Biomedical Engineering Reference
In-Depth Information
20.9 Conclusions and Perspectives
To.summarize,.nanostructures.have.been.shown.to.induce.signiicant.modulation.of.focal.
adhesion.formation,.cytoskeletal.development.and.cellular.spreading,.changes.that.are.sub-
sequently.transduced.to.signaling.pathways,.affecting.functional.differentiation.through.
integrin-speciic.signaling.pathways..It.seems.that.topographical.disruption.of.focal.adhe-
sion. formation. in. cellular. populations. is. mediated. directly. through. the. perturbation. of.
integrin.activation.and.clustering,.a.phenomenon.that.has.been.shown.experimentally.to.
be.dependent.on.nanotopographical.features.of.critical.dimensions.and.density.
Nanoscale.protrusions.disrupt.the.lateral.spacing.of.integrin.clustering.and.activation.
of.focal.adhesion.proteins.when.feature.dimensions.are.less.than.73.nm.and.feature.spac-
ing.is.>73.nm..Integrin.clustering.and.the.anisotropic.elongation. of.the.adhesion.plaque.
is.restored.as.substrate.features.approach.the.micron.scale..Conversely,.the.inverse.is.true.
on.nanoscale.pit.topographies;.here.a.pit.diameter.and.depth.<73.nm.facilitates.suficient.
integrin.clustering.for.focal.adhesion.reinforcement.
Grooved. substrates. can. be. seen. as. an. anisotropic. collection. of. alternating. nanopits.
(grooves).and.nanoprotrusions.(ridges).and,.as.such,.provide.alternating.planes.for.focal.
adhesion. formation.. Although. it. has. not. been. veriied. experimentally,. it. seems. sensible.
that.reduction.in.the.lateral.dimensions.of.the.ridge.structures.to.<73.nm.and.increase.in.
the.groove.widths.to.73-300.nm.will.bring.about.perturbation.of.integrin.clustering.and.
disruption.of.focal.adhesion.formation.
As.well.as.disrupting.focal.adhesion.formation,.nanofeatures.are.also.reported.to.increase.
focal.adhesion.formation.in.adherent.cells;.the.mechanisms.responsible.would.seem.to.be.
based.on.interplay.between.three.promoting.mechanisms..Firstly,.nanoscale.features.with.
subcritical.dimensions.provide.no.perturbation.to.focal.adhesion.formation,.yet.increase.
the.total.surface.area.over.which.an.adherent.cell.can.establish.cell-substratum.contacts,.
effectively. increasing. integrin-ligand. interactions.. Secondly,. nanoprotrusion. features.
with.edge-edge.spacing.or.vertical.dimensions.of.<73.nm.do.not.perturb.focal.adhesion.
formation.but.may.act.to.trap.proteins.of.the.ECM.that.provide.integrin-binding.motifs,.
again. increasing. the. interactions. between. transmembrane. integrins. and. substratum-
bound.proteins..Thirdly,.nanotopographical.features.may.initiate.cellular.spreading.and.
focal.adhesion.formation.through.an.upregulation.in.ilopodia.activity.
Interestingly,. it. is. known. that. directed. cellular. function. can. be. induced. by. nanoto-
pographical.modiication.in.the.absence.of.modiied.focal.adhesion.frequency,.and.that.
signaling.pathways.crucial.for.cellular.differentiation.can.be.initiated.by.a.diverse.range.
of.nanoscale.features..For.example,.it.has.previously.been.observed.that.the.formation.
of. elongated. rather. than. numerous. focal. adhesions,. a. process. that. relies. on. increased.
integrin. clustering,. is. important. in. osteospeciic. differentiation.. With. this. focal. adhe-
sion. reinforcement,. increased. FAK. is. recruited. and. subsequently. activated. to. initiate.
downstream.signaling.cascades..Conversely,.when.focal.adhesion.frequency.is.reduced.
to.that.of.sparse.focal.complexes,.such.mechanosensitive.signaling.events.are.reduced..
This.balance.between.mature.focal.adhesion.formation.and.related.cell.signaling.seems.
to.be.critical.in.MSC.differentiation.
With. a. growing. number. of. studies. indicating. that. topographical. modiication. of. the.
cell-substrate. interface. is. a. signiicant. regulator. of. cellular. adhesion. and. function,. we.
may.see.modiied.biomaterials.in.clinical.use.in.the.near.future..In.particular,.biodegrad-
able.devices.may.be.functionally.modiied.to.control.cellular.interactions,.with.an.aim.to.
enhance.tissue.regeneration..The.next.stage,.then,.in.the.evolution.of.biomaterial.design.
