temperature-responsive hydrogel composites with micro heater

Materials Science and Engineering C 32 (2012) 1564–1570

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Materials Science and Engineering C journal homepage: www.elsevier.com/locate/msec

Improvement in transdermal drug delivery performance by graphite oxide/temperature-responsive hydrogel composites with micro heater Jumi Yun a, Dae Hoon Lee b, Ji Sun Im a, Hyung-Il Kim a,⁎ a b

Department of Fine Chemical Engineering and Applied Chemistry, BK21-E2M, Chungnam National University, Daejeon 305-764, Republic of Korea Environment Research Division, Korea Institute of Machinery and Materials, 171 Jang-dong, Yusong-gu, Daejeon 305-343, Republic of Korea

a r t i c l e

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Article history: Received 25 October 2011 Received in revised form 29 February 2012 Accepted 22 April 2012 Available online 28 April 2012 Keywords: Transdermal drug delivery system Temperature-responsive hydrogel Graphite oxide Micro heater Joule heating method

a b s t r a c t Transdermal drug delivery system (TDDS) was prepared with temperature-responsive hydrogel. The graphite was oxidized and incorporated into hydrogel matrix to improve the thermal response of hydrogel. The micro heater was fabricated to control the temperature precisely by adopting a joule heating method. The drug in hydrogel was delivered through a hairless mouse skin by controlling temperature. The efficiency of drug delivery was improved obviously by incorporation of graphite oxide due to the excellent thermal conductivity and the increased interfacial affinity between graphite oxide and hydrogel matrix. The fabricated micro heater was effective in controlling the temperature over lower critical solution temperature of hydrogel precisely with a small voltage less than 1 V. The cell viability test on graphite oxide composite hydrogel showed enough safety for using as a transdermal drug delivery patch. The performance of TDDS could be improved noticeably based on temperature-responsive hydrogel, thermally conductive graphite oxide, and efficient micro heater. © 2012 Elsevier B.V. All rights reserved.

1. Introduction Transdermal drug delivery systems (TDDS), also known as “patches,” are designed to deliver a drug across the skin of patient therapeutically. TDDS has become to be in clinical use since 1981 [1–3]. The first attempt for a transdermal patch was carried out by Alza Corporation as a treatment for motion sickness [4]. Since then, patches have been studied in various applications such as hormonal therapy, pain relief, and smoking cessation aid. Such patches allow the controlled release of drugs over several hours or even days [5–7]. One of the crucial bottlenecks for using TDDS is the sensitivity in controlling the amount of drug delivered through a skin. So far various attempts have been carried out based on two different aspects. One is the study on patch matrix to modify the estimated therapeutic period. The other is the treatment of skin or modeling of drug for the higher penetration through skin. However, these methods are not effective in the case where the drug delivery should be controlled depending on the condition of patient. Therefore, TDDS, which can control the release of drug conveniently depending on the variation of external conditions, needs to be studied for the improved performance [8–12].

⁎ Corresponding author. Tel.: + 82 42 821 6694; fax: + 82 42 821 8999. E-mail address: [email protected] (H-I. Kim). 0928-4931/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.msec.2012.04.043

Hydrogel has been applied as a material for TDDS because hydrogel can load and release a drug effectively by swelling and shrinking effects, respectively. In addition, it is responsive to external stimuli such as temperature and pH. To improve the response of hydrogel against external stimuli, the external stimuli should be transferred properly to the hydrogel matrix. The failure of proper transfer of external stimuli resulted in the inappropriate response of hydrogel such as local shrinking [13–17]. It is well known that the graphite has excellent thermal and electrical conductivities based on its sp2 hybrid orbital structures. The high thermal conductivity is attributed to the strong bond between carbon atoms leading to the efficient transfer of phonon [18–22]. In this study, TDDS was investigated in terms of temperatureresponse of hydrogel and temperature variation control of micro heater. The temperature-responsive hydrogel was used as a base material for TDDS. The role of hydrogel is loading and releasing the drug based on the response to temperature stimulus. The micro heater was designed and fabricated for precise control of temperature with a small voltage less than 1 V. The role of micro heater is an accurate and easy control of drug release from temperature-responsive hydrogel by simple controlling of the applied voltage. The micro heater was located on the outer side of hydrogel. Graphite oxide (GO) was used as an additive for an efficient heat transfer within hydrogel matrix based on its high thermal conductivity. The principles of improved performance of TDDS were discussed based on temperatureresponsive hydrogel, thermally conductive GO, and effective micro heater.

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2. Theory for designed micro heater The electrical resistance R of conductive material is defined to be the product of specific resistivity, ρ, and geometric factor, L/A, as in Eq. (1) [23,24]. R¼ρ

L A

ð1Þ

Because geometric factor has dimension of reciprocal of length, the reduction of length scale can enhance the resistance of conductive materials. The heat generated by resistance is expressed as in Eq. (2) for the joule heating process. Therefore, micro scale heater is more effective in producing heat than macro scale heater due to the enhanced resistance.   2 P ¼ ∫ðI  V Þdt ¼ ∫ I  R dt

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was cut into disc-like pieces having approximately 10 mm in diameter and 5 mm in thickness for the following studies. Swollen hydrogel discs were dried in vacuum oven. The preparative compositions of GOcontaining PVA/PNIPAAm composite hydrogels are as follows: PVA: 1.84 mol, NIPAAm: 1.42×10− 3 mol, GA: 1.60×10− 1 mol, MBAAm: 6.40×10− 4 mol, KPS: 5.00×10− 2 mol, (S)-(+)-ketoprofen: 0.1 g, graphite: 0.5, 1.0, 1.5, 2.0 g, and GO: 0.5, 1.0, 1.5, 2.0 g. The samples were named as hydrogel/graphite composite (HG) and hydrogel/graphite oxide composite (HGO) with the following number indicating the content of conductive additives used in gram. 3.4. Fabrication of micro heater The meander type pattern was adopted for the design of micro heater to make the path of resistor long enough within the given

ð2Þ

where P, I, V, and R are heat generated, current, voltage, and resistance, respectively. Resistance of conductive material varies generally with temperature because the mobility of electron is a function of temperature. Therefore, the specific resistance can be expressed as in Eq. (3). However, in the temperature range of this study, the expression can be linearized with rather high accuracy as in Eq. (4) where α is the temperature coefficient of resistance (TCR).   2 n R ¼ R0 1 þ a1 T þ a2 T þ … þ an T

ð3Þ

R ¼ R0 ð1 þ αT Þ

ð4Þ

Therefore, the temperature of heater can be controlled precisely by the variation of resistance based on this relation followed by the calibration procedure. 3. Experimental 3.1. Materials Poly(vinyl alcohol) (PVA), acrylic acid (AAc), glutaraldehyde (GA), ethylene glycol dimethacrylate (EGDMA), and potassium persulfate (KPS) used in this study were obtained from Sigma Chemical Company. N-isopropylacrylamide (NIPAAm) was purchased from TCI Co. N,N′methylenebisacrylamide (MBAAm) was purchased from Fluka Co. The model drug, (S)-(+)-ketoprofen, was obtained from Sigma Chemical Company. 3.2. Oxidation of graphite GO was prepared by Hummers method [25,26] using the graphite obtained from Samchun Chemical. Graphite was oxidized with fuming nitric acid and sulphuric acid. HCl (35%) was used as a catalyst. 3.3. Synthesis of PVA/PNIPAAm composite hydrogel containing GO PVA/PNIPAAm hydrogels were synthesized by the free radical polymerization. The polymerization was carried out in de-ionized water using GA and MBAAm as the crosslinker of PVA and PNIPAAm, respectively. KPS was used as an initiator. They were dissolved in de-ionized water to form the aqueous solution with dispersed GO. The model drug was added to the mixed solution. The reaction mixture was stirred for 30 min at room temperature followed by nitrogen bubbling for 20 min to remove the oxygen dissolved in the reaction mixture. The mixture was reacted by stirring for 2 h at 70 °C to produce GO-containing PVA/ PNIPAAm composite hydrogel. The composite hydrogels were washed with distilled water at room temperature by replacing with fresh distilled water every few hours. GO-containing PVA/PNIPAm composite hydrogel

Fig. 1. Experimental setup diagrams for (a) fabrication procedure of micro heater prepared by e-beam evaporator and (b) Franz-type diffusion cell for transdermal drug release.

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area of heater. Pt and Ti layers are deposited by e-beam evaporator that is one of the most common instruments in semiconductor fabrication. The instrument controls a thickness of thin film with angstrom scale. It is based on the standardized procedures and calibration [27,28]. Pt thin film was deposited on the glass substrate with thickness of 100 nm resulting in small cross cut area of 10 μm 2. The overall process of fabrication is schematically given in Fig. 1 and explained as follows: (1) Glass wafer with thickness of 700 μm was used for the non-conductive substrate. (2) Photoresist (PR) was spin-coated on the glass substrate for patterning. (3) PR was patterned with mask by UV exposure, baking, and development, respectively. (4) Ti layer with thickness of 10 nm was deposited using e-beam evaporator. Ti layer was required as seed layer for the following adhesion of Pt layer on the glass substrate. (5) Pt layer with thickness of 100 nm was deposited using e-beam evaporator. (6) Lift-off process was carried out by stripping PR resulting in Ti/Pt layer on the glass substrate. (7) The wafer was cleaned and diced into proper dimension for the micro heater. (8) Non-conductive film was located to protect the current path from hydrogel. (9) Four different micro heaters (18 mm × 15 mm) were prepared with the following pattern widths (W) and pattern spaces (G). The dimensions of W/G of micro heater A, micro heater B, micro heater C, and micro heater D are 50/50 um, 100/100 um, 200/200 um, and 500/500 um, respectively. 3.5. Characterization of PVA/PNIPAAm composite hydrogel Fourier-transform infrared spectrometer (FT-IR, FTS-175 C, Cambridge, USA) was used to investigate the functional groups on GO. The FT-IR spectra of samples were obtained in the range of 400– 4000 cm − 1. To investigate the elements present in graphite and GO, the X-ray photoelectron spectroscopy (XPS) spectra were obtained using a MultiLab 2000 spectrometer (Thermo Electron Corporation, UK). Al Kα (1485.6 eV) was used as the X-ray source with a 14.9 keV anode voltage, a 4.6 A filament current, and a 20 mA emission current. All samples were treated at 10 − 9 mbar to remove impurities. The survey spectra were obtained at a 50 eV pass energy and a 0.5 eV step size. Field emission scanning electron microscopy (FE-SEM, S-5500, Hitachi, Japan) was used to investigate the surface morphology. Images were taken without prior treatment such as Pt coating to ensure the acquisition of accurate images. The sheet resistance (Rs, Ω/□) was measured five times with the four-probe method at room temperature under ambient conditions with the probe head station (Dasol Eng., Korea) based on the ASTM F1529-97 method. The electrical conductivity (σ) was calculated using the following equations [29,30]: ρ ¼ Rs  t ðΩcmÞ

ð5Þ

σ ¼ 1=ρðS=cmÞ

ð6Þ

where ρ is the bulk resistivity and t is the thickness of the sample. 3.6. Equilibrium swelling ratio of PVA/PNIPAAm composite hydrogel The equilibrium swelling ratio (ESR) was determined by gravimetric method with varying the temperature using micro heater. The dried samples were located on a micro heater in the isotonic phosphate buffered saline (PBS, pH 7.4) for a certain period until the swelling equilibrium was reached and then these hydrogels were taken out followed by removing excess buffer solution on the surface with tissue paper. They were weighed immediately. ESR (%) of the hydrogels was calculated as follows: ESRð% Þ ¼ ðW s −W d Þ=W d  100

ð7Þ

where Wd and Ws are the weights of dry and swollen samples, respectively. 3.7. Shrinking kinetics of PVA/PNIPAAm composite hydrogel The shrinking kinetics of composite hydrogels were studied at 37 °C gravimetrically after wiping off water on the surfaces with filter paper. The shrinking temperature was selected to be above the lower critical solution temperature (LCST) of hydrogel in order to attain the dramatic change in volume of hydrogel. For a start, the hydrogel samples were immersed in distilled water at 4 °C to reach equilibrium swelling. The weight changes of the hydrogels were recorded at regular time intervals during the course of shrinking. Water retention of hydrogel is defined as follows: Water retentionð% Þ ¼ ½ðW t −W d Þ=ðW s −W d Þ  100

ð8Þ

where Wt is the weight of wet hydrogel at a predetermined time at 37 °C and the other symbols are the same as defined above. 3.8. In vitro release of drug from PVA/PNIPAAm composite hydrogel The drug release experiments were conducted in vitro with vertical Franz-type diffusion cells (Disa, Milan, Italy). The diffusion cell was set as following orders from top to bottom: fabricated micro heater, thin cupper film (10 μm), drug-loaded PVA/PNIPPAm composite hydrogel, and hairless mouse skin. The hairless mouse skin was mounted between the donor and the receptor compartments of diffusion cells with the epithelial side facing the donor compartment. The surface area of diffusion was 3.14 cm 2. PBS (pH 7.4, 15 ml) was used for the receptor phase and maintained at 37 ± 1 °C using a circulating water bath. The setup of diffusion cell for transdermal drug release is depicted in Fig. 1(b). Uniform mixing of the receptor medium was provided by magnetic stirring. PVA/PNIPPAm composite hydrogel was heated with micro heater at the applied electric voltage of 0.9 V. 2 ml PBS was withdrawn from the receiver compartment and an equivalent volume of fresh PBS was replaced immediately at 37±1 °C. The samples were assayed by a UV spectrometer at 290 nm to determine the amount of released drug [31]. 3.9. Indirect cytotoxicity evaluation of PVA/PNIPAAm composite hydrogel Mouse fibroblasts (L 929, ATCC CCL-1) were cultured at 37 °C under a 5% CO2 humidified atmosphere in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine serum (FBS), penicillin (5000 Uml− 1), and streptomycin (50 μg ml− 1). Evaluation of the indirect cytotoxicity of PVA/PNIPPAm composite hydrogel was carried out using a Cell Counting Kit-8 (CCK-8, Dojindo Laboratory, Japan) with the experimental conditions recommended by the CCK-8 manual. L 929 cells were seeded in 96-well microtiter plates at 5×103 cells per well and treated for 24 h with doxorubicin (0.8 μg ml− 1) and for 0.5 h with tumor necrosis factor (500 Uml). Then 10 μl of CCK-8 solution was added to each well of the plate, which was then placed in an incubator (37 °C and 5% CO2) for 2 h. The absorbance was measured at 450 nm using an automated ELISA microplate reader (BioTek Instruments, Winooski, VT). The cell viability was determined by optical density (OD) as follows [32]: Cell viabilityð% Þ ¼ ½ðDrug−treated group OD−Blank ODÞ=ðControl OD−Blank ODÞ  100 ð9Þ

The analysis was carried out in triplicate.

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4. Results 4.1. Introduction of functional groups on graphite by oxidation FT-IR spectra of both graphite and GO are presented in Fig. 2(a). The graphite has a characteristic peak at 1,610 cm − 1 due to the aromatic C = C skeletal vibrations. The spectra of GO showed several new peaks such as OH group at 3,000–3,600 cm − 1, COOH group at 1,700 cm − 1, and C–O–C/C–OH vibrations at 1,000–1,400 cm − 1, which were in accordance with the literature data [33,34]. These results indicated that many oxygen-containing functional groups were produced during the oxidation of graphite. The shift of aromatic C = C peak from 1,610 cm − 1 to 1,650 cm − 1 for GO showed that some electron-withdrawing groups such as oxygen-containing functional groups were bonded to the aromatic rings after oxidation [34]. The introduced functional groups were evaluated quantitatively by XPS analysis as shown in Fig. 2(b). C1s peaks shown at 284.1 eV decreased after oxidation. Whereas O1s peaks shown at 532.9 eV increased through oxidation indicating the introduction of oxygencontaining functional groups on graphite [35–37]. Both C1s and O1s peaks were evaluated to get the amount of functional groups by elemental survey data. The elemental ratios of carbon and oxygen for graphite and GO were 74.1/25.9% and 59.9/40.1%, respectively. 4.2. Surface morphologies of samples FE-SEM images of surface morphologies of graphite and GO are presented in Fig. 3. The space between graphite layers increased generally for GO via oxidation treatment. The increased interlayer space

Fig. 3. FE-SEM images of (a) graphite and (b) GO.

is beneficial for forming a uniform dispersion of GO in hydrogel matrix. The surface morphologies of HG and HGO are shown in Fig. 4. More graphite and GO phases were observed on the surface as more amounts of graphite and GO additives were incorporated in hydrogel. The large agglomerate of graphite is observed for the graphitecontaining composite hydrogels as shown in Fig. 4(a)–(c). On the other hand, GO was more uniformly dispersed in hydrogel without forming any noticeable agglomerate as shown in Fig. 4(d)–(f). The improved interfacial affinity between GO and hydrogel was also confirmed for the GO-containing composite hydrogel as observed in Fig. 5. The crack at the interface between graphite and hydrogel was clearly observed for the graphite-containing composite hydrogel. However, the interface between GO and hydrogel showed good interfacial adhesion without any noticeable crack. The difference in the interfacial affinity is attributed to the hydrophobic nature of graphite [38–40] and the hydrophilic functional groups introduced on GO. The interfacial affinity between hydrophobic graphite and hydrophilic hydrogel could be improved effectively by introducing the hydrophilic functional groups on the surface of graphite through an oxidation treatment. Eventually, the improved dispersion of graphite in hydrogel matrix and the improved interfacial affinity play important roles in transferring heat through a hydrogel matrix due to the excellent thermal conductivity of graphite [41–43]. 4.3. Heating performance of micro heater depending on applied voltage The relation between the applied voltage in several micro heaters and the resultant temperature of composite hydrogel is presented in Fig. 6. Micro heater A heated the composite hydrogel to its LCST (32 °C) with the smallest applied voltage about 0.9 V. As the less voltage is applied to skin for heating, the less dangerous and harmful influence is exerted on human body. Therefore, micro heater A was selected as the heater for heating PVA/PNIPPAm composite hydrogels. 4.4. Effect of graphite additives on electrical conductivity of composite hydrogel

Fig. 2. (a) FT-IR and (b) XPS spectra of graphite and GO.

Fig. 7 shows the increase of electrical conductivities of HG and HGO samples with increasing the content of graphite due to the excellent electrical conductivity of graphite. It is well known that electrons moving readily through sp 2 hybrid orbital structures of carbon resulted in high electrical conductivity. The higher electrical conductivity corresponds generally with the higher thermal conductivity because the high thermal conductivity is also attributed to the sp 2 hybrid orbital structures allowing the phonon movement through carbon structures [18–22,42–44]. The electrical conductivities of composite hydrogels were improved drastically up to the content of 1 wt% graphite. However, further increase in graphite content was not efficient in the improvement of electrical conductivity due to the possible saturation of electrical network formation. The even higher electrical conductivity of composite hydrogel was obtained in case of using GO as conductive additive. This result is attributed to the uniform dispersion of GO and better interfacial affinity which were responsible for the formation of electrical networks in the composite hydrogels. This result coincides with the results presented by

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Fig. 4. SEM images of (a) HG0.5, (b) HG1.0, (c) HG1.5, (d) HGO0.5, (e) HGO1.0, and (f) HGO1.5.

around LCST of PNIPAAm (32 °C). Both HG and HGO showed the similar temperature-sensitive swelling behavior as that of PVA/PNIPAAm hydrogel even though the swelling was hindered a little bit by the graphitic additives. The more uniform dispersion of GO with improved interfacial adhesion was responsible for the less swelling of GO-containing PVA/PNIPPAm composite hydrogel over the whole temperature region.

Fig. 5. SEM images of fractured surface of (a) HG1.0 and (b) HGO1.0.

other groups [45,46]. The graphitic additives worked effectively for increasing the electrical and thermal conductivities of composite hydrogels based on sp 2 hybrid orbital structures of carbon. 4.5. Temperature-sensitive swelling behavior of composite hydrogel The swelling of PVA/PNIPAAm composite hydrogel showed the temperature-sensitivity as shown in Fig. 8. The temperature sensitivity of composite hydrogel is attributed to variation of hydrophilicity of PNIPAAm depending on temperature. PNIPAAm molecule contains both hydrophilic amino groups and hydrophobic polymeric chains. Extensive hydrogen bonding formation between hydrophilic groups of PNIPAAm chains and surrounding water at lower temperature leads to the increased swelling of hydrogel in water. As the temperature increases, the decreased hydrogen bonding formation induced the shrinking of hydrogel. The swelling behavior varied dramatically

Fig. 6. Relation between applied voltage in micro heater and temperature reached in composite hydrogel.

Fig. 7. Electrical conductivities of HG and HGO depending on content of graphite additives. (Average values were obtained from seven measurements).

Fig. 8. Temperature-sensitive swelling behavior of PVA/PNIPAAm, HG, and HGO. (Average values were obtained from five measurements).

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Fig. 10. Transdermal drug release profiles of various composite hydrogels at 37 °C. (Average values were obtained from five measurements).

played an important role in improving the transdermal drug release from the temperature-sensitive hydrogel. Both the faster release of drug and the more feasible control of release are attributed to the combination of the improved thermal conductivity of GO-containing hydrogel and the effective micro heater operated simply by applying a relatively small voltage. 4.8. Cell viability of composite hydrogel

Fig. 9. Kinetic shrinking behavior of (a) HG and (b) HGO samples at 37 °C. (Average values were obtained from five measurements).

4.6. Kinetic shrinking behavior of composite hydrogel Fig. 9 shows the shrinking behavior of PVA/PNIPAAm, HG, and HGO samples after transferring the swollen specimen equilibrated at 4 °C to the distilled water at 37 °C quickly. The shrinking rate increased with increasing the content of graphite in hydrogel because the heat transfer in hydrogel matrix was accelerated by graphitic additive due to its excellent thermal conductivity. GO-containing PVA/ PNIPAAm composite hydrogels showed the even faster shrinking compared to the graphite-containing composite hydrogels. The faster shrinking of the composite hydrogel results in the faster release of drug loaded in the composite hydrogel even at a smaller content of GO additive. The more uniform dispersion of GO with improved interfacial adhesion also played an important role in the efficient heat transfer in hydrogel matrix.

The cytotoxicity test is important for TDDS which should neither release toxic products nor induce adverse reactions through in vitro cytotoxicity tests. The cytotoxicity of samples was evaluated using an indirect cytotoxicity assay after the cells were cultured with the extracted media from composite hydrogel samples for 24 h. The cell viability results are seen in Fig. 11. The cell viability was not significantly different regardless of the kind of hydrogel samples. The cell viability showed over 80% in all the samples no matter which graphitic additive was incorporated into hydrogel. The cell viability over 80% could be considered as non-toxic and highly biocompatible [12]. 5. Discussion The operating mechanism of temperature-sensitive TDDS was discussed based on the swelling and shrinking behavior of composite hydrogel. There are three steps for the operating mechanism of TDDS:

4.7. Transdermal drug release behavior of composite hydrogel The transdermal drug release behavior of various composite hydrogels was investigated at 37 °C depending on release time as shown in Fig. 10. Various composite hydrogels were tested for evaluating the effects of graphite and surface modification on the transdermal release behavior. The drug release was fast up to 150 min and then slowed down. The transdermal drug release increased generally with increasing the content of graphitic additive in composite hydrogel. GOcontaining PVA/PNIPAAm composite hydrogels showed the faster transdermal drug release compared to the graphite-containing composite hydrogels based on the same reason in the shrinking behavior. GO

Fig. 11. Cell viability of PVA/PNIPAAm, HG1.0, and HGO1.0 samples. (Average values were obtained from three measurements).

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TDDS could be prepared based on temperature-sensitive hydrogel, thermally conductive GO with improved interfacial affinity, and efficient micro heater. References

Fig. 12. Surface morphology of (a) and (b) PVA/PNIPAAm hydrogel and (c) and (d) HGO1.0. ((a) and (c): after swelling at 4 °C for 72 h, (b) and (d): after shrinking at 37 °C for 10 h).

(1) drug loading, (2) heat transfer within hydrogel matrix, and (3) drug releasing. As a first process, drug was loaded in hydrogel matrix by swelling behavior of hydrogel as studied in Section 4.5. As a next step, the thermal energy supplied by micro heater was transferred effectively to hydrogel matrix based on the higher thermal conductivity of graphitic additive and the improved interfacial affinity between graphitic additive and hydrogel matrix by oxidation of graphite as explained in Section 4.4. As a final procedure, the loaded drug was released from hydrogel matrix by shrinking of hydrogel based on temperature-sensitive nature of PVA/PNIPAAm hydrogel as elucidated in Sections 4.6 and 4.7. To support the suggested operating mechanism, the surface morphologies of swollen and shrunken HGO1.0 sample are compared with those of PVA/PNIPAAm hydrogel as presented in Fig. 12. The pores formed by swelling of hydrogel matrix are observed in Fig. 12(a) and (c). There was no big difference in the morphology of swollen PVA/PNIPAAm hydrogel and HGO samples. The drug is loaded in the pores at 4 °C and released at 37 °C by shrinking of hydrogel matrix. The pores reduced in size by shrinking of hydrogel matrix are observed in Fig. 12(b) and (d). There was noticeable difference found in the morphology of shrunken samples. HGO sample showed the smaller pore size after shrinking due to the effective heat transfer of GO dispersed uniformly in hydrogel matrix as seen in Fig. 12(d). 6. Conclusions TDDS was prepared with temperature-sensitive hydrogel. The drug was loaded by swelling behavior of hydrogel and was released by shrinking behavior of hydrogel depending on the temperature variation. The temperature variation for TDDS was carried out using the fabricated micro heater adopting a joule heating method at less than 1 V for the skin safety. The efficiency of TDDS was improved by combining the improved thermal conductivity of GO and the effective control of temperature by micro heater with the temperatureresponse of hydrogel. The cell viability test also showed the nontoxicity for a patch to the skin. As a result, the high-performance

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