Biomedical Engineering Reference
In-Depth Information
1992a, b, 1994; Hu
et al.
, 1995
, 1998;
Mitsumata
et al.
,
2001; Kaneko
et al.
, 2002; Gao and Hu, 2002
). Okano
and co-workers have developed smart gels that collapse
very rapidly, by grafting PNIPAAm chains to the
PNIPAAm backbone in a cross-linked PNIPAAm
hydrogel (
Yoshida
et al.
, 1995; Masahiko
et al.
, 2003
).
Smart hydrogel compositions have been developed that
are both thermally gelling and biodegradable (
Zhong
et al.
, 2002; Yoshida
et al.
, 2003
). These sol-gel systems
have been used to deliver drugs by
in vivo
injections
and are discussed in the section on smart polymers in
solution.
Hoffman and co-workers were among the first to
recognize the potential of PNIPAAm hydrogels as bio-
materials; they showed that the smart gels could be used
(a) to entrap enzymes and cells, and then turn them on
and off by inducing cyclic collapse and swelling of the gel,
and (b) to deliver or remove biomolecules, such as drugs
or toxins, respectively, by stimulus-induced collapse or
swelling (
Dong and Hoffman, 1986, 1987, 1990; Park
and Hoffman, 1988, 1990a, b, c
)(
Fig. 3.2.6-6
). One
unique hydrogel was developed by
Dong and Hoffman
(1991)
. This pH- and temperature-sensitive hydrogel
was based on a random copolymer of NIPAAm and AAc,
and it was shown to release a model drug linearly over
a 4-hour period as the pH went from gastric to enteric
conditions at 37
C. At body temperature the NIPAAm
component was trying to maintain the gel in the collapsed
state, while as the pH went from acidic to neutral con-
ditions, the AAc component was becoming ionized,
forcing the gel to swell and slowly release the drug (see
Fig. 3.2.6-6B
).
Kim, Bae, and co-workers have investigated smart gels
containing entrapped cells that could be used as artificial
organs (
Vernon
et al.
, 2000
). Matsuda and co-workers
have incorporated PNIPAAm into physical mixtures with
natural polymers such as hyaluronic acid and gelatin, for
use as tissue engineering scaffolds (
Ohya
et al.
, 2001a
,b).
Peppas and co-workers (
Robinson and Peppas, 2002
)
have studied pH-sensitive gels in the form of nano-
spheres. Nakamae, Hoffman, and co-workers developed
novel compositions of smart gels containing phosphate
groups that were used to bind cationic proteins as model
drugs and then to release them by a combination of
thermal stimuli and ion exchange (
Nakamae
et al.
, 1992
,
1997;
Miyata
et al.
, 1994
).
Smart gels that respond
to biological stimuli
A number of drug delivery devices have been designed to
respond to biologic signals in a feedback manner. Most of
these gels contain an immobilized enzyme.
Heller and
Trescony (1979)
were among the first to work with smart
enzyme gels. In this early example, urease was immobi-
lized in a gel, and urea was metabolized to produce am-
monia, which caused a local pH change, leading to
a permeability change in the surrounding gel.
Ishihara
et al.
(1985)
also developed a urea-responsive gel containing
immobilized urease. Smart enzyme gels containing glucose
oxidase (GOD) were designed to respond to a more rel-
evant signal, that of increasing glucose concentration. In
a typical device, when glucose concentration increases, the
entrapped GOD converts the glucose in the presence of
oxygen to gluconic acid and hydrogen peroxide. The
former lowers pH, and the latter is an oxidizing agent.
Each of these byproduct signals has been used in various
smart hydrogel systems to increase the permeability of
the gel barrier to insulin delivery (
Horbett
et al.
,1984;
Albin
et al.
, 1985; Ishihara
et al.
,1983
, 1984a;
Ishihara
and Matsui, 1986; Ito
et al.
, 1989; Iwata and Matsuda,
1988
).
In one case, the lowered pH due to the GOD by-
product, gluconic acid, accelerated hydrolytic erosion of
the polymer matrix that also contained entrapped in-
sulin, releasing the insulin (
Heller
et al.
, 1990
). Siegel
and co-workers have used the glucose-stimulated swell-
ing and collapse of hydrogels containing entrapped GOD
Δ
(T)
Burst release
of drug out of HG
(A) Swollen smart HG,
loaded with drug
H
2
O
Δ
(pH)
H
2
O
(B) Collapsed and dry,
smart HG loaded with drug
pH-controlled
swelling, with diffusion
of drug out of HG
Δ
(T)
(C) Solution of smart
copolymer containing
dissolved or dispersed drug
Gel forms and drug
gradually diffuses out of gel
Fig. 3.2.6-6 Schematic illustration showing three ways that smart
gel formulations may be stimulated to release bioactive agents:
(A) thermally induced collapse, which is relevant to skin or mucosal
drug delivery; (B) pH-induced swelling, which is relevant to oral
drug delivery, where the swelling is induced by the increase in pH
in going from the gastric to enteric regions; and (C) sol-to-gel
formation, which is relevant to injectable or topical formulations of
a triblock copolymer solution that are thermally gelled at body
temperature. For in vivo uses, the block copolymer is designed to
be degradable. The first two apply to cross-linked gels applied
topically or orally, and the third is relevant to thermally induced
formation of gels from polymer solutions that are delivered
topically or by injection.
