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Update on Biologics in Orthopedic Sportsmedicine Cells and Growth Factors

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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Update on Biologics in Orthopedic Sportsmedicine Cells and Growth Factors

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  1. Update on Biologics in Orthopedic SportsmedicineCells and Growth Factors William F Bennett MD

  2. 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

  3. 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

  4. Growth Factors • Transforming Growth factor-beta(TGFB)-Largest group • Over 100 members • Anabolic effect on all components of Musculoskeletal tissue

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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 !!!!!!!!!!!!!!!

  10. 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

  11. 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

  12. 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

  13. 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

  14. Cartilage Systems-U.S. • Lavage and debridement • Chondroplasty • Microfracture • Oats • Polymer bone plugs • Osteochondral allografts • Cartilage cultures- Genzyme only • Cambridge Ma

  15. 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

  16. 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.

  17. 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.

  18. 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.

  19. 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!

  20. 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

  21. 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.

  22. 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.

  23. Stem Cell Exhaustion • Stem cells may be exhausted • Has been shown to happen in degenerative conditions, especially osteoarthritis.

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

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