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
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-Beta cont’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 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

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 Cartilage Healing 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 chondrocytes Stem 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 Types Myth 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 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.
Adult-
-rare, difficult to identify, unknown origin, partially understood function and life history
-defined by complex list of features.
-can not divide indefinitely.

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.