Research Article Achilles Tendon Repair by Decellularized and Engineered Xenografts in a Rabbit Model Marta Bottagisio, 1 Daniele D’Arrigo, 2 Giuseppe Talò, 2 Matilde Bongio, 2 Marco Ferroni, 3 Federica Boschetti, 3 Matteo Moretti , 2,4,5 and Arianna B. Lovati 2 1 Laboratory of Clinical Chemistry and Microbiology, IRCCS Istituto Ortopedico Galeazzi, Milan 20161, Italy 2 Cell and Tissue Engineering Laboratory, IRCCS Istituto Ortopedico Galeazzi, Milan 20161, Italy 3 Department of Chemistry, Materials and Chemical Engineering Giulio Natta, Politecnico di Milano, Milan 20133, Italy 4 Regenerative Medicine Technologies Lab, Ente Ospedaliero Cantonale, Lugano 6900, Switzerland 5 Cardiocentro Ticino, Lugano 6900, Switzerland Correspondence should be addressed to Arianna B. Lovati; arianna.lovati@grupposandonato.it Received 30 April 2019; Revised 1 July 2019; Accepted 10 July 2019; Published 29 August 2019 Academic Editor: Valeria Sorrenti Copyright © 2019 Marta Bottagisio et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Tendon tissue ruptures often require the replacement of damaged tissues. The use of auto- or allografts is notoriously limited due to the scarce supply and the high risks of immune adverse reactions. To overcome these limitations, tissue engineering (TE) has been considered a promising approach. Among several biomaterials, decellularized xenografts are available in large quantity and could represent a possible solution for tendon reconstruction. The present study is aimed at evaluating TE xenografts in Achilles tendon defects. Specifically, the ability to enhance the biomechanical functionality, while improving the graft interaction with the host, was tested. The combination of decellularized equine-derived tendon xenografts with or without the matrix repopulation with autologous bone marrow mesenchymal stem cells (BMSCs) under stretch-perfusion dynamic conditions might improve the side-to-side tendon reconstruction. Thirty-six New Zealand rabbits were used to create 2 cm long segmental defects of the Achilles tendon. Then, animals were implanted with autograft (AG) as the gold standard control, decellularized graft (DG), or in vitro tissue-engineered graft (TEG) and evaluated postoperatively at 12 weeks. After sacrifice, histological, immunohistochemical, biochemical, and biomechanical analyses were performed along with the matrix metalloproteinases. The results demonstrated the beneficial role of undifferentiated BMSCs loaded within decellularized xenografts undergoing a stretch-perfusion culture as an immunomodulatory weapon reducing the inflammatory process. Interestingly, AG and TEG groups exhibited similar results, behaved similarly, and showed a significant superior tissue healing compared to DG in terms of newly formed collagen fibres and biomechanical parameters. Whereas, DG demonstrated a massive inflammatory and giant cell response associated with graft destruction and necrosis, absence of type I and III collagen, and a higher amount of proteoglycans and MMP-2, thus unfavourably affecting the biomechanical response. In conclusion, this in vivo study suggests a potential use of the proposed tissue-engineered constructs for tendon reconstruction. 1. Introduction The increasing number of traumatic events resulting in ten- don loss and/or degenerative tendinopathy causing compli- cated ruptures often requires the replacement of the damaged tissue, especially in elderly patients and athletes. As a matter of fact, the tendon self-repairing ability is poor due to both the scarce presence and the metabolic activity of resident cells that cannot properly guide the healing pro- cess required to restore the native tissue function [1, 2]. The surgical procedures commonly performed to treat ten- don ruptures with auto- or allografts might not guarantee the successful restoration of the tendon function and, besides that, relapses are frequent [3]. Furthermore, the use of either auto- or allografts is notoriously limited due to the scarce supply and the high risks connected to immune adverse Hindawi Stem Cells International Volume 2019, Article ID 5267479, 14 pages https://doi.org/10.1155/2019/5267479