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HST 535HST 535
CARTILAGE REPAIRCARTILAGE REPAIR
M. Spector, Ph.D.M. Spector, Ph.D.
Massachusetts Institute of TechnologyMassachusetts Institute of TechnologyHarvard Medical SchoolHarvard Medical School
Brigham and Women’s HospitalBrigham and Women’s HospitalVA Boston Healthcare SystemVA Boston Healthcare System
Harvard-MIT Division of Health Sciences and Technology HST.535: Principles and Practice of Tissue Engineering Instructor: Myron Spector
Figure by MIT OCW.Figure by MIT OCW.
Figure by MIT OCW.Figure by MIT OCW.
Figure by MIT OCW.Figure by MIT OCW.
Implantation of the matrix alone, or supplemented with growth factors or genes for the GFsStem cells from
bone marrow infiltrate the defect
Implantation of a cell-seeded matrix
Photo removed for copyright
reasons.
Diagram removed for copyright reasons.
Future Clinical Practice Implementing Tissue Engineering
Microfracture Figure by MIT OCW.Figure by MIT OCW.
ELEMENTS FOR TISSUEELEMENTS FOR TISSUE ENGINEERINGENGINEERING
Tissue Engineering Triad*Tissue Engineering Triad*•• CELLSCELLS•• MATRIX (INSOLUBLE REGULATOR)MATRIX (INSOLUBLE REGULATOR)
–– Porous, absorbable biomaterialsPorous, absorbable biomaterials•• SOLUBLE REGULATORSSOLUBLE REGULATORS
–– Cytokines (Growth Factors)Cytokines (Growth Factors)Environmental FactorsEnvironmental Factors•• Mechanical loadingMechanical loading
** Used individually or in combination, but probablyUsed individually or in combination, but probablyalways best with a matrix (always best with a matrix (i.ei.e., with a biomaterial)., with a biomaterial)
ARTICULAR CARTILAGEARTICULAR CARTILAGE
Limits to RegenerationLimits to Regeneration•• Avascular (andAvascular (and aneuralaneural))•• Relatively low cell densityRelatively low cell density•• Cells of low mitotic activityCells of low mitotic activity•• Cells cannot freely migrateCells cannot freely migrate
Image removed for copyright reasons.
TISSUE ENGINEERINGTISSUE ENGINEERING
CellsCells•• Autologous, allogeneic, orAutologous, allogeneic, or xenogeneicxenogeneic•• Differentiated cell of the same tissueDifferentiated cell of the same tissue
type or another tissue type, or stem celltype or another tissue type, or stem cell
Autologous Chondrocyte Implantation
M Brittberg, et al., NEJM 33:889 (1994)
This process has been commercialized by Genzyme (for USD$11,500).
Diagram removed for copyright reasons.
UntreatedUntreateddefectsdefects
CellsCellsharvestedharvested
CellsCellsisolated isolated **
Cells suspended Cells suspended **
Periosteum harvestPeriosteum harvestsitesite
Cells cultured Cells cultured **
Cells injectedCells injectedunder periosteumunder periosteum
* by Genzyme * by Genzyme BiosurgeryBiosurgery
Canine StudyCanine StudyAutologous Chondrocyte ImplantationAutologous Chondrocyte Implantation
AUTOLOGOUS CHONDROCYTEAUTOLOGOUS CHONDROCYTE-SEEDED COLLAGEN MATRIXSEEDED COLLAGEN MATRIX
4 mm4 mm
ChondrocyteChondrocyte--seededseededtype II collagentype II collagen implant*implant*
* Cells seeded into the matrix* Cells seeded into the matrix 24 hours24 hours**andand 4 weeks4 weeks prior to implantationprior to implantation
* HA Breinan,* HA Breinan, et alet al. J . Orthop. Res. 2000;18:781. J . Orthop. Res. 2000;18:781--789789and C.R. Lee,and C.R. Lee, et alet al. J. Orthop. Res. 2003;21:272. J. Orthop. Res. 2003;21:272--281281
Seeding of Collagen Matrices with CAC
Diagram removed for copyright reasons.
Collagen discs 9 mm diam x 3 mm thick
CR Lee, et al, Biomat. 2001;22:3145.
Chondral defect immediately postoperative. Arrow shows perforation of calcified cartilage and subchondral bone (SCB)
Defects treated by autologous chondrocyte implantation, 6 months postoperative
H. Breinan, et al. J. Orthop. Res. 2001;19:282-292
Photo removed for copyright
Photo removed for copyright
reasons.
reasons.
12 mo. Degraded tissue
6 mo. Art. cart. and fibrocartilage
H. Breinan, et al. JOR 2001;19:282
1.5 mo. Fibrous tissue
3 mo. Hyaline cartilage (some articular cartilage), fibrocartilage, and fibrous tissue
Tissue that formed after 3 and 6 months did not function longer term. Is the problem a lack of fill or the tissue types comprising the material?
AUTOLOGOUS CHONDROCYTE IMPLANTATION
Photo removed for copyright
Photo removed for copyright
reasons.
reasons.
Summary of Results: Canine Model
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%Untreated CAC CAC/ CAC/Control Alone Collagen II Collagen II
24 hr 4 wk
15 Wks Post-op, Mean, n=6
% O
rigi
nal D
efec
t Are
a Cultured Autologous
Chondrocytes Hyaline Fibrocartilage Fibrous
HA Breinan, et al. J . Orthop. Res. 2000;18:781-789and C.R. Lee, et al. J. Orthop. Res. 2003;21:272-281
Implantation of the matrix alone, (or supplemented with growth factors or genes for the GFs)
“Microfracture”: Stem cells from bone marrow infiltrate the defect
Implantation of a cell-seeded matrix
Photo removed for copyright
reasons.
Diagram removed for copyright reasons.
Figure by MIT OCW.Figure by MIT OCW.
Future Clinical Practice Implementing Tissue Engineering
CANINE MICROFRACTURE STUDYCANINE MICROFRACTURE STUDYTREATMENT GROUPSTREATMENT GROUPS
4 mm4 mm
Collagen (II)Collagen (II) filmfilm
MicrofractureMicrofracture
MicrofractureMicrofracture++
CollagenCollagenImplantImplant
ACACBoneBone
Collagen (II)Collagen (II) spongesponge
* HA Breinan,* HA Breinan, et alet al. J . Orthop. Res. 2000;18:781. J . Orthop. Res. 2000;18:781--789789
Hyaline Summary of Results: Canine Model Fibrocartilage
15 Wks Post-op, Mean, n=6
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Untreated Control
CAC Alone
CAC/Collagen II
24 hr
CAC/Collagen II
4 wk
% O
rigi
nal D
efec
t Are
a
Fibrous Cultured Autologous Chondrocytes
µfxAlone
µfx/Collagen II
Microfracture
Procedures currently used
• One scaffold for both cartilage and bone or two different scaffolds?
• Separate layer for calcified cartilage? • Scaffold(s) alone or cell-seeded? • One cell type for both cartilage and bone?
• Two cell types? –Seeded as a mixture? –
Articular Cartilage
Approaches for osteochondral defects? Diagrams removed for
Separate cell types in each scaffold?
copyright reasons.
