Biomedical Engineering Reference
In-Depth Information
programming, allow production of scaffolds with very
regular and ultrafine structures. The control over scaffold
architecture using these fabrication techniques is highly
process driven and not design driven.
In the case of hydrogels, the freeze-dry processing does
not require additional chemicals, relying on the water al-
ready present in hydrogels to form ice crystals that can be
sublimated from the polymer, creating a particular micro-
architecture. Because the direction of growth and the size
of ice crystals are a function of the temperature gradient,
linear, radial, and/or random pore directions and sizes can
be produced with this methodology.
For the freeze-drying process, the solvent vapor
pressure at the drying temperature (usually very low)
needs to be high enough to allow its removal. Dime-
thylcarbonate can also be used as a solvent because it
exhibits high vapor pressure and melting point around
0
C which makes it suitable for sublimation. Because of
a solubility parameter close to that of dioxane, this sol-
vent might be convenient as an alternative to dioxane
(potentially carcinogen) for freeze drying of poly(a-
hydroxyacid)s. Dimethyl sulfoxide (DMSO) cannot be
used as the solvent for PLGA for the freeze-drying pro-
cess due to its low vapor pressure. This limitation of
choosing solvent may be lifted when the scaffolds are
prepared by a freeze-extraction method. Freeze extrac-
tion and freeze gelation are of a type of phase separation.
These methods also fix the porous structure under freez-
ing condition, but in the subsequent drying stage the
freeze-drying process is not needed. The principle of the
freeze-extraction method is to remove the solvent by
extraction with a non-solvent. After the removal of sol-
vent, the space originally occupied by the solvent is taken
by the non-solvent and the polymer is then surrounded
with the non-solvent. Under this circumstance, even at
room temperature, the polymer would not dissolve.
Hence, drying can be carried out at room temperature to
remove the non-solvent, leaving space that becomes
pores in the scaffold. For the freeze-extraction process,
DMSO can be used as the solvent for preparation of
PLGA scaffolds, because it can be easily extracted out by
ethanol aqueous solution.
7.2.3.1 Phase separation (freeze drying)
A widely used method for preparation of porous scaf-
folds is the thermally induced phase separation, in which
the solution temperature is lowered to induce phase
separation of the homogeneous polymer solution. The
phase separation mechanism may be liquid-liquid
demixing, which generates polymer-poor and polymer-
rich liquid phases. The subsequent growth and co-
alescence of the polymer-poor phase would develop to
form pores in scaffolds. On the other hand, when the
temperature is low enough to allow freeze of the solu-
tion, the phase separation mechanism would be solid-
liquid demixing, which forms frozen solvent and
concentrated polymer phases. By adjusting the polymer
concentration, using different solvents, or varying the
cooling rate, phase separation could occur via different
mechanisms, resulting in the formation of scaffolds with
various morphologies. ''Freeze drying'' is one of the most
extensively used methods that produce matrices with
porosity greater than 90%. The pore sizes depend on the
growth rate of ice crystals during the freeze-drying
process.
After removal of the liquid or frozen solvent contained
in the demixed solution, the space originally occupied by
the solvent would become pores in the prepared scaffolds.
Obviously, in the stage of solvent removal, the porous
structure contained in the solution needs to be carefully
retained. Without freeze drying, a rise in temperature
during the drying stage could result in remixing of the
phase-separated solution or remelting of the frozen solu-
tion, leading to destruction of the porous structure. Thus,
the reason of using freeze drying to remove solvent is quite
obvious: to keep the temperature low enough that the
polymer-rich region would not redissolve and possesses
enough mechanical strength to prevent pore collapse
during drying. Although freeze drying is a widely used
method to prepare porous scaffolds, it is time consuming
and energy consuming. For instance, it often takes 4 days
to remove solvent by freeze drying. During this 4-day
period, a lot of energy is consumed to keep vacuum and to
maintain the low temperature needed for drying. Another
problem encountered in the application of freeze drying is
the occurrence of surface skin. During the freeze-drying
stage, if the temperature is not controlled low enough, the
polymer matrix in the demixed solution would not be
rigid enough to resist the interfacial tension caused by the
evaporation of solvent. Thus, the porous structure col-
lapses and dense skin layers occur in the prepared scaffold.
7.2.3.2 Porogen leaching
The porogen leaching method has also been widely used
to prepare porous scaffolds, because of easy operation
and accurately controlling pore size and porosity. The salt
leaching technique consists of adding salt particulates to
a polymer solution. The overall porosity and level of pore
connectivity are regulated by the ratio of polymer/salt
particulates and the size of the salt particulates.
7.2.3.3 Fiber bonding
Fiber mesh consists of individual fibers either woven or
knitted into 3-D patterns of variable pore sizes. They can
