engineering design - bioreactors for bone tissue engineering 2

8/10/2019 Engineering Design - Bioreactors for Bone Tissue Engineering 2

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Bioreactors for Bone

Tissue EngineeringEngineering Design

SESM3001

Fras Wasim



Fras Wasim 24580505

1 IntroductionCurrent medica met!ods for treating "one defects caused "# traumatic in$uries

and diseases are imited% &uto'graft trans(ants are most common )!ere "one is

!ar*ested from t!e iiac crest% T!e "one a*aia"e is often imited and t!e(rocedure often eads to medica com(ications suc! as infection and c!ronic

(ain +1,% Tissue engineering a((roac!es oo-. instead. to)ards in'*itro cuturing

of "one marro) mesenc!#ma stem ces for trans(ant% T!e main aim of t!is

(ro$ect is to design a "io'reactor to create a 1cm3 (iece of s(ong# "one tissue%

Current#. most tissue engineering soutions can on# (roduce tissue t!ic-nesses

of a fe) miimetres +2, % T!is is "ecause of t!e c!aenges associated )it!

emuating in'*i*o conditions% T!e most common# used reactors for "one tissue

engineering incude/ s(inner as-. rotating )a. com(ression. magnetic and

(erfusion s#stems +3,% T!is re(ort )i in*estigate t!eir ad*antages and

disad*antages in order to nd an o(timum design%

2 Design Requirements T!e (rocess of cuturing "one tissue in*o*es t!ree (!ases% First. t!e stem ces

are seeded onto a scaod for gro)t!% steo"astic dierentiation must t!en "e

initiated "# introducing stimui and c!emica agents% nce t!e osteo"asts !a*e

formed. "one matri (roduction can occur +4,% T!ere are se*era (arameters t!at

need to "e controed to (ro*ide o(timum gro)t! conditions% T!ese incude/

o#gen and nutrient su((# (6 e*es tem(erature "ioc!emica agents and

mec!anica stresses +4,% 7niformit# of conditions t!roug!out t!e scaod is asoneeded to form "one )it! consistent (ro(erties%

First#. )!en t!e stem ces are seeded onto t!e scaod. an e*en distri"ution is

reuired% T!is is ac!ie*ed "# carefu design of t!e o) conditions% T!e (arit# of

nutrient and o#gen su((# is aso aected "# t!is% 9n static cuture. on# ces on

t!e surface of t!e scaod recei*e !ig! concentrations% T!e su((# gradient

needs to "e reduced in order to a*oid ce necrosis +5,% Waste (roducts aso need

to "e remo*ed e:cient#% 6o)e*er. if t!e rate of transfer is too !ig!. t!is disru(ts

ce communication deterring "one formation%

T!e o) aso im(oses *iscous s!ear stresses on t!e ces% Fuidic s!ear stresscaused "# oading in "ones !as "een !#(ot!esised to stimuate osteo"asts

)!ic! are res(onsi"e for matri (roduction +;,% W!en mec!anica forces are

a((ied. t!e ces a# do)n etraceuar matri in res(onse to t!e oading%

9ncrease in matri (roduction )i reduce t!e cuture time and create a more

functiona tissue +<,% T!e reuired in'*i*o s!ear stresses are estimated to "e in

t!e range of 0%8 to 3=a +8,% 6o)e*er. stimuation !as "een seen for *aues as o)

as 0%01 =a +>,% 9n addition to o) im(osed s!ear stress. c#cica !#drostatic

(ressure "# com(ression as )e as tensie straining !as "een s!o)n to increase

ce (roiferation as )e +10, +11,% Fei"iit# in oading conditions is desira"e as

o(timum conditions are sti un-no)n%

=age ? 1



Figure 1 ' @otating Bed Bioreactor +13,ure 2 ' Sc!ematic *ie) of s(inner as- )it! scaods attac!ed "# needes +3,

Fras Wasim 24580505

9n terms of commerciait#. t!e o*era design needs to "e sim(e and cost

eecti*e% 9t s!oud ao) for ease of use as )e. reuiring itte e(ert -no)edge

to o(erate% Steriit# issues are aso of utmost im(ortance% n# materias t!at

can "e autoca*ed or c!emica# treated ma# "e used% Scaod materia design is

aso im(ortant and is aected "# a t!e factors isted a"o*e t!is )i "e

discussed furt!er in Section 4%3%

3 Literature Review T!e sim(est "ioreactor is t!e s(inner as- )!ic! introduces magnetic stirring to

static cuture. as s!o)n in Error/ @eference source not found% T!is im(ro*es mass

transfer to t!e (eri(!er# of t!e scaod "ut not to t!e interior ce ingro)t! is

t!erefore imited% S(inner as- "ioreactors usua# rotate at 50rAmin +<,% T!is

needs to "e increased as ce necrosis sti occurs in t!e centre of t!e scaod%

6o)e*er. furt!er increases resuts in tur"uent o) )!ic! causes !ig! s!ear

stress on t!e (eri(!er# of t!e scaod destro#ing ces +<, +>,% @otating *esse"ioreactors so*e t!is (ro"em "# creating d#namic aminar o) to reduce

diusiona imits +12,% T!e# consist of a c#indrica outer and inner )a t!e

former. t!e atter or "ot! can "e rotated in order to generate increased mass

transfer% T!e !#drod#namic forces are "aanced )it! t!e gra*itationa forces

resuting in a microgra*it# en*ironment% Des(ite t!e en!anced mass transfer.

rotating )a "ioreactors !a*e seen o) success rates in com(arison to s(inner

as- and static cutures +>,% Some studies !a*e s!o)n t!is coud "e "ecause of

)a coisions resuting in ce damage and (oor ce attac!ment +1,% =romising

resuts !a*e

"een found "# attac!ing t!e scaod rigid# as s!o)n in Error/ @eference source

not found +13,% ig!ter t!an )ater scaods can aso "e used to imit t!e stresses

caused due to coision +1,%

=erfusion s#stems are "# far t!e most eecti*e in "one tissue engineering

"ecause t!e# ao) for t!e greatest (enetration for nutrient and o#gen su((ies%

T!e medium is forced t!roug! a tig!t# t scaod )it! !ig!# interconnected

(ores% =orosit# is im(ortant for t!ese s#stems in one stud#. it )as s!o)n t!at

greater cacium de(osition is seen for <5 (orosit# as com(ared to 50 +5,%

Moreo*er. t!e s!ear stress (roduced "# o) in (erfusion can "e su:cient for t!e

a((ication% T!e o) rate can "e used to ater it "ut t!is aects nutrient transfer%

=age ? 2



ure 3 ' Com"ined =erfusion and Com(ression S#stem +11,Figure 4 ' =erfusion C!am"er +1<,

ure 5 ' Com(arati*e stud# "et)een (erfusion and !#drostatic com(ression on "one marro) stroma cesFigure ; steocacin (roduction e*es in a (erfusion and com(ression stud#

Fras Wasim 24580505

7sing Euation 1. it "ecomes a((arent t!at c!anging *iscosit# is a more

desira"e o(tion% 9n a stud# )!ic! incor(orated detran to ater *iscosit#. a 3 fod

increase in *iscosit# resuted in a < fod increase in cacium de(osition +5,%

τ = μ du

dy 1

Com(ression s#stems a((# oading to t!e scaod materia eit!er t!roug! a

(iston or "# !#drauic (ressure and a dia(!ragm% T!e atter is more desira"e as

it ao)s for "etter steriit#% T!ese s#stems !a*e aso seen !ig! success rates instimuating ces% T!oug!. in order to a((# t!e (ressure. t!e scaods need to "e

stronger )!ic! )i aect t!eir degradation rates% Ge*ert!eess. com(ression'

(erfusion s#stems !a*e "een a"eed t!e o(tima design for "one tissue gro)t!

+14, an eam(e is s!o)n in Error/ @eference source not found%

=age ? 3



Fras Wasim 24580505

T!e resuts for a (erfusion and com(ression stud# are seen in Error/ @eference

source not found and Error/ @eference source not found% T!e com"ination of

(erfusion and !#drostatic com(ression does not increase ce (roiferation%

6o)e*er. it does resut in signicant# uic-er dierentiation rates as indicated

"# t!e osteocacin e*es in t!e atter diagram% Error in measurement is !ig! so it

is di:cut to te )!et!er t!ese resuts are concusi*e% & dua s#stem is muc!

more com(e t!an a singe one and t!e costs associated must "e $ustied

against t!e resuting im(ro*ements%

Fina#. magnetic stimuation is aso (ossi"e "# attac!ing magnetic nano(artices

direct# to t!e ce mem"rane or to ion c!anne (roteins% Time'*ar#ing magnetic

eds can "e used to a((# com(e and (recise oading direct# to t!e ces% T!e

scaoding does not need to "e strengt!ened as it )oud in ot!er mec!anica

stimuation met!ods% Degradation rates can "e decided more easi# as a resut% 9t

is non'in*asi*e so it is aso easier to -ee( steriit#% 9n addition. s(atia# *ar#ing

oad (roes can "e gi*en "# controing t!e (articesH magnetic (ro(erties +<,%

6o)e*er. studies !a*e s!o)n t!at magnetica# osciating forces do not increase

ce (roiferation "ut on# "one gene e(ression +15,% T!is is simiar to

com(ression oading% =rediction of forces ana#tica# can "e more c!aenging as

)e "ut t!e o*era mec!anica design is sim(e% Ce seeding can aso "e

controed to create a more e*en distri"ution%

4 Bio-Reactor Design

4.1 Main Design=erfusion is a necessar# reuirement for t!e design of t!e s#stem as it is t!e on#

)a# to ensure e:cient mass transfer% 9n terms of additiona oading conditions.

com(ression and magnetic s#stems !a*e "ot! !ad (ositi*e resuts% Magnetic

forces. e*en )it!out nano(artice addition. can im(ro*e ce cuture signicant#%9n a (articuar stud#. t!e a((ication of osciating eectromagnetic eds

increased matri cacication "# 5 fod +1;,% T!us. a t!ree (arameters )ere

incor(orated in t!e na design% Error/ @eference source not found to Error/

@eference source not found s!o) roug! modes of t!e cuti*ating c!am"er%

Furt!er dimensions and dra)ings are gi*en in t!e &((endi%

9n order to ac!ie*e (erfusion. t!e scaod )as made as a 111010 cu"oid for

cam(ing% 9t )as (aced in a cassette "# assuming a (ress t% Geo(rene rings are

used to sea t!e cassette in t!e c!am"er t!e ca( at t!e to( scre)s into t!e

outer case to create a com(ressi*e t +1<,% T!e rest of t!e materias )i main#"e made of =ers(e as it is easi# steriised "# et!#ene oide gas +<,% 9ts

=age ? 4



Figure < ' Fina C!am"er Design

Figure 8 ' Cross'sectiona *ie) of c!am"er designFigure > ' Cross'sectiona *ie) )it! (neumatic com(ression s#stem

Fras Wasim 24580505

trans(arenc# mig!t aso ao) for microsco(#% 9n terms of com(ression. a

(neumatic s#stem is used )it! t)o dia(!ragms at eit!er side of t!e cassette as

s!o)n in Error/ @eference source not found% T!e dia(!ragm aso scre)s into t!e

outer case to create tig!t seas% Fina#. t!e magnetic forces )ere ac!ie*ed "#

t)o soenoids/ 6em!otI coi +3,% B# ensuring t!at t!e cois are )ound in t!e

same direction and t!e distance. a . "et)een t!em is eui*aent to t!e radius

of t!e oo(s. a uniform ed can "e generated at t!e mid'(ane +18,% T!e num"er

of turns. G. and t!e current. 9. in t!e coi can "e set for a desired u densit#% &

=EMF generator can "e used to cause sinusoida *ariations in t!e magnetic ed

)!ic! im(ro*es cuture times% For ce seeding. a constant magnetic ed coud

aso "e used to ad$ust t!e distri"ution of ces%

¿=5√ 5Ba

32π 10

7

2

=age ? 5

@u""er Tu"e

for main o) Coi

=neumatico) tu"e to

incor(orate

com(ression

Geo(rene

Dia(!ragm

scre)ed into

t!e side for(neumatic

oading

Coi

Mounting

CassetteScaod



Figure 10 ' E(oded *ie) for C!am"er Design

Figure 11 ' Sc!ematic diagram of o*era s#stem

Fras Wasim 24580505

& sc!ematic for t!e o*era s#stem is aso s!o)n in Error/ @eference source not

found% T!e detais of sensors !a*e "een omitted for sim(icit#% For t!e (neumatic

s#stem. a 4A2 directiona contro *a*e is (rescri"ed% W!en t!e *a*e is in t!e eft

setting. t!e com(ressor )oud increase t!e (ressure on eft !and dia(!ragm%

W!en it is in its rig!t setting. t!e rig!t side )i "e (ressurised% Soenoid *a*es

ao) direct contro of t!e oading% C!ec- *a*es )i aso "e reuired at a

entrances to t!e cuture c!am"er to ao) for oad !oding%

=age ? ;

Geo(rene @ings for

seaing

Scaod

!oderACasse

uter casing To( )!ic!

!as ne

t!reads to

scre) and

cam( t!e

Dia(!ragms on

scre) in ca(s for



Fras Wasim 24580505

4.2 Fow !"aracteristics T!e main aim )oud "e to ac!ie*e a aminar o) as t!is )i create uniform

conditions and imit ce damage% For o) in circuar (i(es. t!e @e#nods num"er

must "e "eo) 2300 for t!is to occur t!e densit#. *iscosit#. o) *eocit# and

diameter "eing -e# (arameters% 9n t!is case. t!e o) c!am"er is uite sma and

!as a"ru(t# c!anging "oundaries t!e o) )i not "e fu# de*eo(ed so ana#tic

resuts "ecome di:cut to retrie*e% & CFD ana#sis is t!erefore reuired to fu#

understand t!e o) c!aracteristics%

9n terms of design met!odoog#. it )oud "e necessar# to see )!at o) rates

o(timise mass transfer of nutrients rst% Most studies use o) rates )it!in t!e

region of 0%;mAmin to 4mAmin +8,% 6ig! rates can interfere )it! ce'ce

signaing mec!anisms !indering gro)t! >mAmin is t!oug!t to "e t!e start of

gro)t! in!i"ition +>,% &fter t!e o) c!aracteristics !a*e "een ana#sed. t!e

geometr# and diameter can "e o(timised% Jiscosit# and densit# of t!e o)

medium coud aso "e atered if reuired% S!ear stresses are reuired to "e)it!in 3=a t!is )i t!en set t!e maimum o) rate ac!ie*a"e%

Dierent o) regimes can aso "e used/ continuous o). osciator# or (usatie

o)% =usatie o) !as s!o)n to increase oestrogenic dierentiation rates.

increasing e*es of a-aine (!os(!atase and etraceuar (rotein in com(arison

)it! continuous o) +1>,% T!oug!. most studies su((ort t!e use of continuous

o) regimes +>,% & com"ination of "ot! s!oud "e tested and com(ared%

4.3 #ca$od Materias T!e main design reuirements for t!e scaod are "io'com(ati"iit#.

"iodegrada"iit#. a((ro(riate surface c!emistr#. (ore siIe. s!a(e and mec!anica

strengt!% Bio'com(ati"iit# is fued "# most metas. (o#mers and ceramics%

T!e scaod and degradation (roducts s!oud not "e toic as t!is can (ro*o-e

inammator# res(onse +20,% Ce ad!esion and ce acti*ating (ro(erties are

eua# as im(ortant to ao) for en!anced gro)t! and transmission of forces in'

*itro% Bio'deri*ed "one scaods !a*e s!o)n to "e eecti*e in en!ancing

(roiferation "ut are dismissed due to t!e (ro"em of !ost re$ection%

9n addition. on# (o#mers and some ceramics are "iodegrada"e% T!e

degradation rate needs to "e controed (recise# to su((ort t!e tissue unti it

!as oad "earing ca(acit#% T!oug!. Kstress s!iedingH mig!t occur if it "ears toomuc! of t!e oad% Bone remodes itsef according to oading conditions if t!e

scaod ta-es too muc! of t!e stress. surrounding tissue ma# "ecome )ea-er%

T!us. t!e mec!anica strengt! s!oud "e simiar to t!at of t!e "one tissue%

Sig!t# stronger materia ma# "e reuired due to t!e com(ression a((ied in t!e

"ioreactor% T!e degradation rate and t!e mec!anica strengt! are conicting

(arameters increasing one negati*e# aects t!e ot!er% 9dea#. a materia is

reuired )!ere "ot! t!ese (arameters can "e c!anged inde(endent#% T!e time

of degradation *aries for dierent im(ant ocations "ut )i "e "et)een 3'18

mont!s +20,%

=age ? <



Fras Wasim 24580505

9nterconnected (orosit# is aso a reuirement )!ere (ore siIe needs to "e at

east 100 Lm 200'350Lm !as "een found t!e o(timum for "one in'gro)t! +21,%

S(ong# "one reuires !ig!# (orous and resistant scaods +20,% 9ts mec!anica

(ro(erties *ar# "ut its oungHs Moduus is "et)een 2 and 20M=a +21,% 9ncreased

(orosit# )i decrease t!e mec!anica strengt! "ut im(ro*e t!e nutrient and

o#gen circuation%

S#nt!etic (o#ester "ased (o#mers suc! as =&. =N& and =N& are t!e o"*ious

c!oice as t!eir degradation (ro(erties can "e taiored to needs% T!oug!. t!eir

mec!anica strengt! can "e on t!e o) side% For t!is reason. 9='C6& is c!osen as

t!e scaod materia% 9t is a !#dro#a(atite ceramic t!at !as "een "uit )it!

inter'(orous connections to im(ro*e ce ingro)t!% 9t !as a com(ressi*e strengt!

of 10'12M=a. an a*erage (ore siIe of 150 Lm and a !ig! (orosit# of <0% T!ese

are suita"e (arameters for canceous "one and (erfusion% 9t !as "een used in

*arious cinica situations and s!o)n good "iocom(ati"iit# and (ositi*e resuts

+22,% 6#dro#a(atite is a ma$or constituent of "one and so !as "een -no)n toim(ro*e ce (roiferation%

4.4 Monitoring Met"ods T!e common feed"ac- *aria"es are 2 and gucose consum(tion. C2

(roduction. (6 e*es and tem(erature% First#. t!e current design is sma

enoug! for incu"ation to ao) for tem(erature contro% T!e ot!ers need to "e

controed "# feed"ac-% T!e sensors used to measure t!ese *aria"es can "e

eit!er in*asi*e or non'in*asi*e% Direct contact )it! t!e uid or ces )i im(ro*e

t!e uait# of data !o)e*er. t!e sensors used must "e a"e to )it!stand

steriisation (rocesses and once (aced. re'cai"ration )i "ecome di:cut +<,%

Micro'eectrodes and "re o(tic sensors can "e used to measure o#gen e*es

res(ecti*e#% Gon'in*asi*e met!ods incude o(tica met!ods suc! as

s(ectro(!otometr# or uorimetr# "ut t!ere is a di:cut# to ac!ie*e !ig!

sensiti*it#% D#es can "e used )!ic! are sensiti*e to dierent (arameters%

Steriisation issues can "e a*oided and cai"ration "ecomes easier +<,%

% !oncusion To concude. it )as found t!at (erfusion s#stems are necessar# to su((# an

e*en distri"ution of nutrients and mineras% Com(ression s#stems and magnetic

eds are aso (romising as t!e# increase ce dierentiation and matri

(roduction res(ecti*e#% & s#stem )as de*ised )!ic! incor(orated a t!ese

designs% T!is ao)s for greater *ersatiit# and a arge range of cuture conditions

(ossi"e%

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