A biocompatible, biodegradable and functionalizable copolyester and

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Characterization, Synthesis, and Modifications

A biocompatible, biodegradable and functionalizable copolyester and its application in water-responsive shape memory scaffold Yangfen Xie, Dong Lei, Shaofei Wang, Zenghe Liu, Lijie Sun, Jingtian Zhang, Feng-Ling Qing, Chuanglong He, and Zhengwei You ACS Biomater. Sci. Eng., Just Accepted Manuscript • DOI: 10.1021/acsbiomaterials.8b01337 • Publication Date (Web): 28 Feb 2019 Downloaded from http://pubs.acs.org on March 1, 2019

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ACS Biomaterials Science & Engineering

A biocompatible, biodegradable and functionalizable copolyester and its application in water-responsive shape memory scaffold

Yangfen Xiea, Dong Leia, Shaofei Wangb , Zenghe Liua, Lijie Sunb, Jingtian Zhanga, Feng-Ling Qinga,c, Chuanglong Hea*, Zhengwei Youa,b* a

State Key Laboratory for Modification of Chemical Fibers and Polymer Materials,

College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, 2999 North Renmin Road, Shanghai 201620, China b International

Joint Laboratory for Advanced Fiber and Low-dimension Materials,

College of Chemistry, College of Materials Science and Engineering, Donghua University, 2999 North Renmin Road, Shanghai 201620, China c

Shanghai Institute of Organic Chemistry, Chinese Academy of Science, No. 345,

lingling road, Shanghai. * Corresponding authors. E-mail: [email protected], [email protected]. Tel: +86-2167874253. Fax: +86-21-67792588.

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ACS Biomaterials Science & Engineering 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

ABSTRACT: Shape memory polymers are of great interest for biomedical applications. However, most stimuli to trigger shape memory process including heat, light, electricity, magnetism and pH are inconvenient and maybe harmful to body. Here, we designed and fabricated a new shape memory porous scaffold using biocompatible and readily available water as the trigger. This scaffold based on poly (fumaricacid-co-1, 7-octadiene diepoxideco-terephthalic acid) (PFOT) synthesized via epoxide ring-opening polymerization in one step. PFOT scaffold promoted the adhesion, spreading, proliferation and function of cardiomyoblast H9C2 cells comparable to poly (lactic-co-glycolic acid) scaffold. It exhibited an excellent water-responsive shape memory effect with fixity and recovery ratio above 97% and a shape-recovery process of several minutes, suitable for surgery operation. In addition, PFOT scaffold presented good in vitro biodegradation. More importantly, PFOT contains extensive free hydroxyl groups and could be facilely functionalized and would be a promising smart material for multiple biomedical applications. KEYWORDS: functional polyester, water-responsive shape memory, shape memory scaffold, aliphatic and aromatic copolyester 1. Introduction Shape memory polymers (SMPs) have been investigated extensively for biomedical applications such as on-demand drug delivery, tissue regeneration, minimally invasive surgery, biosensing and artificial muscles since 2000s, due to its dual (multiple) shape capability at specific stimuli including heat, light, electricity, magnetism, water and pH. [1-9]

So far, thermo-responsive SMPs polymers are most widely investigated because of


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their simple triggering process. However, it is difficult to exactly control the switching temperature of the materials within the rangeof room temperature to body temperature, which limits the wide biomedical applications of thermo-responsive SMPs. [10] On the other hand, other stimuli for biomedical applications such as light, electricity, magnetism or pH may be harmful to body and are inconvenient. Using water as a stimulation to trigger shape recovery effect has been emerging a promising way to overcome aforementioned problems since water is readily available in the body and intrinsically biocompatible.

[11-14]Some

water-responsive SMPs are based on natural materials, such as luffa sponge, animal hair, peacocks’ tail covert feather.

[15-17]

But they are usually of short resource, difficult to

be modified, not constant between batches. Some water-responsive SMPs are based on composites such as PEG-based composites and PVA/Al2O3 nanocomposites.

[18-20]

Alginate-based or poly(N-isopropylacrylamide) based water-responsive shape-memory cryogels have also be developed.

[21,22]

But their preparation processes are relatively

complex. In addition, some of them are not biocompatible and some of them are not biodegradable. [23-25] Recently, poly(lactic-co-glycolic acid) (PLGA) with water-responsive shape memory effect was reported for potential nerve regeneration.

[26]

But the response

was very slow (7 h), which may limit its applications. Therefore, new water-responsive SMPs are highly desirable for biomedical applications. Here, we designed and synthesized a water-responsive SMP based on poly (fumaric acid-co-1, 7-octadiene diepoxide-co-terephthalic acid) (PFOT) (Figure 1) for biomedical applications according to following considerations. (1) Suitable hydrophilicity.



Hydrophilic component (hydroxyls) is in conjunction with hydrophobic components (aromatic units and aliphatic chains) to yield a potential water-responsive effect while keeping the stability of morphology in water. (2) Balance of aromatic and aliphatic moieties. PFOT contains both aliphatic polyester units for expected biodegradability, and aromatic units for potentially good mechanical properties and high glass transition temperature (Tg) to fix temporary shape.

[27-29]

(3) Facile functionalization.

Functionalization can modulate the physical, mechanical and biological properties of materials in a wide range. PFOT contains hydroxyl and alkenyl groups, which are available for various chemical modifications including the bioconjugation with biomolecules. [30] (4) Concise synthesis. PFOT can be synthesized via epoxide ring-opening polymerization that we recently developed, in one step. [31,32] Here, we report the synthesis, characterization, cytocompatibility of PFOT and its preliminary application on fabricating water-responsive shape memory porous scaffolds.

Figure 1.

Design and synthesis of PFOT based water-responsive SMP


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2. Experimental Section 2.1. Chemical Reagents Chemical reagents: 1,7-Octadiene diepoxide (Alfa Aesar, 97%). Fumaric acid (Aladdin, 99.5%)was recrystallized from Ethanol (J&K Chemical, 99.8%)for three times.. tetrabutyl ammonium bromide (TCI, 98%), N,N-dimethyl formamide (DMF, J&K Chemical, 98.8%), terephthalic acid (Ourchem, 99%), tetrahydrofuran (THF, Sinopharm Chemical Reagent Co., Ltd, China, HPLC). 2.2. Synthesis of PFOT. PFOT was synthesized via our previous reported method with slightly modifications. [313]One

equimolar amount of fumaric acid and terephthalic acid, two equimolar amount of 1,

7-Octadiene diepoxide reacted in presence of 0.6 mol% tetrabutyl ammonium bromide in DMF at 90 ℃ for 8 h. The reaction mixture was purified via precipitation in de-ionized water. Then the crude product was dissolved in a mixed solvent (tetrahydrofuran: water = 9:1) and precipitated in de-ionized water and anhydrous ether twice respectively. Finally the product was vacuum dried at 65 ℃ for 24 h to yield PFOT. 2.3. Characterization of PFOT. The 1H NMR and 13C NMR were carried out on a Bruker 400 NMR. The attenuated total reflectance-Fourier transformed infrared (ATR-FTIR) was carried out on a Thermo Nicolet 6700 spectrometer. The molecular weight and its distribution were determined via Waters gel permeation chromatography (GPC) using a differential refractive index detector and a Brookhaven multi-angle light scattering detector. The measurement was performed at 40 ℃



using THF (HPLC grade) as the eluent. Polystyrene was used for calibration. Thermo gravimetric analysis was performed on Discovery TGA (TA, American) from 40 oC to 450 oC

at a heating rate of 10 oC min-1 under a nitrogen atmosphere. The decomposition was

defined at 5% weight loss degree. Differential scanning calorimetry (DSC) was performed on a NETZSCH DSC 204 F1 Phoenix from -50 oC to 200 oC at a heating rate of 10 oC min-1 under a nitrogen atmosphere. The Tg was defined as the midpoint of the glass transition and was determined using the analysis software from NETZSCH. The air-water contact angles of PFOT film in glass slides were measured by a water contact angle Instrument (Contact Angle SystemOCA40, Dataphysics Co., Germany) at room temperature. Four replicates were averaged. 2.4. Fabrication and characterization of PFOT scaffold The porous PFOT scaffold was prepared by a salt leaching method. [33] The preparing process was described as follows. Salt particles (75-150 μm) were placed into a cylinder mold. The final scaffold was 8 mm in diameter and 7 mm in height which was controlled by the amount of salt and the mold. The molds were placed in a humidity chamber at 37 oC

and 85% relative humidity for 1 h. The templates were then vacuum dried. The PFOT

solution in mixed solvent (THF: H2O = 9:1) was dripped gently into the mold. The PFOTimpregnated mold was placed in a fume hood for 30 min, then cured in a vacuum oven (1 Torr, 150 oC) for 24 h. Then the salt was removed by distilled water, and the scaffold was dried in oven.


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The attenuated total reflectance-Fourier transformed infrared (ATR-FTIR) spectra of dried and wet scaffolds were recorded on a Thermo Nicolet 6700 spectrometer and compared. The porosity of each scaffold was tested via the ethanol infiltration method as equal (1): Porosity (%) =

𝑉1 ― 𝑉3

× 100%

𝑉2 ― 𝑉3

(1)

The volume of ethanol in the measuring cylinder before and after the scaffold immersion was set as V1 and V2, respectively. After 15min, the scaffold was removed from the ethanol, and the remaining volume was marked as V3. The results of three scaffolds were averaged. The morphology of the scaffolds was investigated by scanning electron microscopy (SEM, Phenom Pro, USA). 2.5. Thermal properties of the PFOT scaffold. Thermogravimetric analysis of scaffold was carried out on Discovery TGA (TA, American) from 40 oC to 500 oC at a heating rate of 10 oC min-1 under a nitrogen atmosphere. DSC was performed on a NETZSCH DSC 204 F1 Phoenix from -20 oC to 200 oC

at a heating rate of 10 oC min-1 under a nitrogen atmosphere. The Tg was analyzed by

software from NETZSCH. 2.6. Mechanical properties of the PFOT scaffold. The mechanical properties of the PFOT scaffolds were evaluated by compression tests in water using a universal testing machine equipped with a 25 N sensor (MTS Echo, Exceed 40). [35] Cylinder-shaped specimens (8 mm diameter by 7 mm height) were punched from the PFOT scaffold. Each specimen was compressed to a strain of 30% at a rate of 0.2 mm



min-1 with an initial load of 0.01 N. The compression modulus was calculated by taking the initial slope of the stress–strain curve. The data from 3 specimens were averaged. In the cyclic compression test, the sample was compressed to a strain of 30% and then allowed to recover to 0% at a rate of 0.2 mm min-1 for 5 times. Solid cured PFOT sheet were made in Teflon mould (heated at 120 oC for 24 h then heated at 150 oC under vacuum for another 24 h) and cut into strips (30 × 7 × 1.8 mm) for tensile tests using an universal testing machine equipped with a 100 N sensor (MTS Echo, Exceed 40). The specimens preconditioned in water for 48 h were elongated to failure at a rate of 50 mm min-1. The data from 3 specimens were averaged. 2.7. The functionalization of PFOT. FITC/acetone solution (0.2 mg mL-1, 0.25 mL) was coated onto the PFOT scaffold. The sample was heated at 40 oC for 3 h in order to evaporate the solvent, and then rinsed with distilled water for 0.5 h for three times to remove the physically absorbed FITC and the sample was vacuum-dried at 60 oC for 2 h .The fluorescence of the scaffold was excited by 365 nm UV light and photographed by camera. 2.8. Water-responsive shape memory effects of PFOT scaffolds. To characterize the swelling behavior of PFOT scaffolds in water, samples were processed into cylinder shape with typical 8 mm in diameter and 7 mm in height, and were then immersed in water at room temperature for 30 min. Then, the samples were taken out and dried. Swelling degree were quantified using eq (2): [14]


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Swelling degree (%) =

Wwet ― 𝑊dry 𝑊dry

× 100%

(2)

Where Wdry and Wwet was the mass before and after being immersed in water respectively. Four specimens were tested and averaged. Shape fixity ratio (Rf) and shape recovery ratio (Rr) are two parameters usually used to characterize the shape memory properties, which are defined as eq (3) and (4): Rf = Rr =

εu εm

(3)

× 100%

εm ― εp(N) εm ― εp(N ― 1)

× 100%

(4)

Where εm is the maximum strain in the compression cycle. εu is the residual strain after unloading in dry state (through heating at 50 oC in this case). εp (N) and εp (N-1) are the residual strain values for two successive cycles after shape recovery is triggered by water immersion (water immersion of 15 min for each cycle). N is the cycle number, starting from 1 (εp (0) = 0). Rf and Rr of PFOT scaffolds were measured from the wettingcompression-drying shape recovery cycles. Hence, Rf is the ratio of the strain in the stressfree state after the retraction of the tensile displacement in one cycle to the pre-set maximum strain of 55%. The parameter Rr quantifies the ability of the materials to memorize its shape between two successive deformation cycles. Initially, the cylinder sample was immersed in distilled 37 oC water for 15 min. It was then taken out from the water and compressed with devices at ambient temperature. After being kept in oven (50 oC) for 4 h, the residual strain ε

u (N) was measured in the stress-free state. Then, the scaffold

was immersed in the water again for next cycle.



2.9. In vitro degradation of PFOT scaffold. An in vitro degradation test was performed in Dulbecco’s phosphate buffered saline (PBS). [36]The scaffolds were weighed, placed in the PBS solution (6 mL per sample) and then incubated at 37 oC for 7 days intervals. At harvest time, samples were taken out washed with distilled water and dried overnight at 50 oC under vacuum. The degradation degree was tested by the change of dry scaffold weight. Four sample results were averaged. 2.10. Cytocompatibility of PFOT. PFOT was coated on tissue-culture-treated polystyrene (TCPS) surfaces. PFOT was dissolved in 2, 2, 2-trifluoroethanol. The solution of polymer (1 g L-1) was filtered through a 0.2 μm filter and added to 48-well (40 μL well-1) or 6-well (425 μL well-1) TCPS plates. The plates were placed in air to evaporate the solvent, vacuum dried overnight, and after that were sterilized by UV light for 24 h. then washed with PBS (500×3 μL well-1 for 48well plates, 3×3 mL well-1 for 6-well plates) and culture medium (500×1 μL well-1 for 48well plate and 3×1 mL well-1 for 6-well plate). As control group, Pristine TCPS and PLGA coating on TCPS surfaces were adopted. The H9C2 cells line was purchased from Tipical Culture Collection cell bank of Chinese Academy of Sciences Committee and and the cells were subcloned from colon cell strain of rat embryonic heart tissue. The cells were cultured in high glucose (4,500 mg L-1) Dulbecco's modified Eagle's medium (DMEM) supplemented with 10.0% fetal bovine serum (FBS) and 1% penicillin-streptomycin (Gibco-BRL Inc., Grand Island, NY, USA) at 37 °C in a fully humidified incubator (95% air/5% CO2). H9C2 cells were seeded at a


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density of 10,000 cells mL-1 in a 6-well flat-bottom plate. After 24 h, the culture medium and unattached cells were aspirated and fresh medium was added. At 2-day intervals, the medium together with unattached cells was removed and fresh medium was added again. H9C2 single cell suspensions (2×104 cells well-1) were cultured on PFOT, PLGA and TCPS surfaces respectively in 48-well plates (n = 4) and placed at 37 °C in a fully humidified incubator (95% air/5% CO2). After 2, 6 and 12 hours, the culture medium and unattached cells were aspirated, and the cell adhesion was measured by Cell Counting Kit-8 （CCK-8）. H9C2 single cell suspensions (5×103 cells well-1) were cultured on PFOT, PLGA and TCPS surfaces respectively in 48-well plates (n = 4) and placed at 37 °C in a fully humidified incubator (95% air/5% CO2). After 1, 4, 7, 11, 14 days, the culture medium and unattached cells were aspirated, and the cell proliferation was measured by CCK-8. 2.11. Cell morphology. H9C2 single cell suspensions (2×104 cells well-1) were cultured on PFOT, PLGA and TCPS surfaces respectively in 24-well plates which was kept in a humidified incubator. The cytoskeleton structure was shown by F-actin fluorescence images after seeding the cells for 3 days recorded with an inverted microscope (Olympus, Tokyo, Japan). Briefly, the cells were fixed with 4.0% paraformaldehyde, permealilized with 0.1% triton-X 100 for 5 min, and then was immersed in 2.0% bovine serum albumin (BSA) for 30 min at room temperature to block nonspecific protein interaction. Then the cells were incubated in 200 μL phalloidin (phalloidin was diluted in PBS with 5 μg mL-1) for 30 min at room



temperature (in darkness). Nuclei were stained with 200 μL DAPI (DAPI was diluted in PBS with 5 μg mL-1) for 5 min at room temperature (in darkness). Cells were rinsed with DPBS (3×1 mL) between each step. Fluorescent micrographs were recorded with the Olympus microscope. 2.12. Immunofluorescence staining of cardiac specific proteins. H9C2 single cell suspensions (2×105 cells well-1) were cultured on PFOT, PLGA and TCPS surfaces in 6-well plates (n = 2) and placed at 37 °C in a fully humidified incubator (95% air/5% CO2). After 4 and 7 days, the cells were routinely processed, 4% formamintfixed, paraffin-embedded blocks were achieved. The blocks were washed with PBS (3 times) and cells were covered with 3% bovine serum albumin (BSA) for 30 min at room temperature, then incubated with primary antibodies Connexin 43 protein (Cx43, GB11234, Servicebio) or Cardiac Troponin T (cTnT, Ab47003, abcam) overnight at 4 oC. After washed with PBS thrice, they were incubated with secondary antibodies, Cy3- goat (GB21303, Servicebio) for 50 min at room temperature. Those samples were rinsed again with PBS and mounted in a mounting medium, with 6-diamidino2-phenylindole (G1012, Servicebio) treatment. Fluorescence was observed using a confocal laser scanning microscope (Nikon Eclipse C1). Semiquantitative analysis of the immunofluorescence intensity was performed using the NIH ImageJ version 1.51. 2.13. Statistical analysis. Statistical analysis was performed using one-way ANOVA and a LSD Post Hoc multiple comparison with a minimum confidence level of p < 0.05 for statistical significance. All values are reported as the mean ± standard deviation.


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3. Results and Discussion 3.1. Synthesis and characterization of PFOT PFOT (Mw = 4150, PDI = 1.5) was prepared in 86.1% yield from commercially available fumaric acid, 1, 7-octadiene diepoxide and terephthalic acid via the acid-induced epoxide ring-opening polymerization under a catalytic amount of tetrabutyl ammonium bromide (Figure 1). [31,32] 1HNMR, 13C NMR and FTIR were used to characterize the structure of PFOT. In the 1H NMR spectrum (Figure 2A),the signals marked ‘e’ ,‘f’ at chemical shift 1.24–1.65 ppm corresponded to the CH2 protons of the octanetetrol moiety in the polymer backbone. A series of signals marked ‘d’ at 3.14–3.78 ppm was ascribed to the CH protons connected to OH groups. The signals of CH2 Protons adjacent to ester linkages were split into two series of peaks at 3.98-4.21 ppm and 4.78-5.04 ppm marked ‘c’ due to the influence of the chiral carbon atoms in ortho-position. The peaks around 6.81 ppm were ascribed to the protons marked ‘b’ in the fumaryl moities. Signals of terephthaloyl protons marked ‘a’ appeared at 8.01-8.26 ppm. The relative integration of alkenyl protons and aromatic protons confirmed that the composition of the PFOT backbone was the same as the feed ratio. In the

13C

NMR spectrum (Figure 2B), the signals at around 165 ppm

corresponded to carbonyl carbons. The signals at 128 ppm and 133 ppm marked ‘a’ and ‘g’ corresponded to carbons in terephthaloyl and fumaroyl moieties, respectively. The signals at around 62-71 ppm marked ‘c’ and ‘d’ corresponded to carbons connected to oxygen atoms. The signals marked ‘e’ and ‘f’ corresponded to the alkane carbons in the polyol moiety.



The FTIR spectrum further confirmed the presence of the functional groups (Figure 2C). The broad peaks at 3100-3650 cm-1 corresponded to the O–H bonds. The peaks at 2950 cm-1 corresponded to the C–H bonds in fumaroyl groups. The peaks at 1720 cm-1 corresponded to the C=O bonds. The peaks at 1620-1670 cm-1 corresponded to C=C bonds in fumaroyl groups. The peaks at 1410-1100 cm-1 corresponded to both of C–O and O–H of hydroxyl group. PFOT was found difficult to be dissolved in common solvents including ethyl acetate, ethyl alcohol, methyl alcohol, acetone, chloroform, tetrahydrofuran, etc. To increase its solubility to facilitate processing, the reaction time was reduced to 8 hours to yield PFOT with relatively low molecular weight (Mw = 4150, PDI = 1.5), which could be well dissolved in a mixed solvent of THF and H2O. The decomposition temperature of PFOT was 221 oC (Figure 2D), which indicated the material was stable at body temperature. The DSC curve of the PFOT showed a Tg of 34.3 oC and no crystallization between -50 oC and 200 oC (Figure 2E). This indicated that the PFOT was amorphous. The water contact angle of PFOT was 54.5°±1.5, in the range of the suitable water contact angle of biomaterials as previously revealed (45°-76°). [37]


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Figure 2. Characterization of PFOT. (A) 1HNMR spectrum (400 MHZ, dimethylsulfoxide-d6) (B) 13C NMR spectrum (C) FTIR spectrum. (D) TGA curve.（E）DSC curve.

3.2. Fabrication, structure, thermal and mechanical properties, functionalization, and biodegradation of PFOT scaffold. Thermal curing and salt leaching fabricates the porous PFOT scaffolds as described previously. [38] The morphology of the scaffold was characterized by SEM. The crosslinked PFOT scaffold was macroporous with extensive micropores (Figure. 3A). The micropores were likely generated by the escape of the byproduct water during PFOT curing and residual organic solvent. The porosity of PFOT scaffold was 83.3 ± 1.2%. The chemical structure of scaffold was investigated by FTIR. Compared to uncured PFOT, the hydroxyl absorption peak at around 3300 cm-1 decreased in cured PFOT scaffold (Figure S1), which indicated the esterification crosslinking between the hydroxyl and terminal carboxyl groups in PFOT. The decreased signals of C-H and C=C bonds in fumaroyl groups at 2950



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cm-1 and 1695-1540 cm-1 in FTIR spectra after curing suggested alkenes crosslinking (Figure S1). The two combined crosslinkings efficiently built the covalently network. The wide peak at 3410 cm-1 ascribed to hydroxyl groups in wet scaffold was broader than dry scaffold because of the existence of water (Figure 3B). The carbonyl absorption peak of wet scaffold at 1720 cm-1 was weaker than dry scaffold, probably because some of the oxygen atoms on the carbonyl group had been connected with hydrogen atoms in water molecules in the form of hydrogen bonds. The thermal properties of PFOT scaffold were investigated by TGA and DSC. The decomposition temperature (Td) of PFOT scaffold was 279 oC at 5.0 % weight loss degree (Figure 3C). To get a good water-responsive shape memory effect, a suitable temporary shape fixation mechanism is important. Here we used glassy state to fix the temporary shape. Tg is known to decrease by water as a plasticizer in hydrophilic polymers.

[39]

Accordingly, we expected the designed material had a Tg higher than body temperature to get a good temporary shape fixation during storage and operation, and not too high so that its Tg could readily reduce below 37 oC upon implantation at a wet in vivo environment to ensure a good water-responsive shape memory. The Tg of PFOT was 34.3 oC (Figure 2D), after crosslinking, the resultant PFOT scaffold showed a Tg of 57.9 oC (Figure 3D) probably suitable for water-responsive shape memory effect. Mechanical stimulation has been revealed to have significant effects on various cell behaviors such as adhesion, spreading, and cytoskeletal remodeling. [40,41] The mechanical properties of PFOT scaffold were evaluated by simple and cyclic compression tests (Figure


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3E). The elastic modulus was 19.8 ± 4.4 kPa which was in the range of soft tissues such as heart muscles and smooth muscles,

[42,43]

and similar to previously reported porous

scaffolds.[22,44,45] The chemically crosslinked structure of PFOT scaffolds ensured their mechanical and morphology integrity resulting in a good shape recovery. Furthermore, the wet PFOT scaffold recovered well from cyclic compression with a strain up to 30% for 5 cycles (Figure 3F) which was favorable for applications in mechanically dynamic in vivo environment and indicated that the Tg of wet PFOT scaffold was lower than room temperature. Solid cured PFOT strips were made to evaluate the tensile properties. The ultimate tensile strength of wet cured PFOT was 0.46 ± 0.13 MPa (Figure S3), similar to the one of poly(glycerol sebacate) (0.23-0.47 MPa) designed for myocardial application. [39]

The terephthalate moiety contributed on the mechanical properties. [27] These indicated

the potential of PFOT for soft tissue regeneration. In addition, we used equal molar amount of fumaric acid and terephthalic acid as an example to produce PFOT in current study. Actually the modulation of their relative ratio could readily produce PFOT with various aliphatic and aromatic units resulting in diverse properties. One of the advantages of PFOT was its facile functionalization due to the free hydroxyl groups. The functional groups on synthetic polymers can serve as cell recognition sites and enable post-polymerization modification to modulate the material’s mechanical, physical, chemical, and biological properties.

[46]

However, introducing functional groups to

polyesters is still a challenge, and usually needs complex synthesis. [47,48] Here, using our recently developed acid-induced epoxide ring-opening polymerization,


[31,32]

we


successfully synthesized hydroxylated PFOT in one step from commercially available reagents. Fluorescein isothiocynante (FITC), as a model molecule was selected to prove the potential of the functionalization of the hydroxyl groups of the scaffold. The FITC was readily chemically conjugated with the scaffold at mild conditions resulting in a fluorescent sample (Figure 3G). The absence of absorption peak of -N=C=S (around 2200-2050 cm-1) and the presence of absorption peak of thiol ester O-C=S (1100 cm-1) in the FTIR spectrum of FITC functionalized PFOT indicated the reaction between hydroxyl groups of polyester and -N=C=S groups of FITC (Figure S2). The biodegradation of the scaffolds in PBS at 37 oC was investigated (Figure 3H). The scaffolds degraded steadily with a mass loss of 23.8 ± 0.67 % after 4 weeks. In the first three weeks, the weight loss was almost proportional to time, that likely corresponded to the degradation of the aliphatic ester units. At the period of the fourth to sixth week, the biodegradation rate slowed, probably because of the existence of aromatic ester units and at the seventh week, the mass loss was 26.3 ± 1.02 %. PFOT scaffold exhibited good biodegradability and mechanical properties due to its unique structures with suitable combination of aliphatic and aromatic units. Fumaric acid and terephthalic acid was employed simultaneously to synthesize PFOT to produce polyester with both aliphatic and aromatic segments in the chain. The resultant fumarate moiety had a good biodegradability as revealed in a similar polyester (Figure 3H). [46]


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Figure 3. Characterization of PFOT scaffold. (A) SEM image. (B) IR spectra of dry and wet PFOT scaffolds. (C) TGA curve. (D) DSC curve. (E) Typical stress vs. strain curve of wet PFOT scaffolds in a simple compression test with a strain up to 30%. (F) Typical stress vs. strain curve of wet PFOT scaffold in a cyclic compression test with a strain from 0 to 30% for 5 cycles. (G) Opitcal picture of a triangle-shaped PFOT scaffold and the flurescent image of FITC modified PFOT scaffold. (H) In vitro biodegradation in PBS at 37 oC. 3.3. Water-responsive shape memory effect of PFOT scaffold. The weight swelling degree of the scaffolds were up to 904 ± 21% characterized by the water uptake. The water-responsive shape memory effect of PFOT scaffold in 37 oC water was shown in Figure 4. The original height of the cylinder sample was about 11 mm, after being immersed in water at room temperature for 5 min, compressed with device and dried



in oven, the height of scaffold became about 5 mm, which was around 45% of original height. The cylindrical sample almost fully restored to its original height after being put in water again for 5 min. Rf and Rr represent the ability of the scaffold to fix its temporary shape and memorize its permanent shape respectively (Figure 4D-F). The recovery ratio with time was measured (Figure 4D). Rr reached 53.0 ± 1.7% after 1 min and 92.0 ±3.3% after 2 min indicating that the fast recovery ability of deformed scaffold. The Rr and Rf (Figure 4E-F) for five cycles were measured to demonstrate the long-term performance of the shape-memory effect. Rr was 100 ± 0% at 1st cycle and 97.5 ± 4.3% at 5nd cycle, respectively. Rf was 100.0 ± 2.7% at 1st cycle and 97.8± 3.1% at 5nd cycle.

Figure 4. Water-responsive shape memory effect of cylindrical PFOT scaffold in 37oC water. Photo images of original scaffold (A), compressed dry scaffold (B), and shape recovered scaffold (C). (D) Shape recovery ratio (Rr) vs. recovery time. (E) Rr for 5 cycles. (F) Shape fixity ratio (Rf ) for 5 cycles.

Figure 5. showed the water-responsive shape-memory effects of strip-shaped PFOT scaffold. The original shape was a flat strip (Figure 5A). The wet strip was easily coiled


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into spiral shape and fixed well after being dried (Figure 5B). After being immersed in water, the spiral-shape scaffold readily went back to its original strip shape within about 2.5 minutes (Figure 5C-F).

Figure 5. Water-responsive effect of strip-shaped PFOT scaffold in water at room temprature. Photo images of original scaffold (A), temporary shape coiled and dry scaffold (B), partly and fully shape recovered scaffold in water at room temperature (C-F), The scale bar is 5 mm.

As expected, PFOT scaffolds showed a high hydrophilicity confirmed by their high water swelling ratio likely due to their extensive hydroxyl groups. This endowed their good water responsiveness. The resultant PFOT scaffold showed a Tg of 57.9 oC (Figure 3D). Thus, PFOT scaffold was at glassy state at 37 oC and its temporary shape could be well fixed (Figure 4-5). When immersed in water at 37 oC, PFOT scaffold exhibited a good water responsive shape memory effect indicating the Tg was reduced below room temperature. PFOT scaffold showed a good anti-fatigue property, and its fixity and recovery ratios approached above 97% for multiple cycles (Figure 4E-F). In addition, the recovery time of the scaffolds in water were several minutes that provided a suitable window for surgical procedures, significantly shorter than the one of recently reported



PLGA based water-responsive materials (7 h).

[26]

Overall PFOT scaffold is promising

shape memory material for biomedical applications. 3.4 Cytocompatibility and interaction with H9C2 cells Cell morphology was investigated by F-actin staining (Figure 6A). H9C2 cardiomyocytes adhered well on all surfaces of TCPS, PFOT and PLGA. After 3 days’ culture, all the cells expanded well and displayed polygonal and poditic shape. The number of the adhered cells on the difference surfaces with time was recorded to evaluate the adhesion of H9C2 cardiomyoblast on PFOT. The cell adhesion rate on PFOT was similar to that on TCPS and PLGA at all-time points (Figure 6B). This revealed that PFOT support the adhesion of cardiomyoblast as well as TCPS and PLGA. The effect of PFOT on cell proliferation was evaluated by CCK-8 assay. The amount of H9C2 cardiomyoblast on PFOT significantly increased with the time of culture (Figure 6C), comparable to that on TCPS and PLGA (Figure 6C). This indicated that PFOT well support the proliferation of cardiomyoblast. All these results demonstrated that PFOT had a good cytocompatibility.


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Figure 6 Cytocompatibility of PFOT using TCPS and PLGA as controls (A) Fluorescence images of Factin stained cardiomyocytes 3 days after seeding onto TCPS, PFOT and PLGA. Nuclei were counterstained with DAPI (blue). (B) The adhesion of cardiomyocytes on TCPS, PFOT, PLGA evaluated by CCK-8 assay. (C) The proliferation of cardiomyocyte on TCPS, PFOT, PLGA via CCK8 assay. (D) Immunofluorescence images of cardiomyocytes based on Cx43 and cTnT (red) 4 days after seeding on TCPS, PFOT and PLGA. Nuclei were counterstained with DAPI (blue). (E)



Semiquantitative analysis of the immunofluorescence intensity of Cx43 and cTnT. *: Statistically significance (p < 0.05). 3.5 Expression of cardiac specific proteins The H9C2 caridomyoblasts were stained with cardiac specific proteins including Connexin 43 protein (Cx43) and cTnT after 4 days’ culture to evaluate their functions (Figure 6D). The cells on PFOT showed positive signals of Cx43 and cTnT comparable to the ones on PLGA (Figure 6E). The expression of Cx43 on PFOT was significantly higher than the one on TCPS. These results indicated that PFOT was a good substrate to support cardiomyoblast functions. 4. Conclusion A new hydroxylated aliphatic and aromatic copolyester PFOT was designed and synthesized. The suitable combination of aliphatic, aromatic units, and hydroxyl groups endowed a series of favorable properties to PFOT. It exhibited moderate hydrophilicity, and good biocompatibility with cardiomyocytes. PFOT was readily fabricated into a waterresponsive shape memory porous scaffold, which was seldom reported previously. PFOT scaffold exhibited a good biodegradability, and facile functionalizability. Due to the intrinsic biocompatibility and widely availability of water in vivo, we expect functional PFOT and its water-responsive scaffolds will be very useful for soft tissue engineering especially for minimally invasive surgery and other smart applications. Furthermore, the design principle and synthetic method are general and versatile, and can produce a series of functional polymers for a wide range of biomedical applications.


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For Table of Contents Use Only A biocompatible, biodegradable and functionalizable copolyester and its application in water-responsive shape memory scaffold Yangfen Xiea, Dong Leia, Shaofei Wangb , Zenghe Liua, Lijie Sunb, Jingtian Zhanga, Feng-Ling Qinga,c, Chuanglong Hea*, Zhengwei Youa,b* *Corresponding authors. E-mail: [email protected], [email protected].

Table of Contents Graphic

A biodegradable water-responsive shape memory scaffold readily fabricated in two-step process showed a potential for soft tissue engineering.


A biocompatible, biodegradable and functionalizable copolyester and

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