Download Update on Biologics in Orthopedic Sportsmedicine

Update on Biologics in
Orthopedic
Sportsmedicine
Cells and Growth
Factors
William F Bennett MD
Injured Tissue-The Basics of
Healing
Requires Cells and Growth Factors
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Tissue repair relies on vascularity and cellular
migration
Blood escapes, hematoma
Platelets, pluripotential stem cells form scaffold
for neocellular proliferation
Cells respond to Growth Factors(Bioactive
agents)
Some cells respond different to growth factors
based upon tissue
Growth Factors/Bioactive
Agents
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At the time of injury released, Gfs bind to
receptors and effect cellular function.
Part of inflammatory response.
Proteins
Anabolic/catabolic
Cytokines-extracellular proteins
• Effect cell to cell mediation
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Examples- Interferon/interleukin/tumor necrosis
factor
Growth Factors
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Transforming Growth factorbeta(TGFB)-Largest group
• Over 100 members
• Anabolic effect on all components of
Musculoskeletal tissue
Common Types of TGF-Beta
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Bone Morphogenic proteins-BMP’s
• Osteoprogenitor derived cells-promote bone
growth
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Platelet Derived Growth Factor-PDGF
• From platelets and stimulates angiogenesis,
chemotactic influence and mitogenic
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Insulinlike Growth Factor-IGF-1
• From variable cells, broad anabolic effect
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Fibroblast Growth factor-bFGF
• Early differentiation of cells and tissue and in
repair process
Common Types of TGF-Beta
cont’d
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Epidermal Derived Growth FactorEGF
• Proliferates ectoderm and mesoderm
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Growth and differentiation FactorGDF-5
• Chondrocyte, fibroblast and
mesenchymal cell expansion
Bone Healing
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Two clinically available BMP’s-stimulates bone growth
• rhBMP2-Recombinant BMP- (Infuse, Medtronic Sofamor
Danek, Minneapolis, Mn.)
• BMP 7-(osteogenic protein-1- OP1)
 Stryker, Biotech, Hopkinton, Ma,
LMP1-Lyophilized Mineral protein
• Stimulates BMP
PDGF and Platelet Rich Plasma may interfere with bone
healing
BMPs help reduce non-union rate, spinal fusion rate and
possibly open wedge osteotomy non-healing
Bone To Tendon Healing
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BMP2 and OP1 have been shown to
aid in the tendon to bone healing
Although the exact mechanism for
this repair process is not well known
Tendon To Tendon
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Mechanism not well defined
GDF5 may play a role
IGF1 and PDGF2
• Increased collagen synthesis
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These factors can be found in
augmentation tissues like porcine
submucosa, bovine, equine collagen and
human allograft dermis
Cascade- shows to repair tissue- platelet
rich plasma !!!!!!!!!!!!!!!
Ligament Healing
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Cell Proliferation, Type 1 Collagen
• and proteoglycan synthesis are
stimulated by bFDF, PDGF and bTGF
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Method of delivery will be a geneenhanced delivery system via
fibroblast cells transduced by
plasmid or virus carrying these
growth factors
Meniscus Healing
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Meniscal tears heal better when ACL
reconstruction is done at the same time.
Suggests that something in the blood
augments healing
Arnozcky has shown a fibrin clot to help
healing.
Platelet Rich Fibrin Matrix(PRFM)
• Cascade- ultracentrifuge of blood
• Platelt rich ultracentrifugate is further
centrifuged down to a volume-stable suturable
fibrin matrix
Articular Cartilage
Healing is not regeneration
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Articular cartilage is Hyaline cartilage
• Type 2 collagen
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Heals to injury with fibrocartilage
• Type 1 collagen
• No vascular supply
• No nerves
• More of a scar tissue than normal
tissue
Articular Cartilage Repair
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Fissuring- chondroplasty, smooths
edges only, no healing
Osteochondral defects- microfracture
technique or marrow stimulation
techniques-forms fibrocartilage
Cartilage-growth factors
• Bmp2/1IGF/bTGF
• Add these to cell colonies, like genzyme
cell cultures- get better hyaline cartilage
Cartilage Systems-U.S.
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Lavage and debridement
Chondroplasty
Microfracture
Oats
Polymer bone plugs
Osteochondral allografts
Cartilage cultures- Genzyme only
• Cambridge Ma
Cartilage Cultures
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Carticel- Genzyme-using
chondrocytes, cartilage cells as
opposed to stem cells.
• Bx, 4-6 weeks later can replant with
cultured cells, use periosteal patch,
open surgery, collagen membrane 2nd
generation……using presently.
• Next gen Carticel, MACI-matrix
impregnated with cells, no periosteal
patch
Other source of Cells than
chondrocytes
Stem Cells
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Both an evolution and a revolution in
modern biomedicine.
Concept is rather than introduce organ
transplant, one would implant certain
population of cells to allow regeneration
Bone marrow transplantation is
intermediate between organ and stem cell
transplant.
Present Applications
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Bone Marrow transplant- for
radiation loss of blood cells and their
progenitor lines.
Stem cell skin grafts for burn
victims.
Corneal stem cell implants.
Pancreatic islet cell implantation.
Applications in genetically
defective cell lines
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Genetically corrected stem cells used
to treat;
• Muscular dystrophy
• Other disease processes
• Future will be in musculoskeletal areas
as well.
Stem Cell Types
Myth and Fact
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Adult stem cells identified from brain to
muscle.
Fetal Stem cells- aborted fetuses or
umbilical chord
Embryonic stem cells• Discarded from in vitro fertilization
• Somatic Nuclear Transfer- a nucleus from a
normal body cell is placed into a fertilized egg
with its nucleus removed.
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The fertilized egg has the effect of “resetting” the
nucleus to a primordial state.
No ethical considerations with fetuses here!
Embryonic versus Adult
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Embryonic• Ubiquitous component
of the embryo.
• Defined by position in
the embryo
• Divide in culture
without changing
charcteristics.
• Single cell can give rise
to a colony of cells.
Adult-rare, difficult to
identify, unknown
origin, partially
understood function
and life history
-defined by complex
list of features.
-can not divide
indefinitely.
Stem Cells
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Maintain undifferentiated phenotype
until exposed to appropriate signals.
With signals can differentiate into
specialized cells that have structure
and function
Mesenchymal Stem cells are of this
type-MScs- bone marrow.
Mesenchymal is from a layer in the
developing embryo.
What we know and do not know
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Know some signals
Don’t know all intermediate steps
Don’t know how exactly how one cell
changes to another.
Don’t understand the microenvironment
completely.
Adult and MSC have limited differentiation
potential compared to embryonic stem
cells and limited number of replication
cycles.
Stem Cell Exhaustion
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Stem cells may be exhausted
Has been shown to happen in
degenerative conditions, especially
osteoarthritis.
Future
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Over next 5-10 years there will be
major commercial development in
the area of stem cell enterprises.