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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

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.


-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.
  • Over next 5-10 years there will be major commercial development in the area of stem cell enterprises.