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Humanized Mice: A Superior Animal Model for Fat Graft Retention
Paneed Jalili1, Michael Stigliano1, Michael B. Amrami*1, Sophia Arbuiso1, Jonathan Dyke2, Eric Aronowitz2, Carson Gundlach1, Fiona R. Fragomen1, Kristy A. Brown3, David Otterburn1
1Plastic and Reconstructive Surgery, Weill Cornell Medicine, New York, NY; 2Radiology, Weill Cornell Medicine, New York, NY; 3The University of Kansas Cancer Center, Kansas City, KS

Introduction
Autologous fat grafting is widely used in breast reconstruction, yet volume retention remains variable and incompletely understood. Most preclinical models rely on athymic mice, which lack functional T lymphocytes and may not capture immune-mediated graft remodeling. We hypothesized that host immune phenotype influences fat graft retention in a controlled, donor-matched model.

Methods
Human lipoaspirate from individual donors was implanted subcutaneously into paired athymic and humanized mice (n=7 per group), with each donor serving as an internal control. Humanized mice were engrafted with human CD34+ hematopoietic stem cells. Graft volume was quantified at 12 weeks using 7-Tesla MRI with standardized segmentation normalized to injected volume. Donor-matched comparisons were performed between murine models and, in a subset (n=4), compared to corresponding human patient clinical retention. Exploratory contrast-enhanced MRI was performed following tail vein gadolinium administration.

Results
Donor-matched analysis demonstrated significantly greater 12-week retention in humanized mice compared to athymic controls (44.4% vs. 21.8%; mean paired difference +14.3%, p=0.035), which remained significant after adjustment for interval weight change. In the donor subset, mean clinical retention was 67.9%. Both murine models underestimated clinical retention; however, the humanized model demonstrated lower mean absolute error compared to the athymic model (30% vs. 40%, p=0.25). Exploratory contrast-enhanced imaging demonstrated increased mean graft enhancement in humanized mice, suggesting differences in vascular or inflammatory remodeling.

Conclusion
In a donor-matched model, host immune phenotype is associated with significant differences in fat graft retention. Humanized mice demonstrate improved volume preservation and distinct remodeling characteristics compared to athymic controls, supporting the role a host immune response in graft remodeling and providing a more clinically relevant platform for mechanistic investigation.
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