Biomedical Engineering Reference
In-Depth Information
they.can.signiicantly.improve.the.MRI.resolution.in.cellular.imaging..Most.cells,.includ-
ing.stem.cells,.do.not.have.endogenous.magnetic.resonance.contrast,.and.for.visualizing,.
they.need.to.be.labeled.by.either.endogenous.or.exogenous.contrast.agents..In.the.external.
magnetic. ield,. contrast. agents. generate. an. induced. magnetic. ield,. which. perturbs. the.
magnetic. relaxation. processes. of. the. protons. of. the. hydrogen. nucleus. surrounding. the.
magnetic. contrast. agents.. In. fact,. using. the. contrast. agent. shortens. the. relaxation. time.
and.results.in.a.consequent.darkening.of.the.MR.images.(Figure 2.2)..Contrast.strength.is.
quantitatively.represented.as.the.relaxivity:.r1.for.the.longitudinal.rate.(1/T1).or.r2.for.the.
transverse.rate.(1/T2)..T1.agents.usually.have.r2/r1.ratios.of.1-2,.whereas.the.value.for.T2.
agents.is.as.high.as.10.or.more.
189
The.small.but.positive.magnetic.natures.of.paramagnetic.materials.make.them.ready.to.
change. their. alignment. in. the. external. magnetic. ield. to. act. as. atomic. magnetic. dipoles..
Their.interaction.with.water.protons.through.dipole-dipole.interaction.shortens.the.water.
MR. relaxation. times,. which. results. in. an. increase. of. relaxation. rates. (1/T1. and. 1/T2)..
Paramagnetic.materials.such.as.Mn
2+
.or.Gd
3+
.commonly.act.like.positive.(bright).contrast.
agents..They.reduce.both.T1.and.T2.times,.but.since.T1.is.usually.1-2.orders.of.magnitude.
greater. than. T2,. signal. increase. due. to. T1. shortening. is. more. signiicant. on. T1-weighted.
images.
Superparamagnetic.particles.as.negative.(dark).agents.are.a.different.class.of.MRI.contrast.
agents.that.are.extremely.strong.in.enhancing.proton.relaxation..Superparamagnetism.is.
primarily.associated.with.very.small.crystalline.iron.oxides.(1-14.nm).
190
.The.single-crystal.
nature. of. superparamagnetic. iron. oxides. (SPIOs). leads. them. to. form. a. single. magnetic.
domain.after.applying.the.external.magnetic.ield..They.shorten.T2.and.T2*.times.more.
than.T1.and.generate.a.negative.(dark).effect.on.MRI.
191,192
Gd.chelates.(Gd-DTPA,.Gd-DOTA,.and.Gd-DO3A).and.Mn.chloride.are.paramagnetic.
contrast.agents.used.in.experimental.and.clinical.studies..Gadopentate.dimeglumine.was.
the. irst. safe. MRI. contrast. agent. approved. by. the. U.S.. Food. and. Drug. Administration,.
and.is.widely.used.to.enhance.pathology.in.the.brain,.heart,.liver,.tumors,.and.other.tis-
sues. imaged. on. MRI.. Intravenous. administration. of. Gd-DTPA,. Gd-DOTA,. or. Gd-DO3A.
has.relatively.minimal.side.effects,.and.more.than.99%.of.the.dose.is.rapidly.cleared.and.
excreted.along.the.renal.pathway.
193
.Crich.and.colleagues.used.Gd-HPDO3A.for.tracking.
endothelial.progenitor.cells.(EPCs)..They.injected.10
6
.labeled.cells.under.the.mouse.kid-
ney.capsule.and.studied.the.cell.locations.on.T1-weighted.MRI.
194
.They.estimated.that.the.
number. of. Gd. chelates. needed. to. visualize. cells. is. approximately. 10. to. 100. µM. per. cell,.
which.could.have.quite.a.toxic.effect..However,.it.seems.that.Gd.chelates.are.not.safe.for.
cell. labeling,. because. of. the. unknown. clearance. mechanism,. long-term. retention. of. GD.
chelates.inside.the.cell,.and.production.of.Gd
3+
.ions.through.rapid.dechelation.due.to.low.
pH.in.the.lysosomes.and.endosomes.of.cells.
195
.Recently,.Gd.fullerenol.has.been.used.for.
tracking.mesenchymal.stem.cells.at.7T.MRI.following.direct.injection.of.10
6
.cells.into.the.
rat.thigh.
196
.Anderson.et.al..showed.that.Gd.fullerenol.initially.decreased.the.mesenchy-
mal.stem.cell's.ability.to.proliferate.by.altering.the.mitochondrial.function.
Mn.chloride.is.another.paramagnetic.contrast.agent.that.is.employed.for.in.vivo.imaging..
It.is.taken.up.by.cells.through.calcium.channels.in.the.cell.membrane.
197,198
.Lymphocytes.
can. be. successfully. labeled. with. Mn. chloride. and. have. been. studied. on. T1-weighted.
MRI.. However,. they. lack. suficient. contrast. enhancement. to. be. detected. as. labeled. cells.
in. vivo.
199
. The. major. limitation. of. using. Mn. as. an. MRI. contrast. agent. is. its. signiicant.
cardiotoxicity.
191
Uniform.and.high.magnetic.moment,.high.stability.under.physiological.conditions.(e.g.,.
high. salt. concentration. and. pH. changes),. ability. to. escape. from. the. reticuloendothelial.
