!"# %&#'( )% *&)+#(&,-' ,).

/0)'
121/#+1 &1 0#'-/&3#'2 2)4.5
,)+6-0#( /) -#0)16-,#7
-4/)+)/&3#7 -.( /"# ,"#+&,-'
60),#11 %&#'(18 9#3#0/"#'#117 1)+#
.)/#:)0/"2 0#,#./ (#3#')6+#./1
"-3# #+#05#( &. /:) ;#2
-66'&,-/&). -0#-1< ,-0(&)3-1,4'-0
121/#+1 -.( #.(),0&.)')528

=0-.,&1 >8 ?)2'# @@@7 A8 B-2.# A#C4#//#7 D&,; E&(('#/).7 A-*-/4.(# F54..-&;#7 A0-( G-(#.7
D)*#0/ H8 G-0;#07 -.( E-/"4;4+-''& I&(2-1-5-0
"#$%&'()$*&#
1he fleld of conLrol and sysLems has been connecLed Lo blologlcal sysLems and bloLechnology for many
decades, golng back Lo Lhe work of norberL Wlener on cyberneLlcs ln 1963, Lhe work of WalLer Cannon
on homeosLasls ln 1929, and Lhe early work of Claude 8ernard on Lhe +&'&#4 &./#0&#40 ln 1863.
noneLheless, Lhe lmpacL of conLrol and sysLems on devlces and appllcaLlons ln Lhe fleld of blology has
only emerged ln recenL years.
lor Lhls reporL, we wlll concenLraLe on Lhe so-called 0#( bloLechnology, LhaL ls, Lhe medlcal fleld of use,
as opposed Lo *'4# bloLechnology (aquaLlc use of blologlcal Lechnology), 50##. bloLechnology
(agrlculLure and planL use), and :"&/# bloLechnology (lndusLrlal appllcaLlons).
1
lor energy and process
appllcaLlons, Lhe reader ls referred Lo oLher secLlons of Lhls reporL.
Pence, Lhe emphasls ln Lhls secLlon ls on medlcal appllcaLlons of conLrol sysLems Lechnology, whlch ls
very dlfferenL from oLher areas ln Lhls sLudy for mulLlple reasons:
lL ls much less maLure.
lL has far wlder lmpacL on human llfe.
lL ls much less esLabllshed.
1hls reporL ls noL meanL Lo be a comprehenslve revlew of all developmenLs ln blomedlcal conLrol
sysLems Lechnology, lnsLead Lhe reader ls referred Lo selecLed revlews, books, and LuLorlals on Lhe Loplc
[1]-[3].
+()),--.(/ 011/*)2$*&#- &. 3&#$%&/4 32%'*&52-)(/2% +6-$,7- 2#' 8#'&)%*#, +6-$,7-
As noLed above, Lhe fleld of blomedlcal conLrol
sysLems ls relaLlvely young compared Lo aerospace,
auLomoLlve, and Lhe chemlcal process flelds.
neverLheless, some noLeworLhy recenL developmenLs
have emerged ln Lwo key appllcaLlon areas:
cardlovascular sysLems and endocrlnology.
!"#$%"& ())%)* +,-%&,)
1he area of cardlac asslsL devlces has had a relaLlvely
long hlsLory of developmenL, alLhough advanced
conLrol Lheory and process modellng have only
recenLly been applled Lo Lhese devlces [6]-[10]. ln

1
See, for example, Lhe Wlklpedla enLry for *&)/#,".)')528
3&#$%&/ *# 9*&/&:*)2/ +6-$,7-
lrom: !"# @+6-,/ )% J)./0)' !#,".)')52, 1. Samad and A.M. Annaswamy (eds.), 2011. Avallable aL www.leeecss.org.

effecL, cardlac asslsL devlces are mechanlcal pumps LhaL supplemenL endogenous cardlac ouLpuL aL an
appropriate pressure to allow normal circulation through the patients body. The control challenges
include the changing demands for cardiac output as a function of the patients state (for example,
level of exerclse, emoLlon, posLure). 1he flrsL such lmplanLable devlce Lo recelve approval by Lhe luA
(1998) ls Lhe 8axLer/novacor lefL venLrlcular asslsL devlce (LvAu). Clearly, Lhe ldeal devlce would mlmlc
the bodys own mechanisms for maintaining cardlac ouLpuL aL LargeL levels, however, Lhe devlces
currenLly on Lhe markeL are raLher prlmlLlve ln Lerms of auLomaLlon, requlrlng Lhe paLlenL Lo ad[usL
seLpolnLs dlrecLly [6]. 8ecenL developmenLs for Lhe pacemaker lnclude real-Llme analysls and adapLlve
conLrol [11]. venLrlcular asslsL devlces (vAus) are explorlng feedback and model-based conLrol Lo
compensaLe for changes ln paLlenL needs (such as exerclse) [12].
A more recenL developmenL ls Lhe use of magneLlc levlLaLlon ln Lhe World PearL lnc. venLrlcular asslsL
devlce called Levacor. World PearL recenLly recelved an luA lnvesLlgaLlonal devlce exempLlon (luL) ln
preparaLlon for cllnlcal Lrlals. 1he conLrol sysLem ls a hybrld passlve/acLlve magneLlc bearlng where Lhe
acLlve magneLlc bearlng employs a slngle acLlve feedback loop deslgned by loop shaplng. A key
componenL of Lhe Lechnology ls Lhe hlgh-rellablllLy elecLronlc deslgn know-how Lransferred from alrcrafL
conLrol sysLems Lo Lhls devlce.
ln Lhe cardlovascular area, anoLher applled Lechnology has been developed by MagneLecs: a
magneLlcally gulded caLheLer sysLem for elecLrophyslology and oLher procedures. 1he conLrol sysLem ls
a comblnaLlon of slmple feedforward meLhods lnvolvlng coordlnaLe changes, feedback, and adapLlve
synLhesls of vlsual models of Lhe hearL.
./00$ 1#,))2#, !03*#0/
1he lvAC 1lLraLor was developed Lo regulaLe mean arLerlal pressure ln hyperLenslve lnLenslve care unlL
(lCu) paLlenLs by lnfuslng sodlum nlLroprusslde. 1he devlce recelved luA approval ln 1987 and was
markeLed for a shorL Llme, buL was dlsconLlnued afLer a few years. 1he reasons for lLs fallure ln Lhe
markeLplace lnclude Lhe followlng: (1) no conslsLenL communlcaLlon sLandards exlsLed aL Lhe Llme, so
Lhe devlce had lLs own blood pressure sensor LhaL was noL parLlcularly easy Lo seL up, (2) Lhe compuLer
lnLerface Lechnology was noL advanced, (3) Lhe unlLs were overprlced (lvAC chose Lo recoup 8&u cosLs
wlLhln a shorL Llme perlod), and (4) alLhough sLudles showed less varlablllLy ln blood pressure Lhan wlLh
manual conLrol, Lhe effecL of Lhe reduced varlablllLy on paLlenL ouLcomes was unclear [13]. Some sLudles
suggesLed LhaL paLlenLs were able Lo reduce hosplLal sLays by a day. WlLh new communlcaLlon sLandards
and advances ln mlcroprocessor-based pump Lechnology, a closed-loop blood pressure sysLem could
probably succeed ln Lhe markeLplace Loday.
(3,)*4,)%" +,/%-,#5
1he effecL of Lhe lnLravenous anesLheLlc propofol ls dlrecLly relaLed Lo lLs concenLraLlon ln Lhe blood.
1argeL-conLrolled lnfuslon (1Cl) ls a model-based open-loop sLraLegy deslgned Lo regulaLe Lhe
concenLraLlon of a drug ln Lhe blood by glvlng an lnlLlal lnLravenous bolus (shoL), followed by Llme-
dependenL lnfuslon. A commerclal devlce, Lhe ulprlfusor (AsLraZeneca harmaceuLlcals), has been
avallable LhroughouL much of Lhe world slnce 1996 [14], [13], wlLh mllllons of successful propofol
lnfuslons admlnlsLered [16]. lor a varleLy of reasons, no 1Cl devlce has recelved luA approval ln Lhe
unlLed SLaLes [17]. Approval may be more llkely lf Lhe lnfuslon sysLem lncorporaLes a depLh of
anesLhesla monlLor, such as Lhe blspecLral lndex (8lS) manufacLured by AspecL Medlcal SysLems, Lo form
a fully closed-loop sysLem.

!"# 6-,#+-;#07 :&/" KLM7MMM
&+6'-./#( 6#0 2#-0 :)0'(:&(#7 &1
- 4*&C4&/)41 *&)+#(&,-' (#3&,#
0#'&-./ ). ,)./0)' -'5)0&/"+1 /)
,)./&.4# %4.,/&).&.58
6*4,# (77/%&"*%03)
8eyond Lhose hlghllghLed here, a number of blomedlcal devlces LhaL have been successfully LranslaLed
lnLo commerclal producLs uslng closed-loop Lechnology lnclude Lhe lmplanLable cardloverLer
deflbrlllaLor (lCu), Lhe lnLracardlac elecLrogram (lLCM), and Lhe oxygen saLuraLlon monlLor. ln oLher
blomedlcal devlce areas, sensors are used Lo provlde feedback Lo conLrol and dellver elecLrlc slgnals LhaL
stimulate the brain to ease the tremors of Parkinsons disease and epilepsy by determining the extent
and Llmlng of sLlmulaLlon. AddlLlonally, closed-loop blomedlcal devlces are used Lo LreaL perlpheral
vascular disease by using sensors to measure blood flow in a patients limbs and determine the level of
splnal cord or perlpheral nerve sLlmulaLlon requlred Lo lmprove blood flow, Lhereby reduclng lschemlc
paln ln Lhe llmbs. Closed-loop LemperaLure conLrol has been employed ln ablaLlon sysLems (such as Lhe
ALakr from MedLronlc) wlLh Lhermocouple feedback for safeLy.
;2%<,$ +*=,- 2#' "#5,-$7,#$
1he poLenLlal markeL for Lhe venLrlcular asslsL devlce ls roughly 33,000 end-sLage hearL dlsease paLlenLs
per year ln Lhe u.S. alone. 1he markeL caplLallzaLlon of vAu companles exceeds $18 ln Lhe u.S. 1he
pacemaker, wlLh 230,000 lmplanLed per year worldwlde [11], ls a ublqulLous blomedlcal devlce rellanL
on conLrol algorlLhms Lo conLlnue funcLlonlng. CaLheLer
sysLem companles have a collecLlve markeL
caplLallzaLlon on Lhe order of $0.38.
ApproxlmaLely 17 mllllon lndlvlduals ln Lhe u.S. are
dlagnosed dlabeLlcs, 3-10 of whom have Lype 1 and
requlre lnsulln Lherapy. Slmllar lncldence raLes apply Lo
oLher reglons of Lhe world. A 2003 esLlmaLe puL Lhe
number of lnsulln pump users worldwlde aL 400,000
and growlng by 10-12 per annum [18].
lL ls worLh noLlng LhaL regulaLory facLors and Lhe cosL of cllnlcal Lrlals ofLen mean LhaL markeL lnLeresL ls
less Lhan paLlenL demand. 8egardless of Lhe regulaLory lssues, however, Lhe medlcal lnLeresL ln
developlng Lools LhaL asslsL paLlenLs remalns hlgh because of Lhe poLenLlal for lmpacL aL Lhe paLlenL level
lf a LreaLmenL lnLervenLlon or devlce ls successful.
Several governmenL agencles are lnvesLlng ln research Lechnology (lncludlng conLrol sysLems) for Lhe
arLlflclal pancreas (see below). 1he u.S. naLlonal lnsLlLuLes of PealLh (nlP) recenLly announced a
competition for the artificial pancreas (Closed Loop Technologies: Clinical and Behavioral Approaches
to Improve Type 1 Diabetes Outcomes, total of $5.5M funding). The EU sponsors mulLlple lnlLlaLlves on
the topic of the artificial pancreas, including Development of a bio-arLlflclal pancreas for Lype 1
diabetes therapy and AP@home. The NIH National Institute for Biomedical Imaging and
8loenglneerlng (nl8l8) ls a key player ln research lnvesLmenL for blomedlcal devlces. Several prlvaLe
foundaLlons fund research ln Lhls area as well, lncludlng Lhe Plllblom loundaLlon (endocrlne and
neurodegeneraLlve dlsorders) and Lhe !uvenlle ulabeLes 8esearch loundaLlon (!u8l). 1he !u8l funds
Lhe ArLlflclal ancreas ConsorLlum aL a level of over $3.3M per year. A relaLed Loplc ls closed-loop
conLrol of blood glucose ln Lhe lnLenslve care unlL, several companles (such as Lumlnous Medlcal) are
fundlng Lhe developmenL of sensors and closed-loop conLrol algorlLhms for Lhls appllcaLlon. Medlcal
Lechnology companles are hlrlng ln Lhls fleld, lncludlng !ohnson & !ohnson, 8oche, MedLronlc, and

oLhers. Small sLarL-ups ln Lhls fleld have aLLracLed venLure caplLal (vC) fundlng aL slgnlflcanL levels:
World PearL recelved $30M ln vC supporL ln 2009, and MagneLecs has also aLLracLed vC supporL.
>11&%$(#*$*,- .&% ?,@ 011/*)2$*&#- 2#' A,-,2%)B
Red biotechnology is an emerging and vibrant area for research in control systems. Below we discuss
Lwo Loplcs of parLlcular lnLeresL and Lhen offer some general remarks on new research and developmenL
opporLunlLles.
84, (#*%9%&%"/ 1"3&#,")
ln Lhe area of endocrlne sysLems,
Lhe mosL acLlve area for conLrol
sysLems developmenL has been
Lhe arLlflclal pancreas for Lype 1
dlabeLes (llg. 1). Such a devlce
would be composed of a con-
Llnuous glucose sensor, an lnsulln
lnfuslon pump, and an algorlLhm
Lo regulaLe Lhe lnsulln doslng ln
accordance wlLh Lhe measured
glucose levels. lollowlng ls a brlef
summary of some of Lhe key
conLrlbuLlons, conslsLlng prlmarlly
of Lhe appllcaLlon of llnear and
nonllnear proporLlonal-derlvaLlve
(u) algorlLhms Lo emulaLe Lhe
naLurallsLlc blphaslc lnsulln
secreLlon proflle. Some of Lhe
earllesL work lncludes Lhe glucose-
conLrolled lnsulln lnfuslon sysLem
(CCllS) [19], whlch used some paLlenL daLa (10-sec glucose sampllng wlLh a 4- Lo 3-mln delay). 1he
8losLaLor [20] also feaLures a nonllnear u algorlLhm, wlLh Lhe added nuance of a flve-measuremenL
wlndow for fllLerlng glucose measuremenLs. lL was lmplemenLed bedslde and requlred speclflc paLlenL
cusLomlzaLlon. A nlce revlew of Lhe early algorlLhms ls provlded by Alblsser [21], along wlLh some
paLlenL daLa. AnoLher deLalled revlew ls glven by 8roekhuyse eL al. [22]. 1hese revlews concluded LhaL
no conLroller was unlformly superlor and LhaL much more developmenL was needed.
More recenLly, advanced conLrol Lechnologles have been developed for Lhe arLlflclal pancreas, lncludlng
varlaLlons on lu conLrol [23], run-Lo-run conLrol [24], and model predlcLlve conLrol [23]. ln Lhe lasL
several years, cllnlcal sLudles of advanced conLrol meLhods have shown promlse for fuLure devlce
developmenLs [26]-[31]. MosL of Lhese Lrlals use some degree of human lnLervenLlon, for example, Lo
lnpuL Lhe slze of a meal ln advance of eaLlng Lhe meal.
1o daLe, however, Lhe sLaLe of Lhe arL ln feedback conLrol Lechnology for lnsulln pumps and glucose
sensors is limited mainly to bolus wizards and hypoglycemic alarming. The bolus wizards are
effecLlvely feedforward manual conLrol algorlLhms LhaL allow a paLlenL Lo calculaLe an approprlaLe bolus
of insulin to cancel the expected glucose rise from an anLlclpaLed meal or Lo recover from an elevaLed
llgure 1. ComponenLs and communlcaLlon proLocols for
Lhe arLlflclal pancreas [32].

Notebook Computer
(APS, controller, and in silico patient model)
Sensor
Cradle
RS-232/USB
USB
DAQ
RS-232
CSII Pump
Investigational
PDM
Sensor
Receiver
Serial IR
Interface
Glucose Sensor
and Transmitter
APS/Controller/Patient Model
R
F

S
ig
n
a
l
I
R
R
F

S
ig
n
a
l
Notebook Computer
(APS, controller, and in silico patient model)
Sensor
Cradle
RS-232/USB
USB
DAQ
RS-232
CSII Pump
Investigational
PDM
Sensor
Receiver
Serial IR
Interface
Glucose Sensor
and Transmitter
APS/Controller/Patient Model
R
F

S
ig
n
a
l
I
R
R
F

S
ig
n
a
l

hyperglycemlc sLaLe [33]. Pypoglycemlc alarmlng refers Lo Lhe predlcLlon of low blood sugar ln advance
(say 30 mlnuLes or more), generaLlng an audlble warnlng alarm so LhaL Lhe paLlenL can Lake correcLlve
acLlon or, wlLh newer producLs, shuL off Lhe lnsulln pump. 1he hypoglycemlc alarmlng Lechnology ls
appearlng ln Luropean markeLs and ls expecLed Lo appear ln Lhe u.S. soon.
6770#*23%*%,) %3 *4, :%,/$ 09 ;5)*,<) .%0/0=5
Pere we brlefly summarlze some of Lhe key Lechnlcal lssues ln Lhe area of sysLems blology. A broad
specLrum of maLhemaLlcal and analyLlcal meLhods can be applled ln Lhe developmenL of models for
blomolecular regulaLory neLworks and
Lhelr subsequenL analysls, wlLh Lhe Lwln
goals of predlcLlng Lhelr dynamlcs and
generaLlng concepLual lnslghLs abouL
Lhelr operaLlon. 1hese meLhods range
from hlghly absLracLed (such as parLlal
leasL-squares regresslon) Lo hlghly
speclfled (for example, mass acLlon
klneLlc dlfferenLlal equaLlons, dlscreLe
sLochasLlc and mulLlscale models). llg. 2
lllusLraLes only parL of Lhe range of
compuLaLlonal mlnlng and models.
1he hlghly absLracLed meLhods are mosL
powerful when llLLle prlor knowledge
exlsLs concernlng Lhe key neLwork
componenLs, and Lhe mosL hlghly
speclfled meLhods are mosL powerful
when a deep and comprehenslve amounL of knowledge ls avallable concernlng noL only Lhe
componenLs, buL also Lhelr connecLlvlLy and Lhe mechanlsms of Lhelr assoclaLed lnLeracLlons.
lnLermedlaLe Lo Lhese Lwo exLremes are meLhods LhaL enable deLermlnaLlon of loglcal lnfluences
characLerlzlng neLwork componenL lnLeracLlonsgolng a vlLal sLep beyond mere connecLlvlLy buL noL
mandaLlng lnLense knowledge of klneLlc mechanlsms. 1hese meLhods lnclude 8ayeslan neLwork, Markov
chaln, declslon Lree, 8oolean loglc, and fuzzy loglc models. AL Lhe more deLalled end of Lhe modellng
specLrum ls Lhe developmenL of numerlcal meLhods and sofLware for ordlnary dlfferenLlal equaLlon
(CuL) soluLlon, dlfferenLlal-algebralc equaLlon (uAL) soluLlon, and senslLlvlLy analysls of Lhese Lypes of
sysLems. ulscreLe sLochasLlc slmulaLlonand hence mulLlscale slmulaLlon, slnce dlscreLe sLochasLlc
slmulaLlon by lLself ofLen lnvolves so much compuLaLlonal complexlLy LhaL boLh algorlLhmlc (mulLlscale
algorlLhms) and hlgh-performance compuLlng musL be broughL Lo bear Lo speed up Lhe slmulaLlonls a
necessary parL of Lhe compuLaLlonal arsenal for blochemlcal slmulaLlon.
Larly advances ln Lhe fleld of modellng and analysls for sysLems blology have gulded LherapeuLlc
lnLervenLlons. Speclflc drug/dlsease comblnaLlons lnclude heparln/anLlcoagulaLlon (opLlmal conLrol) and
PAA81/Plv (plasma k LargeLs) [34]. 1argeLlng measurable quanLlLles ln a paLlenL-Lallored way (paLlenL-
speclflc medlclne) ls becomlng more common as models and measuremenLs colnclde ln dlseases such as
Plv [34] and dlabeLes [33].
Source: u. Lauffenburger, Ml1
llgure 2. SpecLrum of compuLaLlonal mlnlng/modellng
meLhods.

Specified Abstracted
Differential Equations
Markov Chains
Bayesian Networks
Boolean/Fuzzy Logic Models
Statistical Mining
Mechanisms
Influences
Relationships
(including
molecular
structure-
based
computation)
Appropriate Approach Depends on Question and Data
Specified Abstracted
Differential Equations
Markov Chains
Bayesian Networks
Boolean/Fuzzy Logic Models
Statistical Mining
Mechanisms
Influences
Relationships
(including
molecular
structure-
based
computation)
Appropriate Approach Depends on Question and Data

C,#,%2/ 3&77,#$-
1he mosL promlslng opporLunlLles are Lhose problems LhaL formulaLe ln a manner mosL closely
associated with traditional systems engineering problems: medical problems subject to high
economic burden and having a suitable number of easily accessible measurements that
characLerlze effecL or from whlch LreaLmenL effecL can be esLlmaLed.
1he maxlmum poLenLlal for (economlc) lmpacL of conLrol ln medlclne and medlcal devlces ls
probably ln Lhe area of poorly undersLood dlseases havlng complex dynamlc responses and
sparse (ln Llme or sLaLe dlmenslon) measuremenLs. Lxamples of Lhls class lnclude lnflammaLlon
and hlghly prevalenL cancers. Low cusLomer expecLaLlons furLher moLlvaLe Lhese appllcaLlons for
conLrol-LheoreLlc approaches.
Measurlng lmpacL on a soclal scale provldes a dlfferenL perspecLlve. Pere lmpacL can be made ln
Lhose dlsease populaLlons LhaL are Loo small (for example, Lhose wlLh low-prevalence cancers)
Lo economlcally [usLlfy lnvolvemenL by a ma[or drug company. AnoLher soclally moLlvaLed
poLenLlal lmpacL ls Lhe developmenL and deploymenL of blomedlcal devlces and medlcal
LreaLmenLs Lo Lhe geographlcally or economlcally dlsadvanLaged (for example, Lhose llvlng far
from a ma[or medlcal cenLer ln developed counLrles or paLlenLs ln Afrlca). Agaln, low cusLomer
expecLaLlons furLher moLlvaLe Lhese appllcaLlons for conLrol-LheoreLlc approaches.
1he vAu appllcaLlon could employ exLremal seeklng meLhods ln a perlodlc sysLem. AdapLlve
lmaglng based on caLheLer Llp poslLlon daLa comblned wlLh lmaglng Lechnology ls an
opporLunlLy. AnoLher lmaglng challenge, Lhls Llme ln cancer, ls auLomaLed lmage ldenLlflcaLlon
for cancer volume assessmenL.
Model sLrucLure analysls and sLrucLure selecLlon Lools, used Lo qulckly evaluaLe when Lhe
avallable measuremenLs are adequaLely capLured by Lhe model sLrucLure chosen, are lmporLanL
Lo medlcal declslon maklng. redlcLlon quallLy may depend on model accuracy and Lhe ablllLy Lo
qulckly ldenLlfy a model LhaL ls lacklngand Lo slmulLaneously hlghllghL Lhe porLlons of Lhe
model ln need of reflnemenLcould provlde boLh beLLer healLhcare declslons and rapld model
lmprovemenL. As alluded Lo above, Lhe conLlnued developmenL of parameLer ldenLlflcaLlon
Lools for daLa-sparse sysLems, as well as nonllnear ldenLlflablllLy Lools Lo esLabllsh whlch model
sLrucLures can be supporLed from a glven daLa seL, would asslsL ln dlseases where lnsufflclenL
sLaLe or measuremenL lnformaLlon (elLher spaLlally or Lemporally) ls a concern.
AnoLher need ls for lmproved (whlLe box) Lools for modellng daLa from populaLlons of
lndlvlduals and lndlvlduals of a glven populaLlon, and for maklng sure Lhe populaLlon and
lndlvldual models are conslsLenL. WlLh Lhe levels of uncerLalnLy lnvolved and Lhe nonllnear
dynamlcs of populaLlons, mulLlple sLaLlsLlcal and parameLer-esLlmaLlon Lools wlll need Lo be
used ln comblnaLlon.
3B2//,#:,- 2#' 92%%*,%- $& D%2#-/2$*&#
As noLed ln Lhe lnLroducLlon, Lhe fleld of blologlcal sysLems ls relaLlvely young ln Lerms of pracLlcal
appllcaLlons (markeL producLs), and several challenges musL be overcome ln LranslaLlng closed-loop
Lechnologles Lo pracLlce. 1he sheer complexlLy of (non-englneered) blologlcal (neLworked) sysLems ls
Lhe overarchlng daunLlng challenge. More speclflc obsLacles lnclude:

1he LranslaLlon of relevanL cllnlcal ouLcomes for paLlenL healLh lnLo correspondlng meLrlcs on
Lhe measured varlables ln Lhe body remalns a challenge for sensors and conLrol deslgn.
ln Lhe case of venLrlcular asslsL devlces, hlgh-level physlologlc conLrol ls a promlslng Lechnology.
Pow does one conLrol Lhe speed of Lhe pump and ln response Lo whaL sensors?
Notably, the objective in many medically oriented problems is patient quality of life, a soft
ob[ecLlve. Changlng Lo quallLy-ad[usLed llfe years (CAL?s) can provlde a numerlc meLrlc, buL Lhls
ls only ln Lhe aggregaLe, lL ls also conLroverslal because lL may lead Lo some paLlenLs noL belng
LreaLed due Lo Lhe lnsenslLlvlLy of Lhelr CAL? score Lo a parLlcular lnLervenLlon or LreaLmenL.
A crlLlcal LheoreLlcal challenge for conLrolled drug dellvery ls Lhe handllng of boLh lnLrapaLlenL
and lnLerpaLlenL varlablllLy. 1hls problem ls qulLe dlfferenL from englneerlng sysLems where
uncerLalnLy may be presenL, buL lL ls Lyplcally of flxed (for example, sLaLlonary) sLrucLure. ln
blology, Lhe varlablllLy ls profound, and Lhe same sub[ecL can dlffer slgnlflcanLly from one day Lo
Lhe nexL, dependlng on such facLors as sLress and envlronmenL. ln some speclflc slLuaLlons, such
as dlabeLes, Lhe lnLrasub[ecL varlaLlon ln crlLlcal sub[ecL parameLers (such as lnsulln senslLlvlLy)
far exceeds Lhe lnLerpaLlenL varlablllLy.
1he advances made ln blomedlcal devlces wlLh closed-loop conLrol capablllLles have been
enabled by developmenLs ln senslng and acLuaLlon. Conversely, Lhe lack of approprlaLe and safe
measuremenL and acLuaLlon devlces precludes many appllcaLlons.
8arrlers LhaL have delayed Lhe markeLlng of some conLrol-enabled devlces lnclude:
8egulaLory approval (by Lhe luA ln Lhe u.S.) for Lhe arLlflclal pancreas (see below). 1hese
agencles have noL handled feedback algorlLhms ln Lhe pasL, so Lhey are adapLlng Lo speclfy
requlremenLs for regulaLory approval. 1he conLrol communlLy could play a role here ln deslgnlng
protocols for stress testing, in other words, suitable disturbance scenarios to challenge the
closed-loop deslgns.
1he barrlers for cardlovascular devlces are comparable Lo oLher aspecLs of luA approval.
1he need for approprlaLe models and especlally modellng paradlgms for model-based conLrol
sysLems ralses quesLlons LhaL do noL have easy answers. Pow does one develop a rellable model
for paLlenLs wlLh wldely varylng physlologlcal characLerlsLlcs, how does one malnLaln such
models, whaL model paradlgm wlll faclllLaLe model developmenL for blomedlcal appllcaLlons?
CommunlcaLlon beLween sysLems englneers and cllnlclans ls also a barrler. Lach group speaks lLs
own language, wlLh assoclaLed [argon. unLll represenLaLlves of Lhe Lwo groups develop a
common language, ofLen as a naLural ouLcome of a close collaboraLlon, englneerlng soluLlons
may noL be solvlng cllnlcal problems ln an opLlmal way (lf aL all).
lrom a regulaLory sLandpolnL, Lhe focus should be on devlce (raLher Lhan drug) developmenL, as Lhe
paLhway Lo accepLance ls generally fasLer. A furLher concern ln conLrol algorlLhm developmenL ls Lhe
burden of proof requlred for algorlLhm-based devlce approval (superlorlLy vs. non-lnferlorlLy Lrlals), Lhe
Lechnlcal complexlLy ln Lhe algorlLhm (for example, closed loop, model-based, predlcLlve, adapLlve?),
and Lhe poLenLlal lnablllLy Lo a prlorl provlde bounds on devlce performance for all lndlvlduals, may
cause devlce re[ecLlon unless all posslble fallure modes are characLerlzed and evaluaLed ln slgnlflcanL

+,/,)$,' %,)&77,#'2$*&#- .&% %,-,2%)B *# $B, )&#$%&/ &. E*&/&:*)2/ -6-$,7-4
Success ln Lhe developmenL of Lhe arLlflclal pancreas, and of oLher closed-loop blomedlcal
devlces, wlll be conLlngenL on Lhe developmenL of robusL, verlflable advanced conLrol
algorlLhms.
AlgorlLhms for conLrolled drug dellvery are an exclLlng research opporLunlLy, advances are
needed Lo characLerlze and Lo accommodaLe Lhe conslderable lnLrapaLlenL as well as
lnLerpaLlenL varlablllLy LhaL exlsLs ln dlsease (and healLhy) populaLlons.
8lologlcal conLrol and dlagnosLlc appllcaLlons requlre modellng and sysLem ldenLlflcaLlon
approaches LhaL lnLegraLe sLrucLure deLermlnaLlon, parameLer esLlmaLlon, and model
verlflcaLlonand human undersLandablllLy of generaLed models ls an lmporLanL crlLerlon.
deLall. A secondary Lechnlcal concern ls Lhe lnherenL varlablllLy or uncerLalnLy encounLered ln a cllnlcal
paLlenL populaLlon, whlch ls Lyplcally greaLer Lhan 100 (parameLrlcally). A flnal compllcaLlng facLor ls
economlcs. 1he prlce of a devlce ls boLh markeL and developmenL cosL drlven. uevlces are ofLen Loo
expenslve for Lhe vasL ma[orlLy of paLlenLs, lack of lnsurance coverage may make lL lmposslble Lo reallze
proflLable sales volumes.
1he regulaLory approval process and Lhe economlcs of Lhe healLhcare sysLem are probably Lhe greaLesL
barrlers and are also Lhe leasL Lechnlcal ln naLure.
3&#)/(-*&#-
All of Lhe opporLunlLles dlscussed ln Lhls secLlon are effecLlvely worLhless ln Lhe medlcal arena lf Lhey
cannoL be LranslaLed Lo cllnlcal pracLlce. 1hls facL slmply hlghllghLs (1) Lhe need Lo communlcaLe more
effecLlvely Lhe sLrengLhs and weaknesses of conLrol Lools and calculaLlons wlLh nonconLrol experLs, and
(2) Lhe requlremenL LhaL lnLerfaces for any or all of Lhe aforemenLloned Lools be consLrucLed such LhaL
Lhe Lools can be deployed ln a cllnlcal envlronmenL by convenLlonal healLhcare provlders such as nurses.
llnally, Lo underscore Lhe lmporLance of Lhe promlse of blologlcal sysLems as a LargeL domaln for Lhe
conLrols communlLy, we noLe LhaL Lhree of Lhe naLlonal Academy of Lnglneerlng Crand Challenges [36]
have dlrecL relevance for conLrol sysLems Lechnology ln medlclne:
Lnglneer beLLer medlclnes. Lnglneers are developlng new sysLems Lo use geneLlc lnformaLlon,
sense small changes ln Lhe body, assess new drugs, and dellver vacclnes.
Advance healLh lnformaLlcs. SLronger healLh lnformaLlon sysLems noL only lmprove everyday
medlcal vlslLs, buL Lhey are essenLlal Lo counLerlng pandemlcs and blologlcal or chemlcal aLLacks.
8everse-engineer the brain. For decades, some of engineerings best minds have focused their
Lhlnklng skllls on how Lo creaLe Lhlnklng machlnescompuLers capable of emulaLlng human
lnLelllgence.

A,.,%,#),-
[1] W.8. Cannon. !"# B&1()+ )% /"# A)(28 new ?ork: W.W. norLon & Company, 1932.
[2] l.S. Crodlns. J)./0)' !"#)02 -.( A&)')5&,-' H21/#+18 new ?ork: Columbla unlverslLy ress, 1963.
[3] C.W. Swan. Optimal conLrol appllcaLlons ln blomedlcal englneerlng a survey, F6/8 J)./0)' N66'18 E#/")(1,
vol. 2, pp. 311-334, 1980.
[4] M.C.k. khoo. G"21&)')5&,-' J)./0)' H21/#+1< N.-'21&17 H&+4'-/&).7 -.( O1/&+-/&).8 new ?ork: Wlley, 1999.
[3] l.!. uoyle lll, L. !ovanovlc, u.L. Seborg, 8.S. arker, 8.W. 8equeLLe, A.M. !effrey, x. xla, l.k. Cralg, and 1.
McAvoy, A LuLorlal on blomedlcal process conLrol, >8 G0),#11 J)./0)', vol. 17, pp. 371-630, 2007.
[6] !. 8osLon, M. Slmaan, !. AnLakl, and ?. ?u. Control lssues ln roLary hearL asslsL devlces, in roc. Amerlcan
ConLrol Conference, 2000, pp. 3473-3477.
[7] L. A. Ceddes. PlsLorlcal hlghllghLs ln cardlac paclng, O.58 E#(8 A&)'8 E-587 vol.2, pp. 1218, 1990.
[8] B. Paden, J. Ghosh, and J. Antaki. Control sysLem archlLecLures for mechanlcal cardlac asslsL devlces, in
roc. Amerlcan ConLrol Conference, 2000, pp. 3478-3482.
[9] L. Baloa, D. Liu, and J. Boston. Control of roLary asslsL devices, in Proc. American Control Conference, 2000,
pp. 2982-2986.
[10] C. Clrldharan and M. Skliar. Nonlinear conLroller for venLrlcular asslsL devlces, N0/&%&,&-' F05-.17 vol. 26, pp.
980-984, 2002.
[11] S.A.. Paddad, 8..M. Pouben, and W.A. Serdl[n. 1he evoluLlon of pacemakers. O.58 E#(8 A&)'8 E-587 vol.
23, pp. 3848, 2006.
[12] P. Schlma, M. vollkron, u. !anLsch, 8. Crevenna, W. 8oeLhy, 8. 8enkowskl, C. Morello, M. CulLLan, M.
Plesmayr, and C. WleselLhaler. llrsL cllnlcal experlence wlLh an auLomaLlc conLrol sysLem for roLary blood
pumps durlng ergomeLry and rlghL-hearL caLheLerlzaLlon, >8 P#-0/ Q4.5 !0-.16'-./7 vol. 23 no. 2, pp. 167-73,
2006.
[13] 8.W. Bequette. A LuLorlal on blomedlcal process conLrol. lll. Modellng and conLrol of drug lnfuslon ln crlLlcal
care, >8 G0),#11 J)./0)'7 vol. 17, no. 7, pp. 382-386, 2007.
[14] S. Schraag. Theoretical basis of target control anaesthesia: Pistory, concept and clinical perspectives, A#1/
G0-,/&,#1 R D#1#-0," J'&.&,-' N.#1/"#1&)')527 vol. 13, no. 1, pp. 1-17, 2001.
[13] 8.C. Coudra and !.L. Mandel. Target-conLrolled lnfuslons/paLlenL-conLrolled sedation, !#,".&C4#1 &.
S-1/0)&./#1/&.-' O.()1,)627 vol. 11, pp. 181-187, 2009.
[16] 1.u. Lgan and S.L. Shafer. Target-conLrolled lnfuslons for lnLravenous anesLheLlcs. Surflng uSA not!
N.#1/"#1&)')527 vol. 99, no. 3, pp. 1039-1041, 2003.
[17] .!. Manberg, C.M. vozella, and S.u. kelley. Regulatory challenges facing closed-loop anesLheLlc drug
infusion devices, J'&.&,-' G"-0+-,)')52 R !"#0-6#4/&,17 vol. 84, no. 1, pp. 166-169, 2008.
[18] Medical News Today. New generation of insulin pump SLarbrldge secures global dlabeLes conLracL
[Cnllne], 19 november 2003. Avallable aL hLLp://www.medlcalnewsLoday.com/arLlcles/ 33847.php.

[19] E. Pfeiffer, C. Thum, and A.H. Clemens. The arLlflclal beLa cell a conLlnuous conLrol of blood sugar by
exLernal regulaLlon of lnsulln lnfuslon (glucose conLrolled lnsulln lnfuslon sysLem), P)0+8 E#/-*8 D#18, vol.
487, pp. 339-342, 1974.
[20] A. Clemens. Feedback conLrol dynamlcs for glucose conLrolled lnsulln lnfuslon sysLem. E#(8 G0)508
!#,".)'8, vol. 6, pp. 91-98, 1979.
[21] A. Alblsser. uevlces for Lhe conLrol of dlabeLes melllLus, ln G0),8 @OOO, vol. 67, pp. 1308-1322, 1979.
[22] H. Broekhuyse, J. Nelson, B. Zinman, and A. Albisser. Comparison of algorlLhms for Lhe closed-loop conLrol of
blood glucose uslng Lhe arLlflclal beLa cell, @OOO !0-.18 A&)+#(8 O.58, vol. 28, pp. 678-687, 1981.
[23] C.M. SLell and M.l. Saad. Automated lnsulln dellvery for Lype 1 dlabeLes, J4008 F6&.8 O.(),0&.)'8 ?&-*#/#1,
vol. 13, pp. 203-211, 2006.
[24] C. Cwens, P. Zlsser, L. Jovanovic, B. Srinivasan, D. Bonvin, and F.J. Doyle III, Run-Lo-run conLrol of blood
glucose concenLraLlons for people wlLh Lype 1 dlabeLes melllLus, @OOO !0-.18 A&)+#(8 O.58, vol. 33, pp. 996-
1003, 2006.
[23] 8. arker, l. uoyle, and N. Peppas. A model-based algorlLhm for blood glucose conLrol ln Lype l dlabeLlc
paLlenLs, @OOO !0-.18 A&)+#(8 O.58, vol. 46, pp. 148-137, 1999.
[26] 8. Povorka, L.!. Chassln, M.L. Wlllnska, v. Canonlco, !. Akwe, C.M. lederlcl, M. Massl-8enedeLLl, l. PuLzll, C.
Zaugg, P. kaufmann, M. 8oLh, 1. verlng, P. Schaller, L. Schaupp, M. 8odenlenz, and 1. leber, Closing the
loop: 1he adlcol experlence, ?&-*#/#1 !#,".)')52 R !"#0-6#4/&,17 vol. 6, pp. 307-318, 2004.
[27] C.M. SLell, k. 8ebrln, C. uarwln, l. Parlrl, and M.l. Saad. FeaslblllLy of auLomaLlng lnsulln dellvery for Lhe
LreaLmenL of Lype 1 dlabeLes, ?&-*#/#17 vol. 33, pp. 3344-3330, 2006.
[28] C. alerm, P. Zlsser, W. 8evler, L. !ovanovlc, and l.!. uoyle lll. Prandial lnsulln doslng uslng run-Lo-run
conLrol: AppllcaLlon of cllnlcal daLa and medlcal experLlse Lo deflne a sulLable performance meLrlc, ?&-*#/#1
J-0#, vol. 30, pp. 1131-1136, 2007.
[29] C. Llllngsen, L. uassau, P. Zlsser, 8. Crosman, M.W. erclval, L. !ovanovlc, and l.!. uoyle lll. Safety
ConsLralnLs ln an arLlflclal -cell: An lmplemenLaLlon of model predlcLlve conLrol wlLh lnsulln on board, >8
?&-*8 H,&8 !#,"87 vol. 3, pp. 336-344, 2009.
[30] l.P. Ll-khaLlb, S.!. 8ussell, u.M. naLhan, 8.C. SuLherlln, and L.8. uamlano. A blhormonal closed-loop arLlflclal
pancreas for Lype 1 dlabeLes, H,&8 !0-.1'8 E#(87 vol. 2, no. 27, pp. 1-12, 2010.
[31] 8. Povorka, !.M. Alle, u. Lllerl, L.!. Chassln, !. Parrls, u. xlng, C. kollman, 1. Povorka, A.M. Larsen, M. nodale,
A. ue alma, M.L. Wlllnska, C.L. Acerlnl, and u.8. uunger. Manual closed-loop lnsulln dellvery ln chlldren and
adolescenLs wlLh Lype 1 dlabeLes: A phase 2 randomlsed crossover Lrlal, Q-.,#/7 leb. 4, 2010.
[32] L. uassau, C. alerm, P. Zlsser, 8.A. 8ucklngham, L. !ovanovlc, and l.J. Doyle III. In slllco evaluaLlon plaLform
for arLlflclal pancreaLlc -cell developmenL a dynamlc slmulaLor for closed-loop conLrol wlLh hardware ln
Lhe loop, ?&-*#/#1 !#,"8 !"#08, vol. 11, pp. 187-194, 2009.
[33] P. Zlsser, L. 8oblnson, W. 8evler, L. uassau, C. Llllngsen, l.!. uoyle lll, and L. !ovanovlc. Bolus calculaLor: A
revlew of four smarL lnsulln pumps. ?&-*#/#1 !#,"8 !"#087 vol. 10, pp. 441-444, 2008.
[34] C.v. lleLcher, 8.C. 8rundage, 1. lenLon, C.C. Alvero, C. owell, L.M. Mofenson, and S.A. SpecLor.
harmacoklneLlcs and pharmacodynamlcs of efavlrenz and nelflnavlr ln Plv-lnfecLed chlldren parLlclpaLlng ln
an area-under-Lhe-curve conLrolled Lrlal., J'&.8 G"-0+-,)'8 !"#087 vol. 83, no. 2, pp. 300-6, 2008.

[33] lank eL al. 2006 !. lank, !. 8laha, !. Cordlngley, M.L. Wlllnska, L.!. Chassln, C. Morgan, S. Squlre, M. Paluzlk,
!. kremen, S. Svaclna, W. 1oller, A. lasnlk, M. Lllmerer, 8. Povorka, and 1.8. leber. MulLlcenLrlc,
randomlzed, conLrolled Lrlal Lo evaluaLe blood glucose conLrol by Lhe model predlcLlve conLrol algorlLhm
versus rouLlne glucose managemenL proLocols ln lnLenslve care unlL paLlenLs, ?&-*#/#1 J-0#7 vol. 29, pp.
271-6, 2006.
[36] naLlonal Academy of Lnglneerlng. Crand Challenges for Lnglneerlng [Cnllne], 2008. Avallable aL
hLLp://www.englneerlngchallenges.org/.
A,/2$,' 3&#$,#$
!"# @+6-,/ )% J)./0)' !#,".)')52 reporL also lncludes more Lhan 40 flyers describing specific success
sLorles and grand challenges in control engineering and science, covering a variety of application
domalns. 1he ones below are closely relaLed Lo Lhe Loplc of Lhls secLlon.
S0-.( J"-''#.5#1
8lophyslcal neLworks =8>8 ?)2'# @@@
uynamlcs and ConLrol for Lhe ArLlflclal ancreas =8>8 ?)2'# @@@
Plgh-erformance ConLrol wlLh Slow CompuLlng! D8 E400-2
8edeslgnlng a 8acLerlum ConLrol SysLem D8 E400-2
1hese flyersand all oLher reporL conLenLare avallable aL hLLp://leeecss.org/maln/loC1-reporL.