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Background:
Autologous fat grafting is a powerful technique for aesthetic and reconstructive surgery, but suffers from a lack of predictability and maintenance of volume over time. A significant contributing factor is the lack of adequate revascularization of the transplanted fat. We postulated that loss of a functional adipose-associated microvasculature during the ischemic period following transplantation accounts for loss of the graft over time. Here, we explored the use of the FDA approved phosphodiesterase 5 inhibitor sildenafil citrate as targeted protection of the donor microvasculature during the ischemic period and its effects on survival and retention of transplanted fat.
Methods:
Using a novel modification of published murine fat transplantation models, 0.5cc of processed inguinal fat pads from tie2/lacZ mice were grafted onto the dorsum of wildtype FVB mice. In group 1 the donor fat pads were infiltrated with sildenafil solution prior to harvest. In the second group, saline was used as a control. The third group was treated with intra-arterial trypsin for 20 minutes prior to fat harvest to denude the endothelium of the fat graft vasculature prior to harvest. Weekly Doppler scans were performed to monitor revascularization. Dorsal skin and associated engrafted fat were harvested at 2, 8, and 12 weeks for volumetric and molecular analysis. Whole mount and histologic sections were stained with X-gal to differentiate donor (B-gal +) from recipient (B-gal -) vasculature.
Results:
Compared to saline treated fat grafts, sildenafil treated grafts demonstrated a marked improvement in blood flow at 1 and 2 weeks following transplantation (77.3 and 162.7 flux units (FU) vs. 33.7 and 97.3 FU, p<0.05, respectively). Furthermore, trypsin treated grafts showed significantly decreased blood flow at 2 weeks (47.0 FU)
despite viability of fat and intact histologic structure. Molecular markers of ischemia-reperfusion injury were significantly decreased in sildenafil treated grafts compared to saline treated grafts. While there was no difference in volume at 2 weeks among the three groups, analysis at 12 weeks demonstrated a marked increase in fat graft survival in the sildenafil treated group compared to control of trypsin treated grafts (79.1% vs. 40.2%, p<0.05, respectively). Doppler ultrasound of sildenafil treated grafts showed internal blood flow without evidence of central necrosis. Histological analysis of the surviving revealed that the transplanted fat graft vasculature was derived exclusively from the donor fat with patterns of inosculation to the donor bed in the peripheral portions of the graft.
Conclusion:
Here we demonstrate that the donor microvasculature accounts for the vast majority of blood supply to transplanted autologous fat grafts. Furthermore, we show that a functional intact microvasculature associated with donor fat grafts at the time of harvest is critical for graft survival following transplantation. Finally, targeted protection of the donor graft vasculature with the Phosphodiesterase 5 inhibitor sildenafil markedly increases the volume of long-term fat survival. These data demonstrate an FDA approved rapidly translatable method to significantly increase the predictability and survival of autologous fat grafting in clinical practice.