Tissue Eng Lecture_102413

Methods agent based model rules govern the behavior of

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Unformatted text preview: Effect of pore size on vascularization 58 Effect of pore size on vascularization 59 Effect of pore size on vascularization 60 Model predictions vs. experimental results 61 Summary • Computational model of vascularization in polymer scaffolds • The model predicts the effect of pore size on vessel growth • • Model predictions match in vivo experimental data • The model can be applied to examine strategies to accelerate vascularization Illustrates clinical barrier of vascularizing engineered constructs 62 Case study: VEGF pathway in tumor angiogenesis 63 VEGF family: target for cancer therapy Vascular Endothelial Growth Factor (VEGF) • • • • • • • Potent regulator of angiogenesis Acts in response to many stimuli, including hypoxia Stimulates cell proliferation, migration, and survival Targeted in cancer therapies • drawing by Florence Wu VEGF family: target for cancer therapy adapted from Kut et al., Br J Cancer, 2007 65 VEGF family: prime for systems biology modeling VEGF-B167 VEGF-B186 VEGF-B PlGF1 PlGF PlGF2 VEGF-A>121 PlGF2 VEGF-B186 VEGF-A121 VEGF-A145 VEGF-A165 VEGF-A189 VEGF-A VEGF-A209 VEGF-A165 VEGF-A145 VEGF-B167 VEGF-A165 VEGF-C VEGF-B186 VEGF-C VEGF-D PlGF2 PlGF2 GAG s1 11 22 33 N N 1 2 Neuropilins VEGF receptors Objective: to develop a molecular-detailed computational model of VEGF and predict the effect of therapeutics that target the VEGF pathway Methods: Multi-scale whole-body compartment model TUMOR Tumor Cells Interstitial space Abluminal endothelium Permeability BLOOD Luminal endothelium Plasma Clearance Luminal endothelium NORMAL Abluminal endothelium Stefanini et al., 2008; Stefanini et al., 2010; Finley et al., 2011 Lymph flow Interstitial space Muscle Fibers 67 Methods: VEGF-VEGFR molecular interactions 121 121 121 121 121 121 121 165 + + + + + + + + + + N 11 121 11 N 11 11 11 N N N 11 N 11 11 121 121 121 + + N + N N 11 165 165 165 165 + + + N + 22 121 22 165 165 22 N 165 + + N N 22 165 + 22 165 22 N + + 11 + + 11 N N 11 11 11 N + N N 22 165 11 N 165 11 121 121 α-2-macroglobulin 11 121 165 165 + N 165 + 165 + A 121 A 165 + 11 + GAG 165 165 + N N 11 A 165 A Model predicts the concentrations of all molecular species in each compartment 11 Methods: Model equations and numerical methods System is described by 154 ordinary differential equations d [V165 ]N N = qV 165 − koN ,V 165,MEBM [V165 ]N [ M EBM ]N + koNf ,V 165,MEBM [V165 M EBM ]N n f dt − koN ,V 165,MPBM [V165 ]N [ M PBM ]N + koNf ,V 165,MPBM [V165 M PBM ]N n f − koN ,V 165,MECM [V165 ]N [ M ECM ]N + koNf ,V 165,MECM [V165 M ECM ]N n f −k [V165 ]N [ R1 ]N + k N on ,V 165, R1 N off ,V 165 R1 [V165 R1 ]N − koN ,V 165,R 2 [V165 ]N [ R2 ]N + koNf ,V 165 R 2 [V165 R2 ]N n f − koN ,V 165,N 1[V165 ]N [ N1 ]N + koNf ,V 164 N 1[V165 N1 ]N n f my − koN ,,V 1o5,N 1[V165 ]N [ N1 ]N ,myo + koNf,my1o65 N 1[V165 N1 ]N ,myo n6 f ,V − koN ,V 165, A [V165 ]N [ A]N + koNf ,V 165 A [V165 A]N n f ⎛ k L + k S NB ⎞ [V ] U BN S 165 N −⎜ + k pV NB B [V165 ]B − kdeg [V165 ]N ⎟ UN UN UP ⎝ ⎠ K AV ,N NB pV Secretion Binding Lymphatics Permeability Degradation Clearance Insertion Internalization 69 Methods: Model parameters • Parameters governing molecular interactions based on experimental data • Receptor density is based on in vitro and in vivo data • Secretion ratio of VEGF165:VEGF121 is from published literature • 92:8 for muscle fibers • 90:10 for endothelial cells • 50:50 for tumor cells • VEGF-neutralizing agents are: • Bevacizumab (Avastin, Genentech) • Aflibercept (VEGF Trap, Regeneron) 121 + 165 + A A 121 165 A A Block Formation of VEGF/VEGFR Complexes 70 Model...
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This note was uploaded on 01/20/2014 for the course BME 410 taught by Professor Han during the Spring '08 term at USC.

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