![Figure 1. Main Steps in Measuring with a Mass Spectrometer ... · Figure 35. Tandem mass spectrum of the [M+2H]+2 ion m/z 955.03 in LC/ESI/MS analyses of tryptic peptides from a 70](https://static.fdocuments.in/doc/165x107/5ec3c9afdab3ba42a1499c9d/figure-1-main-steps-in-measuring-with-a-mass-spectrometer-figure-35-tandem.jpg)
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Lay
er A
: PD
MS
Mic
roflu
idic
s
Test
ing
and
Prot
ocol
Opt
imiz
atio
nTe
stin
g an
d Pr
otoc
ol O
ptim
izat
ion
Step
s To
war
ds M
ass
Prod
uctio
nSt
eps
Tow
ards
Mas
s Pr
oduc
tion
Seba
stia
n J.
Ost
erfe
ldSe
bast
ian
J. O
ster
feld
11 , , Sh
uSh
u --Je
n H
anJe
n H
an11 ,
Stef
ano
Car
amut
a, S
tefa
no C
aram
uta22
, , Lia
ngL
iang
Xu
Xu11
, , Hen
gH
eng
Yu
Yu22
, Jin
Xie
, Jin
Xie
33
Shou
heng
Shou
heng
Sun
Sun33
, , Nad
erN
ader
Pour
man
dPo
urm
and22
, Sha
n X
. Wan
g, S
han
X. W
ang11
1. S
tanf
ord
Uni
vers
ity1.
Sta
nfor
d U
nive
rsity
2. S
tanf
ord
Gen
ome
Tec
hnol
ogy
Cen
ter
2. S
tanf
ord
Gen
ome
Tec
hnol
ogy
Cen
ter
3. B
row
n U
nive
rsity
3. B
row
n U
nive
rsity
(Pro
ject
fund
ed b
y D
AR
PA
)(P
roje
ct fu
nded
by
DA
RP
A)
Tes
ting
and
Fabr
icat
ion
of th
e M
agA
rray
Tes
ting
and
Fabr
icat
ion
of th
e M
agA
rray
®®B
ioch
ipB
ioch
ip
Our
aim
is
to r
epea
tedl
y te
st p
roto
type
chi
ps w
ith a
var
iety
of
Our
aim
is
to r
epea
tedl
y te
st p
roto
type
chi
ps w
ith a
var
iety
of
nano
part
icle
sna
nopa
rtic
les ,
bio
logi
cal
mol
ecul
es,
and
vario
us
, bi
olog
ical
mol
ecul
es,
and
vario
us
expe
rimen
tal
prot
ocol
s, t
o de
term
ine
and
impr
ove
the
perf
orm
ance
expe
rimen
tal
prot
ocol
s, t
o de
term
ine
and
impr
ove
the
perf
orm
ance
char
acte
ristic
s of
the
Mag
Arr
ay.
For
max
imum
ch
arac
teris
tics
of t
he M
agA
rray
. Fo
r m
axim
um
flexi
bilit
y, e
ach
chip
nee
ds t
o be
ind
ivid
ually
fun
ctio
naliz
ed w
flexi
bilit
y, e
ach
chip
nee
ds t
o be
ind
ivid
ually
fun
ctio
naliz
ed w
ith
ith b
iom
olec
ules
biom
olec
ules
. A
s a
resu
lt, t
he p
roto
type
chi
ps e
mpl
oy
. A
s a
resu
lt, t
he p
roto
type
chi
ps e
mpl
oy
sens
ors
on a
fre
ely
acce
ssib
le s
urfa
ce,
and
mac
rosc
opic
flu
idic
sse
nsor
s on
a f
reel
y ac
cess
ible
sur
face
, an
d m
acro
scop
ic f
luid
ics
are
empl
oyed
ins
tead
of
are
empl
oyed
ins
tead
of
mic
roflu
idic
sm
icro
fluid
ics
to d
eliv
er t
he
to d
eliv
er t
he
reag
ents
dur
ing
the
mea
sure
men
t.re
agen
ts d
urin
g th
e m
easu
rem
ent.
Left:
A p
roto
type
Mag
Arr
ay4
chip
, mad
e Le
ft: A
pro
toty
pe M
agA
rray
4 ch
ip, m
ade
at S
tanf
ord.
Ins
ide
the
wel
l are
two
free
ly
at S
tanf
ord.
Ins
ide
the
wel
l are
two
free
ly
acce
ssib
le
arra
ys,
each
co
ntai
ning
16
ac
cess
ible
ar
rays
, ea
ch
cont
aini
ng
16
indi
vidu
ally
add
ress
able
sen
sors
. A
t th
e in
divi
dual
ly a
ddre
ssab
le s
enso
rs.
At
the
Stan
ford
Gen
ome
Tech
nolo
gy C
ente
r, th
e St
anfo
rd G
enom
e Te
chno
logy
Cen
ter,
the
16
sens
ors
on
the
left
are
man
ually
16
se
nsor
s on
th
e le
ft ar
e m
anua
lly
func
tiona
lized
w
ith
a di
ffer
ent
func
tiona
lized
w
ith
a di
ffer
ent
bioc
hem
istry
tha
n th
e 16
sen
sors
on
the
bioc
hem
istry
tha
n th
e 16
sen
sors
on
the
right
. Add
ition
al s
enso
rs, i
n th
is c
ase
32,
right
. Add
ition
al s
enso
rs, i
n th
is c
ase
32,
are
cove
red
with
epo
xy a
nd s
erve
as
an
are
cove
red
with
epo
xy a
nd s
erve
as
an
abso
lute
con
trol.
abso
lute
con
trol.
25m
m
Rig
ht:
Afte
r fu
nctio
naliz
atio
n,
the
Rig
ht:
Afte
r fu
nctio
naliz
atio
n,
the
chip
is
re
turn
ed
to
Stan
ford
ch
ip
is
retu
rned
to
St
anfo
rd
Uni
vers
ity fo
r mea
sure
men
ts. D
urin
g U
nive
rsity
for m
easu
rem
ents
. Dur
ing
the
prot
otyp
e ex
perim
ents
, th
e pr
otot
ype
expe
rimen
ts,
mac
roflu
idic
sm
acro
fluid
ics
are
empl
oyed
to
ar
e em
ploy
ed
to
repe
ated
ly t
rans
port
the
reag
ents
to
repe
ated
ly t
rans
port
the
reag
ents
to
and
from
the
chip
. Not
sho
wn
are
the
and
from
the
chip
. Not
sho
wn
are
the
read
out
elec
troni
cs
and
mag
netic
re
adou
t el
ectro
nics
an
d m
agne
tic
field
gen
erat
ors f
or th
e ch
ip.
field
gen
erat
ors f
or th
e ch
ip.
Whi
le t
he p
roto
type
chi
ps r
each
mat
urity
, we
also
wor
k to
W
hile
the
pro
toty
pe c
hips
rea
ch m
atur
ity, w
e al
so w
ork
to t
otoen
sure
tha
t th
e fu
nctio
naliz
atio
n pr
otoc
ol a
nd e
xper
imen
tal
ensu
re t
hat
the
func
tiona
lizat
ion
prot
ocol
and
exp
erim
enta
l pr
oced
ure
can
be q
uick
ly m
igra
ted
to a
mas
spr
oced
ure
can
be q
uick
ly m
igra
ted
to a
mas
s --pr
oduc
ed v
ersi
on o
f th
e M
agA
rray
. Thi
s ef
fort
enc
ompa
sses
thr
ee
prod
uced
ver
sion
of
the
Mag
Arr
ay. T
his
effo
rt e
ncom
pass
es t
hree
crit
ical
cr
itica
l ar
eas:
Who
lear
eas:
Who
le-- w
afer
rob
otic
bio
func
tiona
lizat
ion,
alig
nmen
tw
afer
rob
otic
bio
func
tiona
lizat
ion,
alig
nmen
t --an
d to
pogr
aphy
tol
eran
t an
d to
pogr
aphy
tol
eran
t m
icro
fluid
ics
mic
roflu
idic
sfo
r re
agen
t tr
ansp
ort,
for
reag
ent
tran
spor
t, an
d m
ass
and
mas
s --pr
oduc
ible
pr
oduc
ible
mic
roflu
idic
mic
roflu
idic
inte
rcon
nect
s th
at d
o no
t req
uire
the
drill
ing
of h
oles
. All
thin
terc
onne
cts
that
do
not r
equi
re th
e dr
illin
g of
hol
es. A
ll th
ese
thre
e ar
eas
are
desi
gned
es
e th
ree
area
s ar
e de
sign
ed
to b
ecom
e in
tegr
al p
arts
of t
he m
anuf
actu
ring
proc
ess.
to b
ecom
e in
tegr
al p
arts
of t
he m
anuf
actu
ring
proc
ess.
Who
leW
hole
-- Waf
er R
obot
ic B
iofu
nctio
naliz
atio
nW
afer
Rob
otic
Bio
func
tiona
lizat
ion
Mas
sM
ass --
Prod
ucib
le
Prod
ucib
le M
icro
fluid
icM
icro
fluid
icIn
terc
onne
cts
Inte
rcon
nect
s
Sens
ors 1
-16:
D
NA
or A
ntig
en1
Sens
ors 4
9-64
:B
are
or A
ntig
en2
The
Prot
otyp
e M
agA
rray
4 C
hip
The
Prot
otyp
e M
agA
rray
4 C
hip
Rep
rese
ntat
ive
Func
tiona
lizat
ion
and
Rep
rese
ntat
ive
Func
tiona
lizat
ion
and
Expe
rimen
tal P
roto
col
Expe
rimen
tal P
roto
col
Mag
netic
nan
opar
ticle
w/ S
trept
avid
inA
ntig
en 1
: Fer
ritin
Bio
tinA
ntib
ody
(Ant
i-Fer
ritin
)A
ntig
en 2
: BSA
Nan
opar
ticle
Solu
tion
Sens
ors 1
7-48
Sens
ors 4
9-64
Sens
ors 1
-16
Epox
y
Ant
ibod
y So
lutio
n
Sens
ors 1
7-48
Sens
ors 4
9-64
Sens
ors 1
-16
Epox
y
BSA
Sol
utio
nFe
rriti
nSo
lutio
n
Sens
ors 1
7-48
Sens
ors 4
9-64
Sens
ors 1
-16
Epox
y
Func
tiona
lizat
ion
1. T
he a
ntig
ens a
re a
pplie
d se
lect
ivel
y
Mea
sure
men
t Res
ults
Mea
sure
men
t Res
ults
Show
n on
the
rig
ht i
s a
mea
sure
men
t cu
rve
that
was
Sh
own
on t
he r
ight
is
a m
easu
rem
ent
curv
e th
at w
as
reco
rded
as
MA
CS
reco
rded
as
MA
CS
nano
parti
cles
nano
parti
cles
, coa
ted
with
, c
oate
d w
ith s
trept
avid
inst
rept
avid
in, ,
wer
e bi
ndin
g to
a M
agA
rray
4 ch
ip.
Som
e se
nsor
s on
the
w
ere
bind
ing
to a
Mag
Arr
ay4
chip
. So
me
sens
ors
on t
he
chip
wer
e ba
re.
Thes
e re
sulte
d in
the
yel
low
sig
nal
curv
e ch
ip w
ere
bare
. Th
ese
resu
lted
in t
he y
ello
w s
igna
l cu
rve
with
a fi
nal v
alue
of c
a. 1
w
ith a
fina
l val
ue o
f ca.
1 µµ
V.
V.
Oth
er s
enso
rs o
n th
e sa
me
chip
wer
e fu
nctio
naliz
ed w
ith
Oth
er s
enso
rs o
n th
e sa
me
chip
wer
e fu
nctio
naliz
ed w
ith
sing
le s
trand
ed
sing
le s
trand
ed b
iotin
ylat
edbi
otin
ylat
edD
NA
. Th
ese
sens
ors,
in r
ed,
DN
A.
Thes
e se
nsor
s, in
red
, sh
ow a
rapi
d in
crea
se in
sig
nal t
o ca
. 38
show
a ra
pid
incr
ease
in s
igna
l to
ca. 3
8 µµ V
as
soon
as
the
V a
s so
on a
s th
e na
nopa
rticl
esna
nopa
rticl
esar
e ap
plie
d ar
ound
t =
25 m
inut
es. T
hus,
the
are
appl
ied
arou
nd t
= 25
min
utes
. Thu
s, th
e na
nopa
rticl
esna
nopa
rticl
esar
e cl
early
reve
alin
g th
e pr
esen
ce o
f DN
A o
n ar
e cl
early
reve
alin
g th
e pr
esen
ce o
f DN
A o
n th
e ch
ip w
ith a
sig
nal t
o no
ise
ratio
of c
a. 3
1 dB
. The
sig
nal
the
chip
with
a s
igna
l to
nois
e ra
tio o
f ca.
31
dB. T
he s
igna
l ris
e tim
e of
the
red
cur
ve c
an a
lso
give
ins
ight
s in
to t
he
rise
time
of t
he r
ed c
urve
can
als
o gi
ve i
nsig
hts
into
the
bi
otin
biot
in-- s
trept
avid
inst
rept
avid
inbi
ndin
g ki
netic
s. bi
ndin
g ki
netic
s.
Not
e th
at th
e w
ashi
ng th
e ch
ip w
ith
Not
e th
at th
e w
ashi
ng th
e ch
ip w
ith d
eion
ized
deio
nize
dw
ater
(H2O
) w
ater
(H2O
) le
ads
to t
empo
rary
shi
fts i
n th
e si
gnal
, bu
t it
does
not
le
ads
to t
empo
rary
shi
fts i
n th
e si
gnal
, bu
t it
does
not
re
mov
e th
e re
mov
e th
e na
nopa
rticl
esna
nopa
rticl
es. T
he w
ash
at t
= 73
min
utes
onl
y . T
he w
ash
at t
= 73
min
utes
onl
y m
inim
ally
redu
ces t
he si
gnal
m
inim
ally
redu
ces t
he si
gnal
--M
AC
S ar
e bo
und
stro
ngly
.M
AC
S ar
e bo
und
stro
ngly
.
In th
e se
cond
fig
ure,
a d
iffer
ent f
unct
iona
lizat
ion
base
d on
In
the
seco
nd f
igur
e, a
diff
eren
t fun
ctio
naliz
atio
n ba
sed
on
antib
odie
s w
as u
sed.
The
red
cur
ve s
how
s th
e bi
ndin
g of
an
tibod
ies
was
use
d. T
he r
ed c
urve
sho
ws
the
bind
ing
of
nano
parti
cles
nano
parti
cles
to t
he
to t
he f
errit
infe
rriti
n --fu
nctio
naliz
ed s
ites.
The
larg
e fu
nctio
naliz
ed s
ites.
The
larg
e si
gnal
incr
ease
of t
hese
site
s re
veal
s th
e pr
esen
ce o
f an
anti
sign
al in
crea
se o
f the
se s
ites
reve
als
the
pres
ence
of a
n an
ti --fe
rriti
nfe
rriti
nan
tibod
y. O
n th
e ot
her
hand
, the
lac
k of
a d
istin
ct
antib
ody.
On
the
othe
r ha
nd, t
he l
ack
of a
dis
tinct
si
gnal
inc
reas
e of
the
BSA
sign
al i
ncre
ase
of t
he B
SA-- f
unct
iona
lized
sen
sors
rev
eals
fu
nctio
naliz
ed s
enso
rs r
evea
ls
that
no
anti
that
no
anti --
BSA
ant
ibod
ies w
ere
pres
ent.
BSA
ant
ibod
ies w
ere
pres
ent.
The
rise
time
of th
e an
tiTh
e ris
e tim
e of
the
anti --
ferr
itin
ferr
itin
sign
al is
slo
wer
than
in th
e si
gnal
is s
low
er th
an in
the
expe
rimen
t usi
ng D
NA
, pos
sibl
y in
dica
ting
a lo
wer
den
sity
ex
perim
ent u
sing
DN
A, p
ossi
bly
indi
catin
g a
low
er d
ensi
ty
of a
vaila
ble
biot
in s
ites
on t
he c
hip
surf
ace.
The
exa
ct
of a
vaila
ble
biot
in s
ites
on t
he c
hip
surf
ace.
The
exa
ct
rela
tion
of s
igna
l and
bin
ding
kin
etic
s is
bei
ng in
vest
igat
ed
rela
tion
of s
igna
l and
bin
ding
kin
etic
s is
bei
ng in
vest
igat
ed
in m
ore
deta
il.in
mor
e de
tail.
The
elec
tron
mic
rosc
ope
imag
es o
n th
e rig
ht, t
aken
afte
r the
Th
e el
ectro
n m
icro
scop
e im
ages
on
the
right
, tak
en a
fter t
he
expe
rimen
t, sh
ow c
lear
ly th
at s
igna
l diff
eren
ces
corr
espo
nd
expe
rimen
t, sh
ow c
lear
ly th
at s
igna
l diff
eren
ces
corr
espo
nd
to
to n
anop
artic
lena
nopa
rticl
eco
vera
ge d
iffer
ence
s.co
vera
ge d
iffer
ence
s.
Subs
trate
SVSi
O2
SiO
2
Au
Au
lead
Au
lead
Spot
ting
Nee
dle
Upp
er R
ight
:U
pper
Rig
ht:
Show
n he
re is
the
resu
lt of
a s
ampl
e Sh
own
here
is th
e re
sult
of a
sam
ple
run
of o
ur f
unct
iona
lizat
ion
robo
t. ru
n of
our
fun
ctio
naliz
atio
n ro
bot.
The
robo
t ha
s pl
aced
di
ffer
ent
The
robo
t ha
s pl
aced
di
ffer
ent
func
tiona
lizat
ions
func
tiona
lizat
ions
on
diff
eren
t on
di
ffer
ent
sens
ors
as p
rogr
amm
ed w
ith g
ood
sens
ors
as p
rogr
amm
ed w
ith g
ood
accu
racy
.ac
cura
cy.
Low
er R
ight
:Lo
wer
Rig
ht:
Show
n he
re is
a
Show
n he
re is
a m
icro
fluid
icm
icro
fluid
icM
agA
rray
4 ch
ip. I
nste
ad o
f the
ope
n M
agA
rray
4 ch
ip. I
nste
ad o
f the
ope
n w
ell t
hat t
he p
roto
type
has
, thi
s chi
p w
ell t
hat t
he p
roto
type
has
, thi
s chi
p fe
atur
es c
lose
d fe
atur
es c
lose
d m
icro
fluid
icm
icro
fluid
icst
ruct
ures
that
car
ry th
e re
agen
ts
stru
ctur
es th
at c
arry
the
reag
ents
ac
ross
the
chip
. Som
e of
the
larg
er
acro
ss th
e ch
ip. S
ome
of th
e la
rger
m
icro
fluid
icm
icro
fluid
icfe
atur
es a
re v
isib
le in
fe
atur
es a
re v
isib
le in
th
e ce
nter
of t
he c
hip.
Not
e al
so th
e th
e ce
nter
of t
he c
hip.
Not
e al
so th
e th
ree
thre
e ““ D
NA
Alig
nD
NA
Alig
n ””m
arks
that
aid
m
arks
that
aid
th
e ro
bot
the
robo
t -- toto
-- chi
p al
ignm
ent.
chip
alig
nmen
t.
The
robo
tic fu
nctio
naliz
atio
n is
Th
e ro
botic
func
tiona
lizat
ion
is
appl
ied
first
, and
then
enc
apsu
late
d ap
plie
d fir
st, a
nd th
en e
ncap
sula
ted
by th
e by
the
mic
roflu
idic
mic
roflu
idic
stru
ctur
es.
stru
ctur
es.
400µ
m
12m
m
Left:
Le
ft:
A
sche
mat
ic
repr
esen
tatio
n of
th
e A
sc
hem
atic
re
pres
enta
tion
of
the
chip
and
the
rob
otic
ally
con
trolle
d ch
ip a
nd t
he r
obot
ical
ly c
ontro
lled
spot
ting
need
le
used
fo
r th
e sp
ottin
g ne
edle
us
ed
for
the
func
tiona
lizat
ion.
func
tiona
lizat
ion.
In a
cus
tom
In a
cus
tom
-- bui
ld a
pplic
atio
n, th
e bu
ild a
pplic
atio
n, th
e fu
nctio
naliz
atio
n fo
r eac
h of
the
64
func
tiona
lizat
ion
for e
ach
of th
e 64
(o
r mor
e) se
nsor
s can
be
indi
vidu
ally
(o
r mor
e) se
nsor
s can
be
indi
vidu
ally
pr
ogra
mm
ed. A
vid
eo c
amer
a is
use
d pr
ogra
mm
ed. A
vid
eo c
amer
a is
use
d to
con
trol t
he fu
nctio
naliz
atio
n an
d to
to
con
trol t
he fu
nctio
naliz
atio
n an
d to
ai
d in
the
alig
nmen
t of t
he ro
botic
ai
d in
the
alig
nmen
t of t
he ro
botic
ap
plic
ator
to e
ither
a si
ngle
chi
p, o
r ap
plic
ator
to e
ither
a si
ngle
chi
p, o
r to
an
entir
e w
afer
. The
pro
gram
is
to a
n en
tire
waf
er. T
he p
rogr
am is
hi
ghly
flex
ible
and
ada
ptab
le to
a
high
ly fl
exib
le a
nd a
dapt
able
to a
va
riety
of c
hips
. It c
an a
pply
up
to
varie
ty o
f chi
ps. I
t can
app
ly u
p to
38
4 di
ffer
ent
384
diff
eren
t fun
ctio
naliz
atio
nsfu
nctio
naliz
atio
ns––
e.g.
e.
g.
antib
odie
s or g
enes
of i
nter
est
antib
odie
s or g
enes
of i
nter
est ––
to a
n to
an
arbi
traril
y si
zed
and
posi
tione
d ar
bitra
rily
size
d an
d po
sitio
ned
subs
trate
.su
bstra
te.
Show
n in
the
low
er im
age
is th
e Sh
own
in th
e lo
wer
imag
e is
the
robo
tic a
pplic
ator
and
vid
eo c
amer
a ro
botic
app
licat
or a
nd v
ideo
cam
era
durin
g a
test
run.
durin
g a
test
run.
Topo
grap
hyTo
pogr
aphy
-- and
Alig
nmen
tan
d A
lignm
ent --
Tole
rant
To
lera
nt M
icro
fluid
ics
Mic
roflu
idic
s
Opt
ical
mic
rosc
ope
and
elec
tron
mic
rosc
ope
imag
es o
f the
two
mic
roflu
idic
laye
rs
com
bine
d an
d se
para
ted.
The
rea
gent
s are
gui
ded
tow
ards
the
sens
or in
the
larg
e an
d,
sinc
e th
ey a
re o
n a
sepa
rate
waf
er, c
oars
ely
alig
ned
PDM
S ch
anne
ls. T
he r
eage
nts t
hen
trav
erse
the
actu
al se
nsor
in th
e m
uch
narr
ower
and
pre
cise
ly a
ligne
d Si
O2
chan
nel.
Lay
er B
: SiO
2 M
icro
fluid
ics
Flow 20
µm
To b
e su
itabl
e fo
r hi
ghTo
be
suita
ble
for
high
-- yie
ld m
ass
prod
uctio
n, it
is im
porta
nt th
at
yiel
d m
ass
prod
uctio
n, it
is im
porta
nt th
at
the
the
mic
roflu
idic
sm
icro
fluid
ics
are
som
ewha
t to
lera
nt t
o sm
all
alig
nmen
t an
d ar
e so
mew
hat
tole
rant
to
smal
l al
ignm
ent
and
proc
ess
varia
tions
. Thi
s is
ach
ieve
d w
ith a
2pr
oces
s va
riatio
ns. T
his
is a
chie
ved
with
a 2
-- laye
r pro
cess
. Lay
er A
la
yer p
roce
ss. L
ayer
A
carr
ies
larg
e ch
anne
ls a
nd i
s fa
bric
ated
on
a se
para
te w
afer
fro
carr
ies
larg
e ch
anne
ls a
nd i
s fa
bric
ated
on
a se
para
te w
afer
fro
m
m
poly
dim
ethy
lsilo
xane
poly
dim
ethy
lsilo
xane
(PD
MS)
. Lay
er B
is
fabr
icat
ed r
ight
on
the
(PD
MS)
. Lay
er B
is
fabr
icat
ed r
ight
on
the
Mag
Arr
ay4
subs
trate
waf
er f
rom
SiO
2 w
ith p
hoto
litho
grap
hic
Mag
Arr
ay4
subs
trate
waf
er f
rom
SiO
2 w
ith p
hoto
litho
grap
hic
prec
isio
n. L
ayer
B c
onta
ins
the
smal
l pr
ecis
ion.
Lay
er B
con
tain
s th
e sm
all m
icro
fluid
icm
icro
fluid
icfe
atur
es, s
uch
as
feat
ures
, suc
h as
su
bsu
b --m
icro
n ch
anne
ls o
ver t
he a
ctiv
e se
nsin
g el
emen
ts. T
he o
verla
p m
icro
n ch
anne
ls o
ver t
he a
ctiv
e se
nsin
g el
emen
ts. T
he o
verla
p of
the
laye
rs is
gen
erou
sly
size
d to
acc
omm
odat
e al
ignm
ent e
rror
of th
e la
yers
is g
ener
ousl
y si
zed
to a
ccom
mod
ate
alig
nmen
t err
ors s
(see
fini
shed
sam
ple
stru
ctur
e on
the
right
).(s
ee fi
nish
ed sa
mpl
e st
ruct
ure
on th
e rig
ht).
Afte
r th
e M
agA
rray
4 su
bstra
te
waf
er
has
been
ro
botic
ally
A
fter
the
Mag
Arr
ay4
subs
trate
w
afer
ha
s be
en
robo
tical
ly
func
tiona
lized
, the
sup
port
waf
er c
arry
ing
laye
r A is
col
d se
ale
func
tiona
lized
, the
sup
port
waf
er c
arry
ing
laye
r A is
col
d se
ale d
to
d to
th
e su
bstra
te w
afer
. Si
nce
PDM
S is
th
e su
bstra
te w
afer
. Si
nce
PDM
S is
ela
stom
eric
elas
tom
eric
, it
can
seal
ove
r ,
it ca
n se
al o
ver
unev
en to
pogr
aphy
and
eve
n ac
com
mod
ate
an o
ccas
iona
l par
ticle
un
even
topo
grap
hy a
nd e
ven
acco
mm
odat
e an
occ
asio
nal p
artic
le ––
this
wou
ld b
e im
poss
ible
with
the
sta
ndar
d pr
oced
ure
of a
nodi
c th
is w
ould
be
impo
ssib
le w
ith t
he s
tand
ard
proc
edur
e of
ano
dic
bond
ing.
bond
ing.
Sens
or
Elec
tric
lead
Con
nect
ing
the
Con
nect
ing
the
mic
roflu
idic
mic
roflu
idic
stru
ctur
es t
o th
e ou
tsid
e w
orld
is
one
of t
he e
ngin
eerin
g st
ruct
ures
to
the
outs
ide
wor
ld i
s on
e of
the
eng
inee
ring
chal
leng
es. W
e ha
ve d
evel
oped
an
auto
mat
able
app
roac
h w
hich
doe
sch
alle
nges
. We
have
dev
elop
ed a
n au
tom
atab
le a
ppro
ach
whi
ch d
oes
not r
equi
re th
e dr
illin
g no
t req
uire
the
drill
ing
of h
oles
into
any
of t
he w
afer
s, w
hich
wou
ld b
e la
borio
us a
nd u
nof
hol
es in
to a
ny o
f the
waf
ers,
whi
ch w
ould
be
labo
rious
and
un w
ante
d fo
r waf
er p
roce
ssin
g.
wan
ted
for w
afer
pro
cess
ing.
Th
e m
ain
feat
ure
cons
ists
of
clea
vabl
e ed
ges
that
, on
ce r
emov
ed,
The
mai
n fe
atur
e co
nsis
ts o
f cl
eava
ble
edge
s th
at,
once
rem
oved
,pr
ovid
e op
enin
gs t
o th
e pr
ovid
e op
enin
gs t
o th
e m
icro
fluid
ics
mic
roflu
idic
s . T
hese
ope
ning
s ca
n be
rob
otic
ally
sea
led
to a
com
plem
enta
ry, s
. The
se o
peni
ngs
can
be r
obot
ical
ly s
eale
d to
a c
ompl
emen
tary
, sel
fel
f --ce
nter
ing
cent
erin
g m
icro
fluid
icm
icro
fluid
icho
lder
, w
hich
can
be
a ch
eap
mas
sho
lder
, w
hich
can
be
a ch
eap
mas
s --pr
oduc
ible
pla
stic
par
t. O
n th
e rig
ht,
a pr
oduc
ible
pla
stic
par
t. O
n th
e rig
ht,
a M
agA
rray
pro
toty
pe w
ith w
orki
ng tw
oM
agA
rray
pro
toty
pe w
ith w
orki
ng tw
o --la
yer
laye
r mic
roflu
idic
sm
icro
fluid
ics
and
and
mic
roflu
idic
mic
roflu
idic
hold
ers i
s sho
wn.
hold
ers i
s sho
wn.
Mic
roflu
idic
Hol
der
Mic
roflu
idic
Cha
nnel
IV T
ubin
g
Laye
r A
P
DM
S
1
0µm
thic
k
Supp
ort W
afer
(gla
ss)
Larg
e ch
anne
l,C
a. 1
0µm
dee
pC
a. 2
-100
µm w
ide
Subs
trate
Waf
er (s
ilico
n)
Sens
or
Shal
low
tren
ch,
Ca.
200
nm d
eep
Ca.
1-5
µm w
ide
Laye
r B
Si
O2,
200
nm th
ick
PDM
S
Supp
ort W
afer
(gla
ss)
Subs
trate
Waf
er (s
ilico
n)
Sub-
mic
ron
chan
nel,
Ca.
180
nm d
eep
Laye
r ALa
yer B
Laye
r A
P
DM
S
1
0µm
thic
k
Supp
ort W
afer
(gla
ss)
Larg
e ch
anne
l,C
a. 1
0µm
dee
pC
a. 2
-100
µm w
ide
Subs
trate
Waf
er (s
ilico
n)
Sens
or
Shal
low
tren
ch,
Ca.
200
nm d
eep
Ca.
1-5
µm w
ide
Laye
r B
Si
O2,
200
nm th
ick
PDM
S
Supp
ort W
afer
(gla
ss)
PDM
S
Supp
ort W
afer
(gla
ss)
Subs
trate
Waf
er (s
ilico
n)
Sub-
mic
ron
chan
nel,
Ca.
180
nm d
eep
Laye
r ALa
yer B
PDM
S
Supp
ort W
afer
(gla
ss)
Subs
trate
Waf
er (s
ilico
n)
Laye
r ALa
yer B
Parti
al
Cut
PDM
S
Supp
ort W
afer
(gla
ss)
Subs
trate
Waf
er (s
ilico
n)
Laye
r ALa
yer B
Inse
rt bl
ade
and
twis
t edg
e of
f
PDM
S
Supp
ort W
afer
(gla
ss)
Subs
trate
Waf
er (s
ilico
n)
Laye
r ALa
yer B
Mic
roflu
idic
op
enin
g
PDM
S
Supp
ort W
afer
(gla
ss)
Subs
trate
Waf
er (s
ilico
n)
Laye
r ALa
yer B
Parti
al
Cut
PDM
S
Supp
ort W
afer
(gla
ss)
Subs
trate
Waf
er (s
ilico
n)
Laye
r ALa
yer B
Parti
al
Cut
PDM
S
Supp
ort W
afer
(gla
ss)
Subs
trate
Waf
er (s
ilico
n)
Laye
r ALa
yer B
Inse
rt bl
ade
and
twis
t edg
e of
f
PDM
S
Supp
ort W
afer
(gla
ss)
Subs
trate
Waf
er (s
ilico
n)
Laye
r ALa
yer B
Inse
rt bl
ade
and
twis
t edg
e of
f
PDM
S
Supp
ort W
afer
(gla
ss)
Subs
trate
Waf
er (s
ilico
n)
Laye
r ALa
yer B
Mic
roflu
idic
op
enin
g
PDM
S
Supp
ort W
afer
(gla
ss)
Subs
trate
Waf
er (s
ilico
n)
Laye
r ALa
yer B
Mic
roflu
idic
op
enin
gPD
MS
Supp
ort W
afer
(gla
ss)
Subs
trate
Waf
er (s
ilico
n)
Laye
r ALa
yer B
Adh
esiv
eM
icro
fluid
ic H
olde
r Inle
t / O
utle
t
PDM
S
Supp
ort W
afer
(gla
ss)
Subs
trate
Waf
er (s
ilico
n)
Laye
r ALa
yer B
Adh
esiv
eM
icro
fluid
ic H
olde
r Inle
t / O
utle
t
PDM
S
Supp
ort W
afer
(gla
ss)
Subs
trate
Waf
er (s
ilico
n)
Laye
r ALa
yer B
Adh
esiv
eM
icro
fluid
ic H
olde
r Inle
t / O
utle
t
DN
A D
etec
tion
(ssD
NA
w/ B
iotin
) on
the
Mag
Arr
ay4
Waf
er R
B2,
Chi
p 2-
2, N
ov-2
9-20
05, u
sing
Str
epta
vidi
n N
anop
artic
les
(MA
CS)
-1001020304050
010
2030
4050
6070
Tim
elin
e, M
inut
es
Signal Amplitude, µV
ssD
NA
-Bio
tinB
are
Sens
or
H2O
H2O
H2O
H2O
Nan
opar
ticle
s
<-- SNR ~ 31 dB -->
Figu
re 1
: DN
A D
etec
tion Ant
ibod
y D
etec
tion
(Ant
i-Fer
ritin
w/ B
iotin
) on
the
Mag
Arr
ay4
Waf
er R
B2,
Chi
p X-
1, J
an-1
8-20
06, u
sing
Str
epta
vidi
n N
anop
artic
les
(MA
CS)
-1001020304050
010
2030
4050
6070
Tim
elin
e, M
inut
es
Signal Amplitude, µV
Ferr
itin
BSA
PBS
H2O
PBS
PBS
PBS
PBS
PBS PBS
PBS
PBS
H2O
H2O
Nan
opar
ticle
s
<-- SNR ~ 21dB -->Fi
gure
2: A
ntib
ody
Det
ectio
n
The
mea
sure
men
t is c
arrie
d ou
t whi
le th
e na
nopa
rticl
esbi
ndFu
nctio
naliz
atio
n 2.
The
bio
tinyl
ated
antib
ody
is a
pplie
d gl
obal
ly
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