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Update on Biologics in Orthopedic Sportsmedicine Cells and Growth Factors William F Bennett MD.

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Presentation on theme: "Update on Biologics in Orthopedic Sportsmedicine Cells and Growth Factors William F Bennett MD."— Presentation transcript:

1 Update on Biologics in Orthopedic Sportsmedicine Cells and Growth Factors William F Bennett MD

2 Injured Tissue-The Basics of Healing Requires Cells and Growth Factors Tissue repair relies on vascularity and cellular migration Tissue repair relies on vascularity and cellular migration Blood escapes, hematoma Blood escapes, hematoma Platelets, pluripotential stem cells form scaffold for neocellular proliferation Platelets, pluripotential stem cells form scaffold for neocellular proliferation Cells respond to Growth Factors(Bioactive agents) Cells respond to Growth Factors(Bioactive agents) Some cells respond different to growth factors based upon tissue 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. At the time of injury released, Gfs bind to receptors and effect cellular function. Part of inflammatory response. Part of inflammatory response. Proteins Proteins Anabolic/catabolic Anabolic/catabolic Cytokines-extracellular proteins Cytokines-extracellular proteins Effect cell to cell mediationEffect cell to cell mediation Examples- Interferon/interleukin/tumor necrosis factor Examples- Interferon/interleukin/tumor necrosis factor

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

5 Common Types of TGF-Beta Bone Morphogenic proteins-BMP s Bone Morphogenic proteins-BMP s Osteoprogenitor derived cells-promote bone growthOsteoprogenitor derived cells-promote bone growth Platelet Derived Growth Factor-PDGF Platelet Derived Growth Factor-PDGF From platelets and stimulates angiogenesis, chemotactic influence and mitogenicFrom platelets and stimulates angiogenesis, chemotactic influence and mitogenic Insulinlike Growth Factor-IGF-1 Insulinlike Growth Factor-IGF-1 From variable cells, broad anabolic effectFrom variable cells, broad anabolic effect Fibroblast Growth factor-bFGF Fibroblast Growth factor-bFGF Early differentiation of cells and tissue and in repair processEarly differentiation of cells and tissue and in repair process

6 Common Types of TGF-Beta cont d Epidermal Derived Growth Factor- EGF Epidermal Derived Growth Factor- EGF Proliferates ectoderm and mesodermProliferates ectoderm and mesoderm Growth and differentiation Factor- GDF-5 Growth and differentiation Factor- GDF-5 Chondrocyte, fibroblast and mesenchymal cell expansionChondrocyte, fibroblast and mesenchymal cell expansion

7 Bone Healing Two clinically available BMP s-stimulates bone growth Two clinically available BMP s-stimulates bone growth rhBMP2-Recombinant BMP- (Infuse, Medtronic Sofamor Danek, Minneapolis, Mn.)rhBMP2-Recombinant BMP- (Infuse, Medtronic Sofamor Danek, Minneapolis, Mn.) BMP 7-(osteogenic protein-1- OP1)BMP 7-(osteogenic protein-1- OP1) Stryker, Biotech, Hopkinton, Ma, Stryker, Biotech, Hopkinton, Ma, LMP1-Lyophilized Mineral protein LMP1-Lyophilized Mineral protein Stimulates BMPStimulates BMP PDGF and Platelet Rich Plasma may interfere with bone healing 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 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 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 Although the exact mechanism for this repair process is not well known

9 Tendon To Tendon Mechanism not well defined Mechanism not well defined GDF5 may play a role GDF5 may play a role IGF1 and PDGF2 IGF1 and PDGF2 Increased collagen synthesisIncreased collagen synthesis These factors can be found in augmentation tissues like porcine submucosa, bovine, equine collagen and human allograft dermis 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 !!!!!!!!!!!!!!! Cascade- shows to repair tissue- platelet rich plasma !!!!!!!!!!!!!!!

10 Ligament Healing Cell Proliferation, Type 1 Collagen Cell Proliferation, Type 1 Collagen and proteoglycan synthesis are stimulated by bFDF, PDGF and bTGFand 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 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. Meniscal tears heal better when ACL reconstruction is done at the same time. Suggests that something in the blood augments healing Suggests that something in the blood augments healing Arnozcky has shown a fibrin clot to help healing. Arnozcky has shown a fibrin clot to help healing. Platelet Rich Fibrin Matrix(PRFM) Platelet Rich Fibrin Matrix(PRFM) Cascade- ultracentrifuge of bloodCascade- ultracentrifuge of blood Platelt rich ultracentrifugate is further centrifuged down to a volume-stable suturable fibrin matrixPlatelt rich ultracentrifugate is further centrifuged down to a volume-stable suturable fibrin matrix

12 Articular Cartilage Healing is not regeneration Articular cartilage is Hyaline cartilage Articular cartilage is Hyaline cartilage Type 2 collagenType 2 collagen Heals to injury with fibrocartilage Heals to injury with fibrocartilage Type 1 collagenType 1 collagen No vascular supplyNo vascular supply No nervesNo nerves More of a scar tissue than normal tissueMore of a scar tissue than normal tissue

13 Articular Cartilage Repair Fissuring- chondroplasty, smooths edges only, no healing Fissuring- chondroplasty, smooths edges only, no healing Osteochondral defects- microfracture technique or marrow stimulation techniques-forms fibrocartilage Osteochondral defects- microfracture technique or marrow stimulation techniques-forms fibrocartilage Cartilage-growth factors Cartilage-growth factors Bmp2/1IGF/bTGFBmp2/1IGF/bTGF Add these to cell colonies, like genzyme cell cultures- get better hyaline cartilageAdd these to cell colonies, like genzyme cell cultures- get better hyaline cartilage

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

15 Cartilage Cultures Carticel- Genzyme-using chondrocytes, cartilage cells as opposed to stem cells. 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 2 nd generation……using presently.Bx, 4-6 weeks later can replant with cultured cells, use periosteal patch, open surgery, collagen membrane 2 nd generation……using presently. Next gen Carticel, MACI-matrix impregnated with cells, no periosteal patchNext gen Carticel, MACI-matrix impregnated with cells, no periosteal patch

16 Other source of Cells than chondrocytes Stem Cells Both an evolution and a revolution in modern biomedicine. 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 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. 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. Bone Marrow transplant- for radiation loss of blood cells and their progenitor lines. Stem cell skin grafts for burn victims. Stem cell skin grafts for burn victims. Corneal stem cell implants. Corneal stem cell implants. Pancreatic islet cell implantation. Pancreatic islet cell implantation.

18 Applications in genetically defective cell lines Genetically corrected stem cells used to treat; Genetically corrected stem cells used to treat; Muscular dystrophyMuscular dystrophy Other disease processesOther disease processes Future will be in musculoskeletal areas as well.Future will be in musculoskeletal areas as well.

19 Stem Cell Types Myth and Fact Adult stem cells identified from brain to muscle. Adult stem cells identified from brain to muscle. Fetal Stem cells- aborted fetuses or umbilical chord Fetal Stem cells- aborted fetuses or umbilical chord Embryonic stem cells- Embryonic stem cells- Discarded from in vitro fertilizationDiscarded from in vitro fertilization Somatic Nuclear Transfer- a nucleus from a normal body cell is placed into a fertilized egg with its nucleus removed.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. The fertilized egg has the effect of resetting the nucleus to a primordial state. No ethical considerations with fetuses here! No ethical considerations with fetuses here!

20 Embryonic- Embryonic- Ubiquitous component of the embryo.Ubiquitous component of the embryo. Defined by position in the embryoDefined by position in the embryo Divide in culture without changing charcteristics.Divide in culture without changing charcteristics. Single cell can give rise to a colony of cells.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. Maintain undifferentiated phenotype until exposed to appropriate signals. With signals can differentiate into specialized cells that have structure and function With signals can differentiate into specialized cells that have structure and function Mesenchymal Stem cells are of this type-MScs- bone marrow. Mesenchymal Stem cells are of this type-MScs- bone marrow. Mesenchymal is from a layer in the developing embryo. Mesenchymal is from a layer in the developing embryo.

22 What we know and do not know Know some signals Know some signals Don t know all intermediate steps Don t know all intermediate steps Don t know how exactly how one cell changes to another. Don t know how exactly how one cell changes to another. Don t understand the microenvironment completely. Don t understand the microenvironment completely. Adult and MSC have limited differentiation potential compared to embryonic stem cells and limited number of replication cycles. 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 Stem cells may be exhausted Has been shown to happen in degenerative conditions, especially osteoarthritis. 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. Over next 5-10 years there will be major commercial development in the area of stem cell enterprises.


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