Thermoresponsive Gel Embedding Adipose Stem Cell-Derived Extracellular Vesicles Promotes Esophageal Fistula Healing in a Thermo-Actuated Delivery Strategy

  • Journal and date :

ACS Nano ; 2018

  • Authors :

Amanda K. A. Silva, Silvana Perretta, Guillaume Perrod, Laetitia Pidial, Véronique Lindner, Florent Carn, Shony Lemieux, Damien Alloyeau, Imane Boucenna, Philippe Menasché, Bernard Dallemagne, Florence Gazeau, Claire Wilhelm, Christophe Cellier, Olivier Clément, and Gabriel Rahmi

  • Abstract :

Extracellular vesicles (EVs) are increasingly envisioned to be the next-generation of biological proregenerative nanotherapeutic agents, as already demonstrated for heart, kidney, liver, lung injury, brain and skin regeneration. Herein, we explore another potential EV therapeutic application, for fistula healing, together with a local minimally-invasive delivery strategy. Allogenic extracellular vesicles (EVs) from adipose tissue-derived stromal cells (ASCs) are administered in a porcine fistula model through a thermoresponsive pluronic F127 (PF-127) gel, injected locally at 4°C and gelling at body temperature to retain EVs in the entire fistula tract. Complete fistula healing is reported to be 100% for the gel + EVs group, 67% for the gel group and 0% for the control, supporting a therapeutic use of Pluronic F-127 gel alone or combined with EVs. However, only the combination of gel and EVs results in a statistically significant (i) reduction of fibrosis, (ii) decline of inflammatory response, (iii) decrease in the density of myofibroblasts and (iv) increase of angiogenesis. Overall, we demonstrate that ASC-EV delivery into a PF-127 gel represents a successful local minimally invasive strategy to induce a therapeutic effect in a swine fistula model. Our study brings prospects in EV administration strategies and in the management of postoperative fistulas.

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