[Hedgehog pathway antagonist-induced oromandibular limb hypogenesis in mouse].

Objective: To analysis teratogenic effect of GDC-0449 to fetus and set up the animal model of GDC-0449 induced oromandibular limb hypogenesis in mouse for further research of its pathogenesis. Methods: Twenty-seven pregnant Institute of Cancer Research (ICR) mice were randomly divided into: control group, embryonic day 8.5 (E8.5) exposed groups, E9.5 exposed groups, E10.5 exposed groups, E11.5 exposed groups, E12.5 exposed groups, E13.5 exposed groups, E14.5 exposed groups and E15.5 exposed groups. Each group had 3 mice. Exposed groups were treated with the Hedgehog pathway antagonist GDC-0449 at a single dose 150 mg/kg by oral gavage from E8.5 to E15.5. At E16.5, embryonic phenotypes were analyzed in detail by stereo microscope and histology. After establish an optimal dysmorphogenic concentration, 6 pregnant ICR mice were randomly divided into control group and the optimal group, embryonic phenotypes were analyzed by whole-mount skeletal staining and micro-computed tomography at E18.5. Results: The mice were exposed to GDC-0449 on E11.5 and E12.5 had a high incidence of cleft palate. GDC-0449 exposed between E9.5 and E10.5 caused craniofacial and limb dysmorphology, including micrognathia, microglossia, ectrodactylia, partial anodontia and cleft palate. Most interestingly, these are extremely similar to oromandibular limb hypogenesis syndrome. Conclusions: The results of this study indicate that GDC-0449 can be used to induce micrognathia, microglossia, ectrodactylia, partial anodontia and cleft palate. This work established a novel mouse model for oromandibular limb hypogenesis.

The influence of the gap size on the interfacial union between the bone and the tendon.

An in-vivo model of New Zealand white rabbit was used to study the influence of gap size on the interfacial union between bone and tendon through histological observation and mechanical testing. In the model, the anterior cruciate ligament (ACL) was cut and reconstructed by autografted semitendinosus tendon (with average diameter of 1.48 mm +/- 0.12 mm). Mechanical testing of the interfacial healing tissue was done on the 15th post-operative day. At that time the mean maximal tensile strength was 2.511 +/- 0.293 kg to a bone tunnel size of 1.5 mm. The maximal tensile strength lowered to 1.853 +/- 0.563 kg to a bone tunnel size of 1.8 mm. The maximal tensile strength lowered to 1.302 +/- 0.657 kg to a bone tunnel size of 2.0 mm. Using a paired-t test, the gap size was found to have great influence on the tensile strength of the interfacial healing tissue (p < 0.05). The histological study showed that the interfacial gap was connected by the new growing collagen fibers. The healing tissue appeared much denser and much more maturated and organized in the smaller interfacial gap in comparison with specimens with a larger gap so that it can tolerate higher tensile strength. From this study, we concluded that the gap size really plays an important role in the process of maturation and organization of interfacial healing tissue. Furthermore, we recommend that in order to achieve greater anchoring strength of the grafted tendons, the bone tunnel should be made with approximately the same diameter of grafted tendon.