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					Scaffolds, Growth Factors,
  and Tissue Constructs
            Delivery Systems

               Hasan Uludag

Department of Chemical & Materials Engineering,
  Department of Biomedical Engineering, and
Faculty of Pharmacy & Pharmaceutical Sciences,
      University of Alberta, Edmonton, AB
                          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
   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)
• Osteogenic Cells: cells that can differentiate under the
  influence of local factors (bone marrow cells or
  engineered cells)
    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)                             TORONTO


                                                BOSTON
     GENETICS INSTITUTE INC.

•    1988-2000 ~ Development of a delivery system
•    >2000 ~ Regulatory approval, publications on specific
     clinical indications, success rates, and alternatives.
       Osteoinductive Devices in Clinics




BMP-2 Soaked Collagen Sponge     Wet Sponge in Fusion Cage




                 Demineralized Bone Powder to
                  be Soaked with OP-1 (BMP-7)
Representation of an Osteoinductive Device


                  cell flux


                              BMP release




  cell flux                        cell flux




                biomaterial
                 scaffold
                      Effect of biomaterial scaffold on BMP
                      release kinetics from implants

                                 release kinetics ≈ 'retention'

   Initial (3 hr) Recovery of 125I-BMP-2 in
               Rat Ectopic Model                                                Subsequent Pharmacokinetics
Collagen Sponge (1)
Collagen Sponge (2)
                                                                            1
    Gelatin Sponge




                                                  Fractional Retention
       human DBM
            rat DBM
           coral HA                                                        0.1

     human Mineral
     bovine Mineral                                                                    Collage n
                TCP                                                       0.01         DBM (huma n)
        Synhetic HA                                                                    Synthtic HA
 deLip-Bovine Bone                                                                     Bovine mineral
             Dexon                                                                     Bone mineral (huma n)
                                                                         0.001
                      0    20   40    60     80                                  0      5             10       15

                          % Implanted Dose                                               Time (days)
                                Retention of different BMPs in implants



                             Collagen Sponge                   Poly(glycolic acid)
             100                                    100
Percent Retention




                    10                               10
                                                                                          rhBMP-2

                                                                                          rhBMP-4

                                                                                          rhBMP-6
                     1                                1
                                                                                          rhBMP-2 (E.coli)

                                                                                          Acet. rhBMP-2
                0.1                                  0.1                                  Succ. rhBMP-2



          0.01                                      0.01
                         0      5      10      15          0        5      10        15

                                            Time (days)
       Relationship between BMP retention and
       osteoinductive activity in implants




             Biomaterial-1
Strategy-1                        BMP-X
             Biomaterial-2



                                  BMP-Y
Strategy-2    Biomaterial
                                  BMP-Z
   BMP-2 vs. BMP-4: Comparison of protein
   retention and bone formation in the rat
   ectopic model


Pharmacokinetics        Osteoinduction
                Engineered biomaterials for increased
                retention of BMPs after injection

                                                             NiPAM/EMA-49 kD

                                         NiPAM
                                 (N-isopropylacrylamide)
Temperature-Sensitive Polymers
                                           O
                                                  H        NiPAM/EMA/NASI-50 kD
                                              N
         BMPs
                                   Alkyl-methacrylates
                                           O
                                                             NiPAM/EMA-404 kD
                                                R
                                              O


BMP-biomaterial interactions              NASI
                                 (N-acryloxysuccinimide)
                                             O             NiPAM/EMA/NASI-422 kD
                                          O
                                               N
                                            O
                                                  O
                        BMP-2 Retention by NiPAM-Polymers
                        (intramuscular injection model in rats)

              100




                                                       BMA/NASI (24.7 oC)
% Retention




               10
                                                       BMA/NASI (15.6 oC)



                                                       BMA (14.8 oC)
                1




              0.1                                       BMA (25.6 oC)
                                                        BMP-2 alone

                    0            7              14

                           Time (days)
    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
   Growth Factors for Systemic Bone Therapy

                        BP conjugation as a means to impart bone
Medicinal   Medicinal   affinity (Zhang et al., Chem. Soc. Rev. 2006)
 Agent       Agent




                                    Protein                      Bisphosphonates
                                     QuickTime™ and a
                                 TIFF (LZW) decompressor
                              are neede d to see this picture.
Medicinal
 Agent             Protein chemistry to couple bisphosphonates
                   therapeutic proteins




        aminoBP (                              )                                              QuickTime™ and a
                                                                                          TIFF (LZW) decompressor
                                                                                       are neede d to see this picture.




                                                           O   O

                                                                                   O   sulfoSMCC
                   QuickTime™ and a
                                                           N   O               N
               TIFF (LZW) decompressor
            are neede d to see this picture.
                                                   NaO3S                   O
                                                           O   sulfoSMCC




              Protein
Medicinal
 Agent         New bisphosphonates engineered
               specifically for targeting proteins to bone



      Di-Bisphosphonate                     Tetra-Bisphosphonate




                            (Bansal et al., J. Pharm. Sci. 2004; Bansal et al., Angew Chem. 2005)
 Medicinal
                  Effectiveness of BP-coupled proteins to
  Agent           seek bone after systemic administration ?
                                                 Bone Delivery of BP-Conjugate
                    Targeting Efficiency:
                                                 Bone Delivery of Native Protein
                                             3-6 Hours         1 Day        2-4 Days
  Protein      Linker   Substitution Route Tibia Femur    Tibia Femur     Tibia Femur
 BSA-aBP       SMCC        11.0       IV    2.2     2.0    3.7      3.7
 BSA-aBP*      SMCC        11.0       IV                   2.2      3.0    7.5       5.9
 BSA-aBP       SMCC        11.0       SC                   2.5      1.9

 LYZ-aBP       SMCC        3.9      IV                    4.1     5.3      5.6       3.7
 LYZ-aBP       SMCC        3.9      SC                    3.1     4.5

Fetuin-aBP   SMCC          6.1       IV    0.9    1.0     0.9     0.6      0.6       0.8
Fetuin-aBP   SMCC          6.1       IP                   0.7     0.6
Fetuin-aBP MMCCH           7.1       IV                                    1.0       1.0
Fetuin-diBP EDC/NHS        1.2       IV                                    1.8       2.1

 BSA-diBP     EDC/NHS      2.6       IV                                    3.7       2.9
BSA-tetraBP   EDC/NHS      3.6       IV                   4.1     4.7
BSA-tetraBP   EDC/NHS      3.6       IP                   3.4     3.7
 IgG-diBP     EDC/NHS      6.3       IV                                    2.6       1.5

BMP-2-aBP      SMCC         ~3       IV                   2.8     4.3

                                                                  (Zhang et al., Chem. Soc. Rev. 2006)
               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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