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In vivo study of osteostimulating effect of locally delivered PTH1-34 out of a fibrin hydrogel

Dinah Streifeneder, 2008

Vetsuisse-Fakultät Universität Zürich, Departement Pferde, Musculoskeletal Research Unit (MSRU)

Contact: gschmid@vetclinics.uzh.ch

The aim of this study was to evaluate the ability of locally delivered PTH1-34 and its specific concentration in fibrin to promote the synthesis of new bone in a segmental, full thickness defect in the midshaft of the ovine tibia. Different concentrations of bioactive PTH1-34 were tested and their performance analysed; in addition, each concentration was tested against empty defects, defects receiving fibrin alone and those receiving an autograft (autologous bone spongiosa) to assess the efficacy of PTH1-34. 28 female sheep were randomized into 5 groups of 5 (Empty), 6 (Fibrin), 6 (PTHlow), 6 (PTHhigh), 5 (Autograft) animals each. In group Empty the defect was left empty, group Fibrin received fibrin alone, group PTHlow received a low concentration of PTH1-34, group PTHhigh a slight higher concentration of PTH1-34 in a fibrin based hydrogel and positive control group received transplantation of autologous cancellous bone (Autograft). The study was based on the hypothesis that locally applied PTH1-34 enhances new bone formation when delivered in a fibrin hydrogel. A standardized 1 cm full thickness cortical defect in the mid tibial diaphysis was chosen to test the bone healing potential of this osteogenic gel. After osteotomy and careful resection of the periosteum the tibia was stabilized using an 11-hole 3.5mm LC-DCP. The affected hindlimb was protected with a cast and the animals were kept in special suspension systems for four weeks after surgery to avoid spontaneous refracturing of the limb. Radiographs were taken directly after surgery as well as 4, 8 and 12 weeks thereafter. The animals were sacrified after a postoperative period of 12 weeks and the tibia was removed. The osteotomy sites were examined radiographically, histologically and histomorphometrically. Transplantation of autologous cancellous bone resulted in bridging of the segmental tibia defect and complete bone healing. Radiological and morphometric evaluation showed a significant higher bone density and new bone formation rate than in the other groups. New bone formation increased and fracture healing was enhanced with rising concentrations of PTH1-34. However, no significant difference in defect replenishment compared with fibrinhydrogel alone (Fibrin) could be seen. Histologic assessment showed a hypertrophy of osteoblasts and no hydrogel persisted after the use of fibrinhydrogel without or with the highest PTH1-34. However, lymphocyte infiltration was present in all groups treated with fibrinhydrogel. This inflammatory response was significantly reduced in the presence of the highest PTH1-34 concentration (PTHhigh). This study showed that the protracted, local delivery of PTH1-34 from a fibrinhydrogel is safe and feasible and the combination with PTH1-34 decreases the inflammatory reaction of fibrinhydrogel. Larger studies with higher PTH1-34 concentrations are required to find the optimum PTH1-34 concentration and to examine its efficacy in promoting bone synthesis. Again, the impact of inflammation on bone healing and the interaction of PTH1-34 with leucocyte infiltration has to be assessed in future trials.

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