Biologically Safe Poly(l-lactic acid) Blends with Tunable Degradation

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Biologically safe poly(L-lactic acid) blends with tunable degradation rate: Microstructure, degradation mechanism, and mechanical properties Hideko T. Oyama, Daisuke Tanishima, and Ryohei Ogawa Biomacromolecules, Just Accepted Manuscript • DOI: 10.1021/acs.biomac.7b00016 • Publication Date (Web): 09 Mar 2017 Downloaded from http://pubs.acs.org on March 19, 2017

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Manuscript ID: bm-2017-000163

Biologically safe poly(L-lactic acid) blends with tunable degradation rate: Microstructure, degradation mechanism, and mechanical properties

Hideko T. Oyama,*† Daisuke Tanishima,† and Ryohei Ogawa‡ †

Department of Chemistry, College of Science, Rikkyo University, 3-34-1 Nishi-Ikebukuro, Toshima-ku, Tokyo 171-8501, Japan

‡

Functional Materials Laboratory, Mitsui Chemicals Inc., 580-32 Nagaura, Sodegaura, Chiba 299-0265, Japan

* Corresponding author. Tel/fax.: +81 3 3985 2363. E-mail address: [email protected] (H. T. Oyama)

submitted to Biomacromolecules (2017): revised version

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ABSTRACT:

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Although poly(L-lactic acid) (PLLA) is reputed to be biodegradable

in the human body, its hydrophobic nature lets it persist for ca. 5.5 years. This study demonstrates that biologically safe lactide copolymers, poly(aspartic acid-co-L-lactide) (PAL) and poly(malic acid-co-L-lactide) (PML), dispersed in the PLLA function as detonators (triggers) for its hydrolytic degradation at physiological conditions.

The

copolymers significantly enhance hydrolysis and consequently the degradation rate of PLLA becomes easily tunable by controlling the amounts of PAL and PML.

The

present study elucidates the effects of uniaxial drawing on the structural development, mechanical properties, and hydrolytic degradation at physiological conditions of PLLA blend films.

At initial degradation stages the mass loss was not affected by uniaxial

drawing, however, at late degradation stages less developed crystals were degradable at low draw ratio (DR), whereas, not only highly developed crystals but also the oriented amorphous chains became insensitive to hydrolysis at high DR.

Our work provides

important molecular level results that demonstrante that biodegradable materials can have superb mechanical properties and also disappear in a required time at physiological conditions. KEYWORDS: poly(L-lactic acid); poly(aspartic acid-co-L-lactide); poly(malic acid-co-L-lactide); uniaxial drawing; hydrolytic degradation; mechanical properties

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INTRODUCTION Drawing of semi-crystalline poly(L-lactic acid) (PLLA) has been widely applied because it introduces anisotropy in the structure and significantly alters properties of the PLLA such as mechanical strength and thermal recovery.1-19

Therefore, studies on the

structural development upon drawing of neat PLLA have been carried out intensively, with the molecular orientation of PLLA investigated by various techniques, such as birefringence,1,2,7 two dimensional wide-angle x-ray diffraction (WAXD),1-3,9,11-13 solid-state 13C nuclear magnetic resonance (13C NMR),4,5 and polarized infrared6 and Raman7 spectroscopies.

Depending on the drawing conditions, the drawing of neat

PLLA results in not only molecular orientation, but also even transformation of crystals from the α- to the β-form8-11 or formation of mesophases with an intermediate ordering between amorphous and crystalline states.11-13 In spite of intensive studies on the drawing of neat PLLA films, there are a limited number of studies on the drawing of PLLA blends in the literature.20-22

For example, in a study on uniaxially drawn PLLA

/ poly(vinylidene fluoride) (PVDF) blends, the stretched PLLA domains dispersed in the PDVF matrix formed oriented crystals in the drawing direction, due to the heteroepitaxy of the PLLA α crystals formed along the PVDF β crystals.20

In a study

on PLLA / poly[(R)-3-hydroxybutyrate] (PHB) blends uniaxially drawn at ca. the Tg of the major component polymer (Tg of PHB = 2 oC, and Tg of PLLA = 60 oC), it was 3


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demonstrated that the molecular weight of the component polymers and blend composition significantly affect the orientation of the component polymers and their mechanical properties.21 Here, PLLA is biodegradable, biocompatible, and bioresorbable so that it is used in the medical field, as structural scaffolds, sutures, screws, fixation plates, and drug delivery.23-26

However, the hydrophobic nature of PLLA suppresses the degradation

so that it is estimated to remain in the human body for ca. 5.5 years in the form of extended-chain crystallites.26

As for studies on the effects of the molecular orientation

on the degradation of PLLA, Rangari et al. investigated the enzymatic degradation of neat PLLA films that were uniaxially drawn to a draw ratio (DR) of 1 ~ 3, and found that the overall enzymatic degradation of PLLA at 37 oC under pH 8.5 in the presence of proteinase K was significantly suppressed by uniaxial drawing.6

It was observed

that the higher the crystallinity, the lower the enzymatic degradation rate.

Tsuji et al.

also studied the enzymatic degradation of PLLA fibers at pH 8.6 and 37 oC in the presence of proteinase K at low DR values of 1.2 and 1.4.19

Uniaxial drawing of the

PLLA fibers at such low DR values dramatically suppressed enzymatic degradation, which proceeded on the fiber surface due to the relatively high molecular weight of the enzyme (28,930 g mol-1).

However, DSC and GPC were insensitive to the changes

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caused by uniaxial drawing in their study. On the other hand, hydrolytic degradation of drawn PLLA in a phosphate buffer solution was also studied.15-18

It was reported that the hydrolysis rate of uniaxially

drawn PLLA in a phosphate-buffered solution was controlled by both crystallinity and orientation.

In drawn PLLA specimens with comparable crystallinity, a tendency for

higher orientation to be associated with slower degradation rates was observed.18

Mai

et al. also obtained similar results comparing two uniaxially drawn PLLA tapes (one tape drawn at DR = 4 with Herman’s orientation factor, fc, = 0.99, crystallinity, Xc, = 53%, and Tg = 85 oC, and the other tape drawn at DR = 8 with fc = 0.55, Xc = 55%, and Tg = 92oC), in which their Xc values were comparable and a collapse of the existing crystals upon overdrawing was observed at DR = 8.17

The extent of hydrolysis

monitored by the decrease in the number average molecular weight of PLLA was in the order of DR = 1 > 4 > 8 in a phosphate buffer solution at 50 oC.

Furthermore, Tsuji et

al. studied effects of orientation on degradation in a phosphate buffer solution at pH 7.4 and in a Tris-HCl buffer solution at pH 8.6 using biaxially drawn PLLA films.16

In

their study, however, effects of orientation on hydrolysis were insignificant, where the degrees of orientation, estimated by x-ray diffractometry, were in the range of 67 ~ 92 %.

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Depending on whether enzymatic or hydrolytic degradation was applied, the location sensitive to degradation in drawn PLLA differed.

For example, Rangari et al.

reported that enzymatic degradation in drawn PLLA films occurred in the free and restricted amorphous regions, but that the degradation in annealed films occurred only in the free amorphous region.6

Tsuji et al. reported that in enzymatic degradation, both

extended chains in the amorphous region19 and folded chains16 in the restricted amorphous region were much more hydrolysis-resistant than tie chains and chains in the free amorphous region located outside of spherulites.

On the other hand, they

mentioned that in autocatalytic and alkaline degradation, all kinds of chains, i.e., tie chains, folded chains, and chains with free terminal groups, were degradable.16 In our previous study, PLLA was blended with biologically safe oligomers, poly(aspartic acid-co-L-lactide) (PAL) and poly(malic acid-co-L-lactide) (PML), and the effects of the addition of these oligomers on the degradation behavior were elucidated at 40 oC in a phosphate buffer solution.27

It was demonstrated that PML is a

more effective degradation accelerator for PLLA than PAL, with the initial hydrolysis rate constants of the PLLA blends at 20 wt% loading enhanced 15 times by PAL and 34 times by PML.

It was also demonstrated that PLLA/PAL and PLLA/PML do not

possess a risk to initiate the degradation in air (25 oC, 60% RH), which is different from

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conventional PLLA blends with hydrophilic polymers exhibiting the acceleration of degradation by blending.28

Therefore, as a next step, the present study attempts to

clarify the effects of uniaxial drawing and addition of PAL and PML on the mechanical properties and the hydrolytic degradation behavior of PLLA/PAL and PLLA/PML blends. In the present study, various techniques were utilized for the analyses, including gel permeation chromatography (GPC), differential scanning calorimetry (DSC), two dimensional wide angle x-ray diffraction (2D-WAXD), elemental analysis, and scanning electron microscopy (SEM).

The hydrolytic degradation of neat PLLA and

PLLA blends with either PAL or PML was carried out in a phosphate buffer solution (pH 7.4) at 40 oC.

The degradation of drawn PLLA materials proceeding to an

advanced stage at physiological conditions has hardly been studied yet, whereas in this study it could be investigated by the addition of the degradation accelerators. Furthermore, as for PLLA blends, to our knowledge there are no studies reporting the effects of molecular orientation on their hydrolytic degradation.

EXPERIMENTAL SECTION

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Materials and Sample Preparations. Poly(L-lactic acid) (PLLA) with a number-average molecular weight (Mn ) of 1.3x105 g/mol and a weight-average molecular weight (Mw ) of 2.2x105 g/mol was supplied by Mitsui Chemicals Co. Ltd. (Tokyo, Japan).

It contained 1.4 % of D-lactyl units with the rest being L-lactyl units.

The PLLA used in the present study has a Tg of 60 oC and a Tm of 166 oC.

Two kinds

of biodegradable copolymers, poly(aspartic acid-co-L-lactide) (PAL) and poly(malic acid-co-L-lactide) (PML), were synthesized without catalysts, in which both molar ratio of L-lactyl (LA) to aspartic acid (Asp) units, [LA]/[Asp], and of LA to malic acid (Mal) units, [LA]/[Mal], were fixed to be 10/1.

PAL is a block copolymer with a y-shaped

architecture (See more details in Supporting Information), in which the Asp block is located at a junction and three LA blocks are at the chain ends, whereas PML synthesized from D, L-malic acid and L-lactic acid monomers is a linear copolymer, as shown in Figure 1.27,29,30

The malic acid unit in the PML can take two types, α-Mal

and β-Mal, depending on which carboxylic acid group in the malic acid monomer with two such groups participates in the polycodensation.

The detailed recipes for synthesis

of PAL and PML were described in our previous paper and patent.29,30 are both amorphous, with Tg’s of 47 oC and 44 oC, respectively.

PAL and PML

They are oligomers

with exactly the same molecular weights; i.e. Mn of 1.6x103 g/mol and Mw of 3.5x103

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g/mol.

The specific optical rotations of PML, PAL, and PLLA were −11.60, −8.66,

and −13.44 (deg cm2 g-1), respectively, which were measured by Autopol V Polarimeter (Rudolph Research Analytical, USA) at 25 oC.

(a) Poly(aspartic acid-co-lactide) (PAL)

β-Mal

α-Mal

(b) Poly(malic acid-co-lactide) (PML)

Figure 1. Chemical structures of (a) poly(aspartic acid-co-lactide) (PAL) and (b) poly(malic acid-co-lactide) (PML).

The PLLA/PAL and PLLA/PML blend films were prepared by melt mixing the component materials at given ratios, where details are described in our previous paper.27 The molten blends were hot-pressed either at 170 oC (PLLA/PML) or at 180 oC

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(PLLA/PAL) in vacuo followed by cold-pressing at 0 oC to obtain quenched films with dimensions of 90 mm x 90 mm x 0.2 mm or 90 mm x 90 mm x 0.5 mm. The so-prepared films with ca. 500 µm thickness were uniaxially drawn by a large scale biaxial film stretcher (Toyo Seiki, EX10-B1, manufactured in Japan), fixing the film width.

The basic drawing conditions were set up to be the initial film length

between grippers = 70 mm, pre-heating = 3 min, strain rate = 0.714/min, drawing temperature, Td = about 10 degrees higher than the Tg of the specimen, and cooling = air gun.

In preliminary experiments, films with a stamped plaid pattern were uniaxially

drawn at various temperatures.

The optimum drawing temperature was determined for

each specimen with a given composition under such conditions that the plaid pattern stamped on the quenched film was homogeneously elongated without causing rupture nor whitening of the film.

Furthermore, various draw ratios (DR) were tested in a

range of 2.5 ~ 6, during which the films were ruptured at DR = 6 so that the highest DR applied to the specimens was chosen to be 4.5.

Since the films with an original

thickness of 500 µm became ca. 200 µm thick at DR = 2.5, compression-molded films with 200 µm were used as quenched and annealed films for comparison. Neat PLLA, (80/20)PLLA/PAL and (80/20)PLLA/PML quenched films were placed in a metal frame of 0.2 mm thickness, and then annealed in vacuo with a hot-press

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under the following conditions; 120 oC(60 min) for neat PLLA, 105 oC(10 min) for (80/20)PLLA/PAL, and 100 oC(10 min) for (80/20)PLLA/PML.

The annealing

temperature was chosen for each specimen from its cold crystallization temperature obtained from differential scanning calorimetry (DSC) measurements.

It was

confirmed by the DSC measurements that the annealing time was long enough to complete crystallization for each specimen.

Hydrolytic Degradation at Neutral Conditions. The quenched and annealed films prepared by compression molding as well as the uniaxially drawn films at different DR’s were subjected to hydrolytic degradation at 40 oC in a phosphate buffer solution (Sigma Medical Co. Ltd. in Japan, 1 M, pH = 7.4).

The film specimens

with a dimension of 20 mm x 20 mm x 0.2 mm were placed in a glass vial filled with the buffer solution, and were immersed in a concussive water bath controlled at 40 oC. The specimens were removed from the buffer solution at different hydrolysis stages to measure remaining mass, water uptake, and molecular weight of the remaining films. The detailed procedures were described in our previous paper.27

Structural, Thermal, and Optical analyses. Gel permeation chromatography (GPC).

The change in molecular weight of the

specimens upon hydrolytic degradation was investigated by GPC using a setup with a

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refractive index detector detailed in our previous paper.31 Chloroform was used as eluent and twelve monodisperse polystyrene standards were used for calibration. Differential scanning calorimetry (DSC).

The glass transition temperature (Tg),

melting temperature (Tm), and cold crystallization temperature (Tc) of the specimens were estimated under a nitrogen atmosphere with a TA Instruments DSC-Q200 (manufactured in the USA) at a heating rate of 10 oC/min.

The crystallinity (Xc) of the

whole blends was estimated, assuming the melting enthalpy of 100% crystalline PLLA to be 93 J/g,32 in which the respective enthalpies of melting, cold crystallization, and recrystallization of PLLA chains were used for the calculation.27,31 The specimens were usually placed in a desiccator with a drying agent for over ten days before the measurements.

Two dimensional wide angle x-ray diffraction (2D-WAXD).

2D-WAXD

measurements were conducted with an x-ray diffractometer (Rigaku, RINT2550, manufactured in Japan) with the Cu Kα line as a x-ray source (λ = 1.5418 Å) at 40 kV and 370 mA, with the images measured with an imaging plate (BAS-SR127 manufactured by Fujifilm in Japan).

Here, the molecular chain axis of the 103 helical

chain conformation of the crystals, i.e., c-axis with our interest, is perpendicular to the normal vectors of the (110) and (200) planes.

So the intensity of the diffraction peak

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of the (110) and (200) planes at 2θ = 16.6o was measured as a function of the azimuthal angle, ϕ, as shown in S1 of Supporting Information.

The average cosine of the angle

between the crystal c-axis and the film Z-axis, < cos2ϕ c >, was calculated using Equations (2) – (4), from which the Herman orientation function, fc, was estimated from Equation (1). 3,7,33

where

3 < cos 2ϕ c > −1 fc = 2

(1)

< ܿ‫ ݏ݋‬ଶ ϕ c > = 1 − < ܿ‫ ݏ݋‬ଶ ϕ 110 > − < ܿ‫ ݏ݋‬ଶ ϕ 200 >

(2)

< ܿ‫ ݏ݋‬ଶ ϕ110 > = < ܿ‫ ݏ݋‬ଶ ϕ200 >

(3)

ഏ

ଶ

< ܿ‫ ݏ݋‬ϕ 110 > =

‫׬‬బ ூభభబ ሺఝሻ௖௢௦ మ ఝ௦௜௡ఝௗఝ ഏ

‫׬‬బ ூభభబ ሺఝሻ௦௜௡ఝௗఝ

(4)

The fc takes a value from −0.5 to 1, where 0 means no orientation, 1 means perfect orientation parallel to the machine direction, and −0.5 means perfect normal orientation, i.e. transverse direction orientation.

Birefringence.

The birefringence was measured using a polarization optical

microscope, Olympus BX51 (manufactured in Japan) equipped with an Olympus Berek Compensator, U-CTB, having a calcite plate.

The birefringence was calculated by the

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phase difference between the extraordinary (refracted) and ordinary rays measured experimentally and the sample thickness, d, measured by a film gauge.

Retardation, R,

was calculated from Equation (5), where C is a constant characteristics of the compensator, ω and ε are refractive indexes of ordinary and extraordinary rays, respectively;

R=C

2 | 1 − sin 2 θ / ω 2 − 1 − sin 2 θ / ε 2 ( 1 2 − 1 2) ω ε

(5)

Then, the birefringence, ∆n, was obtained from Equation (6); ∆n = R/d UV-Vis spectroscopy.

(6) Optical transparency of undrawn and drawn films was

measured by UV-Vis spectrometer (V-630 manufactured by JASCO in Japan) with a film holder attachment (FLH-741, JASCO), following the ISO 14782 procedure.

The

detection angle range of forward scattering was 0.6 degrees and 2.4 degrees for the lateral and longitudinal directions of the rectangular shaped incident light, respectively. Elemental analysis.

The elemental analysis was carried out with an elemental

analyzer, Vario MICRO cube (manufactured by ELEMENTAR Analysensysteme, Hanau, Germany), to investigate the change of the PAL content in (80/20)PLLA/PAL blends during the hydrolytic degradation, using the nitrogen content of the PAL as a

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probe.

Details of the calculations are given in our previous paper.27

The samples

were combusted at 1150 oC and He gas was used as carrier gas. The drawn PLLA/PAL films were cut in a

Scanning electron microscopy (SEM).

direction parallel to the drawing direction and the cross-section was observed by scanning electron microscopy (SEM) (JSM-5200 manufactured by JOEL in Japan) at 20 kV.

All specimens were stained with ruthenium tetraoxide (RuO4) vapor in order to

enhance the contrast between the PLLA and PAL phases, followed by gold coating prior to the observations.

Mechanical Properties. Tensile properties were investigated using a Strograph VES-50D (manufactured by Toyo Seki, Japan) at a tensile speed of 10 mm/min following the ISO 527 procedure at room temperature.34

The same

measurements were repeated at least five times.

RESULTS AND DISCUSSION Effects of Uniaxially Drawing on the Film Transparency.

In the

present study the optimum drawing temperature resulting in homogeneous elongation was found to be about 10 degrees higher than the Tg of the specimen; i.e., Td = 70 oC for neat PLLA and (90/10)PLLA/PAL, Td = 65 oC for (80/20)PLLA/PAL and

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(90/10)PLLA/PML, and Td = 62 oC for (80/20)PLLA/PML.

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Figure 2 shows the

change in transparency of the films upon uniaxial drawing at 600 nm.

First of all, the

undrawn neat PLLA and PLLA/PML films exhibited very high transmittance of 91 ~ 96 %.

In comparison, the undrawn PLLA/PAL exhibited lower transmittance, which

even decreased with increasing PAL content.

This is because PLLA/PML is a nearly

miscible blend, whereas PLLA/PAL is immiscible forming PAL aggregates in the PLLA matrix, as discussed in our previous work.27

Neat PLLA and PLLA/PML

retained their high transparency during uniaxial drawing, in contrast, the transmittance of (80/20)PLLA/PAL decreased significantly upon drawing.

It was found from SEM

observations of the cross-sections of the drawn (80/20)PLLA/PAL films that uniaxial drawing induced detachment of PAL domains from the PLLA matrix forming voids, which resulted in the generation of crazes running in the machine direction (MD). (See S2 in Supporting Information.) This plastic deformation eventually decreased the transmittance of the PLLA/PAL films.

Thus, the transparency of drawn films was

largely affected by the miscibility between PLLA and the oligomeric degradation accelerator.

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100 Transmittance (%)

80 60

Change in transmittance of neat

Figure 2.

PLLA and PLLA blend films at 600 nm upon

40

uniaxial drawing. [◆: PLLA, ○, ▽: (90/10)

20

and (80/20)PLLA/PAL, ●, ▼: (90/10) and

0 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0

(80/20)PLLA/PML]

Draw ratio

Effects of Uniaxially Drawing on the High Order Structure of PLLA/PAL and PLLA/PML Films. Figure 3 shows changes in

Tg, Tc, Tm, and crytallinity of drawn PLLA blend films. Tg

the DSC thermograms of PLLA, (80/20)

Tc

Tm

PLLA/PAL, and (80/20)PLLA/PML upon uniaxial drawing, in which the Tc Endothermic

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(105 ~ 110 oC) of quenched (undrawn) PLLA/PAL and PLLA/PML

(a)

Tc

Tg

Tm

dramatically decreased by over (b) o

30 C. (Table1)

Tc

Tg Figure 3.

Tm

Changes in DSC thermograms of

(a) neat PLLA, (b) (80/20)PLLA/PAL, and (c) (80/20)PLLA/PML upon uniaxial drawing.

[

: undrawn,

: DR = 2.5,

: DR = 3.5,

: DR = 4.5 ]

(c) 30

50

70

90

110 130 150 170 190 o

Temperature ( C) 17


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The change in degree of crystallinity (Xc) of the whole blends calculated from DSC thermograms indicated that the uniaxial drawing significantly increased Xc in all specimens.

At the same time the Tg of neat PLLA significantly increased upon

drawing (+14.0 oC at DR = 4.5 ) due to the confinement of molecular mobility in the amorphous region by the chain orientation and newly formed crystals, but the Tg of the blends slightly decreased instead.

This is most likely because the concentration of

PAL and PML, which function as plasticizers, increases in the amorphous region as a result of their displacement upon strain-induced crystallization of the PLLA component, thereby suppressing the increase in Tg of the blends.

Furthermore, in studies on

uniaxial drawn neat PLLA films, it was reported that the uniaxial drawing increases the Tm of PLLA due to an increase in crystal thickness.3,6,33

However, under our drawing

conditions, the Tm of neat PLLA hardly changed, whereas these of the blends even slightly decreased upon drawing.

The decrease in the Tm of the blends is probably the

result of a balance between the promotion of PLLA chain mobility by the placiticizing effect of PAL and PML and the disturbance of the orientation of PLLA chains in the formation of highly developed crystals, as will be discussed later again.

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Table 1. Thermal properties, crystallinity Xc, and crystalline orientation function fc, determined by DSC (1st scan) and 2D-WAXD measurements.

Sample

DR

PLLA

(80/20)PLLA/PAL

(80/20)PLLA/PML

1 2.5 3.5 4.5 1* 1 2.5 3.5 4.5 1* 1 2.5 3.5 4.5 1*

* : Undrawn annealed films, (

Molecular orientation.

DSC Tg(oC) 58.0 61.4 64.1 72.0 63.8 57.3 53.6 55.4 55.1 50.6 55.7 52.1 52.8 54.6 47.2

Tc(oC) 123.5 77.1 (73.2) (74.6) 110.1 76.7 69.2 74.5 105.6 78.6 70.4 (69.5) -

Tm(oC) 165.0 164.7 164.2 164.6 165.3 165.0 163.0 162.5 161.0 165.0 164.0 162.7 162.6 162.3 164.3

Xc(%) 1.9 19.1 (32.3) (35.2) 52.1 6.8 16.4 26.3 36.5 41.1 7.9 19.2 19.5 (28.8) 42.5

2D -WAXD fc 0.71 0.72 0 0.77 0 0.76 0

) : inaccurate values due to overlapping with another peak

The molecular orientation of neat PLLA film upon drawing

has been widely investigated by birefringence measurements.3,35

Supporting

Information, S3 shows our results on birefringence of neat PLLA, PLLA/PAL, and PLLA/PML, which displays a continuous increase upon uniaxial drawing up to the points of rupture. blends.

The results indicate that neat PLLA is more highly oriented than the

There are two possible explanations.

One is that the presence of PAL and

PML disturbs the molecular orientation of PLLA, and the other is that PAL and PML relax the oriented chains, acting as plasticizers.

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Wong et al. observed that the increase in birefringence upon drawing is more rapid for the neat PLLA film drawn at 120 oC than for that drawn at 85 oC.3

The

birefringence in both films reached final vaues of ca. 2.5x10-2 at DR = 3.5.

The

authors mentioned that in the case of the originally crystallized PLLA, the higher the deformation temperature, the higher the value of birefringence; however, in the case of amorphous PLLA, the tendency became the opposite.

This is because in the PLLA

film, which had high crystallinity, the crystals prevented flow at higher temperature so suppressed relaxation, thereby resulting in high molecular orientation.

This did not

occur at lower temperature. The crystalline structure and the orientation of crystals in annealed and drawn films were investigated by two dimentional WAXD measurements.

It is recognized that

PLLA crystallizes into different crystal forms depending on the drawing or annealing conditions.

Drawing at low temperature and/or lower DR produces α form crystals

composed of two chains with a 103 helical conformation.36

These α form crystals are

the most thermodynamically stable, and are also obtained by quiescent isothermal crystallization above 120 oC.37

It is also reported that quiescent crystallization below

120 °C results in a defective δ form (new designation of the α’ form).37

On the other

hand, the β form crystals are generated upon tensile drawing at high temperature at

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higher DR.8,9

Different structures are proposed for the β form crystals, such as an

orthorhombic unit cell composed of 6 chains with a left-handed 31 helical conformation,9 an orthorhombic unit cell with two parallel chains,38 or a trigonal unit cell with frustrated stacking of three 31 helices.10

Furthermore, γ form crystals with

two in an orthorhombic unit-cell39 are developed via epitaxial crystallization. Figure 4A shows one dimentional WAXD profiles of (i) annealed PLLA at 120 oC for 60 min and (ii) uniaxially drawn PLLA at DR of 4.5.

The main sharp peak at 2θ =

16.6 degrees and the smaller peaks at 2θ = 19.0 and 14.7 degrees of the annealed PLLA are assigned to diffractions from (110)/(200) planes, the (203) plane, and the (010) plane of the α crystals, respectively.40

On the other hand, the diffraction peaks were

much smaller and wider in the uniaxially drawn PLLA film (Figure 4A(ii)) compared to those in the annealed film Figure 4A(i).

The crystalline structure of the drawn PLLA

is probably a mixture of the mesomorphic form and the δ form as indicated by the absence of the (010) diffraction peak.14

Seguela’s group reported that poly(lactic acid)

containing 4 % of D-lactyl units uniaxially drawn at 70 oC (the same as our Td) formed a mesomorphic odering of the chains from the oriented amorphous chains at DR of over 1.3, whose diffraction pattern is very similar to our result in Figure 4A(ii).12

The

strain-induced mesophase appearing as a broad peak at 2θ = 16.2 degrees possesses an

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Biomacromolecules

25

,

[110]/[200] [203] (203)

(ii) (010)

10 ,

Birefringence x 10

(110)/(200)

(i)

,

crystalline phase

C

3

A

Intensity (a.u.)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 22 of 51

15

20

2θ(deg)

(a)

25

30

∆nc

20 15 10

amorphous phase

∆na

5

0 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 Draw ratio

(b)

(c)

,

(203)δ

B

,

,

(200)δ /(110)δ (d)

(e)

,

(203)δ

,

,

,

(203)δ

(203)δ

, ,

(f)

,

, ,

(200)δ /(110)δ

,

,

,

,

(200)δ /(110)δ

,

,

,

(200)δ /(110)δ

Figure 4A.

WAXD profiles of (i) annealed PLLA and (ii) uniaxially drawn PLLA at DR = 4.5.

Figure 4B.

2D-WAXD photographs of uniaxially drawn PLLA and PLLA blends.

[(a) PLLA at DR = 2.5; (b) (80/20)PLLA/PAL at DR = 2.5; (c) (80/20)PLLA/PML at DR = 2.5; (d) PLLA at DR = 4.5; (e) (80/20)PLLA/PAL at DR = 4.5; (f) (80/20)PLLA/PML at DR = 4.5] Figure 4C.

Change in calculated birefringence for the amorphous and crystalline phases of neat

PLLA and PLLA blend films upon uniaxial drawing. [■, □: PLLA, ●, ○: (80/20)PLLA/PAL, ▼, ▽: (80/20)PLLA/PML]

22


,

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intermediate ordering between crystalline and amorphous states, a phenomenon which is also observed in other semi-crystalline polymers such as poly(ethylene terephtalate) and poly(ethylene naphthalate).41

Seguela’s group also reported that PLLA drawn at

Td = 80 oC formed a mixture of the δ form and a mesomorphic form, whereas a mixture at Td ≥ 90 oC forms only the δ form. The two dimensional diffraction patterns of the blends indicate no clear evidence of crystallization at DR of 1, whereas neat PLLA drawn at DR of 2.5 exhibited a pair of diffraction arcs from the (200) and (110) planes of the δ crystals in the equatorial position (Figure 4B(a)).14

This shows that the crystals are highly oriented with their c

crystallographic axis parallel to the drawing direction.

However, in (80/20)

PLLA/PAL (Figure 4B(b)) and (80/20)PLLA/PML (Figure 4B(c)) drawn at the same DR, neither clear arcs nor diffraction spots were observed in any dirrection, implying that the crystalline structure of PLLA did not fully developed in the presence of PAL and PML.

In both blends drawn at DR of 4.5 (Figures 4B(e) and 4B(f)), the diffraction

arcs from the (110)/(200) planes finally appeared in the equatorial position. Furthermore, the 2D-WAXD photograph in Figure 4B(a) showed the orientation of amorphous chains in neat PLLA at DR = 2.5, whereas that was not clearly observed in the blends until DR = 4.5.

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Page 24 of 51

The orientation function of the crystals, fc, was estimated from the two dimentional WAXD measurements, as given in Table 1.

Interestingly, it was found that the fc

values of neat PLLA at DR of 2.5 and 4.5 were the same and that those for neat PLLA and PLLA blends at DR of 4.5 were very similar, i.e., 0.72 ~ 0.77. Here, the measured overall birefringence, ∆n, shown in Supporting Information, S3 is expressed by Equation (7) and Equation (8), where ∆nc and ∆na are the respective birefringence of the crystalline and amorphous phases, ∆nco is the intrinsic birefringence of the crystalline phase, and Xc and Xa are respective volume fractions of the crystalline and amorphous phases.

∆n = Xc ∆nc +Xa ∆na

(7)

o

= Xc fc ∆nc + Xa ∆na

(8)

o

The value of ∆nc = 0.031 was obtained from the literature42 to estimate the respective values of ∆nc and ∆na in this study.

Figure 4C shows the obtained results on

changes in the birefringence of the crystalline region (open symbols) and of the amorphous region (closed symbols) upon uniaxial drawing.

It was demonstrated that

the ∆na gradually increases with increasing DR value, where at the high DR value of 4.5 PAL and PML decrease the orientation of the amorphous phase in a similar manner. On the other hand, the ∆nc values at DR = 4.5 were the same for both the neat PLLA

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and the PLLA blends, while the ∆nc value of the neat PLLA stayed constant irrespective of the change in the DR value.

(The ∆nc values for the blends at DR = 2.5 could not be

obtained due to no apparent diffraction from the crystals, as shown in Figures 4B(b) and 4B(c).) In the present study, since the specimens with low crystallinity were used for the uniaxial drawing, a rotation of the crystals along the drawing direction in order to reduce the force would hardly occur.

Instead, it is considered that the chains aligned

parallel to the drawing direction preferentially formed crystals.

The presence of PAL

and PML would disturb the chain orientation and/or relax the oriented chains generated by drawing, and there was no apparent difference between the y-shaped PAL and the linear PML.

Thus, strain-induced crystallization from aligned amorphous chains

naturally resulted in the oriented crystals in the neat PLLA and the blends with similar fc and ∆nc values. Tanaka et al. investigated the orientation of neat PLLA uniaxially drawn at DR of 1.2 ~ 4.5 by polarized Raman spectroscopy.7

They obtained very similar results to

ours where when neat PLLA films were drawn at 75 ± 0.5 oC, the crystalline region in neat PLLA was preferentially oriented at a low DR of about 2, but that the amorphous region was not oriented enough until the DR value reached above 4.5.

Wong et al.

also mentioned in their study on uniaxially drawn neat PLLA that at a DR higher than

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the yield point, the amorphous phase continuously orients, while the crystalline phase has already reached its limit in orientation, thereby producing no change.3

Mechanical Properties of Uniaxially Drawn PLLA/PAL and PLLA/PML Films. The tensile properties of the drawn neat PLLA and PLLA blend films were investigated, focusing on the effects of the addition of PAL and PML and the uniaxial drawing.

Figure 5A shows the changes in the stress-strain curves of

neat PLLA films in the machine direction at various DR values, which demonstrates 250 200

DR=3.5

150

DR=2.5

100

200

120

40

20 40 60 80 100 120 140 160

Strain (%) Figure 5A. (left) Change in stress-strain curves of neat PLLA films (in the machine direction) upon uniaxial drawing. Figure 5B. (right) Change in tensile properties of neat PLLA and PLLA blends in the machine direction upon uniaxial drawing. [(a) Tensile strength, (b) elongation at break and (c) Young’s modulus of ◆: PLLA, ○: (90/10)PLLA/PAL, ▽: (80/20)PLLA/PAL, ● : (90/10)PLLA/PML, ▼ : (80/20)PLLA/PML]

Elongation at break (%)

0

+ PAL and PML

80

160

Young's modulus (GPa)

DR=1

(a)

160

200

50 0

Tensile strength (MPa)

240 DR=4.5

Stress (MPa)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 26 of 51

2.8

(b)

+ PAL and PML

120 80 40 0

(c)

2.4 2.0 1.6 + PAL and PML

1.2 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0

26


Draw ratio

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that uniaxial drawing significantly alters the tensile properties of the samples. changes were observed in PLLA blends as well.

Similar

Figure 5B summarizes tensile

strength, elongation at break, and Young’s modulus data in the drawing direction.

At a

DR of 1, the tensile properties of the blends were very similar to those of neat PLLA, demonstrating that the addition of oligomeric PAL or PML does not deteriorate the mechanical properties. Upon drawing, the tensile strengths and Young’s moduli significantly increased, however, both tended to be suppressed by the addition of PAL and PML.

Especially in (80/20)PLLA/PML, the Young’s modulus stayed unchanged

up to a DR of 3.5.

On the other hand, the elongation at break exhibited the highest

values at a DR of 2.5 in all specimens, for which higher concentrations of PAL and PML resulted in higher values of the elongation at break.

The emergence of the

maximum elongation at break might be partly caused by the drawing conditions, i.e., the uniaxial drawing under the constant film width, where the molecular orientation in the transverse direction is reported to be similar to that generated by the biaxial drawing.43 The increase in the elongation at break was more significant in PLLA/PML than PLLA/PAL.

Namely, the elongation at break of drawn PLLA blends was enhanced,

probably due to the plasticizing effect of PAL and PML.

The PML, which is miscible

with PLLA, exhibited more significant effects compared to the partially miscible PAL.

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The typical stress-strain curves of neat PLLA and (80/20)PLLA/PML films at DR of 4.5 in the machine direction (MD) and the transverse direction (TD) are also given in Supporting Information, S4A.

It was demonstrated that the elongation at break of neat

PLLA film was enhanced upon drawing in both directions, and the extent was much more significant in TD than in MD. was enhanced only in the MD.

In contrast, the elongation at break of the blends

The tensile strength of both neat PLLA and the blends

was much larger in MD than in TD due to the chain alignment.

Supporting

Information, S4B summarizes results on elongation at break of uniaxially drawn films at DR of 4.5 in both directions.

The elongation at break of neat PLLA and PLLA blends

drawn at DR = 4.5 in the MD increased several times (a value close to 50 %), whereas that of neat PLLA and (90/10)PLLA/PML in the TD was enhanced significantly, exceeding values of over 300 %. Murariu et al. report effects of plasticizers on the tensile properties of PLLA, using bis(2-ethylhexyl) adipate (DOA), glyceryl triacetate (GTA), and tributyl o-acetylcitrate (TBAC) as plasticizers.44

It was demonstrated that GTA, with the lowest molecular

mass and the lowest χ interaction parameter with PLLA, resulted in the best mechanical performance, in which PLLA with 20 wt% of GTA became unbreakable in notched Izod impact tests.

It was observed that the addition of the plasticizers led to enhancement

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Biomacromolecules

of elongation at break and impact strength, but to reduction of glass transition temperature, tensile strength, and Young’s modulus, in agreement with our observations.

Effects of the High Order Structure and the Addition of PAL and PML on In Vitro Hydrolytic Degradation of Uniaxially Drawn PLLA/PAL and PLLA/PML Films. Initial stage of hydrolytic degradation (up to 40~60 days).

The effects of the

degradation accelerators, PAL and PML, and uniaxial drawing on hydrolytic degradation were investigated by immersing the specimens in a phosphate buffer solution at 40 oC for given times.

Figure 6A shows changes in the ratio of the

remaining mass to the original mass of drawn (a) (80/20) PLLA/PAL and (b) (80/20) PLLA/PML films upon hydrolytic degradation.

The figures also show results for the

quenched (undrawn) and annealed blend films.

The mass of neat PLLA films that

were quenched, annealed, and uniaxially drawn were all unchanged by the immersion of the films in the phosphate buffer solution during the whole experimental period of 100 days so that all results are shown by one symbol, ∆, in the figure.

In contrast, the

addition of PAL and PML significantly accelerated the reduction of the mass upon hydrolytic degradation, with the annealed blend films losing their mass most quickly at earlier degradation time compared to other films.

Interestingly, the mass change was

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Page 30 of 51

hardly affected by uniaxial drawing in both blends up to a degradation time of 40 ~ 60 days.

Namely, the initial mass loss of PLLA blends was accelerated by annealing but

not affected by uniaxial drawing. In the annealed blend films with high initial Xc, it is surmised that the amorphous region contained concentrated PAL and PML as a result of displacement from the crystalline region as well as the concentrated terminal carboxylic acid groups of the PLLA chains functioning as acid catalysts for the PLLA hydrolysis.6

This situation

would enhance the hydrophilicity of the amorphous region and induce intensive acceleration of hydrolytic degradation in the amorphous region, in contrast to very slow degradation in the crystalline region.

The different degradation rates in the amorphous

and crystalline regions consequently result in the emergence of multiple GPC peaks, as shown in Figure 6B(c).

This is a reason why the hydrolytic degradation is accelerated

more significantly in the annealed blends, Figure 6B(c), having significant loss of the amorphous phase than in the quenched blends with low Xc, Figure 6B(a), at the initial stage.

The specific peaks appeared at lower molecular weights in Figure 6B(c) were

ascribed to residues of one streched crystalline chain or several folds of the crystalline lamella.27

The blends uniaxially drawn at DR = 4.5, Figure 6B(b), exhibited a similar

change in the GPC spectra to the quenched blends, Figure 6B(a).

30


It is recognized that

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hydrolytic degradation of neat PLLA films is accelerated upon crystallization, where thicker lamellar thickness is associated with faster degradation.25,45

Late stage of hydrolytic degradation (over 40~60 days).

At degradation times of

longer than 40~60 days, the mass loss of the annealed blend films and the films uniaxially drawn at DR = 4.5 were more significantly suppressed than the quenched films and the films drawn at DR = 2.5. (Figure 6A).

This was quite different from the initial period

As a result, at a degradation time of 100 days, the mass loss of the blend

films was enhanced in the following order; drawn at DR of 4.5

Biologically Safe Poly(l-lactic acid) Blends with Tunable Degradation

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