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Scaffolds, Growth Factors, and Tissue Constructs

Delivery Systems. Scaffolds, Growth Factors, and Tissue Constructs. Hasan Uludag Department of Chemical & Materials Engineering, Department of Biomedical Engineering, and Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta, Edmonton, AB. Bone Healing :

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Scaffolds, Growth Factors, and Tissue Constructs

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  1. Delivery Systems Scaffolds, Growth Factors, and Tissue Constructs Hasan Uludag Department of Chemical & Materials Engineering, Department of Biomedical Engineering, and Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta, Edmonton, AB

  2. Bone Healing: an orchestrated process of molecular and cellular events Shier D. et al., Hole's Human Anatomy & Physiology, 1996. Hematoma Angiogenesis Influx of Stem Cells Osteogenic Differentiation Bone Deposition Remodelling • chemotaxis, proliferation, differentiation, osteogenesis, and apoptosis • all processes regulated by growth factors and the extracellular matrix

  3. Approaches for Bone Regeneration: • Extracellular Matrices: dynamic scaffolding capable of modulating cell activity: natural (collagen) or synthetic (apatite fillers) • Growth Factors: endogenous regulators of cellular activity: chemotaxis, proliferation, and differentiation (BMPs) • OsteogenicCells: cells that can differentiate under the influence of local factors (bone marrow cells or engineered cells)

  4. TORONTO BOSTON A Brief History of BMP Development 1965 ~ Description of bone morphogenetic activity from demineralized bone matrix (M. Urist, Science) 1988 ~ Cloning of recombinant human BMP-2 and reproduction of BMP activity by a single protein (Wozney et al., Science) 1988-2000 ~ Development of a delivery system >2000 ~ Regulatory approval, publications on specific clinical indications, success rates, and alternatives. GENETICS INSTITUTE INC.

  5. BMP-2 Soaked Collagen Sponge Wet Sponge in Fusion Cage Demineralized Bone Powder to be Soaked with OP-1 (BMP-7) Osteoinductive Devices in Clinics

  6. Representation of an Osteoinductive Device cell flux BMP release cell flux cell flux biomaterial scaffold

  7. Initial (3 hr) Recovery of 125I-BMP-2 in Rat Ectopic Model Subsequent Pharmacokinetics Effect of biomaterial scaffold on BMP release kinetics from implants release kinetics ≈ 'retention'

  8. Collagen Sponge Poly(glycolic acid) Percent Retention Time (days) Retention of different BMPs in implants

  9. Biomaterial-1 Strategy-1 BMP-X Biomaterial-2 BMP-Y Strategy-2 Biomaterial BMP-Z Relationship between BMP retention and osteoinductive activity in implants

  10. Osteoinduction Pharmacokinetics BMP-2 vs. BMP-4: Comparison of protein retention and bone formation in the rat ectopic model

  11. O NiPAM/EMA-49 kD H N NiPAM (N-isopropylacrylamide) Temperature-Sensitive Polymers NiPAM/EMA/NASI-50 kD BMPs O Alkyl-methacrylates R O NiPAM/EMA-404 kD O NASI (N-acryloxysuccinimide) BMP-biomaterial interactions O N NiPAM/EMA/NASI-422 kD O O Engineered biomaterials for increased retention of BMPs after injection

  12. BMP-2 Retention by NiPAM-Polymers (intramuscular injection model in rats) % Retention Time (days)

  13. An Osteoinductive Device by Gene Delivery cell flux release of osteoinductive (BMP-2) genes ... Lieberman et al. (UCLA) 1998. ... Huard et al. (U. Pittsburg) 1999. ... Helm et al. (U. Virginia) 1999. cell flux cell flux biomaterial scaffold

  14. Bisphosphonates Protein Medicinal Agent Medicinal Agent Growth Factors for Systemic Bone Therapy BP conjugation as a means to impart bone affinity (Zhang et al., Chem. Soc. Rev. 2006)

  15. Protein chemistry to couple bisphosphonates therapeutic proteins Medicinal Agent sulfoSMCC aminoBP ( ) sulfoSMCC Protein

  16. New bisphosphonates engineered specifically for targeting proteins to bone Di-Bisphosphonate Tetra-Bisphosphonate Medicinal Agent (Bansal et al., J. Pharm. Sci. 2004; Bansal et al., Angew Chem. 2005)

  17. Effectiveness of BP-coupled proteins to seek bone after systemic administration ? Bone Delivery of BP-Conjugate Targeting Efficiency: Bone Delivery of Native Protein Medicinal Agent (Zhang et al., Chem. Soc. Rev. 2006)

  18. ACKNOWLEDGEMENTS Co-workers and Collaborators S. Gittens G. Bansal T.J. Gao G. Wohl S. Zhang T. Haque A. Jalil J. Yang C. Kucharski J.E.I. Wright J. Wozney (Genetics Institute) W. Sebald (U. of Würzburg) R.F. Zernicke, J.R. Matyas (UC) A. Lavasanifar (UA) Financial Support Canadian Institutes of Health Research, AHFMR/CFI,Genetics Institute Inc., Millenium Biologics, Whitaker Foundation, NSERC

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