The repair of large long bone defects requires complex surgical procedures as the bone loss cannot simply be replaced by autologous grafts due to an insufficient bone stock of the human body. Tissue engineering strategies and the use of Advanced Therapy Medicinal Products (ATMPs) for these reconstructions remain a considerable challenge, in particular since robust outcomes in well-defined large animal models are lacking. To be suitable as a model for treatment of human sized bone defects, we developed a large animal model in both skeletally immature and mature sheep and made close observations on the spontaneous healing of defects. We warn for the spontaneous repair of large defects in immature animals, which can mask the (in)effectiveness of ATMP therapies, and propose the use of large 4.5 cm defects that are pretreated with a polymethylmethacrylate (PMMA) spacer in skeletally mature animals.
Objective:Autologous chondrocyte implantation (ACI) involves the application of a chondrocyte suspension into a membrane-sealed cartilage defect. Recently, “cell-seeded collagen matrix-supported” ACI has been developed wherein chondrocytes are seeded on a biomembrane. This study aimed at preclinically comparing 4 variant ACI techniques in a refined goat model: 2 traditional procedures, whereby the defect is sealed by a periosteal flap or collagen membrane, and 2 cell-seeding methods, with the collagen membrane either sutured or glued into the defect.Design:The efficacy of the surgical techniques was evaluated in an acute critical size chondral defect in the medial condyle of 32 skeletally mature goats, randomly assigned to 1 of the 4 aforementioned treatment groups. After 10 weeks in vivo, the quality of the repair was graded histologically by 2 independent, blinded readers using the “modified O’Driscoll” score.Results:The cell-seeding procedure whereby the membrane is sutured into the defect has a similar structural repair capacity than traditional ACI techniques. However, when the cell-seeded membrane was glued into the defect, the outcome appeared inferior.Conclusion:These findings indicate that optimizing the goat model and the postoperative recovery does allow preclinical evaluation of ACI-based cartilage implants in a load-bearing setting. This preclinical observation provides support to the clinical utilization of the sutured membrane-seeded (ACI-CS) technique, provided sutures, but not fibrin sealants, are used to fix the cell-seeded membrane in the defect bed.
OBJECTIVES
The newest mechanical valves have low thrombogenicity, making them candidates for anticoagulation with a direct oral anticoagulant. While these drugs hold great promise to replace warfarin, clinical trials have been disappointing so far. We aimed to evaluate apixaban in a porcine model of mechanical valve thrombosis with On-X® (CryoLife) aortic valves implanted in pulmonary position.
METHODS
On-X® valves were implanted in pulmonary valve position in 9 Yucatan pigs. Animals received prophylactic enoxaparin 40 mg for 1 week. Pigs in the low-dose group received 5 mg apixaban twice daily for 10 weeks. The intermediary-dose group received 5 mg twice daily for 6 weeks and then 10 mg twice daily afterwards. The high-dose group received 15 mg twice daily for 10 weeks. After sacrifice, valves were macroscopically evaluated and thrombus weight was documented.
RESULTS
The median weight of the 9 animals was 64.3 kg, range 52.5–70.9. In the low-dose group (2 animals), both valves showed manifest, chronic thrombosis with blocked hinges. In the intermediary-dose group, a normal functioning valve without thrombosis was seen in 2/4 animals. In the high-dose group (3 pigs), there was no valve thrombosis. No bleeding events occurred. In all animals, apixaban plasma levels were low compared to clinical target levels.
CONCLUSIONS
The pulmonary position seems to be an aggressive model for mechanical valve thrombosis in pigs. Apixaban has the potential to prevent valve thrombosis, even in these thrombogenic conditions. Detailed pharmacokinetic studies are needed to determine the ideal apixaban dosage for future experiments and to enable extrapolation to the clinical situation.
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