Poly(lactide) Stereocomplexes: Formation, Structure, Properties, Degradation, and Applications Hideto Tsuji Department of Ecological Engineering, Faculty of Engineering, Toyohashi University of Technology, Tempaku-cho, Toyohashi, Aichi 441-8580, Japan E-mail: [email protected]Received: March 23, 2005; Revised: May 18, 2005; Accepted: May 20, 2005; DOI: 10.1002/mabi.200500062 Keywords: association; biodegradable; biomaterials; blends; polyesters; stereospecific polymers 1. Introduction When the interaction between polymers having different tacticities or configurations prevails over that one between polymers with the same tacticity or configuration, a stere- oselective association of the former polymer pair takes place. Such association is described as stereocomplexation or stereocomplex formation. A well known and typical example of stereocomplexation is the one between isotactic and syndiotactic poly(methyl methacrylate) (PMMA), which was first reported by Fox et al. in 1958. [1] The first example of stereocomplexation (stereoselective associa- tion) for enantiomeric polymers, i.e. between R- and S-configured (or L- and D-configured) polymer chains, was reported by Pauling and Corey for a polypeptide in 1953. [2] However, it seems that the detailed structures of the polypeptide and its assemblies are unclear. With respect to optically active polyesters, Grenier and Prud’homme [3] Summary: Poly(lactide)s [i.e. poly(lactic acid) (PLA)] and lactide copolymers are biodegradable, compostable, produ- cible from renewable resources, and nontoxic to the human body and the environment. They have been used as bio- medical materials for tissue regeneration, matrices for drug delivery systems, and alternatives for commercial polymeric materials to reduce the impact on the environment. Since stereocomplexation or stereocomplex formation between enantiomeric PLA, poly(L-lactide) [i.e. poly(L-lactic acid) (PLLA)] and poly(D-lactide) [i.e. poly(D-lactic acid) (PDLA)] was reported in 1987, numerous studies have been carried out with respect to the formation, structure, properties, degrada- tion, and applications of the PLA stereocomplexes. Stereo- complexation enhances the mechanical properties, the thermal-resistance, and the hydrolysis-resistance of PLA- based materials. These improvements arise from a peculiarly strong interaction between L-lactyl unit sequences and D-lactyl unit sequences, and stereocomplexation opens a new way for the preparation of biomaterials such as hydrogels and particles for drug delivery systems. It was revealed that the crucial parameters affecting stereocom- plexation are the mixing ratio and the molecular weight of L-lactyl and D-lactyl unit sequences. On the other hand, PDLA was found to form a stereocomplex with L-configured polypeptides in 2001. This kind of stereocomplexation is called ‘‘hetero-stereocomplexation’’ and differentiated from ‘‘homo-stereocomplexation’’ between L-lactyl and D-lactyl unit sequences. This paper reviews the methods for tracing PLA stereocomplexation, the methods for inducing PLA stereocompelxation, the parameters affecting PLA stereo- complexation, and the structure, properties, degradation, and applications of a variety of stereocomplexed PLA materials. Macromol. Biosci. 2005, 5, 569–597 DOI: 10.1002/mabi.200500062 ß 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Review 569
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Department of Ecological Engineering, Faculty of Engineering, Toyohashi University of Technology, Tempaku-cho,Toyohashi, Aichi 441-8580, JapanE-mail: [email protected]
Received: March 23, 2005; Revised: May 18, 2005; Accepted: May 20, 2005; DOI: 10.1002/mabi.200500062
When the interaction between polymers having different
tacticities or configurations prevails over that one between
polymers with the same tacticity or configuration, a stere-
oselective association of the former polymer pair takes
place. Such association is described as stereocomplexation
or stereocomplex formation. A well known and typical
example of stereocomplexation is the one between isotactic
and syndiotactic poly(methyl methacrylate) (PMMA),
which was first reported by Fox et al. in 1958.[1] The first
example of stereocomplexation (stereoselective associa-
tion) for enantiomeric polymers, i.e. between R- and
S-configured (or L- and D-configured) polymer chains, was
reported by Pauling and Corey for a polypeptide in 1953.[2]
However, it seems that the detailed structures of the
polypeptide and its assemblies are unclear. With respect to
optically active polyesters, Grenier and Prud’homme[3]
Summary: Poly(lactide)s [i.e. poly(lactic acid) (PLA)] andlactide copolymers are biodegradable, compostable, produ-cible from renewable resources, and nontoxic to the humanbody and the environment. They have been used as bio-medical materials for tissue regeneration, matrices for drugdelivery systems, and alternatives for commercial polymericmaterials to reduce the impact on the environment. Sincestereocomplexation or stereocomplex formation betweenenantiomeric PLA, poly(L-lactide) [i.e. poly(L-lactic acid)(PLLA)] andpoly(D-lactide) [i.e. poly(D-lactic acid) (PDLA)]was reported in 1987, numerous studies have been carried outwith respect to the formation, structure, properties, degrada-tion, and applications of the PLA stereocomplexes. Stereo-complexation enhances the mechanical properties, thethermal-resistance, and the hydrolysis-resistance of PLA-based materials. These improvements arise from a peculiarly
strong interaction between L-lactyl unit sequences andD-lactyl unit sequences, and stereocomplexation opens anew way for the preparation of biomaterials such ashydrogels and particles for drug delivery systems. It wasrevealed that the crucial parameters affecting stereocom-plexation are the mixing ratio and the molecular weight ofL-lactyl and D-lactyl unit sequences. On the other hand,PDLAwas found to form a stereocomplex with L-configuredpolypeptides in 2001. This kind of stereocomplexation iscalled ‘‘hetero-stereocomplexation’’ and differentiated from‘‘homo-stereocomplexation’’ between L-lactyl and D-lactylunit sequences. This paper reviews the methods for tracingPLA stereocomplexation, the methods for inducing PLAstereocompelxation, the parameters affecting PLA stereo-complexation, and the structure, properties, degradation, andapplications of a variety of stereocomplexed PLA materials.
process, in marked contrast to stereocomplexation between
isotactic and syndiotactic PMMA, where an association
Hideto Tsuji is an Associate Professor at the Faculty of Engineering, Toyohashi University ofTechnology (Aichi, Japan). He was born in Osaka (Japan) in 1961. He received his Ph.D. degree inpolymer chemistry in 1992 from the Kyoto University (Japan) under the supervision of ProfessorYoshito Ikada. His Ph.D. work focused on the stereocomplexation between enantiomeric poly(lacticacid)s. After he finished his Ph.D. program, he moved to the Technology Development Center,Toyohashi University of Technology as a Research Associate in 1990. In 1996 as a Visiting Researcher,he joined the group of Professor William Bonfield and Dr. Raymond Smith at the Queen Mary andWestfield College, University of London (U.K.), where he studied the preparation methods ofbiodegradable porous materials. He became an Associate Professor at the Faculty of Engineering,Toyohashi University of Technology, in 1997. His research interests include the developments ofpoly(lactide)s and other biodegradable polyesters for a variety of applications and the manipulation oftheir physical properties and degradability. He has been investigating the synthesis, treatments, blend-ing, physical properties, crystallization, hydrolytic degradation, biodegradation, thermal degradation,and recycling of poly(lactide)s and other biodegradable polyesters. He has authored and coauthoredmore than 75 original research papers, 15 review articles, 5 patent articles, and 25 book chaptersincluding Chapter 5 in ‘‘Polyesters III (Biopolymers, vol. 4, Wiley-VCH, 2002)’’.
a maximum at mixing ratio XD of 0.5 and with a deviation of
XD from 0.5 the DHm of homocrystallites increases. This
reflects the fact that equimolar mixing is favored for
stereocomplexation.
Tsuji and Ikada have estimated the equilibrium melting
temperature (Tm0 ) of PLA stereocomplex crystallites by
extrapolation of Tm0 values for different optical purities,
which were obtained by the Hoffman-Weeks procedure
using experimental Tm values, to 100% optical purity.[23]
The estimated Tm0 value of 279 8C is much higher than the
205 8C (Tsuji and Ikada[38,39]), 212 8C (Tsuji and Ikada[40]),
and 215 8C (Kalbs and Pennings[41]) reported for homo-
crystallites of PLLA. The reported DHm values for the
crystals having an infinite thickness [DHm(100%)] for PLA
Figure 2. Crystallite models for enantiomeric L- and D-poly-mers.[19] (a) a homo-crystallite composed of L-polymer chains; (b)a homo-crystallite composed of D-polymer chains; (c) a stereo-complex (racemic) crystallite where L- and D-polymers are packedside by side; (d) a crystallite where L- and D-polymer chains arepacked randomly; (e) a mixture of (a) and (b).
2y values of 15, 17, and 198,[4] which are comparable with
the results for the a form of PLLA crystallized in a pseudo-
orthorhombic unit cell of dimensions: a¼ 1.07 nm,
b¼ 0.595 nm, and c¼ 2.78 nm, which contains two 103helices.[36,47] The most intense peaks of equimolarly
blended film (XD¼ 0.5) are observed at 2y values of 12,
21, and 248. These peaks are for the PLA stereocomplex[4]
crystallized in a triclinic unit cell of dimensions: a¼0.916 nm, b¼ 0.916 nm, c¼ 0.870 nm, a¼ 109.28,b¼ 109.28, and g¼ 109.88, in which L-lactide and D-lactide
segments are packed parallel taking 31 helical conforma-
tion.[47] The crystal structure of the PLA stereocomplex
proposed by Okihara et al.[47] is demonstrated in Figure 5.
The lattice containing a PLLA or PDLA chain with a 31helical conformationhas the shape of an equilateral triangle,
which is expected to form equilateral-triangle-shaped
single crystals of the PLA stereocomplex.[48] On the other
hand, Okihara et al. found that in the X-ray and electron
diffraction patterns of drawn fibers of the PLA stereo-
complex, the equatorial reflections were sharp, but those on
the layer lines were largely broadened in the direction
parallel to the layer line, becomingmore diffuse as the layer
order increases. On the basis of the paracrystalline theory,
they estimated the degree of shift disorder among polymer
chains in the direction parallel to the molecular axis to be
0.1.[49] Furthermore, Brizzolara et al.[50] compared the
WAXS profiles from actual stereocomplexed specimens
and a Force-Field simulated stereocomplex. They also
proposed the growth mechanism of the stereocomplex
equilateral-triangle-shaped single crystal.
Figure 3. DSC thermograms of PLLA/PDLA blends withdifferent XD values.[21] Viscosity-average molecular weights(Mvs) of PLLA and PLLA are both 3.6� 105 g �mol�1.
Table 3. Physical properties of stereocomplexed PLA and some biodegradable polyesters.[36]
a) Enthalpy of melting of crystal having infinite size.b) Activation energy for thermal degradation estimated by thermogravimetry at a constant temperature (250–270 8C).c) 300 nm, 23 8C.d) Water vapor transmission rate at 25 8C.e) Poly[(R)-3-hydroxybutyrate-co-3-hydroxyvalerate] (94/6).f) Oriented fiber.g) Non-oriented films.
The result obtained from SAXS analysis was solely for
the long period of the PLA stereocomplex precipitated from
acetonitrile solutions at 80 8C and annealed at 216 8C.[43]
The estimated long period was 12 nm, which is much
smaller than the 22–35 nm reported for PLLA films
crystallized at 120–160 8C from the melt.[51] Using the
crystallinity (Xc) value obtained by a WAXS profile (70%),
the estimated thickness values of stereocomplex crystalline
and amorphous regions were 8.4 and 3.6 nm, respec-
tively.[43] The estimated thickness of stereocomplex crys-
talline regions is also much smaller than the 13–22 nm
reported for PLLAfilms crystallized at 120–160 8C.[51] The
differences in long period and crystalline thickness between
the stereocomplex and PLLA are partly ascribed to the
differences in the specimen preparation method and
conditions.
2.3. Infrared (IR) and Raman Spectroscopy
Kister et al.[52] observed IR and Raman spectral changes in
peak shapes and wavelengths upon PLA stereocomplex-
ation. Later, by the use of FT-IR, Zhang et al.[53,54] found
that a very small low-frequency shift (about 1 cm�1) of
nas(CH3) and a larger low-frequency shift (about 5 cm�1) of
n(C O) were observed during stereocomplex crystalliza-
tion from the melt (Figure 6). The low-frequency shifts of
the stretching vibration modes of the methyl and carbonyl
groups confirmed for the first time that the interaction
between the chains in the PLA stereocomplex is ascribed to
the CH3���O C hydrogen bonding. Another interesting
result is that the peak shift of the n(C O) band already
occurs in the induction period, which indicates that the
CH3���O C interaction is the driving force for the racemic
nucleation of the PLA stereocomplex.[53,54] Moreover, 2D
correlation analysis indicates that the structural adjustment
of the CH3 group occurs prior to that of the C–O–C
backbone during the stereocomplexation process. Although
van derWaals interaction between the hydrogen of CH3 and
the oxygen of O C has been suggested by Brizzolara
et al.,[50] Zhang et al. indicated for the first time that the
hydrogen bonding is the driving force for the nucleation of
PLA stereocomplex crystallites.[53,54]
Figure 4. WAXS profiles of PLLA/PDLA blends havingdifferent XD values.[4] Solid line, dashed line, and dashed/singledotted line are for XD¼ 0.5, 0.75, and 1, respectively.
Figure 5. Crystal structure of PLA stereocomplex.[47] The lines between PLLA and PDLAchains were added to original figure.
Poly(lactide) Stereocomplexes: Formation, Structure, Properties, Degradation, and Applications 575
Tsuji et al. estimated the degree of PLA stereocomplexation
in a concentrated solution of equimolar PLLA and PDLA
by theuseof 1HNMRspectroscopy, as shown inFigure7.[26]
Broad peaks in addition to sharp peaks appeared in the
resonance lines of the methine and methyl groups and the
areas of the broad peaks increased with time. These broad
peaks are ascribed to the chains adjacent to stereocomplex
micro-crystallites, i.e. folding chains and tie chains. The
total peak area decreased because the PLA chains in the
stereocomplex crystallites gave no peaks. The shoulder
which appeared in the resonance line of CHCl3 may be due
to the CHCl3 surrounding the folding and tie chains. The
decrease in the peak areas of themethine andmethyl groups
continued for more than fifty days and the peak areas
decreased below 50%of the initial values. Such phenomena
reflect the formation of stereocomplex crystallites in
concentrated solutions and the increase in number and/or
thickness of the stereocomplex crystalline regions.
Figure 6. Temporal changes of the IR spectra in the C–H stretching region ofmethyl group(a) and C O stretching region (b) during the melt-crystallization process of PLLA/PDLAstereocomplex at 220 8C, respectively.[54]
Figure 7. 400 MHz 1H NMR spectra of equimolarly mixed chloroform solution of PLLAand PDLA at 17.5 g � dL�1 and 25 8C.[26]
lites can be formed in the equimolarly blended film of
PLLA and PDLA (Figure 13).[58] The spherulitic structure
of PLA stereocomplex crystallites was different from that
of homo-crystallites with polygonal shapes, which can be
seen for nonblended PLLA or PDLA having low molecular
weights at low temperatures.[59,60] On the other hand, by
the use of POMaswell as the scanning electronmicroscopy,
the porous structure of dried stereocomplex gels can be
observed (Section 3.2.1).[24]
Figure 10. Relative viscosity of mixed chloroform solutions ofequimolar PLLA [viscosity-average molecular weight(Mv)¼ 4.2� 104 g �mol�1] and PDLA (Mv ¼ 4.5� 104 g �mol�1)with different concentrations at 25 8C.[26]
Figure 11. Storage modulus (G0) and loss tangent (tan d) for as-cast nonblended and blended films from PDLA (Mw ¼ 1.2�105 g �mol�1) and PLLA (Mw ¼ 1.0� 105 g �mol�1) with diffe-rent XD values.[24]
Figure 13. Spherulites of PLLA (Mw ¼ 1.0� 104 g �mol�1) (A), PDLA (Mw ¼ 2.2�104 g �mol�1) (B), and their equimolarly blended films (C, D) crystallized at 140 8C (A–C)and 190 8C (D) from the melt at 250 8C.[58]
Figure 14. SEM photographs of PLA stereocomplex particles precipitated fromacetonitrile solutions with different concentrations.[27] (A) 0.1 g � dL�1; (B) 1 g � dL�1; (C)3 g � dL�1; (D) 10 g � dL�1.
Spinu et al.[71–73] proposed a novel method for stereo-
complexation between PLLA and PDLA; polymerization
of LLA and DLA in the presence of PDLA and PLLA,
respectively, after mixing LLA and PDLA (or DLA and
PLLA). With this method, they successfully prepared well-
stereocomplexed PLA materials. In the strict sense of the
word, this method may not be ‘‘template polymeriza-
tion’’,[74] but effectively utilizes the fact that the polymer-
ized chains have strong interaction with the template
chains.
3.1.3. Upon Compression
Bourque et al.[75] and Pelletier and Pezolet[76] reported that
stereocomplexation occurs upon the compression of the
Figure 15. TEM photographs and electron diffraction patternsof PLAstereocomplex single crystal (A) and particle (B) formed indilute acetonitrile solutions.[27]
Figure 16. AFM photographs of equilateral-triangle-shapedsingle crystal (A) and disks (B) of PLA stereocomplex (Courtesyof Prof. Domb).[9] Reprinted from Adv. Drug Delivery Rev., Vol.55, Slager and Domb, ‘‘Biopolymer Stereocomplexes’’, pp. 549–583, 2003, with permission of Elsevier.
Poly(lactide) Stereocomplexes: Formation, Structure, Properties, Degradation, and Applications 581
chains. These three factors enhance PLA stereocomplexa-
tion between remaining L-lactyl unit sequences and D-
lactyl unit sequences. However, when thin specimens
(thickness< 200 mm) were used, no stereocomplexation
was observed for poly(D,L-lactide)[83] and an amorphous-
made equimolar blend of PLLA and PDLA,[84] even when
hydrolytic degradation was continued for 20–24 months.
This supports the fact that core-accelerated hydrolysis
of thick specimens should have induced PLA stereocom-
plexation.
3.2. In Solutions
Once PLA stereocomplex crystallites are formed in solu-
tion, they are insoluble in good solvents for either PLLA or
PDLA (e.g., chloroform, dichloromethane). This means
high stability of the stereocomplex crystallites compared
with that of homo-crystallites of either PLLAor PDLA. The
stereocomplex crystallites can be dissolved in extremely
good solvents at room temperature (e.g. 1,1,1,3,3,3-
hexafluoro-2-propanol) or in generally good solvents at
high temperatures near the boiling points (e.g., chloroform,
1,1,2,2-tetrachloroethane). However, the stereocomplex
crystallites become insoluble in extremely good solvents
even at elevated temperatures when the crystalline thick-
ness is high.
3.2.1. At a Fixed Polymer Concentration
The crystallites of a polymer are formed when the polymer
concentration in a solution exceeds a critical level. The
critical concentration for PLA stereocomplex crystallite
formation (stereocomplex crystallization) is much lower
than that for homo-crystallite formation of either PLLA or
PDLA (homo-crystallization). In other words, some good
solvents [e.g., chloroform and dichloromethane at room
temperature, acetonitrile around boiling temperature (ca.
80 8C)] for either PLLA or PDLA are poor solvents or non-
solvents for stereocomplex crystallites. Therefore, when an
initial polymer concentration is lower than the critical level
for homo-crystallite formation but higher than that for
stereocomplex crystallite formation, mixing two separately
prepared solutions of PLLA and PDLA results in the
formation of stereocomplex crystallites. Such stereocom-
plex crystallite formation induces particulate precipitates or
single crystals in dilute solutions (acetonitrile)[27] or gels in
Figure 17. Radius growth rate of shperulites (G) and inductionperiod of spherulite formation (ti) of PLLA, PDLA, and theirequimolarblendsasafunctionofcrystallizationtemperature(Tc).
In the solution castingmethod, solvent evaporation elevates
the polymer concentration of the solution from an initial
concentration to an infinite one. Therefore, during the
course of solvent evaporation, the polymer concentration
exceeds first the critical level of stereocomplex crystallite
formation, and then that of homo-crystallite formation. This
means that the stereocomplex crystallites are predomi-
nantly formed in equimolarly mixed solutions of PLLA and
PDLAwhen the solvent evaporation rate is sufficiently low.
Figure 18. Polymer concentration in supernatant of acetoni-trile solution as a function of time during stereocomplexation ofPDLA and PLLA [XD¼ 0.5, Mv (PLLA)¼ 4.2� 104 g �mol�1,Mv(PDLA)¼ 4.5� 104 g �mol�1, 1 g � dL�1, 80 8C].[27]
Figure 19. Phase diagram of PDLA/PLLA/chloroform system;homogeneous solution (I); cloudy solution containing stereo-complex microgel (II); stereocomplex macrogel (III). [XD¼ 0.5,Mv (PLLA)¼ 4.2� 104 g �mol�1, Mv(PDLA)¼ 4.5� 104 g �mol�1].[26]
Figure 20. SEM photograph and presumed structure of driedstereocomplex gel.[24]
Poly(lactide) Stereocomplexes: Formation, Structure, Properties, Degradation, and Applications 583
They prepared nonblended and equimolarly blended speci-
mens by solution-casting with dichloromethane. DSC[85]
and WAXS[86] revealed that L- or D-oligomers were
crystallizable forDP above 11, while an equimolar mixture
formed stereocomplex crystallites forDP above 7,meaning
high stability of the stereocomplex crystallites compared
with that of homo-crystallites. However, WAXS analysis
revealed that the mixture of L- and D-lactic acid oligomers
(DP¼ 7) contained homo-crystallites as well as stereo-
complex crystallites. This may have arisen from epitaxial
crystallization of the homo-crystallites on the stereocom-
plex crystallites.[68]
3.2.3. Precipitation into Non-solvent
Amixed solution of PLLA and PDLA into a precipitant or a
non-solvent causes removal of the solvent from the solution
and diffusion of the non-solvent into the solution, resulting
in rapid crystallization. In this method, in addition to the
aforementioned representative parameters such as XD and
the molecular weights of PLLA and PDLA (Table 2), the
shear rate of the non-solvent and polymer concentration
affect greatly the kind and amount of crystallites formed. A
high shear rate of the non-solvent and a low polymer
concentration induce the predominant formation of stereo-
complex crystallites.[21]
3.2.4. Stepwise Assembly
Serizawa et al.[87] reported that stepwise assembly between
PLLA and PDLA on a quartz crystal microbalance (QCM)
substrate gave rise to stereocomplexation. Thiswas attained
by alternate immersion of the substrate into acetonitrile
solutions of PLLA and PDLA. They also indicated that the
assembly of PLLA can grow epitaxially on the surface of
stereocomplex crystallites, as shown by Brochu et al.[68]
4. Homo-Stereocomplexation
The reported examples for the PLA-based stereocomplex
from various types of polymer blends or from copolymers
are summarized in Table 4.
4.1. Stereocomplexation in Polymer Blend
4.1.1. Homopolymers
For homopolymer blends of PLLA and PDLA, intensive
studies have been carried out by Tsuji et al.[6,20–22,26,27,36]
and Murdoch and Loomis et al.,[62–66] with numerous
varying parameters. They found that the dominant para-
meters for stereocomplexation are XD and the molecular
weights of PLLA and PDLA. As stated earlier, the ratio of
stereocomplex crystallites to homo-crystallites decreases
with the deviation of XD from 0.5 (Figure 3) and increasing
molecular weights of PLLA and PDLA (Figure 21).
However, no crystallite formation occurs when the DP
values of PLLA and PDLA are lower than 7.[85]
4.1.2. Random Stereocopolymers
Tsuji and Ikada synthesized L-lactide-rich PLA and
D-lactide-rich PLA having optical purities from 0–100%
and traced the crystallization behavior of their nonblended
and blended films at different Tc from the melt[23] as well as
during solvent evaporation.[28] The DHm and Tm of stereo-
complex crystallites in blended films decreased with
decreasing optical purity (OP), in agreement with those of
homo-crystallites in nonblended films. It was found that
Figure 21. Enthalpies of melting (DHm) of stereocomplexcrystallites and homo-crystallites of equimolar (XD¼ 0.5)PLLA/PDLAblends prepared by solvent evaporation as a functionof the averaged viscosity-average molecular weight (Mav) ofPLLA and PDLA.[20]
and homo-crystallization,[28] in agreement with the results
for the melt-crystallization method.[23] The critical se-
quence unit value is slightly higher than the 7 lactyl units for
pairs of the L-lactic acid oligomer and D-lactic acid
oligomer.[85] In the case of melt-crystallization, by crystal-
lization from the melt at temperatures between the Tmvalues of stereocomplex crystallites and homo-crystallites
(between the solid line and dashed/single dotted line for
blended specimens in Figure 23), well-stereocomplexed
PLA materials can be prepared.[23] On the other hand,
Brochu et al.[68] synthesized PLLA, PDLA, and poly(L-
lactide-co-D-lactide) [P(LLA-DLA)](20/80) and investi-
gated stereocomplexation between PLLA and P(LLA-
DLA)(20/80) as well as that between PLLA and PDLA
during cooling from the melt under various mixing ratios of
the two polymers.
4.1.3. Hetero Random Copolymers
Murdoch and Loomis reported the effects of incorporated
e-caprolactone units on PLA stereocomplexation by pre-
paring equimolar blends of poly(L-lactide-co-e-caprolac-tone) [P(LLA-CL)] and poly(D-lactide-co-e-caprolactone)[P(DLA-CL)][62] having e-caprolactone unit content of upto 32 wt%. The Tm of the stereocomplex decreased with
increasing the e-caprolactone unit content. However, the
critical lactyl unit sequence length for stereocomplexation
was not identified. By a procedure similar to that in Section
4.1.2., Tsuji and Ikada[29] studied the effects of incorporated
glycolyl unit (a half glycolide unit) content on PLA
stereocomplexation. The DHm and Tm of stereocomplex
crystallites in equimolarly (XD¼ 0.5) blended films
decreased with increasing glycolyl unit content, in agree-
ment with those of homo-crystallites in nonblended films.
The stereocomplex crystallites in blended films of poly(L-
lactide-co-glycolide) [P(LLA-GA)] and poly(D-lactide-co-
glycolide) [P(LDA-GA)] are formed with L- and D-lactide
unit content as low as 72.1 and 68.6 wt%, respectively,
Figure 22. Amorphous (A), stereocomplex crystalline (S), andhomo-crystalline (H) phases in as-cast binary equimolar (1:1)blends from PLAs with different D-lactide contents [XD¼D-lactide/(L-lactideþ D-lactide)].[28]
Figure 23. Amorphous (A), stereocomplex crystalline (S), andhomo-crystalline (H) phases in equimolarly blended and non-blended PLA films crystallized from the melt as a function ofoptical purity (OP); highest crystallization (annealing) temper-ature below which stereocomplexation occurs (Tc,s) in equimo-larly (1:1) blended PLAs (solid line) and highest crystallizationtemperature below which homo-crystallization occurs (Tc,h) inequimolarly blended PLAs (dashed/single dotted line) andnonblended PLAs (dashed line).[23]
Poly(lactide) Stereocomplexes: Formation, Structure, Properties, Degradation, and Applications 587
whereas the homo-crystallites in nonblended films are
formed with L- or D-lactyl unit content above 81.0 wt%
(Figure 24). The calculated critical L- or D-lactyl unit
sequence length for stereocomplex crystallization in the
blended films (5.5 lactyl units) is lower than 8.8 lactyl units
for homo-crystallites in the nonblended films, reflecting the
fact that the peculiarly strong interaction between the L-
lactyl unit sequences and D-lactyl unit sequences enhances
the stability of stereocomplex crystallites and the crystal-
lizablity of the blended films. Here, the calculation proce-
dure for the lactyl unit sequence length is similar to the
Equation (3) and (4), and is given in our recent article.[88]
This value of 5.5 lactyl units is slightly lower than the
7 lactyl units for pairs of the L-lactic acid oligomer and
D-lactic acid oligomer.[85] It should be noted that the critical
values shown here are average values and, therefore, the
copolymers contain L- or D-lactyl unit sequences longer
than the average values. The critical value for the lactide-
glycolide copolymer is lower than that for random lactide
stereocopolymers (Section 4.1.2.), suggesting that the
glycolide units in the copolymers must have enhanced the
stereocomplexation between L-lactyl unit sequences and D-
lactyl unit sequences. It seems probable that the lower steric
hindrance of the methylene group of glycolyl units
(compared with the high steric hindrance of the ethylidene
group of L-lactyl or D-lactyl units) raises the chain mobility
of glycolide copolymers, resulting in high stereocomplex-
ationability during solvent evaporation.
4.1.4. Hetero Block Copolymers
4.1.4(a). With Poly(e-caprolactone) (PCL) Blocks
Dijkstra et al.[89] prepared an A-B diblock copolymer
[number-average molecular weight (Mn)¼ 3.87� 104 g �
mol�1] of PLLA (A) and PCL (B) as well as PDLA
(Mn ¼ 9.7� 103 g �mol�1). They indicated that PLA stereo-
complexation takes place even in the presence of polymeric
impurity of a PCL block. In this blend, e-caprolactone unitsequences were phase-separated to form their crystalline
regions.
Stevels et al.[90] synthesized A-B diblock copolymers of
PLLA or PDLA (DP¼ 1–80) (A) and PCL (DP¼ 70) (B).
Upon blending PLLA-b-PCL and PDLA-b-PCL, both
having weight fractions of PLA blocks above 44%, a Tmincrease (ca. 55 8C) of the PLA crystalline regions was
observed due to stereocomplexation, while for the blends
composed of PLLA-b-PCL and PDLA-b-PCL, both having
weight fractions of PLA blocks below 22%, no melting of
the PLA crystalline regions was observed, meaning that the
PLA blocks were noncrystallizable. On the other hand,
crystallization of PCL blocks took place in the blended
specimens aswell as in the nonblended specimens. Portinha
et al.[56] prepared A-B diblock copolymers of PLLA or
PDLA (A) and PCL (B) and monitored their aggregation
behavior in nonblended and blended THF solutions. The
hydrodynamic radii of assemblies in enantiomeric blended
solutions were 200 nm, which were higher than those in
nonblended polymer solutions. The radius distribution in
enantiomeric blend solutions was sharper than that of non-
blended polymer solutions. Furthermore, the same research
group[57] continued studies on the self-assembly of PLLA-
b-PCL and PDLA-b-PCL in THF by the use of DSC,
dynamic LSmeasurements, 1HNMRspectroscopy, and FT-
IR. They revealed that, at higher concentrations such as
10 g � dL�1, stereocomplexation was in competition with a
solvophobically driven aggregation, whereas at lower con-
centrations, only the stereocomplexation process was
involved.
Figure 24. Schematic representation for the phases and Tm in Blend 11 [nonblend P(DLA-GA), Blend 31 and 32 [blended films from PDLA and P(DLA-GA)] (a), Blend 2 [blendedfilms from P(LLA-GA) and P(DLA-GA)], Blend 41 [blended films from PDLA and P(LLA-GA)], and Blend 42 [blended films from PLLA and P(DLA-GA)] (b).[29] The areas withhorizontal stripes, vertical stripes, both horizontal and vertical stripes, and without stripesmeans homo-crystallineþ amorphous, stereocomplex crystallineþ amorphous, stereocom-plex crystallineþ homo-crystallineþ amorphous, and amorphous, respectively. Tm1 andTm2 are the Tm of homo-crystallites and stereocomplex crystallites, respectively.
Pensec et al.[91] synthesized A-B-A triblock copolymers
of PLLA or PDLA (DP¼ 58) (A) and PCL (DP¼ 34) (B)
and A-B diblock copolymers of PLLA (DP¼ 19–54) or
PDLA (DP¼ 20–57) (A) and PCL (DP¼ 24–106) (B).
They indicated that stereocomplexation occurred in all
enantiomeric polymer pairs precipitated from a dichlor-
omethane solution into methanol. The DHm and Tm of
stereocomplex crystallites were affected by the L-lactyl unit
sequence length and D-lactyl unit sequence length, but were
not affected by the e-caprolactone sequence length.
4.1.4(b). With Poly(ethylene glycol) (PEG) Blocks
Brizzolara et al.[50] prepared A-B diblock copolymers
(Mn ¼ 5.6� 104 and 5.9� 104 g �mol�1) of PLLAor PDLA
(A) and PEG (B). The molecular weight ratio of the PLA
block to the PEG block was 1.5/1. They traced stereo-
complexation between enantiomeric copolymer blends by
WAXS, and the difference in the morphology between
precipitates of nonblended and blended specimens by
AFM.
Stevels et al.[92] synthesized A-B-A triblock copolymers
(Mn ¼ 6.7� 103–2.3� 104 g �mol�1, PEG content 27–
86 wt%) of PLLA or PDLA (A) and PEG (Mn ¼ 6 000) (B)
and prepared equimolarmixtures of PLLA-b-PEG-b-PLLA
and PDLA-b-PEG-PDLA by two different procedures,
precipitation and solution-casting. Although they investi-
gated the effects of the procedures on stereocomplexation
as reported for the blends from pure PLLA and PDLA,[20,21]
stereocomplexation occurred readily in specimens prepared
by these two different procedures. Probably, the molecular
weights of the block copolymers were sufficiently low to
form stereocomplex crystallites, irrespective of the proce-
dure. Another probable explanation is that the PEG seg-
ments acted as a plasticizer for the PLA segments and
consequently enhanced stereocomplexation of the block
copolymers. On the other hand, Lim and Park[93] prepared
A-B-A triblock copolymers of PLLA (DP¼ 200, 250) or
PDLA (DP¼ 208, 262) (A) and PEG (DP¼ 23, 77) (B).
Stereocomplexation between the enantiomeric block copo-
lymers was traced by DSC and WAXS. The cumulative
release of bovine serum albumin (BSA) was lower for
stereocomplexed microspheres than for those of non-
blended blockcopolymers, when compared with the same
period. Furthermore, Fujiwara et al.[94] prepared synthe-
sized A-B-A triblock copolymers (Mn ¼ 7 200 and 6 800 g �mol�1) of PLLA or PDLA (A) and PEG (Mn ¼ 4 600 g �mol�1) (B). The enantiomeric triblock copolymers were
separately dissolved in tetrahydrofuran (THF)/water (v/
v)¼ 1/2 and then THF was removed by evaporation,
leaving 10 wt.-% aqueous dispersion. They traced stereo-
complexation between the enantiomeric triblock copoly-
mers upon heating the aqueous dispersion from room
temperature to 37 8C by rheological measurements, the test
tube tilting method, and WAXS.
Li and Vert[95,96] synthesized A-B diblock and A-B-A
triblock copolymers of PLLA or PDLA (DP¼ 12–
52, molar mass¼ 860–3 700) (A) and PEG (DP¼ 104–
454, molar mass¼ 4 600–20 000) (B). The crystallization
of PEG was dominant in these block copolymers. On
blending the enantiomeric block copolymers in an aqueous
medium, gels were formed, as seen for the homopolymer
blends of PLLA and PDLA in organic solvents.[26,62] Such
stereocomplexation was confirmed by Raman spectro-
scopy, WAXS, and rheological measurements.[95,96]
4.1.4(c). With Poly(sebacic acid) (PSA) Blocks
Slivniak and Domb[97] synthesized A-B-A triblock copo-
lymers of PLLA or PDLA (DP¼ 20–30) (A) and PSA
(DP¼ 2–40) (B) and observed stereocomplexation
between these enantiomeric block copolymers.
4.1.5. Graft Copolymers
Lim et al.[98] prepared poly[2-hydroxyethyl methacrylate-
graft-oligo(L-lactide)] and poly[2-hydroxyethyl methacry-
late-graft-oligo(D-lactide)] by radical polymerization of
macromonomers 2-hydroxyethyl methacrylate-graft-
oligo(L-lactide) and 2-hydroxyethyl methacrylate-graft-
oligo(D-lactide), respectively, in the presence of 2,20-azoisobutyronitrile (AIBN). The macromonomers were
synthesized by ring-opening polymerization of L- or
D-lactide in the presence of stannous octoate and 2-
hydroxyethyl methacrylate as initiator and coinitiator, res-
pectively. Stereocomplexation occurred during solution-
casting of mixed solutions of enantiomeric graft polymers.
The stereocomplexed films became hydrogels in aqueous
media.
de Jong et al.[86,99–102] synthesized dextran [degree of
substitution (DS, number of lactic acid side chains per 100
PDLA (Mn ¼ 1.2–1.3� 105 g �mol�1). The thermal degra-
dation of the three specimens proceeds through mechan-
Figure 25. The percentage of remaining weight of the filmsmeasured isothermally at the constant temperature as a function ofheating time.[123] Here, L, D, L/D represent nonblended PLLA andPDLA films, and their equimolarly blended film, respectively.
Poly(lactide) Stereocomplexes: Formation, Structure, Properties, Degradation, and Applications 591
tide)] (Lim et al.[98]) and A-B-A triblock copolymers of
Figure 26. Weight remaining (a),Mn (b), and tensile strength (c)of nonblended films and well-stereocomplexed blended film ofPLLA and PDLA films after hydrolytic degradation in phosphate-buffered solution (pH 7.4, 37 8C).[132]
biodegradable materials such as hydrogels and DDS parti-
cles. The former improvements arise from the peculiarly
strong interaction between L-lactyl unit sequences and
D-lactyl unit sequences. A variety of properties of stereo-
complexed PLAmaterials can bemanipulated bymolecular
characteristics, highly-ordered structures, and additives.
Some Lactobacilli are reported to produce exclusively
D-lactic acid (not the mixture of L- and D-lactic acids) from
numerous kinds of renewable resources,[30,145] and PDLA
can be produced from D-lactic acid by the same procedure
for PLLA production from L-lactic acid. Therefore, the
most crucial issue for stereocomplexed PLA materials,
the reduction of the production cost of PDLA, can be solved
by large-scale facilities. Reduced cost of PDLA will give
stereocomplexed PLA materials further applications, not
only as biomedical materials but also as alternatives for
commercial polymeric materials.
[1] T. G. Fox, B. S. Garrett, W. E. Goode, S. Gratch, J. F.Kincaid, A. Spell, J. D. Stroupe, J. Am. Chem. Soc. 1958,80, 1768.
[2] L. Pauling, R. B. Corey,Proc. Natl. Acad. Sci. Wash. 1953,39, 253.
[3] D. Grenier, R. E. Prud’homme, J. Polym. Sci. Polym. Phys.Ed. 1984, 22, 577.
[4] Y. Ikada, K. Jamshidi, H. Tsuji, S.-H. Hyon, Macro-molecules 1987, 20, 904.
[5] R. Voyer, R. E. Prud’homme, Eur. Polym. J. 1989, 25,365.
[6] H. Tsuji, in:ResearchAdvances inMacromolecules, R.M.Mohan, Ed., Grobal Research Network, Trivandrum,India, Vol. 1, 2000, pp. 25–48.
[7] J. H. G. M. Lohmeyer, Y. Y. Tan, P. Lako, G. Challa,Polymer 1978, 19, 1171.
[8] F. Bosscher, D. Keekstra, G. Challa, Polymer 1981, 22,124.
[9] J. Slager, A. J. Domb, Adv. Drug Delivery Rev. 2003, 55,549.
[10] H. Sakakihara, Y. Takahashi, H. Tadaokoro, N. Oguni, H.Tani,Macromolecules 1973, 6, 205.
[11] K. L. Singfield, G. R. Brown, Macromolecules 1995, 28,1290.
[12] P. Dumas, N. Spassky, P. Sigwalt,Makromol. Chem. 1972,156, 55.
[13] Z. Jiang,M.T.Boyer,A. Sen, J. Am.Chem. Soc. 1995, 117,7037.
[14] T. Yoshida, S. Sakurai, T. Okuda, Y. Takagi, J. Am. Chem.Soc. 1962, 84, 3590.
[15] M. Tsuboi, A. Wada, A. Nagashima, J. Mol. Biol. 1961, 3,705.
[16] I. Iribarren, C. Aleman, C. Regano, A. Martınez deIlarduya, J. J. Bou, S. Munoz-Guerra, Macromolecules1996, 29, 8413.
[17] K. Hatada, S. Shimizu, Y. Terawaki, K. Ohta, H. Yuki,Polym. J. 1981, 13, 811.
[18] F. Sanda, M. Nakamura, T. Endo, Macromolecules 1996,29, 8064.
[19] H. Tsuji, Biomaterials 2003, 24, 537.
[20] H. Tsuji, S.-H. Hyon, Y. Ikada,Macromolecules 1991, 24,5651.
[21] H. Tsuji, S.-H. Hyon, Y. Ikada,Macromolecules 1991, 24,5657.
[22] H. Tsuji, Y. Ikada, Macromolecules 1993, 26, 6918.[23] H. Tsuji, Y. Ikada, Macromol. Chem. Phys. 1996, 197,
3483.[24] H. Tsuji, Y. Ikada, Polymer 1999, 40, 6699.[25] E. Schomaker,G.Challa,Macromolecules 1988, 21, 3506.[26] H. Tsuji, F. Horii, S.-H. Hyon, Y. Ikada, Macromolecules
1991, 24, 2719.[27] H. Tsuji, S.-H. Hyon, Y. Ikada,Macromolecules 1992, 25,
2940.[28] H. Tsuji, Y. Ikada, Macromolecules 1992, 25, 5719.[29] H. Tsuji, Y. Ikada, J. Appl. Polym. Sci. 1994, 53, 1061.[30] G. B. Kharas, F. Sanchez-Riera, D. K. Severson, in:
Plastics from Microbes, D. P. Mobley, Ed., HanserPublishers, New York 1994, pp. 93–137.
[31] M. H. Hartmann, in: Biopolymers from RenewableResources, D. L. Kaplan, Ed., Springer, Berlin 1998, pp.367–411.
[32] H. Tsuji, Y. Ikada, in: Current Trends in Polymer Science,K. L. DeVries, P. Hodge, A. Ledwith, D. W. McCall,A. M. North, D. R. Paul, R. S. Porter, J. C. Salamone, P. L.Taylor, O. Vogl, Editorial Advisory Board, ResearchTrends, Trivandrum, India, Vol. 4, 1999, pp. 27–46.
[33] Y. Ikada, H. Tsuji, Macromol. Rapid Commun. 2000, 21,117.
[34] H. Tsuji, in: Recent Research Developments in PolymerScience, A. B. Salamone, J. Brandrup, R. M. Ottenbrite,Editorial Advisors, Transworld Research Network,Trivandrum 2000, Vol. 4, pp. 13–37.
[35] D. Garlotta, J. Polym. Environ. 2001, 9, 63.[36] H. Tsuji, in: Polyesters 3 (Biopolymers, vol. 4), Y. Doi, A.
Steinbuchel, Eds.,Wiley-VCH,Weinheim 2002, pp. 129–177.
[37] R. Auras, B. Harte, S. Selke, Macromol. Biosci. 2004, 4,835.
[38] H. Tsuji, Y. Ikada, J. Appl. Polym. Sci. 1995, 58, 1793.[39] H. Tsuji, Y. Ikada, Polymer 1996, 37, 595.[40] H. Tsuji, Y. Ikada, Polymer 1995, 36, 2709.[41] B. Kalb, A. J. Pennings, Polymer 1980, 21, 607.[42] G. L. Loomis, J. R.Murdoch, K. H. Gardner,Polym. Prepr.
1990, 31, 55.[43] H. Tsuji, F. Horii, M. Nakagawa, Y. Ikada, H. Odani, R.
Kitamaru, Macromolecules 1992, 25, 4114.[44] E. W. Fischer, H. J. Sterzel, G. Wegner, Kolloid-Z.u.Z.
Polym. 1973, 251, 980.[45] T. Miyata, T. Masuko, Polymer 1998, 39, 5515.[46] K. Jamshidi, S.-H.Hyon,Y. Ikada,Polymer1988,29, 2229.[47] T. Okihara, M. Tsuji, A. Kawaguchi, K. Katayama, H.
Tsuji, S.-H. Hyon, Y. Ikada, J. Macromol. Sci., -Phys.1991, B30, 119.
[48] D. Brizzolara, H.-J. Cantow, K. Diederichs, E. Keller, A. J.Domb, Macromolecules 1996, 29, 191.
[49] T. Okihara, A. Kawaguchi, H. Tsuji, S.-H. Hyon, Y. Ikada,K. Katayama, Bull. Inst. Chem. Res. Kyoto Univ. 1988, 66,271.
[50] D. Brizzolara, H. J. Cantow, R. Mulhaupt, A. J. Domb, J.Computer-Aided Mater. Design 1996, 3, 341.
[51] H. Tsuji, K. Ikarashi, N. Fukuda, Polym. Degrad. Stab.2004, 84, 515.
[52] G. Kister, G. Cassanas, M. Vert, Polymer 1998, 39, 267.[53] J. Zhang, H. Sato, H. Tsuji, I. Noda, Y. Ozaki, Macro-
molecules 2005, 38, 1822.
Poly(lactide) Stereocomplexes: Formation, Structure, Properties, Degradation, and Applications 595
[54] J. Zhang, H. Sato, H. Tsuji, I. Noda, Y. Ozaki, J. Mol.Struct. 2005, 735, 249.
[55] E. J. Vorenkamp, G. Challa, Polymer 1981, 22, 1705.[56] D. Portinha, J. Belleney, L. Bouteiller, S. Pensec, N.
Spassky, C. Chassenieux,Macromolecules 2002, 35, 1484.[57] D. Portinha, L. Bouteiller, S. Pensec, A. Richez, C.
Chassenieux, Macromolecules 2004, 37, 3401.[58] H. Tsuji, Y. Tezuka, Biomacromolecules 2004, 5, 1181.[59] R.Vasanthakumari, A. J. Pennings,Polymer 1983, 24, 175.[60] H. Abe, Y. Kikkawa, Y. Inoue, Y. Doi,Biomacromolecules
2001, 2, 1007.[61] L. Cartier, T. Okihara, B. Lotz,Macromolecules 1997, 30,
6313.[62] US 4719246 (1988), E. I. Du Pont Co., invs.: J. R.
Murdoch, G. L. Loomis.[63] US 4766182 (1988), E. I. Du Pont Co., invs.: J. R.
Murdoch, G. L. Loomis.[64] US 4800219 (1989), E. I. Du Pont Co., invs.: J. R.
Murdoch, G. L. Loomis.[65] US 4902515 (1990), E. I. Du PontCo., invs.: G. L. Loomis,
J. R. Murdoch.[66] US 4981696 (1991), E. I. Du PontCo., invs.: G. L. Loomis,
J. R. Murdoch.[67] H. Tsuji, Y. Ikada, Polymer 1995, 36, 2709.[68] S. Brochu, R. E. Prud’homme, I. Barakat, R. Jerome,
Macromolecules 1995, 28, 5230.[69] A. Soldera, R. E. Prud’homme, PMSE (Am. Chem. Soc.,
Div. Polym. Mater. Sci. Eng.) 1993, 68, 304.[70] H. Urayama, T. Kanamori, K. Fukushima, Y. Kimura,
Polymer 2003, 44, 5635.[71] US 5317064 (1994), E. I. Du Pont Co., inv.: M. Spinu.[72] M. Spinu, K. H. Gardner, PMSE (Am. Chem. Soc., Div.
Polym. Mater. Sci. Eng.) 1994, 71, 19.[73] M. Spinu, C. Jackson, M. Y. Keating, K. H. Gardner,
J. Macromol. Sci.-Pure Appl. Chem. 1996, A33, 1497.[74] G. Challa, Y. Y. Tan, Pure Appl. Chem. 1981, 53, 627.[75] H. Bourque, I. Laurin, M. Pezolet, Langmuir 2001, 17,
5842.[76] I. Pelletier, M. Pezolet,Macromolecules 2004, 37, 4967.[77] H. Tsuji, Y. Ikada, S.-H. Hyon, Y. Kimura, T. Kitao, J.
Appl. Polym. Sci. 1994, 51, 337.[78] S. Li, M. Vert, Macromolecules 1994, 27, 3107.[79] S. Li, M. Vert, Polym. Int. 1994, 33, 37.[80] S. Li, S. Girod-Holland, M. Vert, J. Controlled Release
1996, 40, 41.[81] S. Li, S. McCarthy, Biomaterials 1999, 20, 35.[82] G. Schwach, J. Coudane, R. Engel, M. Vert, Biomaterials
2002, 23, 993.[83] H. Tsuji, Y. Ikada, J. Appl. Polym. Sci. 1997, 63, 855.[84] H. Tsuji, C. A. Del Carpio, Biomacromolecules 2003, 4, 7.[85] S. J. de Jong, W. N. E. van Dijk-Wolthuis, J. J. Kettenes-
van den Bosch, P. J. W. Schuyl, W. E. Hennink,Macromolecules 1998, 31, 6397.
[86] S. J. de Jong,C. F. vanNostrum,L.M. J.Kroon-Batenburg,J. J. Kettenes-van den Bosch, W. E. Hennink, J. Appl.Polym. Sci. 2002, 86, 289.
[87] T. Serizawa, H. Yamashita, T. Fujiwara, Y. Kimura, M.Akashi, Macromolecules 2001, 34, 1996.
[88] H. Tsuji, Y. Tezuka, Macromol. Biosci. 2005, 5, 135.[89] P. J. Dijkstra, A. Bulte, J. Feijen, Preprints for The 17th
Annual Meeting of the Society for Biomaterials 1991, 184.[90] W. M. Stevels, M. J. K. Ankone, P. J. Dijkstra, J. Feijen,
Macromol. Symp. 1996, 102, 107.[91] S. Pensec, M. Leroy, H. Akkouche, N. Spassky, Polym.
Bull. 2000, 45, 373.
[92] W. M. Stevels, M. J. K. Ankone, P. J. Dijkstra, J. Feijen,Macromol. Chem. Phys. 1995, 196, 3687.
[93] D.W. Lim, T. G. Park, J. Appl. Polym. Sci. 2000, 75, 1615.[94] T. Fujiwara, T. Mukose, T. Yamaoka, H. Yamane, S.
Sakurai, Y. Kimura, Macromol. Biosci. 2001, 1, 204.[95] S. Li, M. Vert, Macromolecules 2003, 36, 8008.[96] S. Li,Macromol. Biosci. 2003, 3, 657.[97] R. Slivniak, A. J. Domb,Biomacromolecules 2002, 3, 754.[98] D. W. Lim, S. H. Choi, T. G. Park, Macromol. Rapid
Commun. 2000, 21, 464.[99] S. J. de Jong, S. C. DeSmedt, M. W. C. Wahls, J.
Demeester, J. J. Kettenes-van den Bosch, W. E. Hennink,Macromolecules 2000, 33, 3680.
[100] S. J. de Jong, B. van Eerdenbrugh, C. F. van Nostrum, J. J.Kettenes-van den Bosch, W. E. Hennink, J. ControlledRelease 2001, 72, 47.
[101] S. J. de Jong,C. F. vanNostrum,L.M. J.Kroon-Batenburg,J. J. Kettenes-van den Bosch,W. E. Hennink, S. J. de Jong,G. W. Bos, T. F. J. Veldhuis, C. F. van Nostrum, Int.J. Pharm. 2004, 277, 99.
[102] S. J. de Jong, S. C. Smedt, J. Demeester, C. F. vanNostrum,J. J. Kettenes-van denBosch,W. E. Hennink, J. ControlledRelease 2001, 71, 261.
[103] C. F. van Nostrum, T. F. J. Veldhuis, G. W. Bos, W. E.Hennink,Macromolecules 2004, 37, 2113.
[104] J. Watanabe, K. Ishihara, Chem. Lett. 2003, 32, 192.[105] J. Watanabe, T. Eriguchi, K. Ishihara, Biomacromoleucles
2002, 3, 1109.[106] J. Watanabe, T. Eriguchi, K. Ishihara, Biomacromoleucles
2002, 3, 1375–1383.[107] O. N. Tretinnikov, K. Kato, H. Iwata, Langmuir 2004, 20,
6748.[108] N. Yui, P. J. Dijkstra, J. Feijen, Makromol. Chem. 1990,
191, 481.[109] N. Spassky, M. Wisniewski, C. Pluta, A. Le Borgne,
Macromol. Chem. Phys. 1996, 197, 2627.[110] N. Spassky, C. Pluta, V. Simic, M. Thiam,M.Wisniewski,
Macromol. Symp. 1998, 128, 39.[111] M. Wisniewski, A. Le Borgne, N. Spassky, Macromol.
Chem. Phys. 1997, 198, 1227.[112] J.-R. Sarasua, R. E. Prud’homme, M. Wisniewski, A. Le
Borgne, N. Spassky,Macromolecules 1998, 31, 3895.[113] C. P. Radano, G. L. Baker, M. R. Smith, III, J. Am. Chem.
Soc. 2000, 122, 1552.[114] T. M. Ovitt, G. W. Coates, J. Polym. Sci.: Part A: Polym.
Chem. 2000, 38, 4686.[115] T. M. Ovitt, G. W. Coates, J. Am. Chem. Soc. 2002, 124,
1316.[116] K. Fukushima, Y. Furuhashi, K. Sogo, S. Miura, Y.
Kimura, Macromol. Biosci. 2005, 5, 21.[117] J. Slager, M. Glandnikoff, A. J. Domb, Macromol. Symp.
2001, 175, 105.[118] J. Slager, Y. Cohen, R. Khalfin, Y. Talmon, A. J. Domb,
Macromolecules 2003, 36, 2999.[119] J. Slager, A. J. Domb, Eur. J. Pharm. Biopharm. 2004, 58,
461.[120] J. Slager, A. J. Domb, Biomacromolecules 2003, 4, 1308.[121] J. Slager, A. J. Domb, Biomacromolecules 2003, 4, 1316.[122] J. Slager, A. J. Domb, Biomaterials 2002, 23, 4389.[123] H. Tsuji, I. Fukui, Polymer 2003, 44, 2891.[124] J. R. MacCallum, in: Comprehensive Polymer Science:
The Synthesis, Characterization, Reactions, and Applica-tions of Polymers, Vol. 1 (Polymer Characterization), G.Allen, J. C. Bevington, Editorial Board, Pergamon,Oxford1989, Chapter 37, pp. 903–909.
[125] J. R. MacCallum, J. Tanner, Eur. Polym. J. 1970, 6, 907.[126] J. R. MacCallum, J. Tanner, Eur. Polym. J. 1970, 6, 1033.[127] J. Atkinson, J. R. MacCallum, Eur. Polym. J. 1972, 8, 809.[128] Y. Fan, H. Nishida, Y. Shirai, Y. Tokiwa, T. Endo, Polym.
Degrad. Stab. 2004, 86, 197.[129] C. D. Doyle, J. Appl. Polym. Sci. 1962, 6, 639.[130] L. Reich, Polym. Lett. 1964, 2, 621.[131] T. Ozawa, Bull. Chem. Soc. Japan 1965, 38, 1881.[132] H. Tsuji, Polymer 2000, 41, 3621.[133] H. Tsuji, Polymer 2002, 43, 1789.[134] H. Tsuji, M. Suzuki, Sen’i Gakkishi 2001, 57, 198.[135] T. Serizawa, Y. Arikawa, K. Hamada, H. Yamashita, T.
Fujiwara, Y. Kimura, M. Akashi, Macromolecules 2003,36, 1762.
[136] P. J. Sweeney, J. M. Walker, in: Enzymes of MolecularBiology (Methods in Molecular Biology, vol. 16), M. M.
Burrell, Ed., Humana Press, Totowa, New Jersey 1993,Chapter 6, pp. 305–311.
[137] H. Tsuji, S.Miyauchi,Polym.Degrad. Stab. 2001, 71, 415.[138] H. Tsuji, S. Miyauchi, Polymer 2001, 42, 4465.[139] H. Tsuji, K. Ikarashi, Polym. Degrad. Stab. 2004, 85,
647.[140] H. Tsuji, S. Miyauchi, Biomacromolecules 2001, 2, 597.[141] M. Takasaki, H. Ito, T. Kikutani, J. Macromol. Sci. Part B
Phys. 2003, B42, 403.[142] J. W. Leenslag, A. J. Pennings, Polymer Commun. 1987,
28, 92.[143] S. C. Schmidt, M. A. Hillmyer, J. Polym. Sci., Part B:
Polym. Phys. 2001, 39, 300.[144] H. Yamane, K. Sasai, Polymer 2003, 44, 2569.[145] K. Fukushima, K. Sogo, S. Miura, Y. Kimura,Macromol.
Biosci. 2004, 4, 1021.
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