Temperature and pH responsive 3D printed scaffolds

Sujan Dutta and Daniel Cohn *
Casali Center of Applied Chemistry, Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem 91904, Israel. E-mail: danielc@mail.huji.ac.il

Received 4th September 2017 , Accepted 21st November 2017

First published on 22nd November 2017

This study focused on developing novel materials for 3D printed reverse thermo-responsive (RTR) and pH-sensitive structures, using the stereolithography (SLA) technique and demonstrates the double responsiveness of the constructs printed. Methacrylated poly(ethylene oxide)–poly(propylene oxide)–poly(ethylene oxide) (PEO–PPO–PEO) triblocks are the basic building blocks of the RTR hydrogels, while acrylic acid is responsible for imparting also pH sensitivity to the 3D printed gels. The water absorption behavior and dimensional changes exhibited by the different 3D printed hydrogel constructs, strongly depended on the temperature and pH, varying also as a function of their composition and concentration. All the hydrogels showed a fast and reversible swelling–deswelling response, as they fluctuated between pH 2.0 and pH 7.4 behavior. Structures comprising two different dually responsive hydrogels were 3D printed and their environmentally sensitive dimensional behavior was reported.

1. Introduction

Hydrogels are three-dimensional hydrated polymer networks that are extensively used in the biomedical arena, including in drug and gene delivery systems,1 in tissue engineering2 and as wound dressings.3 The key advantages of hydrogels derive primarily from their high water content, their porous architecture and their softness, that typically mimics that of soft tissues. “Smart” or stimuli-responsive hydrogels are an advanced class of materials tailored to display substantial property changes, as a response to minor chemical, physical or biological stimuli, such as temperature,4 pH,5 biochemical agents,6 and electrical and magnetic fields.7 Among the different stimuli that have been investigated, temperature and pH8 are of special importance due to the broad biomedical applicability of these hydrogels. “Smart” polymers are termed “thermo-responsive” when the trigger is a small temperature differential. The “reverse thermo-responsive” phenomenon relates to water solutions of polymers that display low viscosity at a low temperature and exhibit a sharp and reversible viscosity increase as temperature rises within a very narrow temperature interval, forming a semi-solid gel at body temperature.

A number of reverse thermo-responsive (RTR) polymers have been studied during the last two decades, with much work focusing on poly(ethylene oxide)/poly(propylene oxide)/poly(ethylene oxide) (PEO–PPO–PEO) triblocks. These triblocks, commercially available as PoloxamersRTM or PluronicsRTM[thin space (1/6-em)]9 have been investigated for drug solubilization and controlled release,10 for the prevention of post-surgical tissue adhesions,11 in wound coverings12 and as scaffolds for Tissue Engineering.13 The reverse thermo-responsive behavior14 of PEO–PPO–PEO triblocks stems from their ability to self-assemble into diverse liquid crystalline topologies, driven by the entropy gain provided by the release of bound water molecules structured around the hydrophobic segment.15 Pluronic F127, (EO)99–(PO)65–(EO)99 has attracted special attention and has been widely investigated as a drug delivery system16 due to its sol–gel transition behavior and biocompatibility.17

The impressive progress made in the 3D printing field in recent years has made possible the engineering of a diversity of new objects, many of them of clinical importance.18 That said, and contrary to the vast majority of the 3D structures printed to date, there is a distinct need for stimuli responsive 3D printed architectures, able to respond “on command” to an environmental trigger, such as temperature and pH.

Even though several hydrogels able to be responsive to both temperature and pH have been reported, they were limited to simple geometries, such as films or rods,19 while no dually responsive hydrogels were 3D printed.

Muller et al. prepared nanostructured 3D printed hydrogels by mixing acrylated (EO)99–(PO)65–(EO)99 F127 triblocks with unmodified F127, as a sacrificial component. After printing by extruding the F127 diacrylate/F127 solution, stable gels were created by UV crosslinking and the unmodified F127 was washed away, leaving behind an open nanostructured hydrogel.20 Fedorovich and co-workers21 developed photopolymerizable (EO)–(PO)–(EO) 3D printed bone grafts using a 3D extrusion technique, followed by the covalent photocrosslinking of the printed scaffolds.

In the present work, we aimed at generating temperature- and pH-sensitive 3D printed architectures using the Stereolithography (SLA) method. To render it printable, the reverse thermo-responsive (EO)99–(PO)65–(EO)99 triblock (F127) was reacted with 2-isocyanatoethyl methacrylate (IEMA) to form the crosslinkable F127 dimethacrylate (FdMA) macromonomer. Acrylic acid, in turn, was chosen to perform as the pH-sensitive monomer that was copolymerized with F127 dimethacrylate, and this bi-component ink was 3D printed to create crosslinked F127/acrylic acid constructs.

A series of temperature and pH responsive (FdMA-co-acrylic acid) hydrogels covering a broad range of compositions were 3D printed, and their water absorption behavior and rheological properties were investigated under different temperatures and pH values. The swelling–deswelling response of the hydrogels at different pH values was studied, as the printed constructs fluctuated between pH 2.0 and pH 7.4. Dually responsive constructs comprising two different materials were co-printed and their responsiveness to temperature and pH differentials was investigated.

2. Experimental

2.1. Materials

Pluronic F127 (Mw – 12[thin space (1/6-em)]600) was purchased from Sigma and dried under vacuum for 2 hours at 120 °C and acrylic acid was also purchased from Sigma-Aldrich. 2,4,6-Trimethyl benzoyl-phenyl-phosphinic acid ethyl ester (Irgacure TPO-L) was obtained from BASF and 2-isocyanatoethyl methacrylate was obtained from TCI. 1,4 dioxane and chloroform were purchased from Bio-Lab and were dried over molecular sieves (Merck). Sodium hydroxide, sodium chloride, disodium hydrogen phosphate, sodium dihydrogen phosphate and hydrochloric acid were also purchased from Bio-Lab. All other chemicals were obtained from commercial suppliers and used without purification. Deionized water was used in all experiments.

2.2. Methods

2.2.1. Synthesis of F127 dimethacrylate (FdMA). FdMA was synthesized according to a procedure reported in the literature with a slight modification. In brief, F127 (50 g, 3.96 mmol) was poured into a round bottom flask and dried as described above. Next, 2-isocyanatoethyl methacrylate (1.46 g, 9.52 mmol) and tin(II) 2-ethylhexanoate (0.080 g, 0.198 mmol) were added under a nitrogen atmosphere and reacted for 4 hours at 85 °C, in dry 1,4 dioxane (50 mL). The synthesized F127 dimethacrylate was precipitated in cold diethyl ether and washed several times with diethyl ether. The white solid product was dried under vacuum at room temperature.
2.2.2. 3D printing FdMA hydrogels. FdMA-co-acrylic acid hydrogels coins [7.5 mm diameter, 1 m height] were 3D printed via a photo-polymerization process using an SLA 3D printer (Asiga PICO 2). This printer operates using a top-down SLA system with a digital mirror device and a UV-LED light source (385 nm). The different gels were labeled FAX(Y), where F, A, X and Y denote F127 dimethacrylate, acrylic acid, the weight percentage of acrylic acid in the copolymer and the total monomer content of the aqueous solution being printed, respectively. Therefore, FA20(30) designates an 80 wt%[thin space (1/6-em)]:[thin space (1/6-em)]20 wt% F127 dimethacrylate[thin space (1/6-em)]:[thin space (1/6-em)]acrylic acid crosslinked hydrogel that was 3D printed as a 30 wt% solution.

The 3D printing process is exemplified here for the FA50(80) hydrogel. Initially, FdMA (4.0 g) and acrylic acid (4.0 g) were mixed in 2 g water and the mixture was stirred at 6 °C temperature until the solution became homogeneous. Then, the TPO-L photoinitiator (PI) and vitamin E as an inhibitor were added to the solution. After stirring again, the solution was poured into a custom made monomer bath added to the SLA printer, where it was maintained at 6 °C during the printing process. Once formed, the 3D printed hydrogels were rinsed with water to remove unreacted monomers and were dried in vacuum at 25 °C for 48 hours.

2.2.3. Material characterization. FTIR spectra were carried out with a Bruker alpha-P spectrometer. 1H-NMR spectra of the synthesized FdMA was performed using a Bruker 500 MHz spectrometer using CDCl3 as the solvent and TMS as an internal standard. The morphology of the hydrogels was analyzed by high resolution scanning electron microscopy (Quanta 200 FEG, FEI). To this end, the equilibrated swollen hydrogels were lyophilized for 24 hours and attached to the stub via a carbon tape and coated with gold before taking images. A freezing-point depression protocol was applied to minimize the deformation of the samples. The rheological properties of the hydrogels were measured using a Rheo Stress 6000 Rheometer (Thermo Scientific), operated with parallel 35 mm diameter plates. The hydrogel samples were equilibrated at pH 2.0 and 7.4 and at 6 °C and 37 °C. Each hydrogel was dispensed on the cooled or pre-heated rheometer plate and the test was conducted using an oscillation frequency of 10 Hz. The rheological properties of the different hydrogels were measured for a period of 10 min, at 6 °C and 37 °C. Each test was performed in triplicates and the data represent the average of the three samples measured, with the corresponding standard deviation.
2.2.4. Swelling studies. In order to determine their water uptake behavior, the 3D printed hydrogels were immersed in pH 2.0, 5.0 and 7.4 buffer solutions at 6 °C and 37 °C and their weight increase was followed until equilibrium levels were achieved. The hydrogel samples were periodically taken out of the aqueous medium, the excess surface water was gently blotted with filter paper and the samples were weighed. All of the measurements were done thrice, and the average value was taken. Water uptake at each set of temperature and pH conditions was calculated as follows:
image file: c7tb02368e-t1.tif
where We is the weight of the swollen hydrogel and Wd is the weight of the dry hydrogel.
2.2.5. Swelling–deswelling studies. The cycling swelling–deswelling behavior of the hydrogels was monitored following the immersion of the samples in swelling media at 2.0 and 7.4. Initially, the hydrogels were equilibrated at pH 2.0 and 37 °C for 48 hours and then they were transferred, back and forth, from one pH value to the other for short twenty minutes cycles.

3. Results and discussion

3.1. The 3D printable inks

The F127 triblock was rendered 3D printable via the SLA technique, by reacting it with 2-isocyanatoethyl methacrylate (IEMA), whereby the corresponding dimethacrylate (FdMA) was generated (see ESI S1). 1H-NMR spectroscopy was used to demonstrate the generation of methacrylate end-capped F127 triblocks (see ESI S2).

Aiming at imparting to the gels both temperature and pH responsiveness, acrylic acid was copolymerized during the printing process with FdMA, at different weight ratios. The different gels were labeled FAX(Y), where F, A, X and Y denote F127 dimethacrylate, acrylic acid, the weight percentage of acrylic acid in the copolymer and the total monomers content of the aqueous solution being printed, respectively. Therefore, FA20(30), for example, designates a 80 wt%[thin space (1/6-em)]:[thin space (1/6-em)]20 wt% F127 dimethacrylate[thin space (1/6-em)]:[thin space (1/6-em)]acrylic acid crosslinked hydrogel that was 3D printed as a 30 wt% solution.

The fact that FdMA and acrylic acid did actually copolymerized during the printing process was demonstrated by the NMR and FTIR spectra (see ESI S2 and S3).

To confirm the copolymerization of FdMA with acrylic acid, polyacrylic acid (Mn – 125[thin space (1/6-em)]000) was added to FdMA in a 1[thin space (1/6-em)]:[thin space (1/6-em)]1 weight ratio, followed by the crosslinking of FdMA, whereby a semi-IPN was formed. This system and the FA50(30) copolymer were selectively solubilized in water and their behavior was compared. Both materials were dried and then immersed in water at 6 °C and, once equilibrium was reached, the swollen hydrogels were dried under vacuum. In clear contrast to the 50%[thin space (1/6-em)]:[thin space (1/6-em)]50% FdMA/polyacrylic acid semi-IPN, which showed a 45% weight loss due to the solubilization of the already polymerized polyacrylic acid, printed FA50(30) showed only a 5% weight loss. It can, therefore, be concluded that FdMA and acrylic acid copolymerized during the 3D printing process, generating a crosslinked poly(FdMA-co-acrylic acid) copolymer and not a FdMA/poly(acrylic acid) semi-IPN.

3.2. Swelling studies

Due to solubility restrictions imposed by the partial miscibility of FdMA and acrylic acid, water was used as a co-solvent, and the hydrogels were printed as concentrated aqueous solutions having 30% or 80% total solid content, and not in the molten state. Furthermore, because of these solubility constraints, the FdMA/acrylic acid solutions having 30% and 80% total solid content, covered the 100[thin space (1/6-em)]:[thin space (1/6-em)]0 to 30[thin space (1/6-em)]:[thin space (1/6-em)]70 and 70[thin space (1/6-em)]:[thin space (1/6-em)]30 to 10[thin space (1/6-em)]:[thin space (1/6-em)]90 F[thin space (1/6-em)]:[thin space (1/6-em)]A range, respectively. Fig. 1 shows the water uptake curves of FA(80) (Fig. 1a) and FA(30) (Fig. 1b) hydrogels that differ in their F[thin space (1/6-em)]:[thin space (1/6-em)]A ratio, at pH 2.0, 5.0 and 7.4, at 37 °C. While at pH 2.0 the equilibrium water uptake increased with decreasing acrylic acid content, the opposite takes place at pH 5.0 and 7.4 values.
image file: c7tb02368e-f1.tif
Fig. 1 Water uptake curves of (a) FA(80) and (b) FA(30) hydrogel, at pH 2.0, pH 5.0 and pH 7.4 at 37 °C.

The fact that at pH 2.0 the hydrogels absorb less water, the more acrylic acid they contain, can be attributed to the hydrogen bonds formed between acrylic acid's COOH group and FdMA's ether groups.22 At pH 5.0, and even more so at pH 7.4, above acrylic acid's pKa (∼4.3), the ionization of the COOH moieties has a determinant effect on the behavior of the hydrogel. Additionally, electrostatic repulsion23 and osmotic pressure phenomena,24 cause the polymer network to absorb large amounts of water. FA(30) hydrogels exhibited the same swelling behavior, with even higher water uptake levels being attained (see Fig. 1b), due to their lower total monomers concentration and the resulting less dense networks they form, when compared to FA(80).

The 3D plots shown in Fig. 2 graphically illustrate the combined effect of temperature and pH on the water absorption behavior of the dually responsive FA(30) hydrogels, having different F[thin space (1/6-em)]:[thin space (1/6-em)]A ratios. The pH values were chosen so to be below and above the pKa of acrylic acid, while the temperatures were selected so to be clearly below and above the temperature of transition of these hydrogels, respectively.

image file: c7tb02368e-f2.tif
Fig. 2 3D plot of the equilibrium water uptake of FA(30) hydrogels with different compositions, as a function of pH and temperature. Positions: 1: pH 2.0/37 °C, 2: pH 5.0/37 °C, 3: pH 7.4/37 °C, 4: pH 7.4/6 °C, 5: pH 5.0/6 °C, and 6: pH 2.0/6 °C.

The process starts when the hydrogel is at pH 2.0 and 37 °C (position 1), raising then the pH to 5.0 (position 2) and 7.4 (position 3), while keeping the temperature at 37 °C. In the next step, the temperature is lowered to 6 °C, while the pH is kept at the same 7.4 value (position 4) and then, while keeping the temperature constant at 6 °C, the pH is decreased to 5.0 and 2.0, in positions 5 and 6, respectively. In the case of the FA0 hydrogel, due to the absence of acrylic acid, only reverse thermo-responsiveness is observed. As the acrylic acid content increases, when moving from FA10 to FA70, the pH sensitivity increases, and this is reflected by the steepness of the plane generated by the six positions investigated. Moving, therefore, from position 1 to 3 and 4 to 6 reflects the pH sensitivity of the hydrogel, while shifting from position 3 to 4 and 6 to 1, reflects the reverse thermo-responsiveness of the hydrogels. The whole cycle defines a plane which is characteristic of the dually responsive behavior of each hydrogel. Stemming from the dual environmental responsiveness of these hydrogels, in all cases, the highest point of the plane is defined by 6 °C and pH 7.4, the temperature below the thermal transition and the highest pH studied, respectively. The minimum shown by the plane is given by 37 °C and pH 2.0, the temperature above the thermal transition and the pH value below the pKa value of acrylic acid, correspondingly. It is worth noticing that it is not only the steepness of the plane that changes but also its orientation in the space, defined by the three axes, namely, temperature, pH and water absorption. The same type of study was performed for FA(80) hydrogels and the 3D plots generated followed the same basic pattern.

3.3. Rheological properties

Seeking to shed light on the effect of pH and temperature on the rheological properties of these dually responsive hydrogels, their storage modulus (G′) was measured at pH 2.0 and pH 7.4, at 6 °C and 37 °C. It is apparent from the data shown in Fig. 3 for FA30, FA50 and FA70, that the hydrogels are stiffer at pH 2.0, when compared to pH 7.4, the difference becoming larger, the more acrylic acid the hydrogel contains. For example, FA30 at 37 °C has a 2.2 kPa storage modulus at pH 2.0 that decreases to 1.5 kPa at pH 7.4, while the corresponding values for FA70, at the same temperature, were 2.6 kPa and 1.2 kPa at pH 2.0 and 7.4, respectively. Additionally, the RTR behavior of the gels is reflected by the higher stiffness they display at 37 °C when compared to 6 °C.
image file: c7tb02368e-f3.tif
Fig. 3 Storage modulus (G′) of three FA(30) hydrogels: (a) at 6 °C: pH 2.0/pH 7.4. (b) At 37 °C: pH 2.0/pH 7.4.

3.4. pH dependent cyclic swelling behavior

The response of the hydrogels to pH fluctuations was investigated by performing swelling–deswelling experiments, during which the hydrogels fluctuated between pH 2.0 to pH 7.4 at 37 °C, remaining at each pH value for 20 minutes (Fig. 4). This study was conducted for FA(80) and FA(30) hydrogels, as presented in Fig. 4, and started with the hydrogels equilibrated at pH 2.0. It can be seen that all hydrogels absorb large amounts of water at pH 7.4, and they rapidly deswell when in pH 2.0 medium. Due to its high acrylic acid content, FA90(80) shows the fastest and sharpest response to pH fluctuations. As the acrylic acid content of the hydrogel decreases, expectedly, its pH responsiveness becomes less pronounced. As apparent from the data presented, the water uptake levels increase with the number of cycles, due to the time required for the hydrogels to reach their equilibrium water content at pH 7.4 and pH 2.0. The behavior displayed by FA(80) hydrogels was exhibited also by their respective FA(30) counterparts having the same composition, as seen in Fig. 4.
image file: c7tb02368e-f4.tif
Fig. 4 Cyclic response of FA(80) and FA(30) hydrogels at 37 °C, when fluctuating between pH 2.0 and pH 7.4, at 20 minute intervals.

3.5. 3D printed constructs

Aiming at demonstrating the dual responsiveness of these systems, Fig. 5 presents 3D printed macro-porous structures of FA70(80) hydrogels at pH 2.0 and at 7.4, at 6 °C and 37 °C. In accordance with their dual responsiveness, the 3D printed structure swelled significantly more at pH 7.4 than at pH 2.0, and also more at 6 °C than at 37 °C. To illustrate the remarkable ability of these 3D printed hydrogels to absorb water, suffice to indicate that the overall volume of the dry structure increases more than forty times, at physiological conditions. The cyclic dimensional response of the 3D printed constructs following temperature and pH fluctuations was assessed and nearly reversible swelling–deswelling responses were observed.
image file: c7tb02368e-f5.tif
Fig. 5 3D printed FA70(80) macro-porous structures, dry and swollen at pH 2.0 and 7.4, at 37 °C (above) and at 6 °C (below). (Bar: 2 cm.)

Buckyball structures25 of the same hydrogel were printed and the effect of both temperature and pH on their water absorption behavior was demonstrated (see Fig. 6) [we have introduced the ‘Buckyballs’ in the Fig. 6]. At physiological pH, the buckyball 7 mm dry radius, increased to 23 mm and 32 mm, when swollen at 37 °C and 6 °C, correspondingly.

image file: c7tb02368e-f6.tif
Fig. 6 3D printed buckyball at 37 °C and 6 °C at pH 2.0 (above) and at pH 7.4 (below). (Bar: 2 cm.)

The microfluid devices area is growing very rapidly,26 and valves play an important role when seeking to control flow in response to changes in the flowing solution. Environmentally sensitive hydrogel valves are a candidate in aqueous media such as body fluid. A model system consisting of a macroscopic valve composed of a dually responsive frame and a non-responsive plunger, able to close and open “on command”, responding to fluctuations in temperature and pH, was 3D printed. FA70(80) was used to 3D print the responsive frame of the valve, while the inert plunger was made out of a polypropylene rod. Fig. 7a shows a valve in its dry state, when it is closed, and four degrees of opening of the valve, obtained by controlling the temperature and pH. When the valve was equilibrated at pH 2.0 at 37 °C temperature (Fig. 7b), the valve opened to some extent, generating a larger aperture when below its thermal transition (at 6 °C, Fig. 7d). When raising the pH to 7.4, still at physiological temperature (Fig. 7c), the valve opened almost completely and reached its maximum opening, when the temperature was lowered to 6 °C, below FA70(80)'s relevant thermal transition(Fig. 7e). As readily observed in Fig. 7c and e, when at pH 7.4, due to the ionization of the acrylic acid and the excessive swelling and concomitant internal stresses generated, the structure fractured. This will be avoided by fine tuning the acrylic acid content and optimizing the dual responsiveness and dimensional changes of the valve.

image file: c7tb02368e-f7.tif
Fig. 7 3D printed valve structure of FA70(80) at different conditions. (a) Dry. (b) pH 2.0/37 °C. (c) pH 7.4/37 °C. (d) pH 2.0/6 °C. (e) pH 7.4/6 °C. (Bar: 2 cm.)

Bi-component cylindrical structures comprising two different hydrogels that respond differently to temperature and pH, were 3D printed (see Fig. 8), where the pink part consists of FA70(80) and the colorless one consists of FA20(30). The compositions were selected so to highlight their different environmental response, with FA70 being more pH-responsive and FA20 mainly temperature responsive. Fig. 8a shows the as printed hydrogel, while Fig. 8b and c show the hydrogel after full hydration at pH 7.4, first at 37 °C and then at 6 °C. While both acrylic acid-containing hydrogels swelled markedly at pH 7.4, hydrogel FA70(80) swelled substantially more due to its larger acrylic acid content. As anticipated, once below the thermal transition, the hydrogels swelled even further, demonstrating also their reverse thermo-responsiveness. It is also worth stressing that, in spite of the different degree of swelling of the two hydrogels and the stresses developed across their interface, the printing process generated an integrative structure, with both hydrogels forming one cohesive construct.

image file: c7tb02368e-f8.tif
Fig. 8 3D printed a rod structure (a) as printed. (b) At equilibrium water uptake at 37 °C and (c) at 6 °C temperatures in pH 7.4. The pink part consists of FA70(80) and the colorless part consists of FA20(30). (Bar: 1 cm.)

Seeking to generate 3D printed structures displaying an asymmetric dimensional behavior, bilayer slabs consisting of two different hydrogels were printed. The slab shown in Fig. 9 consists of a FA70(80) pink layer and a yellow FA20(30) layer, with the former being denser and having a higher acrylic acid content than the latter. Because of the different total concentration of the monomers on each side, 80% versus 30%, the bicomponent as printed slab was slightly bent. This effect became much more pronounced after drying the slab, the internal stresses causing the slab to bend to such an extent that its ends came close to each other. Most of this bending phenomenon was reverted when the bilayer slab was placed in a pH 2.0 aqueous solutions at 37 °C, which caused the slab to absorb water and open up. When the temperature was lowered to 6 °C, the FA20(30) layer swelled more than the FA70(80) layer, causing the slab to bend in the opposite direction, towards the FA70(80) side, as shown in the upper row of Fig. 9.

image file: c7tb02368e-f9.tif
Fig. 9 3D printed dual slab at 37 °C and 6 °C at pH 2.0 (above) and at pH 7.4 (below). The brownish part consists of FA70(80) and the yellow part consists of FA20(30). (Bar: 2 cm.)

When the pH of the aqueous solution was raised above the pKa of acrylic acid, to pH 7.4, while keeping the system at physiological temperature, both layers swelled markedly. Since, though, the FA70(80) hydrogel swelled more than FA20(30), the bi-component slab continued to bend towards the side of the FA20(30) layer. During the next step, when the temperature was lowered to 6 °C, the FA70(80) layer absorbed more water than FA20(30) and swelled accordingly, resulting in the straightening out of the almost circular geometry adopted by the slab at 37 °C. It is also worth noticing that the high swelling levels caused the structure to fragment, slightly at 37 °C and much more at 6 °C. It is anticipated that this ability of the bi-component slab to respond differently to temperature and pH, may be harnessed to engineering dynamic medical devices, such as soft actuators.

4. Conclusions

FdMA and acrylic acid were copolymerized and coprinted via a photo-polymerization mechanism, and their tunable temperature and pH responsiveness were demonstrated. 3D plots graphically illustrated the combined effect of temperature and pH on the water absorption of these dually responsive hydrogels, which also display a rapid and reversible pH dependent swelling–deswelling capability. Capitalizing on the responsiveness of these hydrogels to both temperature and pH, various structures were 3D printed and their environmental responsiveness was demonstrated. By combining hydrogels having different compositions, bi-component 3D printed systems were rendered with the ability to respond asymmetrically to temperature and pH, changing their size and geometry accordingly. These novel 3D printed constructs are anticipated to significantly contribute to the medical devices field, since they display the ability to change in space “on command“, following pH and temperature differentials.

Conflicts of interest

There are no conflicts to declare.


The work was supported by Israel Science Foundation Grant No. 183/16 and The Hebrew University of Jerusalem, Israel.

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Electronic supplementary information (ESI) available. See DOI: 10.1039/c7tb02368e

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