Bleed First Harvest Later
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Arjan van den HilEuropean Sales ManagerLeipzig, Dezember 18, 2006
Blut ist ein ganz besonderer Saft!"
Mephisto in Faust Goethe 1808
Frher wurde das Blut als Sitz der Seele und des Lebens angesehen.
Human blood consists of 22% solids and 78% water. Its different components are plasma (with all the different blood cells), fat globules, chemical substances (proteins, carbohydrates, hormones, etc.) and gases (oxygen, nitrogen, carbondioxide, etc.)
circulationspleenDestruction/removal(spleen, liver)Production(bone marrow)platelet countthrombopoietin70%30% Platelets
Wound Healing & Bone RegenerationWhen an injury occurs, platelets attach to the connecting tissue.
The platelets form a loose plug and are activated by thrombin.
Thrombin converts fibrinogen into fibrin. The Healing Process: The Role of Platelets
6A fibrin matrix is formed, which finally results in a blood clot.
Platelets are releasing growth factors and cytokines
The Healing Process: The Role of Platelets
7HaemostasisPrimary haemostasisSecundary haemostasis (coagulation)InflammationAntimicrobial host defenceWound and/or bone healing, through the release of growth factors and other mediators
+ Thrombin activationPlatelets in restPlatelets activated Activation of Platelets: Release of Growth Factors and Cytokines
Activation of Platelets: Release of Growth Factors and Cytokines
PDGF-AA,BB, ABTGF-1, 2VEGFEGFbFGFIGF-IPD-ECGFHGFOsteocalcinFibronectinFibrinogenPlatelet Factor 4P-SelectinCa2+Connective-tissue activating peptide IIILipoxygenasesAntiplasminHistamineEPEALMW-EMAHMA-EMA12-HETE, 15-HETEPGE1, PGE2, PGA2, PGJ2, PGF1a, PGF2aSerotoninADP Growth Factors and Cytokines in Platelets and White Blood Cells
VEGFPDGFFGF Growth Factor Effects: Angiogenesis12Attach a polyethylene plate and cerclage wires to the rat femur, remove a defect about an inch long which will not heal by itself, implant a hollow ceramic cylinder loaded with MSCs into the defect site, and test by biomechanics and histology after 4 and 8 weeks for new bone formationPDGFTGF-IGF Growth Factor Effects: Chemotaxis13TGF-bPDGFEGF Growth Factor Effects: Mitogenesis14Primary Source: Platelets30 kDa dimer (AA, BB, AB), BB isoform most activePotent mitogen for MSCs and osteoblastsActs chemotactically on MSCs and osteoblastsMay stimulate expression of TGF-bRole in the initiation of fracture healingMax. stimulation of DNA synthesis --> mitogenicity of any GFLittle ALP production --> does not act as a differentiationg GFStimulates intramembranous bone formationTGF- Growth Factor Effects: Differentiation15This is the clssic osteoinduction youre familiar with in orthopaedics, and the method of operation of the bone morphogenetic proteins, which Ill cover in more detail later. The concept is that you start with one cell type, and you transform it into another type which is specific for some desired activity. Role of Growth Factors
PDGFStimulates cell replicationPromotes angiogenesisPromotes epithelialisationPromotes granulation tissue formationTGFPromotes formation of extracellulair matrixRegulates bone cell metabolismVEGFPromotes angiogenesisEGFPromotes cell differentiationStimulates re-epithelialisation, angiogenesis and collagenase activityFGFStimulation of angiogenesisPromotes proliferation of endothelial cells and fibroblasts16SerotoninVasoconstriction, increased capillary permeabilityPDGFChemotaxis, vasoconstriction, SMC proliferion, activation of monocytes and neutrophils-TGNeurophil recruitmentTGF-Chemotaxis, inhibits neutrophil apoptosis, fibroblast proliferation
Role of Inflammatory mediators
Toxic O2 metabolites (e.g. O2-, H2O2, OH-)All are potent antimicrobial activity
Antimicrobial peptides (e.g. PF4, PBP, CTAP-3, NAP-2, RANTES, TB-4, FPA, FPB)
Chemotactic receptors (e.g. C3a, CCR, C5a, thrombocidins)Involved in guiding platelets towards sites of microbial infection
Platelets are the first cells to arrive at a site of infection!
Role of Antimicrobial Proteins in Host Defence
Role of Growth Factors in Fracture Healing
19Haemostasis1 dCoagulation CascadeFibrin Matrix Formation
PDGFFGFTGFInflammation1- 4 dLeucos macrophage infiltrationIncreased vasodilatation & permeabilityTGF FGFPDGF IL-1EGF TxA2Proliferation4 d 3 wkMatrix productionNeovascularizationEpithelializationFGF TGFPDGF EGF PDAFRemodelling3 wk 2yrCollagen deposition degradationStable scar formationTGF PDGFFGF TIMP
Role of Growth Factors in Wound Healing
20Vascularisation: VEGF and bFGFAsahara et al. Circulation. 92:365. 1995.
Migration: PDGF and TGF- Lind M. Acta Orthop. Scand. Supp. 283:2. 1998.
Proliferation: PDGF, TGF-, and EGFSlater et al. J. Orthop. Res. 13(5):655. 1995.
Differentiation: FGF, TGF-, and IGF Kasperk et al. Growth Factors. 3:147. 1990. Synergistic Action of Growth Factors
21There has been a great deal of hype about recombinant bone morphogenetic proteins. As the preclinical and clinical trials have stretched over the years, issues such as the optimal carrier, optimal dose, patient to patient variability, and systemic effects have been raised. In addition, Dr. Tom Einhorn raised some valid points in a recent article, saying, You kind of wonder why weve been hearing names like bone morphogenetic protein and others for the last two or three decades and yet we are still talking about them in rats, rabbits, dogs, sheep, and in vitro systems. Everyones trying to artificially mimic a process thats not completely understood. However, if we closely examine the bodys initial activities in bone healing, we see that there is a possible way to get the growth factors necessary to start the healing process to the trauma site. The optimal concentrations of growth factors needed has already been defined by the body, and theyre contained in the optimal delivery vehicle- platelets.
Wound Healing & Bone Regeneration: Role of PlateletsPlatelet Degranulation22