Controlling the Switching Temperature of Biodegradable, Amorphous

Biomacromolecules 2009, 10, 975–982

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Controlling the Switching Temperature of Biodegradable, Amorphous, Shape-Memory Poly(rac-lactide)urethane Networks by Incorporation of Different Comonomers Andreas Lendlein,*,† Jo¨rg Zotzmann,† Yakai Feng,‡ Armin Alteheld,§ and Steffen Kelch⊥ Center for Biomaterial Development, Institute of Polymer Research, GKSS Research Center Geesthacht GmbH, 14513 Teltow, Germany, Department of Polymer Science and Technology, Tianjin University, 92 Weijin Road, Tianjin 300072, People’s Republic of China, BASF Aktiengesellschaft, Polymer Research, Carl-Bosch-Str. 38, 67056 Ludwigshafen, Germany, and Sika Technology AG, Tu¨ffenwies 16, CH-8048 Zu¨rich, Switzerland Received January 9, 2009; Revised Manuscript Received January 28, 2009

Biodegradable shape-memory polymers have attracted tremendous interest as potential implant materials for minimally invasive surgery. Here, the precise control of the material’s functions, for example, the switching temperature Tsw, is a particular challenge. Tsw should be either between room and body temperature for automatically inducing the shape change upon implantation or slightly above body temperature for on demand activation. We explored whether Tsw of amorphous polymer networks from star-shaped rac-dilactide-based macrotetrols and a diisocyanate can be controlled systematically by incorporation of p-dioxanone, diglycolide, or ε-caprolactone as comonomer. Thermomechanical experiments resulted that Tsw could be adjusted between 14 and 56 °C by selection of comonomer type and ratio without affecting the advantageous elastic properties of the polymer networks. Furthermore, the hydrolytic degradation rate could be varied in a wide range by the content of easily hydrolyzable ester bonds, the material’s hydrophilicity, and its molecular mobility.

Introduction 1

Degradable polymeric implant materials such as aliphatic (co)polyesters2-5 are used today in numerous medical applications, including surgical devices and drug release systems. In this area, material research is often driven by the complex requirements of clinical applications. The aim to insert spacious degradable implants through small incisions into the body6,7 or to manipulate their shape on demand during a minimally invasive procedure8,9 motivated the combination of degradability and shape-memory capability resulting in multifunctional polymers.10-12 The shape-memory effect enables the implantation of a bulky device in a compressed temporary shape (A) through a small incision. Upon application of heat and thereby exceeding a certain switching temperature, Tsw, the device changes to its original shape (B). Here, a particular challenge is the precise control of Tsw. According to various application strategies, Tsw must be in different temperature ranges. Tsw between room temperature and body temperature results in an automatically induced shape change after implantation. Tsw slightly above body temperature enables on demand control of the shape change by short time application of heat applied either indirectly through IR-irradiation13 or directly by application of an external heating medium,14 for example, through a catheter. The temporary shape of a shape-memory polymer can be fixed either by crystallization or vitrification of switching domains.15-17 Therefore, Tsw is influenced by the melting point Tm or the glass transition temperature Tg of the switching domains. Recently, we described how Tsw of a degradable shape-memory polymer * To whom correspondence should be addressed. E-mail: andreas.lendlein@ gkss.de. † GKSS Research Center Geesthacht GmbH. ‡ Tianjin University. § BASF Aktiengesellschaft. ⊥ Sika Technology AG.

network with crystallizable switching segments can be adjusted.18 Here, Tsw was related to Tm of the switching domains, which could be controlled by variation of the number average molecular weight Mn of oligo[(ε-caprolactone)-co-glycolide]dimethacrylates used as precursors in the polymer network synthesis. Alteration of the macromolecular architecture from semicrystalline to amorphous networks broadens the diversity of morphology and mechanical properties with respect to the application. In addition, a more homogeneous degradation behavior is expected for completely amorphous polymer networks. An example for amorphous polymer networks whose Tsw could be adjusted by variation of Tg are AB polymer networks from methylmethacrylate and poly(ethylene glycol) dimethacrylate.19 But according to their chemical structure these materials are nondegradable. Degradable polymer networks were achieved by photocrosslinking poly[(L-lactide)-co-glycolide]dimethacrylates. However, these materials are relatively brittle and therefore difficult to handle.20 More favorable elastic properties could be realized with copolyesterurethane networks prepared from star-shaped macrotriols or macrotetrols and a diisocyanate as junction unit.21 These amorphous polymer networks containing poly[(rac-lactide)-co-glycolide] switching segments with a glycolide content between 15 and 18 wt % are limited in their applicability because of their relatively high Tsw between 48 and 66 °C. In this paper we explore whether Tsw for amorphous, degradable copolyesterurethane networks can be adjusted to application relevant temperatures by systematically controlling their Tg by molecular parameters. At the same time, the polymer network’s molecular architecture and its crosslink density as a molecular parameter determining the elastic properties should be maintained. As the polymer network structure is built up by reacting macrotetrols and a low molecular weight diisocyanate (Scheme

10.1021/bm900038e CCC: $40.75  2009 American Chemical Society Published on Web 03/02/2009

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Lendlein et al.

Scheme 1. Synthesis of Copoly(ether)esterurethane Networks

1), the variation of Tg could be achieved by diversifying the chemical structure of the macrotetrols, for example, by using a copolymerization as synthesis route. We aimed at telechelic cooligomers with a random sequence structure to obtain amorphous and homogeneous materials. Our strategy to control Tg is derived from the Fox-Flory theory, which allows estimating Tg of amorphous copolymers from Tgs of the related homopolymers formed by each of the comonomers. In this context two molecular parameters could be identified to adjust Tg: the chemical structure of the comonomer and the comonomer ratio. Two criteria were applied to select suitable monomers for the

ring-opening copolymerization (ROP) of lactones using pentaerythrite (2) as initiator. They should be established in the synthesis of degradable implant materials and must differ in Tg of their respective homopolymers. rac-Dilactide (1) was chosen as basic monomer. Tg of poly(rac-lactide) is about 59 °C.22 As comonomers diglycolide (3), p-dioxanone (5), and ε-caprolactone (4) were selected, whose homopolymers have Tgs at 36 °C,23 -10 and -60 °C.24 Dibutyltin oxide (DBTO) catalyst was added to the initiator/monomer mixture similar as described previously where it catalyzed transesterification besides ROP leading to a random sequence structure in copolyesters.25 An alternative synthesis route could be reacting DBTO with a low molecular weight tetrol under removal of water before adding the comonomers. The spirocyclic tin initiators obtained in this way allowed controlled synthesis of star-shaped homopolymers from lactones.26 Crosslink density of the networks was kept constant by sustaining Mn as well as the four-armed structure of the co-oligomers. Thermal properties of macrotetrols and polymer networks were determined by differential scanning calorimetry (DSC). The correlation between Tg and Tsw was investigated by a stress-controlled thermomechanical tensile test. Finally, the hydrolytic degradation behavior of the polymer networks was studied with film samples in aqueous buffer solution at pH 7 and 37 °C.

Experimental Section Figure 1. Typical strain/temperature course of a stress-controlled thermomechanical experiment (network N-P-LG(17)). The points 1 to 4 characterize the strain of the material after the individual steps of the experiment.

Materials. rac-Dilactide (94 mol % D,D- and L,L-dilactide, and 6 mol % meso-dilactide, Sigma-Aldrich Chemie GmbH, Steinheim) and diglycolide (Boehringer Ingelheim GmbH, Ingelheim) were recrystallized from ethyl acetate. Pentaerythrite (>99%), the isomeric mixture

Temperature of Poly(rac-lactide)urethane Networks


of 2,2,4- and 2,4,4-trimethylhexane-1,6-diisocyanate (>98%, TMDI) and DBTO were used as received from Sigma-Aldrich Chemie GmbH. ε-Caprolactone (Sigma-Aldrich; 99%) was distilled over calcium hydride (Merck; ca. 95%). p-Dioxanone (Boehringer Ingelheim) was distilled under vacuum before use. Synthesis of Macrotetrols 6, 7, and 8. The monomers and the initiator were molten under a nitrogen atmosphere. The catalyst DBTO (0.2 wt %) was added, and the mixture was stirred under nitrogen at 130 °C for 5 days. The melt was cooled to ambient temperature and dissolved in dichloromethane. The solution was poured in hexane fraction and the precipitate was washed with hexane and dried in vacuum (Scheme 1). Formation of Copoly(ether)ester-urethanes. Macrotetrols and diisocyanate (in a molar ratio of isocyanate to hydroxy functional groups of 1.05) were first reacted at room temperature for 1 day and at 80 °C for an additional 4 days. The crude films were extracted with chloroform. Gel content G and degree of swelling Q were calculated according to eqs I and II from the ratios of weights of the swollen ms, the nonswollen m0, and the extracted and dried films me. The density of the polymer network Fp was determined with a pycnometer at 20 °C in water, and Fs is the specific density of the solvent (chloroform). At least three samples were swollen in chloroform, and the determined swelling properties are given as average values ( standard deviation. No error was given if less than three samples were measured. The stoichiometry for the reaction with diisocyanate was optimized empirically by comparing the gel contents of the resulting polymer networks. The highest gel contents were achieved with a molar ratio of isocyanate to hydroxyl groups of 1.05.

G)

Q)1+

me ·100 m0

(

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and polymer networks were measured in a temperature range from 0 to 150 °C only. Tensile tests and thermomechanical experiments were performed on a ZWICK1425 equipped with a thermochamber (Climatic Systems LTD, model 091250). The deformation rate was 10 mm · min-1. The samples were annealed for 20 min at the operating temperature before each experiment. Samples were 10 × 3 × 0.3 mm in dimension. Free sample length was between 3 and 6 mm. Accordingly, the relative strain rate was in the range of 167-333% · min-1. For the determination of mechanical properties at least three samples were tested, values are given as average ( standard deviation. In the stress-controlled thermomechanical experiment for determining the shape-memory properties, sample was heated to 70 °C and kept at this temperature for 20 min. The sample was mechanically conditioned by three cycles of elastic deformation and recovery from the starting elongation ε0 to the maximum elongation εm and back to ε0. For programming, the sample is stretched to εm ) 100% and kept under the resulting stress σm for 5 min. While keeping σm the sample is cooled to 0 °C with a cooling rate of 10 °C · min-1 and kept at the lower temperature for 15 min. The sample now is at the deformation under stress load εl. After about 6 min at 0 °C the stress is released resulting in the temporary shape characterized by εu at σ ) 0 MPa. The sample is now heated to 70 °C with a heating rate of 5 °C · min-1 under stressfree condition, whereas the sample undergoes the recovery step. Tsw is determined as inflection point of the strain/temperature curve. The elongation after the recovery process is εp. A typical strain/temperature curve obtained from this thermomechanical test is displayed in Figure 1. The strain fixity rate Rf and the strain recovery rate Rr are calculated from εl, εu, εp, and ε0.

(I)

)

Fp ms · - 1 ·100 Fs me

Rf )

εu - ε0 ·100 εl - ε0

(III)

Rr )

εl - εp ·100 εl - ε0

(IV)

(II)

Methods. Gel permeation chromatography (GPC) was performed by serial usage of a T60A dual detector of Viscotek Corp. and a RI detector 8721 of ERC. GPC setup consisted of an 1120 HPLC pump of Polymer Laboratories and a 600 × 7.5 mm PL-gel mixed-D column. Chloroform was used as eluent at a flow rate of 1.0 mL per minute. Universal calibration was performed using narrow molecular weight distributed polystyrene standards. Viscometric data and molecular weight calculation were performed with TriSEC GPC-Viscometry Module Software (version 3.0, Viscotek Corp). DSC was performed on a Perkin-Elmer DSC7 apparatus with low temperature cell equipped with a TA7 processor. During the first heating run the samples were heated from 25 to 150 °C with a heating rate of 10 °C/min, kept at this temperature for two minutes and were cooled down to -30 °C with a cooling rate of 10 °C/min. In the second heating run the samples were heated from -30 to 150 °C with a rate of 10 °C/min. Glass transition temperatures (Tg) were determined from second heating run. Error bars in graphics represent the glass transition temperature interval. The diglycolide comonomer containing oligomers

The strain recovery speed νd,r was used to characterize the speed of the recovery process, which was defined as

Vd,r ) 0.8·

βh T90 - T10

(V)

where T10 and T90 were the temperatures corresponding to a reached strain recovery rate of 10 and 90% in the recovery curve and βh was the heating rate in the recovery measurements. The recovery temperature coefficient Rd,r was determined according to eq VI, characterizing the temperature interval of shape-memory transition.

Table 1. Assignment of 1H NMR Signals for the Calculation of Mn of the Macrotetrols and the Conversion of the Monomers during ROP

a

signal

chemical shift (ppm)

assignment

multiplicitya

1 2 3 4 5 6 7 8 9

2.25-2.42 3.70-3.84 4.15 4.23-4.32 4.32-4.44 4.50-4.90 4.96 5.06 5.10-5.30

R-CH2 of hydroxycaproate unit γ-CH2 of hydroxyethoxyacetate unit 4× CH2 of the initiator unit CH2 of terminal glycolate unit CH of terminal lactate unit CH2 of internal glycolate unit 2× CH2 of diglycolide 3 2× CH of dilactide 1 CH of internal lactate unit

m m s m m m s q (J ) 3.4 Hz) m

s, singlet; q, quartet; m, multiplet.

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Biomacromolecules, Vol. 10, No. 4, 2009 Rd,r ) 0.8·

1 T90 - T10

Lendlein et al. (VI)

Table 2. Mn of Macrotetrols Obtained from rac-Dilactide 1 with Comonomers 3, 4, and 5 oligomer IDa,b Mnb (g · mol-1) Mnc (g · mol-1) Mnd (g · mol-1) PDc

1

13

H NMR (400 MHz) and C NMR (100 MHz) spectra were recorded on a Varian Inova 400 in CDCl3 or DMSO-d6. The assignments of the interpreted NMR signals used for the determination of Mn are given in Table 1. Mn of the P-LX precursors was determined according to the following equation

Mn ) (NX·MX + NL·ML)·NI-1 + MI

(VII)

ML and MX are the molecular weights of lactate and the repetitive units from the comonomers 3, 4, and 5, respectively (3, X ) G; 4, X ) C; 5, X ) D), and MI of the initiator 2. The relative number of the monomer segments (NL, NX) and of the initiator (NI) was determined by 1H NMR signal integration. NL is the integral of the signal of the methine protons of lactate units (signals 5 + 9) and NI is the integral of the signal of the methylene protons of initiator unit (signal 3) divided by 8. NG is the integral of the signal of the R-methylene protons of the glycolate units (signals 4 + 6) divided by 2. NC is the integral of the signal of the R-methylene protons of the hydroxycaproate units (signal 1) divided by 2 and ND is the integral of the signal of the γ-methylene protons of the hydroxyethoxyacetate units (signal 2) divided by 2. The conversion (Y) of the monomer X (diglycolide, X ) G; dilactide, X ) L) was determined by 1H NMR measurements according to eq VIII.

YX )

NX NX + 2·NcX

(VIII)

NcX are the relative numbers of the respective cyclic monomers in the reaction mixture with NcG as the integral of the signal of R-methylene protons of the diglycolide monomer (signal 7) divided by 4 and NcL as the integral of the signal of the methine protons of the dilactide monomer (signal 8) divided by 2. Hydrolytic degradation was investigated in aqueous phosphate buffer solution at pH 7 and 37 °C. NaN3 (250 mg · L-1) was added to avoid growth of microorganisms. Samples for degradation experiments were 15 × 10 × 0.3 mm in dimension. The samples were immersed into the buffer and slightly shaken during the degradation time. After removing samples at degradation time period td, its water intake H, the relative mass loss and thermal properties of the dried samples were determined. In addition to G (in chloroform according to eq I), the mass related degree of swelling S for the semidegraded polymer networks was determined with chloroform as swelling agent according to eq IX. Chemical composition and molecular weight of degradation products that were completely soluble in chloroform were determined by 1H NMR and GPC measurements.

S)

ms ·100 me

(IX)

Determination of molecular weights by vapor pressure osmometry (VPO) was carried out with a osmometer model 11.00 (Knauer GmbH, Berlin, Germany) in 1,2-dichloroethane at 25 °C. Five different concentrations between 0.015 mol · kg-1 and 0.2 mol · kg-1 were applied for the measurements, the calibration standard was benzil.

Results and Discussion Synthesis and Characterization of the Oligomers 6, 7, and 8. Amorphous star-shaped oligo[(rac-lactide)-ran-glycolide]tetrols (P-LG) (6), oligo[(rac-lactide)-ran-(ε-caprolactone)]tetrols (P-LC) (7), and oligo[(rac-lactide)-ran-(p-diox-

P-LG(0) P-LG(8) P-LG(13) P-LG(17) P-LG(30) P-LG(48) P-LG(52) P-LC(6) P-LC(12) P-LC(16) P-LC(21) P-LC(31) P-LC(53) P-LD(8) P-LD(12) P-LD(17) P-LD(20) P-LD(25) P-LD(45) P-LD(65)

9200 11600 10500 10500 10700 9700 9900 7700 7400 9200 7400 7200 9100 6500 9500 7200 7200 6900 10100 10000

11100 13400 14000 10800 9200 10800 12600 11900 11200 10500 10700 10300 11200 11200 12300 12300 n.d. 10900 11100 9400

6700 9200 9700 5100 7400 6100 7800 6800 6900 n.d. 8200 7100 7300 3900 4100 4100 n.d. 4400 3200 2500

1.21 1.13 1.27 1.60 1.41 1.36 1.21 1.19 1.27 1.41 1.36 1.42 1.36 1.26 1.37 1.37 n.d. 1.29 1.25 1.21

a Oligomers were denoted as P-LG, P-LC, and P-LD from the initiator P, 2, and the monomers L, 1, G, 3, C, 4, and D, 5 (the comonomer content of 3, 4, and 5 in wt % determined by 1H NMR is given in parenthesis). b 1 H NMR signal integration was used for comonomer content and molecular weight determination. c Determined by multidetector GPC measurements and universal calibration. d Determined by means of VPO; n.d., not determined.

anone)]tetrols (P-LD) (8) were synthesized. Their comonomer content was varied from 0 wt % to 52 wt % for comonomer 3, between 6 wt % and 53 wt % for 4, and between 8 wt % and 65 wt % for 5, respectively (see Table 2). Mn of the oligomers was controlled by the molar ratio of monomers to initiator. Mn was between 6500 and 11600 g · mol-1, determined by 1H NMR spectroscopy, and between 9200 and 14000 g · mol-1 determined by GPC. The values of Mn for the oligomers with p-dioxanon as comonomer determined by VPO are significantly lower in comparison with Mn values from GPC and 1H NMR. This finding is attributed to the residual content of the monomer p-dioxanone. This remaining monomer causes a reduction of Mn determined by VPO. The comonomer composition of the obtained oligomers was investigated by means of 1H NMR measurements. The difference in the determined comonomer contents from the calculated values does not exceed 3%, so that a high extent of monomer conversion during the polymerization can be assumed. For the following investigations, Mn of 10000 g · mol-1 for the oligomers was chosen to ensure that the material is in the Mn range where Tg is independent from the Mn of the star-shaped prepolymers. Furthermore, this relatively high Mn of the starshaped prepolymers leads to a high chain segment length in the network ensuring good elastic properties. The influence of the comonomer composition on the Tg of copolymers with constant molecular mass and randomized comonomer distribution is described by the Fox-Flory equation.27 The obtained dependence of the Tg from the comonomer content is shown in Figure 2. Tg of P-LC decreased from 46 to -23 °C with the content of 4 increasing from 0 to 53 wt %. With increasing contents of 5 (0 to 65 wt %) Tg of P-LD showed similar tendency decreasing from 46 to -16 °C. The influence on the range of Tg for P-LG with content of 3 increasing from 0 to 53 wt % was less pronounced with values for Tg between 46 and 41 °C. For comparable comonomer content Tg of co-oligomers was de-



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Table 4. Mechanical Properties of Copoly(ether)ester-urethane Networks Determined by Tensile Tests at 37 °C

Figure 2. Dependence of Tg of co-oligo(ether)estertetrols in DSC (2nd heating) on comonomer (3, 4, or 5) content in wt %. O, P-LG oligomers; 4, P-LC oligomers; 0, P-LD oligomers. The curves were calculated according to Fox equation. The bars show the temperature interval of the glass transition.

network-IDa E (MPa)

σy (MPa)

εy (%)

σb (MPa)

εb(%)

375 ( 20 380 ( 70 430 ( 80 310 ( 60 390 ( 50 75 ( 15 300 ( 20 86 ( 12 6.8 ( 7.5 1.3 ( 0.2 1.4 ( 0.2 62 ( 26 7.2 ( 5.3 2.7 ( 0.3 1.4 ( 0.1 1.2 ( 0.4

38.7 ( 7.6 39.3 ( 2.1 39.3 ( 2.2 34.0 ( 7.3 35.9 ( 8.5 15.7 ( 6.3 35.0 ( 3.3 13.9 ( 2.9

19 ( 4 15 ( 4 13 ( 4 19 ( 7 17 ( 1 31 ( 9 23 ( 13 35 ( 7

21.8 ( 8.7

5(2

24.9 ( 1.1 23.6 ( 1.3 18.8 ( 1.4 22.7 ( 6.0 21.8 ( 4.3 7.2 ( 0.6 19.7 ( 2.7 13.2 ( 3.7 7.1 ( 2.2 4.0 ( 0.3 1.5 ( 0.4 6.5 ( 0.8 3.9 ( 0.4 4.3 ( 1.3 1.9 ( 0.4 2.2 ( 0.5

40 ( 5 300 ( 60 40 ( 5 275 ( 150 260 ( 65 430 ( 235 370 ( 75 445 ( 215 580 ( 30 570 ( 145 240 ( 125 245 ( 25 335 ( 40 365 ( 40 290 ( 10 470 ( 180

N-P-LG(0) N-P-LG(8) N-P-LG(13) N-P-LG(30) N-P-LG(48) N-P-LG(52) N-P-LC(6) N-P-LC(12) N-P-LC(16) N-P-LC(31) N-P-LC(53) N-P-LD(12) N-P-LD(17) N-P-LD(25) N-P-LD(45) N-P-LD(65) a

For polymer network denotation see Table 3, note a.

Table 3. Gel Content G and Degree of Swelling Q of Copoly(ether)ester-urethane Networks network-IDa

G (%)

Q (%)

N-P-LG(0) N-P-LG(8) N-P-LG(13) N-P-LG(30) N-P-LG(48) N-P-LG(52) N-P-LC(6) N-P-LC(12) N-P-LC(16) N-P-LC(21) N-P-LC(31) N-P-LC(53) N-P-LD(8) N-P-LD(12) N-P-LD(17) N-P-LD(20) N-P-LD(25) N-P-LD(45) N-P-LD(65)

96 ( 4 98 ( 2 98 ( 1 97 ( 0 97 ( 1 97 ( 1 91 90 ( 1 94 ( 0 94 ( 0 95 ( 1 94 98 ( 0 92 ( 1 93 ( 1 97 ( 1 91 ( 2 93 ( 1 90

590 ( 50 540 ( 50 630 ( 60 540 580 ( 50 420 ( 10 710 670 540 ( 30 580 ( 20 600 ( 10 770 610 860 ( 50 820 ( 10 560 690 ( 30 760 ( 30 870 ( 80

a Polymer networks were denoted with “N-” before the ID of the respective star-shaped co-oligomer the polymer network was synthesized from, see Table 2, note a.

scending from P-LG to P-LD to P-LC, as expected from Tg of the respective homopolymers.22,24 The observed Tgs of cooligomers were approximately fitting to the Fox and Flory equation, thus strongly indicating a randomized distribution of the comonomers within the polymer chains of the macrotetrols.27 Synthesis and Characterization of Copoly(ether)esterurethane Networks. The polymer networks were prepared from co-oligo(ether)ester tetrols 6, 7, 8, and TMDI (Scheme 1). The denomination of the synthesized polymer networks is defined in note (a) of Table 3. Swelling properties in chloroform, thermal and mechanical properties (see Table 4) of the polymer networks were investigated. The gel content G determined in chloroform was between 90 and 98%, which indicates a sufficient degree of crosslinking during network synthesis. Q is a measure for comparing the crosslink densities of the different polymer networks. It is determined by the functionality f and the average arm length of the star-shaped prepolymers. Because all used prepolymers have the same functionality f ) 4 and a similar Mn (Table 2), a similar degree of swelling is expected. The measured values of Q summarized in Table 3 strongly indicate a comparable crosslinking density of all networks which is due

Figure 3. Exemplary endotherms from DSC measurements (2nd heating) on polymer networks: 1, N-P-LG(0); 2, N-P-LG(15); 3, N-PLG(30); 4, N-P-LG(45).

to the similar functionality and Mn of the applied star-shaped prepolymers. All synthesized polymer networks N-P-LG, N-P-LC, and N-PLD exhibit only one Tg in DSC and, therefore, are amorphous (Figure 3). Tgs of networks are generally higher than those of the corresponding co-oligomers. This is attributed to the limited mobility of free chain ends upon incorporation into the polymer network. With increasing comonomer content, Tgs of the copolymer networks decreased. The dependence of the Tg from the comonomer content is shown in Figure 4. Polymer networks with Tg in the application relevant temperature range have the following comonomer contents: 15-45 wt % for N-P-LD, 10-25 wt % for N-P-LC, and >50 wt % for N-P-LG. Since biodegradable shape-memory polymers are of high significance for medical applications, the mechanical properties were investigated at body temperature as well (Table 4). Tensile test experiments performed at 37 °C showed a yield point and necking for N-P-LG networks. These networks are glassy, as Tg is above this temperatures. For N-P-LD and N-P-LC, Tg is around 37 °C for comonomer contents between 15 and 25 wt %. For this reason a strong influence of Tg on the mechanical properties is observed in tensile tests performed at 37 °C. N-PLC and N-P-LD with high content of 4 (g15 wt %) or 5 (>25 wt %) showed significantly lower values for the elasticity modulus (E) and the stress at break point (σb), while values for the strain at break point (εb) up to 570% were observed (Table 4). Stress and strain at the yield point (σy and εy) were given for those polymer networks featuring a yield point.

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Lendlein et al. Table 5. Shape-Memory Properties of Biodegradable Copoly(ether)esterurethane Networksa

Figure 4. Dependence of Tg of the polymer networks in DSC (2nd heating) on comonomer (3, 4, or 5) content of oligomers used as precursors in wt %. b, N-P-LG networks; 2, N-P-LC networks; 9, N-P-LD networks. The curves were calculated according to FoxFlory equation. The bars show the temperature interval of the glass transition.

Figure 5. Strain recovery process of polymer networks under a stressfree condition in stress-controlled thermomechanical tests: (s) N-PLG(0), (- -) N-P-LG(17), ( · · · ) N-P-LG(30), (- · -) N-P-LG(52), (- · · ) N-P-LC(16), (---) N-P-LC(31).

Shape-Memory Properties of Copoly(ether)ester-urethanes Networks. The shape-memory properties of selected copoly(ether)ester-urethane networks having a Tg in the range from 13 to 57 °C were quantified in thermomechanical tensile experiments.28 After mechanical preconditioning the samples were programmed under stress-controlled condition. The recovery from their temporary shape characterized by εu to their recovered shape at εp was performed under stress-free conditions. The specimen started strain recovery when a temperature near Tg was reached as shown in Figure 5. Tsw was the temperature at which the highest recovery speed was observed. Strain fixity rate Rf and strain recovery rate Rr were evaluated according to the eqs III and IV.29 For all copoly(ether)esterurethane networks, the values for Rr and Rf were higher than 95%, except for the shape fixity ratio of the tested N-P-LC networks (Table 5). While Tsw of N-P-LG decreased from 56 to 44 °C with content of 3 increasing from 0 to 52 wt %, the temperature interval of strain recovery increased (Figure 5). This might be caused by lower homogeneity of the switching phase for high contents of 3. This is in accordance with the broader temperature interval of Tg for N-P-LG(52) compared to N-PLG(0). The strain recovery speed Vd,r,29 decreased from 0.65 to 0.27 min-1 when the content of 3 increased from 0 to 52 wt %. The recovery temperature coefficient Rd,r decreased with in-

network IDb

Rf (%)

Rr (%)

Tsw (°C)

Rd,r (K-1)

νd,r (min-1)

N-P-LG(0) N-P-LG(17) N-P-LG(30) N-P-LG(52) N-P-LC(16) N-P-LC(31) N-P-LD(12) N-P-LD(20)

95.2 96.3 95.6 96.3 91.4 88.0 >99.0 96.2

95.5 96.0 98.0 99.0 >99.0 >99.0 >99.0 >99.0

56 55 51 45 34 14 49 38

0.131 0.088 0.065 0.055 0.116 0.093 0.148 0.043

0.65 0.44 0.32 0.27 0.58 0.47 0.74 0.22

a Rf, strain fixity rate, and Rr, strain recovery rate, determined from stress-controlled thermomechanical experiments; Tsw, switching temperature, Rd,r, recovery temperature coefficient, νd,r, strain recovery speed, Thigh ) 70 °C, Tlow ) 0 °C, εm ) 100%. b Polymer networks were denoted as N-P-LG, -LC, and -LD (comonomer content of 3, 4, and 5 in wt % in precursors determined by 1H NMR); P, 2; G, 3; C, 4; D, 5; L, 1.

creasing comonomer content.28 Similar results were observed for N-P-LC and N-P-LD with varying comonomer content (Table 5). Tsw is mainly dependent on Tg of the networks. Tsw was obtained to be within the temperature range of the glass transition. Insofar Tsw could be controlled in a temperature range from -15 to 56 °C. A vicinity of Tsw to body temperature is of special interest for biomedical applications, as is the case for N-P-LC(16) (Tsw ) 34 °C) and N-P-LD(20) (Tsw ) 38 °C). Hydrolytic Degradation of Copoly(ether)ester-urethanes Networks. Eight polymer networks were selected for the investigation of their behavior during hydrolytic degradation. Four polymer networks from the N-P-LG series were chosen, which represent the complete range of the comonomer content (0, 17, 32, and 52 wt % diglycolide comonomer content). The polymer networks N-P-LC(12) and N-P-LC(21) from the ε-caprolactone comonomer containing networks were chosen due to their Tg near body temperature (39 and 37 °C, respectively). The networks with the corresponding comonomer content were chosen from the N-P-LD series with Tgs of 44 and 41 °C, respectively. The mass fraction of the networks relative to the original mass mtd · mt0-1 (mtd, sample mass after a degradation period td; mt0, original sample mass) as a function of the degradation time shows the mass loss due to the release of water soluble degradation products. The water uptake H that is expected to increase with decreasing crosslinking density and increasing hydrophilicity of the network due to polar end-groups generated by ester-bond cleavage was calculated from mtd and the mass of the semidegraded buffer-swollen sample at the time td before the drying (mbs) according to eq X. The time dependence of both variables is shown in Figures 6 and 7.

H)

mbs - mtd mtd

(X)

While the determination of G shows the proportion of the remaining crosslinked matrix, the mass related degree of swelling in chloroform S demonstrates the influence of the hydrolysis on the crosslink density. Because S of the networks depend on the segment length of the prepolymers, relative degrees of swelling are given for the swelling behavior. These values represent the ratio of the mass based swelling degree in chloroform during the degradation experiment S(t) to the mass based swelling degree at the onset of the hydrolytic degradation



981

Figure 6. Polymer networks 9 and s N-P-LG(0), 2 and -- N-P-LG(17), b and · · · N-P-LG(30), 1 and - · - N-P-LG(52); curves are guidelines for the eye; (a) mass fraction of the networks relative to the original mass as function of the degradation time; (b) water intake of the degrading network depending on degradation time; (c) quotient S(t)/ S0 in dependence of degradation time; (d) gel content of the polymer networks depending on degradation time.

Figure 7. Polymer networks 2 and -- N-P-LC(12), b and · · · N-PLC(21), 4 and s N-P-LD(12), O and - · - N-P-LD(20), curves are guidelines for the eye; (a) mass fraction of the networks relative to the original mass as function of the degradation time; (b) water intake of the degrading network depending on degradation time; (c) quotient S(t)/S0 in dependence of degradation time; (d) gel content of the polymer networks depending on degradation time.

S0. The results of these measurements are graphically summarized in the Figures 6 and 7. In all test series, an induction period was observed where no time-dependent mass loss occurred. The induction period was significantly decreased for N-P-LG with increasing content of 3 as the ratio of easily hydrolyzable glycolate ester bonds and the hydrophilicity of networks increased (Figure 6a).30 The cleavage of ester bonds in the network leads to a decrease in the crosslink density so that the swelling in buffer solution as

well as in chloroform will be promoted. As expected, the relative swelling degree increases with a shorter time of degradation than the mass loss (Figure 6c). The same tendency of comonomer influence on mass loss is observed for the decrease in G with degradation time when comonomer content of 3 is increased (Figure 6d). However, the decrease of G has a much shorter induction period showing that the hydrolysis of ester bonds first leads to bigger fragments which are soluble only in chloroform and later to small water soluble fragments. The

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networks with varying glycolide contents show a systematic dependence of the swelling degree on the glycolide content. The degradation of N-P-LD and N-P-LC was affected significantly by decreasing Tg, whereby the diffusion of water into the network as well as of degradation products out of the network is favored. Hence, the mass loss of N-P-LC(12) started earlier than N-P-LG(17) although glycolate ester bonds have higher hydrolysis rates than hydroxycaproate ester bonds.25 The influence of this effect on mass loss, swelling, and gel content during degradation is shown in Figure 7. For each polymer network series, higher comonomer content resulted in faster hydrolytic degradation. The results of the swelling experiments and the changes of the relative mass of all investigated networks confirm the bulk degradation model. After a phase of induction with the water absorption within the matrix the rate of the hydrolytic cleavage of ester bonds increases according to autocatalytic processes. The developed end groups and degradation products yield an increasing of hydrophilicity and water absorption. Due to the reduction of the crosslink density via cleavage of chain segments the degree of swelling increases. At first the generated fragments of the network can be removed via extraction with organic solvents. After a further decrease of the molecular weight, these fragments are water soluble and a mass loss takes place in phosphate buffer.

Conclusion Tg of amorphous copoly(ether)ester urethane networks could be varied systematically by two different molecular parameters: the chemical structure of the comonomers and the comonomer ratio of the telechelic precursors used as starting material in the polymer network synthesis. Polymer networks with Tg in the application relevant temperature range have the following comonomer contents: 15-45 wt % p-dioxanone for the N-PLD, 10-25 wt % ε-caprolactone for the N-P-LC, and >50 wt % glycolide for the N-P-LG series. Accordingly, Tsw was varied in a temperature range from 14 to 56 °C. Suitable polymer networks for inducing the shape-memory effect by the temperature increase from room temperature to body temperature can be found in the N-P-LD and the N-P-LC series. Good elastic properties were obtained nearly independently from the chemical composition of the networks. The hydrolytic degradation behavior could be varied in a wide range and increased in each polymer network series with growing comonomer content. Thereby the degradation rate of the copoly(ether)esterurethanes depended not only on the hydrolysis rate of their ester bonds, but also on the materials hydrophilicity and on the molecular mobility, which was significantly different at temperatures above or below Tg. The multifunctional amorphous polymer networks hold great promise to be applied in regeneration therapies such as bioactive implants that require transparency, biodegradability, and shape-memory properties.

Lendlein et al.

Acknowledgment. This work has been financially supported by Bundesministerium fu¨r Bildung and Forschung, BioFuture Award No. 0311867. A.A. is grateful to the Ministerium fu¨r Schule, Wissenschaft, and Forschung of Nordrhein-Westfalen for a “Graduiertenfo¨rderung” grant.

References and Notes (1) Langer, R.; Tirrell, D. A. Nature 2004, 428, 487–492. (2) Albertsson, A. C.; Varma, I. K. Biomacromolecules 2003, 4, 1466– 1486. (3) Hakkarainen, M.; Hoglund, A.; Odelius, K.; Albertsson, A. C. J. Am. Chem. Soc. 2007, 129, 6308–6312. (4) Putnam, D. Nat. Mater. 2006, 5, 439–451. (5) Vert, M. Biomacromolecules 2005, 6, 538–546. (6) Lendlein, A.; Langer, R. Science 2002, 296, 1673–1676. (7) Lu, X. L.; Cai, W.; Gao, Z.; Tang, W. J. Polym. Bull. 2007, 58, 381– 391. (8) Min, C. C.; Cui, W. J.; Bei, J. Z.; Wang, S. G. Polym. AdV. Technol. 2005, 16, 608–615. (9) Nagata, M.; Kitazima, I. Colloid Polym. Sci. 2006, 284, 380–386. (10) Chen, M. C.; Tsai, H. W.; Chang, Y.; Lai, W. Y.; Mi, F. L.; Liu, C. T.; Wong, H. S.; Sung, H. W. Biomacromolecules 2007, 8, 2774– 2780. (11) Zini, E.; Scandola, M. Biomacromolecules 2007, 8, 3661–3667. (12) Ping, P.; Wang, W.; Chen, X.; Jing, X. Biomacromolecules 2005, 6, 587–592. (13) Small, W., IV; Wilson, T. S.; Benett, W. J.; Loge, J. M.; Maitland, D. J. Opt. Express 2005, 13, 8204–8213. (14) Machold, T. R.; Keller, W. A.; Roth, A. T.; Bloom, N. D. Method and System for Control of a Patient’s Body Temperature by Way of a Transluminally Insertable Heat Exchange Catheter. U.S. Patent 7175649, Feb. 13, 2007. (15) Behl, M.; Lendlein, A. Soft Matter 2007, 3, 58–67. (16) Hornbogen, E. AdV. Eng. Mater. 2006, 8, 101–106. (17) Liu, C.; Qin, H.; Mather, P. T. J. Mater. Chem. 2007, 17, 1543–1558. (18) Kelch, S.; Steuer, S.; Schmidt, A. M.; Lendlein, A. Biomacromolecules 2007, 8, 1018–1027. (19) Yakacki, C. M.; Shanadas, R.; Safranski, D.; Ortega, A. M.; Sassaman, K.; Gall, K. AdV. Funct. Mater. 2008, 18, 2428–2435. (20) Choi, N. Y.; Lendlein, A. Soft Matter 2007, 3, 901–909. (21) Alteheld, A.; Feng, Y. K.; Kelch, S.; Lendlein, A. Angew. Chem., Int. Ed. 2005, 44, 1188–1192. (22) Vert, M.; Christel, P.; Chabot, F.; Leray, J. In Macromolecular Biomaterials; Hastings, G. W., Ducheyne, P., Eds.; CRC Press: Boca Raton, FL, 1984; pp 119-142. (23) Gilding, D. K.; Reed, A. M. Polymer 1979, 20, 1459–1464. (24) Middleton, J. C.; Tipton, A. J. Biomaterials 2000, 21, 2335–2346. (25) Lendlein, A.; Colussi, M.; Neuenschwander, P.; Suter, U. W. Macromol. Chem. Phys. 2001, 202, 2702–2711. (26) Finne, A.; Albertson, A.-C. Biomacromolecules 2002, 3, 684–690. (27) Fox, T. G. Bull. Am. Phys. Soc. 1956, 1, 123. (28) Choi, N. Y.; Kelch, S.; Lendlein, A. AdV. Eng. Mater. 2006, 8, 439– 445. (29) Lendlein, A.; Kelch, S.; Schulte, J.; Kratz, K. Shape-Memory Polymers. In Encyclopedia of Materials: Science and TechnologysUpdates; Buschow, K. H. J., Cahn, R. W., Flemings, M. C., Kramer, E. J., Mahajan, S., Veyssiere, P., Eds.; Elsevier Science Ltd.: New York, 2005; pp 1-9. (30) Yoo, J. Y.; Kim, J. M.; Seo, K. S.; Jeong, Y. K.; Lee, H. B.; Khang, G. Biomed. Mater. Eng. 2005, 15, 279–288.

BM900038E

Controlling the Switching Temperature of Biodegradable, Amorphous

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