15216 (2010).

    CAS  Article  Google Scholar 

  26. Liu, L.Y. et al. Reduced foreign body reaction to implanted biomaterials by surface treatment with oriented osteopontin. J. Biomater. Sci. Polym. Ed. 19, 821–835 (2008).

    Article  Google Scholar 

  27. Zhang, Z. et al. Zwitterionic hydrogels: an in vivo implantation study. J. Biomater. Sci. Polym. Ed. 20, 1845–1859 (2009).

    CAS  Article  Google Scholar 

  28. Tsai, A.T. et al. The role of osteopontin in foreign body giant cell formation. Biomaterials 26, 5835–5843 (2005).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank E. Sussman, M. Takeno, H. Ma and K. Hauch in Bioengineering Department at the University of Washington for their help with histological staining and image analysis. This work was supported by the Office of Naval Research (N000140910137), University of Washington and Boeing-Roundhill Professorship.

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L.Z., Z.C., T.B., L.C., J.-R.E.-M. and C.I. conducted the experiments. L.Z., Z.C., B.D.R. and S.J. designed the study and wrote the paper. All authors read the paper and contributed to its final form.

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Correspondence to Shaoyi Jiang.

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The authors declare no competing financial interests.

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Zhang, L., Cao, Z., Bai, T. et al. Zwitterionic hydrogels implanted in mice resist the foreign-body reaction. Nat Biotechnol 31, 553–556 (2013). https://doi.org/10.1038/nbt.2580

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