Biomedical Engineering Reference
In-Depth Information
20.8 Nanotopography and Cellular Function
It.is.becoming.increasingly.clear.that.epigenetic.modulation.of.cellular.function.induced.
by.mechanical.and.topographical.cues.has.a.central.role.in.the.regulation.of.differential.
behavior,. a. property. that. can. be. exploited. in. the. fabrication. of. implantable. materials. to.
direct.cellular.differentiation.and.enhance.construct.biocompatibility..Cellular.mechano-
transduction.relies.on.the.ability.of.proteins.of.the.focal.adhesion.to.change.chemical.activ-
ity.state.when.physically.distorted,.converting.mechanical.energy.into.biochemical.energy.
by. modulating. the. kinetics. of. protein-protein. or. protein-ligand. interactions. within. the.
cell..However,.little.is.known.on.the.effects.of.topographical.modiication.on.cellular.func-
tion.or.the.role.of.nanoscale.features.on.integrin-mediated.activation.of.adhesion.proteins.
and.downstream.signaling.pathways.(Mack.et.al..2004)..The.ability.of.proteins.to.exist.in.
both.the.activated.and.quiescent.state.and.to.shuttle.between.the.cytoplasmic.and.nuclear.
compartments.is.a.key.tenet.of.mechanically.mediated.intracellular.signaling.and.the.cen-
tral.mechanism.behind.mechanically.altered.gene.expression.(Pavalko.et.al..2003).
The.exact.mechanisms.involved.in.integrin.clustering.and.focal.adhesion.formation.are.
still. being. investigated;. however,. recent. studies. indicate. that. the. focal. adhesion. protein.
talin.makes.a.determining.contribution.to.adhesion.disruption.through.nanotopographi-
cal. features.. Although. the. structure. of. talin. and. its. precise. interactions. at. a. focal. adhe-
sion.plaque.are.still.unknown,.it.is.accepted.that.this.protein.provides.a.link.between.the.
transmembrane. integrin. heterodimer. and. the. contractile. apparatus. of. the. cell,. and. it. is.
the.conformation.and.number.of.integrin-binding.domains.of.this.molecule.that.dictate.
the.critical.spacing.of.bound.integrins.required.for.focal.adhesion.activation..Another.pro-
posal.is.based.on.integrin.clustering.and.the.forces.needed.for.protein.reinforcement..It.
seems.likely.that.focal.adhesion.growth.is.a.function.of.intracellular.force—a.parameter.
governed.by.initial.integrin.clustering..Integrin.clustering.in.cells.cultured.on.disruptive.
nanofeatures.can.only.occur.at.the.interfeature.areas,.effectively.limiting.the.cluster.sizes.
and.the.early.forces.that.may.be.generated,.essentially.perturbing.focal.adhesion.forma-
tion.and.downstream.signaling.mechanisms.
The. integrin-dependent. signaling. pathways. are. mediated. by. non-receptor. tyrosine.
kinases.(Schaller.et.al..1992),.most.notably.focal.adhesion.kinase.(FAK),.which.is.consti-
tutively.associated.with.the.β-integrin.subunit..FAK.localizes.at.focal.adhesions.or.early.
focal. complexes. and. can. inluence. cellular. transcriptional. events. through. adhesion-
dependent. phosphorylation.of. downstream.signaling. molecules,. thus. controlling. essen-
tial.cellular.processes.such.as.growth,.survival,.migration,.and.differentiation.(Frisch.et.al..
1996;.Kurenova.et.al..2004;.Saleem.et.al..2009)..Extensive.evidence.has.shown.that.FAK.is.
activated.in.response.to.both.ECM.and.soluble.signaling.factors,.suggesting.that.the.FAK.
family.may.be.at.the.crossroads.of.multiple.signaling.pathways.that.affect.cell.and.devel-
opment.processes..Integrins.are.also.important.signal.transduction.molecules.in.their.own.
right,.activating.multiple.signaling.cascades.including.Ras.and.p38.mitogen-activated.pro-
tein.kinase,.calcium.channels,.and.other.mechanosensor.molecules.(Hynes.2002).
The.extracellular.signal-regulated.kinases.(ERK).1.and.2.(Jaiswal.et.al..2000;.Klees.et.al..
2005).are.members.of.the.mitogen-activated.protein.kinase.pathways.and.are.activated.in.
adherent.cells.by.FAK.to.act.as.mediators.of.both.cellular.differentiation.(Ge.et.al..2007).
and. survival. (Saleem. et. al.. 2009).. Studies. with. MSC. populations. and. primary. human.
osteoblasts. indicate. that. FAK-mediated. ERK1/ERK2. signaling. is. an. important. modula-
tor.of.osteospeciic.and.adipospeciic.differentiation.(Salasznyk.et.al..2007),.implying.that.
topographical.modiication.of.an.orthopedic.construct.may.be.a.viable.strategy.to.regulate.
