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Biomaterials. 2017 Jun;129:98-110. doi: 10.1016/j.biomaterials.2017.03.016. Epub 2017 Mar 11.

Humanized mouse model for assessing the human immune response to xenogeneic and allogeneic decellularized biomaterials.

Author information

1
Department of Bioengineering, Sanford Consortium of Regenerative Medicine, University of California San Diego, 2880 Torrey Pines Scenic Drive, La Jolla, CA 92037, USA.
2
Section of Molecular Biology, Division of Biological Sciences, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Cancer Research Institute, Southern Medical University, Guangzhou, Guangdong, China.
3
Department of Pediatrics (Cardiology), University of California San Diego and Rady Children's Hospital, 9500 Gilman Drive, San Diego, CA 92037, USA.
4
Center for Regenerative Medicine, Department of Cardiovascular Diseases, Mayo Clinic, 200 1st St SW, Rochester, MN 55905, USA.
5
Section of Molecular Biology, Division of Biological Sciences, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
6
Department of Bioengineering, Sanford Consortium of Regenerative Medicine, University of California San Diego, 2880 Torrey Pines Scenic Drive, La Jolla, CA 92037, USA. Electronic address: christman@eng.ucsd.edu.

Abstract

Current assessment of biomaterial biocompatibility is typically implemented in wild type rodent models. Unfortunately, different characteristics of the immune systems in rodents versus humans limit the capability of these models to mimic the human immune response to naturally derived biomaterials. Here we investigated the utility of humanized mice as an improved model for testing naturally derived biomaterials. Two injectable hydrogels derived from decellularized porcine or human cadaveric myocardium were compared. Three days and one week after subcutaneous injection, the hydrogels were analyzed for early and mid-phase immune responses, respectively. Immune cells in the humanized mouse model, particularly T-helper cells, responded distinctly between the xenogeneic and allogeneic biomaterials. The allogeneic extracellular matrix derived hydrogels elicited significantly reduced total, human specific, and CD4+ T-helper cell infiltration in humanized mice compared to xenogeneic extracellular matrix hydrogels, which was not recapitulated in wild type mice. T-helper cells, in response to the allogeneic hydrogel material, were also less polarized towards a pro-remodeling Th2 phenotype compared to xenogeneic extracellular matrix hydrogels in humanized mice. In both models, both biomaterials induced the infiltration of macrophages polarized towards a M2 phenotype and T-helper cells polarized towards a Th2 phenotype. In conclusion, these studies showed the importance of testing naturally derived biomaterials in immune competent animals and the potential of utilizing this humanized mouse model for further studying human immune cell responses to biomaterials in an in vivo environment.

KEYWORDS:

Biocompatibility; Cardiac tissue engineering; Extracellular matrix (ECM); Immune response; Macrophage; Scaffold

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