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7/30/2019 Chapter 14,15,16,17
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Tissue Engineering
Samuel E. Lynch
Robert J. GencoRobert E. Marx
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Part IV:
Periodontal Regeneration14. Periodontal tissue regeneration by polypeptide
growth factors and gene transfer
15. Periodontal regeneration and localizedregeneration in the oral cavity16. Freeze-dried bone allografts in periodontics17. Application of rhBMP-2 to alveolar and
peiodontal defects
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Chap 14. periodontal tissueregeneration by polypeptide
growth factors and gene
transfer
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Polypeptide Growth Factor (GFs)
Natural biologic mediators Regulate crucial cellular events involved in
tissue repair DNA synthesis, chemotaxis, differenciation,matrix synthesis
Growth Factors PDGF, TGF-B, aFGF, bFGF, IGF-I and
IGF-II, CGF, BMPs
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Effects of GF
Growth factors : bone matrix Bone formation & resorption
Several GFs : cementum matrix Not understood
Several in vivo animal studies
Periodontal regeneration Coronal reestablishment of PDL
PLF proliferation, migration, collagenbiosynthesis
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Role of PDGF
Mitogen & Chemoattractant Fibroblast, osteoblast
Wound healing, fracture repair
Suramin (inhibitor of PDGF action) inject Ruduced intramembranous bone formation
Nash et al 4 weeks later Density and volume increased
Three-point bending : Indistinguishable from unoperatedcontrols
PDGF-a receptor deleted mice (Patch mouse) PDGF targets : essential for development
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Role of IGF-I
Pleiotrophic effects on bone homeostasis
Regulate bone cells in an autocrine or paracrinefashion by elevating DNA synthesis, osteocalcin
synthesis, and alkaline phosphatase activity
Promote bone matrix apposition
Effects on the mitogenesis of osteoblasts and PLFs
Chemotactic for PDL fibroblasts, osteoblasts andosteoclast-progenitor cells
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Interactions between GFs
Numerous GFs are sequestered in bonematrix at high concentrations Bone cells release several different GFs
During bone repair : temporal expression ofmultiple GF genes and gene products
IGF-I with PDGF
IGF-I with TGF-b or PDGF-BB IGF-I with bFGF, PDGF, TGF-b IGF-I, PDGF, TGF-b and EGF
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Effects of PDGF and IGF-I
Piche et al PDGF stimulate proliferation of isolate cell from the PDL
Oates et al
Both PDGF-AA and PDGF-BB enhance mitogenic activity ina dose-dependent manner in human PLFs
Matsuda et al Increased mitogenic activity with PDGF-BB and PDGF-AB
on rat PLFs as well as promotion of both PLF chemotaxis
and collagen synthesis P. gingivalis : suppressed
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Periodontal and peri-implant
bone regeneration by PDGF-
based therapeutics
A.PDGF-BB/IGF-I treated site (3M)
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Preclinical Trials
Lynch et al PDGF/IGF-I stimulates bone wound healing (2~3 times of no Tx.)
Becker et al Immediate extraction socket implants
Gore-Tex Mb with PDGF/IGF-1 Bone density and bone-to-implant contacts were twofold greater
than Mb alone or Mb combined with bone graft Failing dental implant sites : significantly higher concentration of
PDGF Chronic inflammaton
PDGF combined with dexamethasone Increases new bone and attachment within 4 weeks Park et al
Class III furcation defect New bone and attachment structures : 5~11 weeks after PDGF and
GTR
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IGF-I Not clearly demonstrate differences in periodontal
regeneration
Dose level, potential role of IGF-1 binding protein
IGFBP Enhance the action of IGF-I
Prolonging the plasma half-life of IGF-I Control the rate of IGF transport from the vasculature
Control the regulation of type I IGF receptor on the cellsurface
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Clinical trials
Howell and coworker Primary objective of this study Assess the safety of PDGF and IGF-I
Obtain preliminary efficacy data on periodontal regeneration
2 dose level treatment group (in 4% methycellulose vehicle) 50 / : rhPDGF-BB rhIGF-I (LD-PDGF/IGF-I)
150 / : HD-PDGF/IGF-I
6~9 month later HD-PDGF/IGF-I : statistically significant increases in alv. bone
2.08 mm new vertical bone height, 43.2% osseous defect fill
(control : 0.75 mm new bone height, 18.5% osseous)
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Comparison of periodontal
regeneration (osseous fill) in non-
human primates and human
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Novel methods of GF delivery by
gene transfer
,
:
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Chap. 15Periodontal Regeneration and
Localized Osseous
Regeneration in the Oral Cavity
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Periodontal regeneration
Autogenous iliac bone grafting No immune response
Obtained in sufficient quantities
Ambulation discomfort
Second surgical site that required hospitalconditions
Root resorption and/or ankylosis
GTR
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Osseous regeneration
DFDBA(demineralized Freeze-dried Bone Allografts) Bowers et al Regeneration of a new attachment apparatus was greater
Cementogenesis occurred more frequently
Predictability of results and the amount of regeneration vary
Utilize different types of lesions
Potential heterogeneity
BMPs Urist : ectopic sites
Sampath & Reddi : reconstitution of the solubilized extracts
Wozney et al : BMP purify and clone
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Biologic activity of commercially
prepared graft materials
Shigeyama et al : freshly obtained humanbone grafts or commercially obtained bonegrafts
Proteins from freshly prepared bone
Higher concentrations of BMP
Significantly greater ability to promote proliferation offibroblasts
But, proteins from commercial bone
Significantly promote cellular proliferation
Some activity was lost as a result of tissue processing
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Methods and materials
6 different bone banks, 200~500,14 sample 17~73years (mean 46.5years), 3 female/11 male Preparation methods : proprietary Sterilization : varied from no sterilization to gas sterilization or
irradiation
3 different mice for 28 days DFDBA particle from six sample : seven mice for 56 days DFDBA 10 ; intramuscular implantation
Two independent observers masked to treatment Score 1 : DFDBA Score 2 : 40% Score 3 : 40%
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Results
Physical properties of DFDBAs Particle size : 200~500 Surface area : 63.8~347.5 *2 pH : 1 hour (4.37~6.43), 48 hours (4.07~6.65)
Not completely neutralized after demineralization
Osteoinductive activity of DFDBAs Amount of bone and cartilage was varied with the source of
the DFDBA particles (Table 15-1) After 4 weeks
7 of the 14 sample : no new bone or cartilage in the tissuearound the particle 1 lot : new bone or cartilage in more than 40% 6 lots : less than 40%
Following 8 weeks 4 of the 7 lots : time-dependent change
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Discussion
Commercially obtained DFDBAs vary greatlyin their ability to induce bone in ectopic sites Different lots from the same tissue bank
Variable inductive ability
Contributing Factors ofvariable osteoinductive activity Donor age, host systemic condition, genetic
factors, and/or sex, differences among and withintissue banks regarding tissue collection andpreparation, size and shape, surface morphologyand roughness, pH, sterilization method.
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Clinical response to rhBMP-2
Method and materials 6 , 41~64( 55), 4/ 2
Results Safety of rhBMP-2/ACS volume : 0.12~0.88( 0.27)
No complication & adverse effect
Osteoconductive activity of rhBMP-2/ACS
Remodeling of the lamina dura : 4 weeks postextraction CT : 0.32 mm
Increased bone density
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6W
7M
6M
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Chap. 16
Freeze-dried bone allografts in
periodontics
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Mineralized freeze-dried bone
allograft (FDBA)
In 1976 : introduced to adult peiodontitis Tx.
89 clinicians 997 periodontal bone defects with FDBA alone,
524 defects with FDBA plus autogenous bone 1 year : complete or more than 50% bone fill FDBA : 220 site (67%)
combine : 137 site (78%)
Especially in furcation defects of multirooted teeth
Regeneration of periodontium 5~12
FDBA : 16/30 defects, Control : 5/30 defects
, ,
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DFDBA
DFDBA, FDBA DFDBA, , FDBA. DFDBA.
11, 27 DFDBA
6 (125~1,000 ) DFDBA : 65% (50% : 78%) Control : 38% (50% : 40%)
(6) 250~500 : 39% 850~1,000 : 35%
Bower et al , ,
Rummelhart et al DFDBA FDBA
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Freeze-dried allografts combined
with antibiotics
The addition of tetracycline to the bone graftwill theoretically enhance its osteogenicpotential.
Enhance fibroblast chemotaxis
Anticollagenolytic
Antibacterial activity DFDBA TC 4:1 : LJP FDBA TC : significant bone fill and defect
resolution AP : DFDBA TC 50 /
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FDBA versus Alloplasts
FDBA DFDBA porous praticulatehydroxyapatite
,
DFDBA polyacetic acid granule DFDBA
:
:
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GTR and FDBA
DFDBA
Anderegg DFDBA,
:
DFDBA, , ,
,
GTR, .
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GBR and FDBA
(naturally space-
making defects), (large non-space-making defects) .
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Safety of FDBA
Donor-specific anti-HLA antibody
20, Amos-modified microcytotoxicity assay
1/8
HIV : AIDS virus
28 1
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Future directions with DFDBA
DFDBA BMP.
BMPs DFDBABMP.
Bower et al DFDBA osteogenin(BMP-3) DFDBA osteogenin 6
DFDBA osteogenin submerged .
Nevin et al rhBMP-2/ACS, , 1.77~3.40 rhBMP-2
8.51 mm
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Chap. 17Application of rhBMP-2 to
alveolar and periodontal defects
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Critical-size, supra-alveolar,
periodontal defect model
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Flap surgery
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10mm implant : 5mm supraalveolar, periimplant defect
If only flap surgery : 10% regeneration
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8 weeks : 75% alv. B. , 40% cementum regeneration
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16 weeks : 20% peri-implant defects regeneration
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rhBMP-2/PLGA
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rhBMP-2/PLGA rhBMP-2/Bio-Oss
8 W
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rhBMP-2/ACS rhBMP-2/Drilac
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rhBMP-2/ACS
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Osseointegration within the extentof the defect(DOSS), within the extent of newly formed bone(BOSS), and within the adjacent resident bone(AOSS)
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rhBMP-2/ACS
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rhBMP-2/ACS
12W 24W
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Osseointegration
AOSS:subantral aug.
OSS:adjacennt resident bone
BG:vertical bone gain
ABD:cancellous b. density
BD:adjacent resident b. density
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rhBMP-2/ACS
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Thank you !
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