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Proangiogenic microtemplated fibrin scaffolds containing aprotinin promote improved wound healing responses

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Abstract

Survival of tissue engineered constructs after implantation depends heavily on induction of a vascular response in host tissue, promoting a quick anastomosis of the cellular graft. Additionally, implanted constructs typically induce fibrous capsule formation, effectively preventing graft integration with host tissue. Previously we described the development of a high density microtemplated fibrin scaffold for cardiac tissue engineering applications with tunable degradation and mechanical properties which promoted seeded cell survival and organization in vitro (Thomson et al., Tissue Eng Part A, 2013). Scaffold degradation in vitro was controllable by addition of the serine protease inhibitor aprotinin and/or the fibrin cross-linker Factor XIII (FXIII). The goal of this study was to assess host tissue responses to these fibrin scaffold formulations by determining effects on scaffold degradation, angiogenic responses, and fibrous capsule formation in a subcutaneous implant model. Aprotinin significantly decreased scaffold degradation over 2 weeks of implantation. A significant increase in capillary infiltration of aprotinin implants was found after 1 and 2 weeks, with a significantly greater amount of capillaries reaching the interior of aprotinin scaffolds. Interestingly, after 2 weeks the aprotinin scaffolds had a significantly thinner, yet apparently more cellular fibrous capsule than unmodified scaffolds. These results indicate aprotinin not only inhibits fibrin scaffold degradation, but also induces significant responses in the host tissue. These included an angiogenic response resulting in increased vascularization of the scaffold material over a relatively short period of time. In addition, aprotinin release from scaffolds may reduce fibrous capsule formation, which could help promote improved integration of cell-seeded scaffolds with host tissue.

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Acknowledgments

The authors sincerely thank Mandy Lund, Matt Coons, Veronica Muskheli and Elizabeth Gay for their assistance with histological sample preparations and analysis, and Marc Takeno and Alex Chen for their assistance with polarized light imaging. This work was supported by National Institutes of Health (NIH) Grant R01HL064387 to MR, MS and CEM, and P01 HL094374, P01 GM081719, U01 HL100405, and R01 HL084642 to CEM.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Bioengineering, University of Washington, Seattle, WA, 98195-5061, USA

    Kassandra S. Thomson, Charles E. Murry, Marta Scatena & Michael Regnier

  2. Center for Cardiovascular Biology, Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA, 98195-8050, USA

    Kassandra S. Thomson, Sarah K. Dupras, Charles E. Murry, Marta Scatena & Michael Regnier

  3. Departments of Pathology and Medicine/Cardiology, University of Washington, Seattle, WA, 98109, USA

    Charles E. Murry

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  1. Kassandra S. Thomson
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Correspondence to Michael Regnier.

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Thomson, K.S., Dupras, S.K., Murry, C.E. et al. Proangiogenic microtemplated fibrin scaffolds containing aprotinin promote improved wound healing responses. Angiogenesis 17, 195–205 (2014). https://doi.org/10.1007/s10456-013-9388-z

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  • DOI: https://doi.org/10.1007/s10456-013-9388-z

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