Effect of Chitosan Nanospheres Loaded with VEGF on Adipose Tissue Transplantation: A Preliminary Report

Abstract

Neovascularization plays an important role in adipose tissue transplantation, because survival of implanted cells strongly relies on sufficient oxygen and nutrient supply. Vascular endothelial growth factor (VEGF) is known as the master regulator of angiogenesis. It is capable of starting the complex cascade of events leading to endothelial cell activation, assembly of new vascular structures, mural cell recruitment, and vessel stabilization. However, consensus is lacking regarding safe and efficient methods for applying VEGF in free fat transplantation in the clinical setting. We investigated whether chitosan nanospheres, a biocompatible high-molecular-weight material, safely improve the efficiency of VEGF application in free fat transplantation. Immunologically compromised nude mice were used as adipose tissue transplantation receptors. Nanospheres loaded with VEGF were mixed with adipocytes and injected subcutaneously to the dorsa of mice. Grafts were harvested at weeks 3, 6, and 12. We found that treated-graft weight and vascularization were significantly higher than controls in a time-dependent manner. We demonstrated that chitosan nanospheres loaded with VEGF significantly promote the fat graft neovascularization and improve adipocyte survival.

Magnetic Resonance Imaging of Human Tissue-Engineered Adipose Substitutes

“…63 Importantly, in our study, although a global decrease from 79.5% to 44.3% of the initial adipose graft volume occurred between 3 and 6 weeks, an excellent persistence of adipocytes was observed, as well as abundant extracellular matrix and the absence of oil cysts or areas of necrosis. On some occasions when the engineered substitutes were grafted closer to the inguinal fat pad, murine AT development was noted (not shown).…”

Effect of N-Acetylcysteine on Adipose-Derived Stem Cell and Autologous Fat Graft Survival in a Mouse Model

“…Counteracting the mechanical, chemical, and oxidative stress experienced by implanted cells following transfer to the recipient bed has been a major focus of preclinical research in autologous fat grafting. 3,5,[11][12][13][14] Research into minimizing the stresses experienced by cells at the time of harvest has focused on tumescent lidocaine and epinephrine concentrations, and the mechanics of various liposuction techniques (e.g., cannula size, negative pressure). 3,5,11 To date, no studies have examined counteracting oxidative stress with antioxidant medications.…”

Targeted Protection of Donor Graft Vasculature Using a Phosphodiesterase Inhibitor Increases Survival and Predictability of Autologous Fat Grafts

“…[5][6][7]26 We can significantly attribute our inconsistent clinical experience with fat grafting to a lack of knowledge about how fat grafts vascularize. We are intrinsically attuned to the importance of rapid tissue vascularization; our own laboratory 10 and others 3,8,9,[11][12][13][18][19][20][27][28][29] have sought to augment tissue fat graft vascularity through methods of "doping" or "enriching" fat grafts with VEGF-based biological compounds or progenitor/stem cells. Although attractive, these methods prove laborious, time-consuming, expensive, and often impractical for clinical translation.…”

“…Although we did not directly examine the role of sildenafil on adipocytes, there is some experimental evidence that phosphodiesterase type 5 inhibition may also encourage adipogenesis. 42 In comparison with VEGF-based or cell-based techniques to increase fat graft survival that report improved graft survival ranging from 25 to 125 percent, 16,[18][19][20]28 these techniques currently require preparation of stem cell-like populations and sensitive biological therapeutics that require significant regulatory hurdles for commercial use. Our approach using a U.S. Food and Drug Administration-approved compound provides a potential for an "off-the-shelf" solution that can easily be adapted to clinical situations where access to highly regulated and sensitive cellular therapeutics may be significantly limited.…”

“…However, current strategies to accelerate graft vascularization are currently limited by their lack of clinical translatability and efficacy. [10][11][12][13][14][15][16][17][18][19][20][21][22] Our own experience has shown that graft vascularization is not simply a process where the recipient bed vasculature invades a "devascularized" graft; rather, the recipient bed vasculature interacts with the endogenous graft microvasculature in a coordinated process to rapidly vascularize the ischemic graft tissue. 23,24 Currently, there are no studies in the literature that characterize the existence or the effect of endogenous graft microvasculature during graft vascularization.…”