Evaluation of the biocompatibility and stability of allogeneic tissue-engineered cartilage in humanized mice

• Published in: PloS one Vol. 14; no. 5; p. e0217183
• Main Authors: Perrier-Groult, Emeline, Pérès, Eléonore, Pasdeloup, Marielle, Gazzolo, Louis, Duc Dodon, Madeleine, Mallein-Gerin, Frédéric
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 20.05.2019; Public Library of Science (PLoS)
• Subjects: Alternating current; Analysis; Animals; Arthritis; Articular cartilage; Autografts; Autologous chondrocyte implantation; Biocompatibility; Biological products; Biology; Biology and Life Sciences; Biomaterials; Biomedical materials; Cartilage; Cartilage (articular); Cartilage diseases; Cartilage, Articular - cytology; CD3 antigen; Cells (Biology); Cells, Cultured; Chondrocytes; Chondrocytes - cytology; Chondrogenesis; Collagen; Engineering; Engineering and Technology; Ethics; Evaluation; Female; Hematopoietic Stem Cell Transplantation - methods; Hematopoietic Stem Cells - cytology; Histocompatibility antigen HLA; HLA antigens; Human behavior; Human health and pathology; Humans; Hydrogels; Immune system; Immunological tolerance; Immunology; Implantation; Infiltration; Inflammation; Laboratories; Laboratory rats; Lesions; Life Sciences; Lymphocytes; Lymphocytes T; Macrophages; Male; Medicine and Health Sciences; Methods; Mice; Mice, Inbred NOD; Mice, SCID; Molecular weight; Monocytes; Orthopedic surgery; Osteoarthritis; Osteoarthritis - therapy; Peripheral blood; Phenotypes; Physical Sciences; Regeneration (physiology); Regenerative medicine; Research and Analysis Methods; Rhumatology and musculoskeletal system; Risk factors; Scaffolds; Spleen; Stability analysis; Stem cells; Subpopulations; Surgical implants; T cells; Tissue engineering; Tissue Engineering - methods; Tissue Scaffolds; Transplantation, Homologous; Transplants & implants; France
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0217183

Articular cartilage (AC) has poor capacities of regeneration and lesions often lead to osteoarthritis. Current AC reconstruction implies autologous chondrocyte implantation which requires tissue sampling and grafting. An alternative approach would be to use scaffolds containing off-the-shelf allogeneic human articular chondrocytes (HACs). To investigate tolerance of allogeneic HACs by the human immune system, we developed a humanized mouse model implanted with allogeneic cartilage constructs generated in vitro. A prerequisite of the study was to identify a scaffold that would not provoke inflammatory reaction in host. Therefore, we first compared the response of hu-mice to two biomaterials used in regenerative medicine, collagen sponge and agarose hydrogel. Four weeks after implantation in hu-mice, acellular collagen sponges, but not acellular agarose hydrogels, showed positive staining for CD3 (T lymphocytes) and CD68 (macrophages), suggesting that collagen scaffold elicits weak inflammatory reaction. These data led us to deepen our evaluation of the biocompatibility of allogeneic tissue-engineered cartilage by using agarose as scaffold. Agarose hydrogels were combined with allogeneic HACs to reconstruct cartilage in vitro. Particular attention was paid to HLA-A2 compatibility between HACs to be grafted and immune human cells of hu-mice: HLA-A2+ or HLA-A2- HACs agarose hydrogels were cultured in the presence of a chondrogenic cocktail and implanted in HLA-A2+ hu-mice. After four weeks implantation and regardless of the HLA-A2 phenotype, chondrocytes were well-differentiated and produced cartilage matrix in agarose. In addition, no sign of T-cell or macrophage infiltration was seen in the cartilaginous constructs and no significant increase in subpopulations of T lymphocytes and monocytes was detected in peripheral blood and spleen. We show for the first time that humanized mouse represents a useful model to investigate human immune responsiveness to tissue-engineered cartilage and our data together indicate that allogeneic cartilage constructs can be suitable for cartilage engineering.