Results and complications of a surgical technique for correction of coxa vara in children with osteopenic bones.

BACKGROUND: Surgical correction of coxa vara in children with osteopenic bone diseases could be very challenging. In this study, we describe a modified surgical technique for the correction of coxa vara in children with bone fragility. We also report the results and complications of this technique in 16 children (21 coxa vara) with osteopenic bone diseases. METHODS: Charts, clinic notes, and radiology images of 16 patients (21 hips) who had a proximal femoral osteotomy for the treatment of coxa vara in osteogenesis imperfecta (18 hips) and fibrous dysplasia (3 hips) in our institution between 1996 and 2005 were reviewed. The modified surgery involved an intertrochanteric osteotomy and the use of Kirshner wires and intramedullary rods. Neck-shaft angle, Hilgenreiner-epiphyseal angle, and head-shaft angle were assessed at preoperative, postoperative, and final follow-up. RESULTS: The average age at surgery was 8.3 years (range, 3.3-15.8 years). The average correction of the neck-shaft angle was from 84.6 to 114.4 degrees, and for the Hilgenreiner-epiphyseal angle, it was from 67.7 to 42 degrees at final follow-up. All osteotomies were healed at 3 months postoperatively. The mean follow-up was 4.29 years (range, 1.70-8.12 years). The average improvement in abduction and external rotation of the hips was 14 and 15 degrees, respectively. There were no cases of infection and 2 cases (12%) of implant-related complications. One patient with fibrous dysplasia needed replacement of the intramedullary rod and additional distal femoral osteotomy 1 week postsurgery. In another patient, the intramedullary rod had migrated proximally, which was corrected 5 months postsurgery by advancing the rod distally. CONCLUSION: Results suggest that this surgical technique provides satisfactory correction of coxa vara in children with osteopenic bone diseases. CLINICAL RELEVANCE: The described surgical technique used to correct coxa vara is reproducible and safe and has few complications. Furthermore, the size of the implants used allows surgery to be performed in very young children.

OP-1 injection increases VEGF expression but not angiogenesis in a rabbit model of distraction osteogenesis.

We have previously shown that a single injection of rhBMP-7 (OP-1) applied to the regenerate early during distraction accelerates bone consolidation in a rabbit model of distraction osteogenesis. In the present study, we hypothesised that the injection of OP-1 improves bone consolidation by increasing blood flow to the distracted site. Blood flow into the regenerate of a rabbit model was measured and vascular endothelial growth factor (VEGF) expression was tested using semi-quantitative PCR. Immunohistochemistry was used for assessing the temporal and spatial expression of platelet endothelial cell adhesion molecule (PECAM), VEGF and its receptors following OP-1 injection. We observed a higher expression of VEGF and its receptors in the regenerate with OP-1 treatment. However, there was no difference in the increase in bone blood flow nor PECAM expression between the treated and control groups of animals. Interestingly, the increased expression of VEGF and its receptors was associated with chondrocyte and fibroblast-like cells, but not with endothelial cells. These results suggest that accelerated ossification by OP-1 may depend on a non-vascular mechanism, possibly involving a non-angiogenic function of VEGF signalling.

Characterizing the BMP pathway in a wild type mouse model of distraction osteogenesis.

Distraction osteogenesis (DO) is a well established surgical technique for limb lengthening and replacement of bone loss due to trauma, infection or malignancies. Although the technique is widely used, one of its limitations is the long period of time required for the newly formed bone to consolidate. We have previously shown that exogenous application of bone morphogenetic proteins (BMPs) can increase bone formation during DO, however, exogenous BMPs have many drawbacks. An alternative method for accelerating the rate of bone formation may be to modulate the intrinsic BMP signaling pathway. The aim of the current study was to analyze the expression of various genes involved in the BMP pathway at various time periods during DO in order to identify potential targets for therapeutic manipulation. DO was applied to the right tibia of 80 adult wild type mice. Distraction began after a latency period of 5 days at a rate of 0.2 mm/12 h for 2 weeks. Mice were sacrificed in groups of 12 at the following times post surgery: day 5 (latency), days 11 and 17 (distraction) and days 34 and 51 (consolidation). Specimens were examined using radiology, microCT, histology, RT(2)PCR, immunohistochemistry and Western analysis. Genes involved in the BMP pathway including the BMP ligands, receptors, antagonists and downstream effectors were examined. A significant upregulation of BMPs 2, 4 and 6 was observed using both PCR and immunohistochemistry during the distraction phase. The expression of BMP7 remained constant throughout the distraction and consolidation process. Surprisingly, the only receptors which were upregulated significantly were the Activin Receptor Type 1 (ActR1) during distraction and Activin Receptor Type 2b (ActR2b) during consolidation. Most interestingly, simultaneously with the ligands, an increase in the expression of the antagonists, Noggin, Chordin, Inhibin and BMP3 was observed. This study provides a clearer understanding of expression patterns during DO, which is a valuable resource for finding therapeutic options to stimulate bone formation. The results suggest that blocking BMP inhibitors may be a possible method for increasing the function of intrinsic growth factors involved in bone regeneration.

Preparation and in vitro analysis of microcapsule thalidomide formulation for targeted suppression of TNF-alpha.

Recent studies have implicated the cytokine tumor necrosis factor-alpha (TNF-alpha) in the inflammation associated with Crohn's disease (CD). Thalidomide has been shown to decrease this inflammation by the suppression of TNF-alpha secretion. However, side effects associated with thalidomide have precluded its widespread usage. In the present study we investigated the efficacy of a "targeted delivery approach" for thalidomide at the site of inflammation. We observed that alginate-poly-l-lysine-alginate (APA) polymer-based microcapsule formulations that encapsulate thalidomide could be designed. These capsules could be delivered at target sites where they almost entirely suppress TNF-alpha secretion in lipopolysaccharide activated RAW 264.7 macrophage cells in vitro. These findings indicate that targeted delivery of thalidomide using APA capsules could facilitate its usage in reducing the inflammation associated with chronic conditions such as Crohn's disease and ulcerative colitis.

A new method for targeted drug delivery using polymeric microcapsules: implications for treatment of Crohn's disease.

Recent research and clinical evidence suggest that thalidomide could potentially be used to treat inflammation associated with Crohn's disease. However, systemic side effects associated with large doses of this drug have limited its widespread use. Treatment with thalidomide would prove more efficacious if the drug could be delivered directly to target areas in the gut, thereby reducing systemic circulation. Microcapsule encapsulation could enable direct delivery of the drug. To assess the latter, we designed and tested drug-targeting release characteristics of alginate-poly-L-lysine-alginate (APA) microcapsules in simulated gastrointestinal environments. The results show that APA capsules enabled delivery of thalidomide in the middle and distal portions of the small intestine. We also compared the APA membrane formulation with an earlier designed alginate chitosan (AC) membrane thalidomide formulation. The results show that both APA and AC capsules allow for successful delivery of thalidomide in the gut and could prove beneficial in the treatment of Crohn's disease. However, further research is required.

Superior cell delivery features of poly(ethylene glycol) incorporated alginate, chitosan, and poly-L-lysine microcapsules.

Microencapsulation is an emerging technology in the development of bioartificial organs for drug, protein, and delivery systems. One of the advancements in establishing an appropriate membrane material for live cell and tissue encapsulation is the incorporation of poly(ethylene glycol) (PEG) to the widely studied alginate microcapsules. The current study investigates the properties of integrating PEG to microcapsules coated with poly-L-lysine (PLL) and chitosan as well as a novel microcapsule membrane which combines both PLL and chitosan. Results show that microcapsules containing PEG can support cell viability and protein secretion. The addition of PEG to PLL and chitosan-coated microcapsules improves the stability of microcapsules when exposed to a hypotonic solution. We also compared the novel microcapsule with two other previously used microcapsules including alginate-chitosan-PEG and alginate-PLL-PEG-alginate. Results show that all three membranes are capable of providing immunoprotection to the cells and have the potential for long-term storage at -80 degrees C. The novel membrane containing PEG, chitosan, and PLL, however, revealed the highest cell viability and mechanical strength when exposed to external rotational force, but it was unable to sustain osmotic pressure. The study revealed the potential of using PEG-incorporated alginate, chitosan, and PLL microcapsules for encapsulating live cells producing proteins and hormones for therapy.

In vitro study of alginate-chitosan microcapsules: an alternative to liver cell transplants for the treatment of liver failure.

The application of alginate-chitosan (AC) microcapsules to liver cell transplantation has not been previously investigated. In the current in vitro study, we have investigated the potential of AC microcapsules for the encapsulation of liver cells and show that the AC membrane supports the survival, proliferation and protein secretion by entrapped hepatocytes. The AC membrane provides cell immuno-isolation and has the potential for cell cryopreservation. The AC microcapsule has several advantages compared to more widely used alginate-poly-L-lysine (APA) microcapsules for the application of cell therapy.