Biomedical Engineering Reference
In-Depth Information
modifying. cell. geometry,. nanotopography. affects. cell. proliferation. and. migration. in.
various. cell. types.. Nanoscale. features. slow. down. the. proliferation. rate,. but. increase.
migration.velocities.(Bettinger.et.al..2009b)..More.recent.work.showed.that.nanotopography.
also.enhances.cell.attachment.and.adhesion.(Mahdavi.et.al..2008).
22.3.2  Capillary Network generation and Hepatocyte Behavior
Major.efforts.in.tissue.engineering.have.focused.on.the.liver.(Kulig.and.Vacanti.2004).for.
several.decades..As.opposed.to.chronic.renal.diseases,.maintenance.therapies.for.the.liver.
have.not.been.established.for.long-term.use,.and.therapeutic.avenues.for.the.treatment.of.
liver.ibrosis.and.a.host.of.infectious.diseases.of.the.liver.are.not.yet.available..Therefore,.
the.development.of.tissue-engineered.livers.for.treatment.of.these.diseases.has.been.the.
subject.of.intense.efforts.for.many.years,.with.signiicant.focus.on.the.need.for.an.intrinsic.
microcirculation.and.for.replication.of.the.liver.microenvironment.to.sustain.liver-speciic.
functions.in.engineered.devices.
The.liver.comprises.complex.structures,.an.integrated.microvasculature,.and.performs.
many.critical.functions..It.is.the.largest.gland.of.the.body,.normally.weighing.about.1.5.kg.
in.adult..Primary.hepatocytes.constitute.60%-80%.of.the.liver.mass.and.play.many.impor-
tant.functions.in.our.body..The.intercellular.channels.between.adjacent.hepatocytes.form.
bile. canaliculi,. thin. tubes. that. collect. bile. secreted. by. hepatocytes.. The. bile. canaliculi.
merge.and.form.bile.ductules,.which.eventually.become.bile.ducts..In.between.each.row.
of.hepatocytes.are.small.cavities.called.sinusoids.comprising.a.fenestrated.monolayer.of.
liver.sinusoidal.endothelial.cells..Each.sinusoid.is.lined.with.Kupffer.cells,.macrophages.
that.remove.amino.acids,.nutrients,.sugar,.old.red.blood.cells,.bacteria,.and.debris.from.the.
blood.that.lows.through.the.sinusoids..The.main.functions.of.the.sinusoids.are.to.destroy.
old.or.defective.red.blood.cells,.to.remove.bacteria.and.foreign.particles.from.the.blood,.
and.to.detoxify.toxins.and.other.harmful.substances..ECM-producing.stellate.cells,.biliary.
epithelial. cells,. hepatocyte. precursor. cells,. and. ibroblasts. are. also. present. and. perform.
important. metabolic. functions.. The. main. functions. played. by. the. liver. include. (1). bile.
production.and.secretion;.(2).excretion.of.bilirubin,.cholesterol,.hormones,.and.drugs;.(3).
metabolism.of.fats,.proteins,.and.carbohydrates;.(4).enzyme.activation;.(5).storage.of.glyco-
gen,.vitamins,.and.minerals;.(6).macromolecules.and.protein.synthesis.(i.e.,.albumin.and.
bile.acids);.and.(7).detoxiication.(Kobori.et.al..2007,.Lal.et.al..2007)..Exogenous.and.endog-
enous.substances.are.detoxiied.in.the.liver,.and.hepatocyte-based.hepatotoxicity.testing.
is. useful. in. rapid. screening. of. chemicals. and. in. mechanistic. evaluation. of. toxicological.
phenomena.
Many.natural.and.synthetic.chemicals.are.hepatotoxins;.often.the.toxicity.is.caused.by.
metabolic.conversion.of.the.parent.compound.into.highly.reactive.metabolites..Hepatocytes.
are. usually. the. irst. cell. types. damaged. upon. hepatotoxic. insult. (DeLeve. 2007).. Loss. of.
liver. functions.such.as.detoxiication,.metabolism,. and.regulation. cause.life-threatening.
complications,.including.kidney.failure,.encephalopathy,.cerebral.edema,.severe.hypoten-
sion,.susceptibility.to.infections,.and.multiple.organ.failure..Therefore,.the.ability.to.regen-
erate.the.function.and.viability.of.hepatocytes.in.response.to.compounds.is.important.for.
drug.discovery.applications.as.well.as.trauma.recovery.
Signiicant. efforts. have. been. made. to. generate. and. maintain. hepatic. tissues. in. vitro.
(Buckpitt.and.Warren.1983,.Rouleau.et.al..1986,.de.Boer-van.den.Berg.et.al..1988,.Rudling.
et.al..1990,.Liu.and.Wells.1995,.Bossard.et.al..1997,.Finch.et.al..2001,.Yokoyama.et.al..2006)..
Hepatocytes. in. vivo. directly. interact. with. ECM. and. each. other. by. aligning. in. highly.
aligned.cell.sheets..ECMs.provide.both.mechanical.support.and.physical.regulation.for.
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