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1 MRI - CT - histology comparison of bone healing in rabbit calvarial critical sized defects using bioactive glass scaffolds with adipose derived stem cells and VEGF or adipose tissue extract Poster No.: C-2374 Congress: ECR 2013 Type: Scientific Exhibit Authors: R. M. Korpi 1, O.-P. Lappalainen 1, J. T. Korpi 2, R. Serpi 1, E. Keywords: DOI: Lammentausta 1, P. Lehenkari 1, S. Miettinen 3, G. K. B. Sándor 1, R. B. Sequieros 1 ; 1 Oulu/FI, 2 Helsinki/FI, 3 Tampere/FI Grafts, Treatment effects, Surgery, Experimental investigations, MR-Diffusion/Perfusion, MR, CT-Quantitative, Head and neck, Bones, Transplantation /ecr2013/C-2374 Any information contained in this pdf file is automatically generated from digital material submitted to EPOS by third parties in the form of scientific presentations. References to any names, marks, products, or services of third parties or hypertext links to thirdparty sites or information are provided solely as a convenience to you and do not in any way constitute or imply ECR's endorsement, sponsorship or recommendation of the third party, information, product or service. ECR is not responsible for the content of these pages and does not make any representations regarding the content or accuracy of material in this file. As per copyright regulations, any unauthorised use of the material or parts thereof as well as commercial reproduction or multiple distribution by any traditional or electronically based reproduction/publication method ist strictly prohibited. You agree to defend, indemnify, and hold ECR harmless from and against any and all claims, damages, costs, and expenses, including attorneys' fees, arising from or related to your use of these pages. Page 1 of 8

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3 Purpose The mechanisms of bone regeneration are highly spesific (Axhausen 1956). Prominent nonunion and loss of skeletal integrity (a critical size defect) (Schmitz and Hollinger 1986) caused by bone loss due iatrogenic cause, pathological process, or due trauma is a major challenge. Bone regeneration therapies, an autogenous bone grafting, the gold standard yet known its pitfalls, and thus tissue engineering, the combination therapies of stem cells, growth factors, and adjunctive techniques, are under research. Reestablishment of the circulation is oft prior, although in the bone regeneration process early hypoxia has shown to stimulate vascular in-growth. Vascular endothelial growth factor (VEGF), a sub-family of the platelet-derived growth factor family of cystine-knot growth factors, is a known key regulator of angiogenesis. Likely, a novel adipose tissue extract (ATE), originating from an adipose tissue, an endocrine organ known to secrete a number of angiogenic factors, has shown to promote angiogenesis in vitro (Sarkanen et al. 2012). Previous studies have shown consistent results with the ability to enhance bone regeneration by using various growth factors in vitro and in vivo (Linkhart et al. 1996, Kaigler et al. 2006). The purpose of this study was to investigate angiogenesis and osteogenesis in bone regeneration using VEGF or a novel adipose tissue extract (ATE) with adipose-derived stem cells (ADSCs). Furthermore, and by using a rabbit critical size (diameter of 15 mm) calvarial defect and magnetic resonance (MR) imaging with advantages of a high spatial resolution, additional anatomical and pathological details, and no exposure to ionizing radiation, we were able to longitudinally monitor angiogenesis also in vivo by using the diffusion weighted (DW) and dynamic contrast-enhanced (DCE) sequences. Methods and Materials ADSCs were isolated from twenty, skeletally mature, New Zealand rabbits. Bilateral calvarial critical size defects, diameter of 15 mm, were induced and subjects were divided to following treatment groups: a negative control (empty defect); a positive control (scaffold); VEGF+ ADSCs+ scaffold; and ATE+ ADSCs+ scaffold. In vivo magnetic resonance (MR) imaging was performed 6 weeks after surgery. Calvarial bone was then harvested for ex vivo computed tomography and histology. Images for this section: Page 3 of 8

4 Fig. 3: Fig. 3 In vivo MR image of rabbit calvarium. T1 coronal image demonstrates the bilateral calvarial defects at six weeks after surgery. Page 4 of 8

5 Fig. 4: Fig. 4 In vivo MR image of rabbit calvarium. T2 coronal image demonstrate the bilateral calvarial defects at six weeks after surgery. Page 5 of 8

6 Results Histology-MRI correlation analysis depicted characteristic findings for neovascularization on diffusion weighted and dynamic contrast enhanced images that were detected at the region of the defect in VEGF group where histology showed enhanced angiogenesis. Images for this section: Fig. 1: Fig.1 An artery (asterix) and a vein in fibrous tissue growing inside the adipose tissue derived stem cells seeded scaffold (INION BioRestore bioglass) with adipose tissue extract (ATE) at week 6. Lectin stain, x40. Page 6 of 8

7 Fig. 2: Fig.2 Neovascular capillaries (arrow) in fibrous tissue inside the adipose tissue derived stem cells seeded scaffold (INION BioRestore bioglass) with adipose tissue extract (ATE) at week 6. CD105 stain, x40. Page 7 of 8

8 Conclusion MRI imaging is a useful tool to assess bone tissue regeneration processes in conjunction with therapeutic tissue engineering, namely VEGF enhanced therapy. References Axhousten W. The osteogenetic phases of regeneration of bone; a historial and experimental study. J Bone Joint Surg Am. 1956;38(3): Beaumont M, DuVal MG, Loai Y, Farhat WA, Sàndor GK, Chen HLM. Monitoring angiogenesis in soft-tissue engineered constructs for calvarium bone regeneration: and in vivo longitudinal DCE-MRI study. NMR Biomed 2010;23:48-55 Langer R, Vaganti JP. Tissue engineering. Science 1993; 920:260 Linkhart TA; Mohan S, Baylink DJ. Growth factors for bone regeneration and repair: IGF, TGFb and BMP. Bone;1996:19:1S Kaigler D, Wang Z, Horger K, Mooney DJ, Krebsbach PH. VEGF scaffolds enhance angiogenesis and bone regeneration in irradiated osseous defects. J Bone Miner Res 2006;21: Kempen DHR, Lu L, Heijink A, Hefferan TH, Creemers LB, Maran A, Yaszemski MJ, Dhert WJA. Effect of local sequential VEGF and BMP-2 delivery on ectopic and orthotopic bone regeneration. Biomaterials 2009;30: Schmitz JP, Hollinger JO. The critical size defect as an experimental model for craniomandibulofacial nonunions. Clin Orthop Relat Res 1986;205: Personal Information Page 8 of 8