Biomedical Engineering Reference
In-Depth Information
both. cellular. adhesion. and. subsequent. osteospeciic. differentiation.. Indeed,. nanotopo-
graphical. modiication. that. induces. an. increase. in. integrin-substratum. interaction. and.
cellular.spreading.has.been.shown.to.upregulate.the.expression.of.FAK.and.ERK1/ERK2.
in.osteoprogenitor.cells.(Biggs.et.al..2008;.Sjostrom.et.al..2009)..Furthermore,.both.ERK1/
ERK2.signaling.and.focal.adhesion.formation.are.decreased.in.MSC.populations.cultured.
on.topographical.features.that.approach.100.nm.in.height.(Park.et.al..2007)..One.obvious.
advantage.of.this.osteodifferential.response.in.progenitor.populations.is.that.of.increased.
implant.stability.and.a.reduction.in.repeat.surgery.
As.well.as.acting.to.promote.differential.function.in.adherent.cells,.it.seems.that.surface.
features. also. induce. a. signiicant. response. in. non-adherent. cell. types.. Although. several.
studies.have.reported.on.the.effects.of.nanotopographical.structures.on.immune.cell.activa-
tion.(Wojciak-Stothard.et.al..1996;.Jakobsen.et.al..2009;.Kim.et.al..2009),.the.mode.of.signal.
transduction.remains.unclear..Emerging.data.suggest.that.the.proteins.involved.in.adhesive.
processes.in.cells.of.the.immune.system.are.analogous.to.those.found.in.focal.adhesions.in.
adherent.cells.(Whitney.et.al..1993;.Torres.et.al..2008;.Hocde.et.al..2009).and.that.leukocyte.
binding.to.ECM.components.and.adsorbed.complement.proteins.can.induce.FAK-mediated.
immune. cell. activation. (Bhattacharyya. et. al.. 1999),. phagocytosis. (Kasorn. et. al.. 2009),. and.
chemokine-mediated.migration.(Cohen-Hillel.et.al..2009)..Although.the.immune.response.
is.tightly.regulated.by.the.complex.interplay.of.events.and.interactions.between.its.constitu-
ent. cells,. preliminary. studies. suggest. that. implantable. materials. could. be. fabricated. with.
nanoscale. structures. to. modulate. the. immune. response. (Hulander. et. al.. 2011),. and. as. in.
adherent.cell.types,.this.may.be.through.FAK-mediated.activation.of.critical.signaling.path-
ways..Interestingly,.a.recent.in.vivo.study.showed.that.an.aluminum.substrate.with.200.nm.
diameter.pits.induced.a.stronger.inlammatory.response.following.implantation.into.a.mouse.
model.than.an.aluminum.substrate.with.20.nm.diameter.pits.(Ferraz.et.al..2011)..Again,.this.
study.provides.further.evidence.to.the.critical.pit.dimensions.discussed.in.Section.20.6.
Recent.work.from.several.laboratories.also.points.to.the.importance.of.FAK.in.inluenc-
ing. the. angiogenic. response. by. mediating. the. synthesis. of. vascular. endothelial. growth.
factor.(Sheta.et.al..2000;.Zhu.et.al..2009).and.modulating.the.activity.of.FAK.(Pezzatini.et.al..
2007)..In.particular,.the.integrins.αvβ3.and.αvβ5.have.been.reported.to.speciically.regu-
late.the.Ras-ERK.pathway.in.endothelial.cells,.(Hood.et.al..2003).and.downstream.ERK.1/2.
phosphorylation.is.important.for.the.enhanced.chemotactic.response.of.vascular.smooth.
muscle. cells. to. ibroblast. growth. factor. (FGF). (Tanaka. et. al.. 1999;. Blaschke. et. al.. 2002)..
Importantly,.FGF.synthesis.and.angiogenesis.have.also.been.shown.to.be.upregulated.on.
nanophase.materials.(Pezzatini.et.al..2007).
Because. a. diverse. variety. of. signals. affect. cellular. differentiation,. it. seems. very. likely.
that.no.single.signaling.pathway.is.responsible.for.regulating.adhesion-mediated.cell.func-
tion..Rather,.a.network.of.signaling.pathways.is.probably.at.work,.and.FAK.is.at.the.helm.
of.integrating.these.signaling.activities..As.well.as.differentiation.through.ERK.signaling,.
autophosphorylation.of.FAK.initiates.the.formation.of.dynamic.molecular.complexes.that.
contain.numerous.signaling.proteins.(e.g.,.Src,.p85.regulatory.subunit.of.phosphatidylino-
sitol-3-kinase,.phospholipase.Cγ,.Grb-7,.and.Shc)..These.pathways.may.be.activated.to.dif-
fering.degrees.by.different.integrin-ECM.interactions,.inluencing.cellular.function.
Thus,. nanotopography. can. be. considered. an. important. mediator. of. both. cellular.
adhesion. as. well. as. differential. function,. acting. to. impart. changes. in. cellular. behavior.
through.the.modulation.of.focal.adhesion.reinforcement.and.protein.interaction.kinetics..
Furthermore,.it.may.be.feasible.to.enhance.the.in.vivo.response.to.a.biomaterial.construct.by.
implementing.nanoscale.modiication.to.regulate.cellular.differentiation,.immunological.
response,.and.angiogenesis.(Table.20.4).
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