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Orthobiologics: Growth factor
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Platelet Rich Plasma (PRP):

 

The working definition of platelet rich plasma (PRP) refers to a 5 ml volume of plasma that contains a concentration of 1,000,000-platelets/micro liter 1. This definition is based on the scientific proof of the concentration considered optimal for bone and soft tissue healing enhancement. PRP must be distinguished from platelet concentrate, which is a pure composition of platelets without any plasma, and thus doesn’t clot2, 3. The process of processing PRP from blood involves a double centrifugation technique: the hard spin and soft spin. The first spin also called as hard spin separates the red blood cells (RBC) from plasma, resulting in a platelet poor plasma (PPP) media containing the platelets, the white blood cells (WBC) and occasional RBCs. The second spin also known as the soft spin produces PRP from PPP by increasing the platelet concentration. This PRP is a combination of both a fresh clot and the supernatant. The PRP can be applied in various forms: as biologic membranes, mixed with the bone graft, sprayed on soft tissue or applied on the surface of the graft. The important precaution that should be taken with use of PRP is that clotting of PRP should be done only at the time of use as the clotting activates the platelets, which begin to secrete the growth factors almost immediately. As much as 70% of the stored growth factors are released in first 10 min and the rest almost completely in first hour.

 

 

PRP contains seven known growth factor: platelet derived growth factor aa (PDGF aa), PDGF bb, PDGF ab, Transforming growth factor (TGF) beta 1, TGF beta 2, vascular endothelial growth factor (VEGF), and epithelial growth factors. PRP contains these seven growth factor within a normal clot acting as carrier. The clot in turn is composed of fibrin, Fibronectin and vitronectin4, which help in cell migration, osseointegration and wound epithelialization. The growth factors present in PRP are proteins that serve as signaling molecules for target cells and orchestrate a large number of physiologic events including cell division, matrix synthesis and tissue differentiation. These agents have been also shown to be involved in the reparative process like the osteogenesis.5-7

 

PDGFs inhibit apoptosis and promote proliferation of cells in particular the capillary endothelium and arterial smooth muscles by activating the survival signal pathways 8 and is also chemo attractant to macrophages and fibroblasts9-11. It has been shown to act in syngerism with IGF I to promote mitogenesis of mesenchymal cells.12. Insulin like growth factors I and II stimulate cell differentiation13. Epidermal growth factors along with PDGF have shown to increase DNA synthesis and cell replication14. TGF Beta has shown to increase the cell differentiation15 and has a direct stimulatory effect on bone collagen synthesis, while the fibro blast growth factor serve to initiate neo angiogenesis16 which is essential for new bone formation.

 

 

The beneficial effect of PRP have been reported both in vitro as demonstrated by increased mitotic activity in osteoblasts like cells17 and in vivo in sinus surgies, alveolar ridge augmentation and periodontal surgeries18-20. Platelet derived growth factors were also reported to be secreted by platelets during the early phases of the fracture healing in mice and humans21, 22 . Marx et al in 1998 proposed that the local application of growth factors in form of platelet rich plasma (PRP) enhances the maturation of bone graft.1 Monoclonal antibody assessment of cancellous cellular bone marrow grafts have shown mesenchymal cells of the graft are responsive to the growth factors and addition of platelet rich plasma containing the growth factors increased the radiographic maturation rates 1.62 to 2.16 times that of graft alone in a series of maxillofacial reconstruction23 Pre clinical animal studies also showed them to be effective in healing the tibial osteotomy site in rabbits24.

 

 How ever similar results were not replicated in humans where platelet gel (AGF) alone or in combination with autologus bone graft failed to increase the fusion rates. In a retrospective study of 76 consecutive patients who underwent one to three level instrumented posterior lumbar fusions using autologus iliac crest bone graft mixed with AGF, the fusion rates were lower compared to the control group in which only autologus bone graft was used.25 Other series evaluating the effect of AGF in transforaminal interbody fusions also failed to demonstrate any clinical effect26, 27. Weiner and walker showed a detrimental effect of AGF on intertransverse arthrodesis when combined with autologus bone graft28. In maxillofacial surgery too, histo-morphometric analysis of the effect of PRP alone failed to demonstrate any positive effect of PRP on augmentation of bone formation on organic bovine bone or autologus bone graft in bone defects in maxillofacial region.29

 

 

 

References:

 

1.         Marx RCE, Eichstaed RM, Schimmele SR,Strauss JE, Georgeff KR. Platelet rich plasma : growth Factor enhancement for bone garfts. Oral surg oral med oral pathol oral radiol endod 851998.

2.         Salter M PJ, Kingham K, et al. Involvement of platelets in stimulating osteogenic activities. J Orthop Res 13:655-663, 1995.

3.            Hollinger J WM. The integerated process of hard tissue regeneration with special emphasis on fracture healing. Oral surg Oral Med Oral path Oral radiol Endodontics 82:594-606, 1996.

4.            Ksander GA SS, Ogawa Y, et al. The effect of platelet release on wound healing in animla models. J Am Acad Dermatol 22:781-791, 1990.

5.         Ross RREB-pD. The biology of platelet derived growth factor. Cell 461986.

6.         Pierce GF MT, Altrock BW, Deuel TF, Thomason A. role of Platelet derived growth factor in wound healing. J Cell Bio chem. 45:19-26, 1991.

7.         Noda MC. In vivo stimulation of bone formation by transforming growth factor -beta. Endocrinology. 1241989.

8.            Maehara K O-HK, Isobe KI:. Early growth responsive- 1- dependent manganese superoxide dismutase gene transcription mediated by platelet derived growth factor. FASEB J 15:2025-2026, 2001.

9.            Savikko J kE, von Willebrand E:. Early induction of plateletderived growth factors and ligands and receptors in acute renal allograft rejection. Transplantation 72:31-37, 2001.

10.       Lind M SB, Soballe K, et al:. Transforming growth factor beta enhances fracture healing in rabbit tibiae. Acta Orthop Scand 64:533-556, 1993.

11.            Ottaviani E FA, Kletsas D:. Platelet derived growth factor and transforming growth factor beta in invertebrate immune and neuroendocrine interactions: another sign of conservation in evolution. Comp Biochem C Toxicol Pharmacol 129:295-306, 2001.

12.       Stiles CD CG, Scher CD, Antoniades HN, Van Wyk JJ, Pledger WJ. Dual control of cell growth by somatomedins and platelet derived growth factor. Proc Natl Acad Sci USA 76:1279-1283, 1979.

13.       Gangji V RS, Gabbitas B, et al. Insulin like growth factor II promoter expression in cultured rodent osteoblasts and adult rat bone. Endocrinology 139:2287-2292, 1998.

14.       Kleuser B MS, Spiegel S,et al. Stimulation of nuclear sphingosine kinase activity by platelet derived growth factor. FEBS Lett. 503:85-90, 2001.

15.       Noda M CJ. In vivo stimulation of bone formation by transforming growth factor beta. Endocrinology 124:2991-2994, 1989.

16.       Plandit AS FD, Caulfield J, et al. Stimulation of angiogenesis by FGF-1 delivered through a modified fibrin scaffold. Growth Factors 15:113-123, 1998.

17.            Weibrich G GS, Otto M, Reichert TE, wagner W. Wachstumstimulation von humanen osteoblastnahnlichen zellen durch Thrombozytenkonzentrate in vitro. Mund keifer Gesichtshir. 6:168-174, 2002.

18.            Kassolis JD RP, Reynolds MA. Alveolar ridge and sinus augmentation utilising platelet rich plasma in combination with freeze dried bone allograft: Case series. J Periodontol 71:1654-1661., 2000.

19.       Anitua E. Platelet rich plasma in growth factors: preliminary results off use in the preperation of future sites for implants. Int J oral Maxillofac Implants 14:529-535, 2000.

20.            Vojislav l CP, Wein lander M, Vasilic N, Kenney EB. Comparison of platelet rich plasma, bovine porous bone mineral, and guided tissue regeneration versus platelet rich plasma and bovine porous bone mineral in the treatment of intrabony defects: a reentry study. J Periodontol 73:198-205, 2002.

21.            Andrew JG HJ, Freemont AJ, Marsh DR. Platelet derived growth factor expression in normally healing human fractures. Bone 16:455-460, 1995.

22.       Trippel SB. Growth factors as therapeutic agents. Instr Course Lect 46:473-476, 1997.

23.       Marx RE CE, Eichstaedt RM, Schimmele SR, Strauss JE, Georgeff KR. Platelet rich plasma: Growth factor enhancement for bone grafts. Oral surgery oral medicine oral pathology oral radiology and endodontics 85:638-646, 1998.

24.       Nash TJ HC, Martin C, Steele J, Jhonson KA, Hicklin DJ. Effect of platelet derived growth factor on tibial osteotomies in rabbit. Bone 5:203-208, 1994.

25.       Yoram Anekstein Sg, Ronaldo Puno, Leah Carreon. Platelet gel (AGF) fails to increase fusion rate. The spinal Journal 3s:89s, 2003.

26.       Castro FP. Role of activated growth factors in lumbar spinal fusions. J Spinal Disord Tech 17:380-384, 2003.

27.       Hee HT MM, Holt RT, Myers L:. Do autologus growth factors enhance transforaminal lumbar interbody fusion?. European spine Journal 12:400-407, 2003.

28.       Weiner BK, Walker M. Efficacy of autologous growth factors in lumbar intertransverse fusions.[see comment]. Spine 28:1968-1970, 2003.

29.            J.Camillo Roldan SJ, Joana Miller, sandra Freitag, David C. Rueger, Yahya Acil, Hendrix Terheyden. Bone Formation in the presence of platelet rich plasma vs. bone morphogenic protein -7. Bone 34:80-90., 2004.

 

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