Noninvasive induction of angiogenesis in tissues by external suction: sequential optimization for use in reconstructive surgery
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In reconstructive surgery, tissues are routinely transferred to repair a defect caused by trauma, cancer, chronic diseases, or congenital malformations; surgical transfer intrinsically impairs metabolic supply to tissues placing a risk of ischemia-related complications such as necrosis, impaired healing, or infection. Pre-surgical induction of angiogenesis in tissues (preconditioning) can limit postsurgical ischemic complications and improve outcomes, but very few preconditioning strategies have successfully been translated to clinical practice due to the invasiveness of most proposed approaches, their suboptimal effects, and their challenging regulatory approval. We optimized a method that adopts noninvasive external suction to precondition tissues through the induction of hypoxia-mediated angiogenesis. Using a sequential approach in a rodent model, we determined the parameters of application (frequency, suction levels, duration, and interfaces) that fine-tune the balance of enhanced angiogenesis, attenuation of hypoxic tissue damage, and length of treatment. The optimized repeated short-intermittent applications of intermediate suction induced a 1.7-fold increase in tissue vascular density after only 5 days of treatment (p < 0.05); foam interfaces showed the same effectiveness and caused less complications. In a second separate experiment, our model showed that the optimized technique significantly improves survival of transferred tissues. Here we demonstrate that noninvasive external suction can successfully, safely, and promptly enhance vascularity of soft tissues: these translational principles can help design effective preconditioning strategies, transform best clinical practice in surgery, and improve patient outcomes.
KeywordsAngiogenesis Tissue preconditioning Reconstructive surgery Soft tissues Soft tissue reconstruction External volume expansion Suction Mechanical forces Animal models Optimization study Translational medicine Flap Graft Plastic surgery Skin Ischemia
Authors are grateful for the technical support and contribution provided by Dr. Roberto Bassi, Dr. Mihail Climov, Dr. Federico Facchin, Dr. Fabrizio Mpungu, Dr. Chenyu Huang, Dr. Kimberly Khouri, Dr. Tania Rogalska, Dr. Xingang Wang, Dr. Hamed Zartab. Authors also thank Ms. Andrea V. Moscoso for her administrative contribution.
This study was funded in part from a grant from the Plastic Surgery Foundation to Brigham and Women’s Hospital, a grant from the Gillian Reny Stepping Strong Fund to Brigham and Women’s Hospital, and a grant from KCI, Inc to Brigham and Women’s Hospital. P.F. thanks the Fondazione Romeo and Enrica Invernizzi for the generous support.
All authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. In addition, all authors equally took part in the different phases of the study. All authors have seen and agreed to the submitted version of the manuscript and bear responsibility for it. GG: contributed to study concept and design, conducted experimental activities, analysis and interpretation of data, manuscript drafting and revision. LC, KJ and AH contributed to acquisition, analysis and interpretation of data, manuscript drafting and revision. LL and JL contributed to study concept and design. P.F. contributed to acquisition and analysis of data. JS and HM contributed to analysis, interpretation, and representation of data, manuscript drafting and revision. DPO supervised the study in all parts, provided critical revision of data and manuscript.
Compliance with ethical standards
Dr. Orgill is a consultant for KCI, Inc. and receives research funding through a grant from KCI, Inc. to Brigham and Women’s Hospital. All other authors declare no actual or potential conflict of interests: in addition, they disclose no commercial or financial associations, personal or other relationships with other people or organizations that could inappropriately influence the reported manuscript or create a conflict of interest with the information presented. Authors (GG, LL, DO) have filed a patent based on methods described in this manuscript (PCT/US2016/018164: “Methods and Apparatus for Promotion of Angiogenesis and Adipogenesis in Tissues Through the Application of Mechanical Forces”) and holds rights as inventors in accordance with their institutional policies.
Data and materials availability
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