## 5 Conclusions  
The present study reports that perfusion preconditioning enhances redifferentiation of chondrocytes in fibrin hydrogel. Here, cells were extracted from human articular cartilage tissue, expanded, and cultured in fibrin gel. From a translational perspective, the approval by the Food and Drug Administration (FDA) of MACI(r)(r) (Vericel, Cambridge, MA, USA)--where cells from the patient's knee are expanded, placed on a scaffold, and then reimplanted into the patient--shows that tissue engineering strategies can be translated into clinical practice and are commercially feasible. Preconditioned grafts contained chondrocytes expressing a better level of redifferentiation at the gene and protein levels, adding potential therapeutic value. While this last point needs to be assessed in a large animal model, our results herein demonstrate that perfusion preconditioning of HACs in fibrin hydrogels generates cartilage-like tissues containing typical components of cartilage extra and pericellular matrix.  
The following are available online at [[https://www.mdpi.com/article/10.3390/app11198923/s1](https://www.mdpi.com/article/10.3390/app11198923/s1)]([https://www.mdpi.com/article/10.3390/app11198923/s1](https://www.mdpi.com/article/10.3390/app11198923/s1)), Figure S1: cell viability in static and perfused gels after a 7 day culture period, Figure S2: Gene expression characterization of human articular chondrocytes cultivated for 21 days in fibrin hydrogel in free swelling (static) or a direct perfusion bioreactor, Figure S3: Quantification of aggrecan core protein and type VI collagen immunofluorescence at the single-cell level.  
Conceptualization, A.D. and E.P.-G.; methodology, A.D. and E.P.-G.; formal analysis, A.D.; data curation, A.D.; writing--original draft preparation, A.D.; writing--review and editing, A.D., F.M.-G. and E.P.-G.; supervision, F.M.-G. and E.P.-G.; project administration, F.M.-G. and E.P.-G.; funding acquisition, F.M.-G. and E.P.-G. All authors have read and agreed to the published version of the manuscript.  
This research was funded by CNRS, Lyon 1 University, and by Fondation de l'Avenir. [PERSON] was supported by a Ph.D. fellowship from the Region Auvergne-Rhone-Alpes (ARC2).  
The study protocol involving human tissues was conducted in accordance with the Declaration of Helsinki and was approved by the ethics committee of COservation D'ELments du COrps Humain (CODECOH: DC-2014-2325) for preservation and research with human samples. The cartilage samples were collected after written informed consent of the donors. The study involving animals was conducted according to the guidelines of the Directive 2010/63/EU and its national transposition and ethical guidelines for care and use of mice of the Plateau de Biologie Experimentale de la Souris (PBES, UMS 3444) at Ecole Normale Superieure (ENS, Lyon) and approved by the Institutional Review Board of ENS Lyon (Committee on the Ethics of Animal Experiments, approval number: ENS_2018_007).  
Informed Consent Statement: Informed consent was obtained from all human donors involved in the study.  
The data presented in this study are available on request from the corresponding author.  
Authors are grateful to the technical facilities of SFR Biosciences Gerland-Lyon (UMS3444/US8) for the quantitative PCR analyses and to [PERSON] for her assistance with preparing and processing histological samples.  
The authors declare no conflict of interest.