Abstract
Background: Cryopreserved bone allografts are often used to reconstruct segmental bone defects. They are non-viable, which can result in infection, non-union and stress-fractures. We aimed to revascularize allografts in porcine and rat models using vascular endothelial growth factor (VEGF), combined with platelet derived growth factor (PDGF) administered through an adeno-associated viral vector. We report the development of vascular tumors resulting from this treatment. Methods: In two separate studies, an identical AAV.VEGF.PDGF vector was used to promote angiogenesis in cryopreserved bone allografts. In 8 Yucatan minipigs, a 3.5 cm segmental tibial defect was reconstructed with a matched allograft, revascularized by placement of a transfected arteriovenous (AV) bundle within the medullary canal. In another experiment, cryopreserved femoral bone allografts coated with AAV.VEGF.PDGF were placed across a 10 mm segmental femoral gap in 10 Lewis rats. Results: Vascular tumors developed in skin and subcutaneous tissues in 5 out of 8 pigs and all of the rats. Histology revealed changes essentially identical to those seen in pyogenic granuloma (lobular capillary hemangioma) in humans. Polymerase chain reaction (PCR) identified the sequence of human VEGF-DNA in all of the sampled tumor tissues. Conclusion: Recombinant AAV gene therapy used to promote angiogenesis in avascular bone risks the development of vascular cutaneous lesions. Gene therapy using an identical AAV.VEGF.PDGF vector should not be considered clinically until safe use can be demonstrated and.concerns regarding chromosomal integration, dose effect and species differences are addressed.
Highlights
Vascular endothelial growth factor (VEGF) is the key player in angiogenesis [1] and can be applied experimentally to facilitate angiogenesis
We report development of vascular tumors resulting from the use of an adenoassociated bi-cistronic viral vector to promote angiogenesis in two biological models of segmental bone loss reconstructed with cryopreserved allograft
During studies of surgical angiogenesis as a means to improve outcomes of cryopreserved bone allografts, we found augmentation of angiogenesis using a bi-cistronic AAV.vascular endothelial growth factor (VEGF).platelet derived growth factor (PDGF) vector to produce cutaneous and subcutaneous vascular tumors in 5 of 8 pigs and 10 of 10 rats
Summary
Vascular endothelial growth factor (VEGF) is the key player in angiogenesis [1] and can be applied experimentally to facilitate angiogenesis. It has been stated that co-expression of these two factors by a single cell type and gene delivery with a single bi-cistronic vector may represent an effective strategy to support angiogenesis We applied this experimental approach to generate a neoangiogenic blood supply within cryopreserved bone allografts, with the long-term goal of improving clinical outcomes for patients with large segments of missing bone. The freezing process diminishes immunogenicity, with some change in mechanical properties [8, 9] Without intrinsic vascularity, they are prone to postoperative infection, non-union and late stress fractures [7, 10]. Cryopreserved bone allografts are often used to reconstruct segmental bone defects They are non-viable, which can result in infection, non-union and stress-fractures. We report the development of vascular tumors resulting from this treatment
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