Comparative study of myocardial infarction treatment with or without microencapsulated stem cells in a porcine model.

Guadalupe Gomez-Mauricio1, Argia Acarregui2, Francisco M Sánchez-Margallo1, Diego Celdrán1, Gorka Orive2,3, Rosa Hernández2,3, Jose Luis Pedraz2,3, María F Martín-Cancho1. 1Minimally Invasive Surgery Centre Jesus Us ó n, C á ceres, Pharmacy Unit, Spain, 2University of the Basque Country, School of Pharmacy, NanoBioCel Group, Laboratory of Pharmaceutics, Spain, 3Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine,Vitoria, (CIBER-BBN), Spain

Introduction: Stem cell transplantation is being investigated as a novel approach to regenerate heart tissue and enhance cardiac function. Encapsulation of therapeutic stem cells may help to increase their retention in the heart tissue while promoting the local and continuous release of proteins and growth factors. In this study, we developed a cell encapsulation system which consisted on porcine adipose tissue-derived stem cells (pASCs) encapsulated in Alginate-based microcapsules labeled with superparamagnetic iron oxide nanoparticles (Endorem®). We investigated the potential use of the microcapsules as a carrier for the cells and as scaffold to increase cell survival and retention and to localize and to monitor the cells non-invasively in real time by MRI.

Material and methods. Eight Large White pigs weighing 30kg were divided into two experimental groups (n=4). Under general anesthesia and sterile conditions, an endoluminal AMI was created. After stabilization, group I received the magnetocapsules and group II received the non-encapsulated cells labeled with Endorem®. The total dose administered had the same volume for both groups, what resulted in a lower dose of cells in the magneto-capsules group. Intramyocardial injections of magnetocapsules (1,5x106±730688 cells) or cells (56×106±5857146 cells labeled with Endorem®) were performed into different sites of the peri-infarct zone via a thoracotomy. Cardiac MRI was performed before the creation of the model (baseline) and 1, 15 and 30 days after infarctation, using a 1.5T MR system. MR images were analyzed for left ventricular volume, mass, function and infarct size. One month after AMI, samples were obtained from the infarction area after animal’s euthanasia and histomorphological studies were performed (H-E and Prussian blue).

Results: MRI confirmed the presence of labeled pASCs and magnetocapsules within the infarct tissue. MRI measured infarct size decreased over time for both treatments groups and no significant differences were observed between both groups. No statistically significant differences between groups were identified regarding infarct size and left ventricular volume changes. The magnetocapsules were found intact at the administration site, while the labeled cells were found as well but dispersed at the surrounding myocardial tissue. Some foci of granulomatous myocarditis were observed surrounding the magnetocpasules. Tissue in which non-encapsulated pASCs were implanted showed more angiogenesis.

Conclusions:

- The magnetocapsules were clearly observed in all the cardiac MRI studies, the non-encapsulated cells labeled with Endorem® were also observed, but the signal detected was smaller than the observed for the magnetocapsules, which results interesting taking in to the account the difference regarding the administered dose.

- Finding the intact capsules at the administration site proves the feasibility of maintaining the administered cells only at the injury site but the inflammatory response observed surrounding the magnetocapsules and not the cells indicates a foreign body reaction to the alginate-based capsules.

- Although no statistically significant differences in hemodynamic function were observed between treatment groups, the relatively big difference in the final cell dose administered to the animals between groups opens the door to future studies in which increasing cell loading with the particles may help to improve the therapeutic results.