update on biologics in orthopedic sportsmedicine cells and growth factors
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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. Tissue repair relies on vascularity and cellular migration Blood escapes, hematoma

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injured tissue the basics of healing requires cells and growth factors
Injured Tissue-The Basics of HealingRequires Cells and Growth Factors
  • 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
Growth Factors/Bioactive Agents
  • 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
      • Examples- Interferon/interleukin/tumor necrosis factor
growth factors
Growth Factors
  • Transforming Growth factor-beta(TGFB)-Largest group
    • Over 100 members
    • Anabolic effect on all components of

Musculoskeletal tissue

common types of tgf beta
Common Types of TGF-Beta
  • Bone Morphogenic proteins-BMP’s
    • Osteoprogenitor derived cells-promote bone growth
  • Platelet Derived Growth Factor-PDGF
    • From platelets and stimulates angiogenesis, chemotactic influence and mitogenic
  • Insulinlike Growth Factor-IGF-1
    • From variable cells, broad anabolic effect
  • Fibroblast Growth factor-bFGF
    • Early differentiation of cells and tissue and in repair process
common types of tgf beta cont d
Common Types of TGF-Betacont’d
  • Epidermal Derived Growth Factor-EGF
    • Proliferates ectoderm and mesoderm
  • Growth and differentiation Factor-GDF-5
    • Chondrocyte, fibroblast and mesenchymal cell expansion
bone healing
Bone Healing
  • Two clinically available BMP’s-stimulates bone growth
    • rhBMP2-Recombinant BMP- (Infuse, Medtronic SofamorDanek, 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
Bone To Tendon Healing
  • 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
Tendon To Tendon
  • Mechanism not well defined
  • GDF5 may play a role
  • IGF1 and PDGF2
    • Increased collagen synthesis
  • 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
Ligament Healing
  • Cell Proliferation, Type 1 Collagen
    • and proteoglycan synthesis are stimulated by bFDF, PDGF and bTGF
  • Method of delivery will be a gene-enhanced delivery system via fibroblast cells transduced by plasmid or virus carrying these growth factors
meniscus healing
Meniscus Healing
  • 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
Articular CartilageHealing is not regeneration
  • Articular cartilage is Hyaline cartilage
    • Type 2 collagen
  • Heals to injury with fibrocartilage
    • Type 1 collagen
    • No vascular supply
    • No nerves
    • More of a scar tissue than normal tissue
articular cartilage repair
Articular Cartilage Repair
  • 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
Cartilage Systems-U.S.
  • Lavage and debridement
  • Chondroplasty
  • Microfracture
  • Oats
  • Polymer bone plugs
  • Osteochondral allografts
  • Cartilage cultures- Genzyme only
    • Cambridge Ma
cartilage cultures
Cartilage Cultures
  • 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
Other source of Cells than chondrocytesStem Cells
  • 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
Present Applications
  • 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
Applications in genetically defective cell lines
  • 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
Stem Cell TypesMyth and Fact
  • 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.
      • The fertilized egg has the effect of “resetting” the nucleus to a primordial state.
      • No ethical considerations with fetuses here!
embryonic versus adult
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.

Embryonic versus Adult
stem cells
Stem Cells
  • 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
What we know and do not know
  • 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
Stem Cell Exhaustion
  • Stem cells may be exhausted
  • Has been shown to happen in degenerative conditions, especially osteoarthritis.
future
Future
  • Over next 5-10 years there will be major commercial development in the area of stem cell enterprises.
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