Lec13 03212007 W PDF

10.
37 Chemical and Biological Reaction Engineering, Spring 2007

Prof. K. Dane Wittrup
Lecture 13: Biological Reactors- Chemostats
This lecture covers: theory of the chemostat, fed batch or semi-continuous fermentor
operations
Biological Reactors (Chemostat)

Concentration/Combustion constant
Biological CSTR
[S]0
[S], x
V
F
Figure 1. Diagram of a chemostat.
F = Volumetric flow rate
x=
biomass
volume
[S]0 = Concentration of growth limiting substrate. (for growing cells)

At steady-state, biomass balance
In Out + Prod = Acc
Sterile feed: In=0
Steady state: Acc=0
Fx + rx V = 0 at steady-state
Cell growth kinetics rx = x
Fx + x V = 0
F
Solve =
V
F 1
=
D=Dilution rate
V
=D
Biological
Mechanical
Cite as: K. Dane Wittrup, course materials for 10.37 Chemical and Biological Reaction Engineering, Spring
2007. MIT OpenCourseWare (http://ocw.mit.edu), Massachusetts Institute of Technology. Downloaded on
[DD Month YYYY].
When at steady-state, can control cell mass.

Allows precisely reproducible cell states.
Not easy to run at steady-state.
Material balance on [S] (sugar concentration)
In Out + Prod = Acc
0
F [ S ]0 F [ S ]
at steady-state
1
x V = 0
Yx
s
mass biomass created
Yield coefficient
mass substrate consumed
Divide by V
x
D ([ S ]0 [S]) =

Yx
change in sugar
concentration
At steady-state
=D
x = Yx ([ S ]0 [S])
s
What is the value of
= f ([S])
[S] ? What more information do we need?
must choose a growth model to connect
and
[S]
Monod growth model:
max [ S ]
K s + [S ]
[S ] =
at steady-state
Ks D
max D
D=
max [ S ]
K s + [S ]
substitute in x equation
10.37 Chemical and Biological Reaction Engineering, Spring 2007

Lecture 13
Page 2 of 6
[DD Month YYYY].

Ks D
x = Yx [ S ]0
max D
s
Specifying
max , K s , Yx , D , [ S ]0 , can predict x , [S] .

s
x < 0 is non-physical but formally in solution
max D
can go to 0. If you turn knobs incorrectly: if D is too high, the cells cannot
grow fast enough to reach steady-state. Washout will occur.

so use x = 0 to find Dmax
Dmax =
max [ S ]0
K s + [ S ]0
For D > Dmax washout, no steady-state.
x, S
x
mass
volume
washout
Dmax
Figure 2. Biomass/volume versus dilution rate. Beyond the maximum dilution rate,
washout occurs.
For real systems K s << [ S ]0 . Most cell growth systems reach maximum at fairly low
concentrations; hence x is flat, then drops off sharply.

If biomass is the product, is there a best operating condition?
What should we consider?
dx
optimize x with respect to D? D=0 (no, because this would be batch reactor)
dD
Define productivity as
biomass
(reactor
volume )( time )
= xD

Lecture 13
Page 3 of 6
[DD Month YYYY].
d ( xD)
= 0 for optimum. (is a maximum)
dD
x
xD
D
Doptimum
Figure 3. Left: Biomass/volume versus dilution rate. Right: Productivity versus

dilution rate.
Ks
Doptimum = max 1
K s + [ S ]0
K s << [ S ]0
Doptimum max
Dmax
Close to washout conditions.
Operability would be difficult. We would not want to run too close to washout
conditions.
Fed-batch fermentor (microbes or mammalian cells)
-used to achieve very high cell densities (e.g. hundreds of grams cell dry weight
(c.d.w)/liter)
If you want x final =
100 g
L
If Yx 0.5 , [S]0 =
wt
200 g
20%
Toxic, sugar content cells will die
L
volume
Why do we not feed all at once? Cells will die.
Calculate medium feed rate in order to hold
constant.

Lecture 13
Page 4 of 6
[DD Month YYYY].
[S]0
x(t)
S(t), very small
Figure 4. Diagram of a fed-batch fermentor.
If
is constant, biomass = biomass t =0 e
There is a dilution term, because as we feed in fresh medium, volume will change.
Volume often doubles.
x V = x0 V0 e t
x0 V0 e t
F[S ] =

0
Feed
sugar feed
Yx
s
sugar consumed
Assume all converted into biomass.
F=
x0 V0
e t
[ S ]0 Yx
s
Exponential flow rate. Typically
specified as small.
Dilution:
dV
=F
dt
x0
V(t ) = V0 1 +
e t 1)
(
[ S ]0 Yx
x=
biomass
x0 e t
=
1+
x0
e t 1)
(
Yx [ S ]0
s
x0 V0 e
V

Lecture 13
Page 5 of 6
[DD Month YYYY].
Logistic equation
Figure 5. Graph of logistic growth.
t
If product is something cells are making:
Product synthesis kinetics
1)
1 dP
=
x dt
P
2)
growth associated (e.g. ethanol)
product
volume
1 dP
=
x dt
t
P = xdt
0
not growth associated (e.g. antibiotics, proteins, antibodies)

integrate for amount of product.

Lecture 13
Page 6 of 6
[DD Month YYYY].

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10.

37 Chemical and Biological Reaction Engineering, Spring 2007

Biological Reactors (Chemostat)

[S]0 = Concentration of growth limiting substrate. (for growing cells)

When at steady-state, can control cell mass.

mass biomass created

mass substrate consumed

What is the value of

[S] ? What more information do we need?

must choose a growth model to connect

Monod growth model:

10.37 Chemical and Biological Reaction Engineering, Spring 2007

max , K s , Yx , D , [ S ]0 , can predict x , [S] .

x < 0 is non-physical but formally in solution

grow fast enough to reach steady-state. Washout will occur.

For D > Dmax washout, no steady-state.

concentrations; hence x is flat, then drops off sharply.

10.37 Chemical and Biological Reaction Engineering, Spring 2007

Figure 3. Left: Biomass/volume versus dilution rate. Right: Productivity versus

Why do we not feed all at once? Cells will die.

Calculate medium feed rate in order to hold

10.37 Chemical and Biological Reaction Engineering, Spring 2007

is constant, biomass = biomass t =0 e

Assume all converted into biomass.

Exponential flow rate. Typically

10.37 Chemical and Biological Reaction Engineering, Spring 2007

Figure 5. Graph of logistic growth.

growth associated (e.g. ethanol)

not growth associated (e.g. antibiotics, proteins, antibodies)

10.37 Chemical and Biological Reaction Engineering, Spring 2007

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