Detergent-enzymatic bioengineered pig tracheal tubular matrices lack of immunogenicity and maintain their structural integrity when implanted heterotopically in an allo- and xeno-transplantation model
Philipp Jungebluth1, Tetsuhiko Go1, Silvia Bellini2, Chiara Calore2, Luca Urbani2, Tatiana Chioato2, Michaela Turetta2, Adelaide M. Asnaghi3, Sara Mantero3, Maria T. Conconi2, Paolo Macchiarini1; 1Dept. of General Thoracic Surgery, Hospital Clinic, University of Barcelona, Barcelona, Spain; 2Dept. of Pharmaceutical Sciences, University of Padua, Padua, Italy; 3Dept. of Bioengineering, Politecnico di Milano, Milano, Italy
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Objective: To bioengineer a non-immunogenic tracheal tubular matrix of 6 cm in length, and test its structural, function and immunological properties in vitro and in vivo.
Methods: Tracheal segments of 12 cm in length were harvested from six male Yorkshire pigs (weighing 42.4±3.3 kg). Each segment was divided into two of 6 cm each to be bioengineered with a detergent-enzymatic method (DEM; contained alternately Sodium deoxycholate/DNase lavations) for 17th cycles or used as a control (native, maintained in PBS at 4°C). Bioengineered and control tracheas were then implanted in HLA-unmatched pigs and mice heterotopically (either inguinal groin) during 30 days. Structural, functional analysis and immunostaining were performed after each DEM-cycle, and at 2, 7 and 30 days post transplantation.
Results: Compared to control tracheas, tracheal matrices showed complete removal of major histocompatibility complex class I and II antigens after 17th DEM-cycles, being only few nuclei of chondrocytes left from the decellularization process, and no significant (p≥0.05) differences in their strain ability (trachea rupture force: 56.1±3.3 vs. 55.5±2.4 newtons; point of tracheal rupture: 12.2±0.8 vs. 12±0.5 cm). Seven days after implantation, the matrices showed in both models a significant (p<0.05) lower inflammatory reaction compared to their control trachea (392 vs. 15 macrophages/mm2, 874 vs. 167 T-lymphocytes/mm2) and P-selectin expression (1/6 vs. 6/6). There was no development of anti-swine leukocyte antigen (SLA) antibodies or deposits of both IgM and IgG in mice.
Conclusion: We created a completely antigenicity-free tracheal matrix of 6 cm length with structural characteristics similar to native tracheas.
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