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Views of the National Institutes of Health ABSTRACT EVALUATION OF BONE MORPHOGENETIC PROTEIN-2 RELEASE FROM KERATIN SCAFFOLDS IN VITRO AND IN VIVO by Jingxuan Li Recombinant human bone morphogenetic protein-2 (rhBMP-2) can be used clinically to promote bone healing as an alternative to bone grafting treatment. The rhBMP-2 can stimulate cellular differentiation of osteoprogenitor cells to promote bone healing. However, delivery of rhBMP-2 is a challenge since rhBMP-2 has a short half-life and has therefore been delivered from collagen sponges implanted at the injury site. While this has led to effective bone regeneration, ectopic bone growth associated with the rapid degradation of collagen and subsequent rhBMP-2 release are clinical problems. We are investigating keratins as alternative rhBMP-2 carriers. Keratins are structural intermediate proteins and can be extracted from human hair. Oxidatively extracted keratin (KOS) cannot achieve disulfide crosslinks whereas reductively extracted keratin (KTN) can form disulfide crosslinks. The rate of degradation of keratin can be tuned by mixing keratose and kerateine in varying ratios. The hypothesis guiding this thesis is that keratin can be formulated with varying ratios of KOS and KTN to modulate the rate of scaffold degradation and thereby control the releasing rate of rhBMP-2. The in vivo release kinetics of rhBMP-2 was assessed by a critically-sized rat femur defect model. The biodistribution of rhBMP-2 after implantation in the critically-sized femur model was assessed in the vital organs. EVALUATION OF BONE MORPHOGENETIC PROTEIN -2 RELEASE FROM KERATIN SCAFFOLDS IN VITRO AND IN VIVO A Thesis Submitted to the Faculty of Miami University in partial fulfillment of the requirements for the degree Master of Engineering Department of Chemical, Paper and Biomedical Engineering by Jingxuan Li MIAMI UNIVERSITY Oxford, Ohio 2016 Advisor ________________________ Justin M. Saul Reader ________________________ Lei Kerr Reader ________________________ Michael Robinson TABLE OF CONTENTS CHAPTER I-Introduction to Bone Regeneration and Keratin Biomaterials .............................................. 1 I.1. The Need for Effective Clinical Treatment for Bone Fracture .......................................................... 2 I.2. Bone Tissue and Fracture Repair ....................................................................................................... 2 I.3. Bone Grafting: Allograft and Autograft ........................................................................................... 4 I.4. BMP-2 and Osteoinduction ............................................................................................................... 5 I.5. A Current Clinical rhBMP-2 Carrier: Collagen ................................................................................ 6 I.6. Keratin Biomaterial as rhBMP-2 Carriers ......................................................................................... 6 I.7. Rationale for Use of Fluorescent Quantification of rhBMP-2 Release ............................................. 9 I.8. Fluorescent Dyes for Quantification of rhBMP-2 Release .............................................................. 10 I.9. Rationale, Hypothesis and Approach of Thesis Work .................................................................... 10 CHAPTER II – Release Kinetics and Biodistribution of rhBMP-2 following Implantation of Keratin Scaffolds in a Critically-sized Rat Femur Defect Model ......................................................................... 17 II.1. Introduction .................................................................................................................................... 18 II.2. Material and Methods .................................................................................................................... 19 II.2.1. Fluorescent Labeling of rhBMP-2 ........................................................................................ 19 II.2.2. Keratin Hydrogel Fabrication ............................................................................................... 21 II.2.3. In vitro rhBMP-2 Release Study .......................................................................................... 21 II.2.4. Rat Femur Defect Model for Release of Fluorescently-tagged rhBMP-2 In Vivo ............... 22 II.2.5. Bruker System Imaging and Photoshop Quantification of Images ...................................... 24 II.2.6. Assessment of Fluorescently-tagged rhBMP-2 in Vivo Biodistribution ............................... 25 II.3. Results/ Discussion ........................................................................................................................ 25 II.3.1. In vitro rhBMP-2 release from keratin hydrogels and collagen scaffolds ........................... 25 II.3.2. Rat Femur Defect Model for Retention of rhBMP-2 at Implant Site ................................... 29 II.3.3. Biodistribution of rhBMP-2 in Vivo ..................................................................................... 32 ii CHAPTER III – Discussion of Results and Future Work ........................................................................ 40 III.1. Discussion of Thesis Results ........................................................................................................ 41 III.2. Future Directions .......................................................................................................................... 48 iii LIST OF TABLES CHAPTER II – Release Kinetics and Biodistribution of rhBMP-2 following Implantation of Keratin Scaffolds in a Critically-sized Rat Femur Defect Model Table 1. Experimental keratin formulation groups. Table 2. Biomaterial formulations for each time points for rats femur defect model for assessing retention of fluorescently-labeled rhBMP-2 in vivo Table 3. 15% (weight/volume) 100%KOS Standard Curve with serial rhBMP-2 concentration. Table 4. Statistical analysis of keratin degradation for samples with rhBMP-2 in vitro. Table 5. Statistical analysis of keratin degradation for samples without rhBMP-2 in vitro Table 6. Number of fluorescent signal positive organs over the total number of each kind of organ of rats with rhBMP-2 loaded collagen, 100%KOS, 50:50 KOS:KTN and 100%KTN scaffold implantation at Day 1 after implantation. Table 7. Number of fluorescent signal positive organs over the total number of each kind of organ of rats with rhBMP-2 loaded collagen, 100%KOS, 50:50 KOS:KTN and 100%KTN scaffold implantation at Day 3 after implantation. Table 8. Number of fluorescent signal positive organs over the total number of each kind of organ of rats with rhBMP-2 loaded collagen, 100%KOS, 50:50 KOS:KTN and 100%KTN scaffold implantation at Day 7 after implantation. iv LIST OF FIGURES CHAPTER II – Release Kinetics and Biodistribution of rhBMP-2 following Implantation of Keratin Scaffolds in a Critically-sized Rat Femur Defect Model Figure 1. Initial standard curve of absorbance with AF488 tagged rhBMP-2 concentration Figure 2. rhBMP-2 percentage releasing profiles of 100:0 KOS:KTN, 70:30 KOS:KTN, 50:50 KOS:KTN, 30:70 KOS:KTN, 0:100 KOS:KTN and collagen biomaterials Figure 3. Standard curve of absorbance with diluted BSA concentration for Lowry protein assay (n=3). Figure 4. Lowry protein assay cumulative protein mass profiles of 100:0 KOS:KTN, 70:30 KOS:KTN, 30:70 KOS:KTN, 0:100 KOS:KTN and collagen biomaterial with or without rhBMP-2 Figure 5. Three kinds of images from Bruker Imaging System for each rats: Fluorescent image (A), optical image (B) and X-ray (C) for experimental rats. Figure 6. Fluorescent images for 15% (weight/volume) rhBMP-2 loaded KOS scaffold standard curve are shown with serial rhBMP-2 concentration for quantification Figure 7. Standard curve of serial concentration of rhBMP-2 that loaded into KOS scaffolds (15% weight/volume) Figure 8. Representative fluorescent images of the average pixel intensity of rhBMP-2 loaded collagen, 100%KOS, 50:50 KOS:KTN and 100%KTN biomaterial at 1, 3 and 7 days post-implant Figure 9. Percentage rhBMP-2 retention from collagen, 100%KOS, 50:50 KOS:KTN and 100%KTN scaffold at 1, 3, or 7 days post-implant. Figure 10. Biodistribution fluorescent image for spleen of each rat, which implanted with rhBMP-2 loaded collagen, 100%KOS, 50:50KOS:KTN and 100%KTN at 1, 3, or 7 days post-impalnt v Figure 11. Biodistribution fluorescent image for liver of each rat, which implanted with rhBMP-2 loaded collagen, 100%KOS, 50:50KOS:KTN and 100%KTN at 1, 3, or 7 days post-implant. Figure 12. Biodistribution fluorescent image for left lung (A) and right lung (B) of each rat, which implanted with rhBMP-2 loaded collagen, 100%KOS, 50:50KOS:KTN and 100%KTN at 1, 3, or 7 days post-implant. Figure 13. Biodistribution fluorescent image for left kidney (A) and right kidney (B) of each rat, which implanted with rhBMP-2 loaded collagen, 100%KOS, 50:50KOS:KTN and 100%KTN at 1, 3, or 7 days post-implant. Figure 14. Biodistribution fluorescent image for heart of each rat, which implanted with rhBMP-2 loaded collagen, 100%KOS, 50:50KOS:KTN and 100%KTN at 1, 3, or 7 days post-implant. Figure 15. Biodistribution fluorescent image for brain of each rat, which implanted with rhBMP-2 loaded collagen, 100%KOS, 50:50KOS:KTN and 100%KTN at 1, 3, or 7 days post-implant. Figure 16. Quantification of rhBMP-2 concentration in spleen for collagen, 100%KOS, 50:50 KOS:KTN and 100%KTN implanted rats at 1, 3, or 7 days post-implant. Figure 17. Quantification of rhBMP-2 concentration in liver for collagen,
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