HYDROGEL BASED DERMAL PATCH WITH INTEGRATED FLEXIBLE ELECTRONICS FOR ON DEMAND DRUG DELIVERY

S. Bagherifard1,2, A. Tamayol1, M. Comotto1, P. Mostafalu3, M. Akbari1, N. Annabi1, M. Ghaderi1, S. Sonkusale3, M. Guagliano2, M.R. Dokmeci1, A. Khademhosseini1* 1Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of

Technology (MIT), Cambridge, MA 02139, USA 2 Department of Mechanical Engineering, Politecnico di Milano, Milan 20156, Italy

3Department of Electrical and Computer Engineering, Tufts University, Medford, MA, USA

ABSTRACT It is now widely accepted that the incorporation of growth factors can improve the healing process of

chronic wounds. In this paper we combined thermo-responsive drug microcarriers and flexible electronics to create a wound dressing capable of on demand drug delivery. Monodisperse thermo-responsive micoparticles containing active molecules were fabricated using a microfluidic system and were embedded inside a hydrogel. A miniaturized closed-loop electrical system with a flexible heater and temperature sensor was used to heat up the hydrogel and maintain its temperature during the release. KEYWORDS: Wound patch, Drug delivery, Thermo sensitivity, Microfluidics

INTRODUCTION

In some cases such as burn and diabetes, the self healing capability of skin is impaired and further in-tervention such as growth factor delivery is required [1]. Currently, there is no commercially available dermal patch that can be used for on demand release of drugs and growth factors. Here, we engineered a hydrogel-based dermal patch with integrated flexible heater and temperature sensor [2]. The hydrogel contained monodisperse thermo-responsive drug microcarriers, fabricated using microfluidic emulsion. The temperature sensor and heater are connected to microcontroller in a miniaturized closed-loop system that can monitor and stabilize the temperature. Integration of the electronic systems was achieved in a compact packaging for compatibility with the flexible, wearable platform (schematic shown in Fig. 1(a)). EXPERIMENTAL

In the microfluidic flow-focusing device, the inner phase was an aqueous solution of N-isopropylacrylamide (NIPAM) (10% w/v), N,N-methylene-bis-acrylamide (0.3% w/v) and photoinitiator (0.5% w/v); the oil phase was 20% v/v Span80 in mineral oil. The particles were polymerized with UV light exposure (5 min, 850 mW, distance 8 cm). The shrinking of the particles was characterized using Zeiss Axio observer D1 microscope equipped with a heating unit. The variations of UV-vis absorption of the crosslinked PNIPAM with temperature was acquired on a BioTek spectrophotometer. Freeze dried microparticles were incubated in a fluorescein isothiocyanate-dextran (FITC–dextran, Mw 70kDa) solution (1 mg/ml). For the release studies, fluorescence intensity of FITC–dextran in the supernatant PBS solution was measured at certain time points. Loaded microparticles were dispersed in a solution of sodium alginate (alginate-Na) in distilled water (2% w/v). the alginate patch was cross linked using a solidified aqueous solution of calcium chloride (CaCl2, 2% w/v) and agarose (Type VII-A, 2% w/v). The patch was mounted on a microfabricated heater with resistance of ~100 Ω on a polymide film. A microcontroller (Arduino) was used to power the heater and the feedback from a temperature sensor was used to stabilize the hydrogel temperature. The flexible heater and read-out electronics were integrated on a 3D-printed flexible bandage using TangoPlus (FLX930). RESULTS AND DISCUSSION

Figure 1 (b) shows the shrinking snapshots of the PNIPAM microparticles. The shrinking ratio (the variation of particles’ diameter from 25 °C to 40 °C / the initial diameter) was around 40% and independent from the initial size in the studied range (Figure 1(c)). The dynamic response of PNIPAM to

978-0-9798064-7-6/µTAS 2014/$20©14CBMS-0001 2532 18th International Conference on MiniaturizedSystems for Chemistry and Life Sciences

October 26-30, 2014, San Antonio, Texas, USA

temperature was investigated through acquiring the variations of UV-vis absorption (Fig. 1(d)). The results indicate that during heating, around 32 °C, the turbidity is abruptly rising, while reaching a plateau around 37 °C; the particles are found to be slower to respond to changes of temperature when cooled down. Percent cumulative release of FITC-dextran from particle at two different temperatures are shown in Fig. 2(a), indicating the dominant effect of temperature on the release kinetics. The loaded patch and electronic parts integrated on the 3D-printed TangoPlus flexible bandage are shown Fig. 2(b).

(a)

(b)

25°C

Heating

33°C

(c)

(d)

Figure 1: (a) Schematic description of the wound dressing with controlled drug delivery (b) PNIPAM microparticles shrinking at different temperatures (c) microparticles’ diameter with different initial size vs. temperature (d) Temperature dependance of UV-vis absorbance for photopolymerized PNIPAM.

(a)

(b)

Figure 2: (a) cumulative release of FITC-dextran from PNIPAM particles at different temperatures (b) assembly of the loaded hydrogel patch, heater, temperature sensor and micro controller CONCLUSION

Herein, we have engineered a topical dermal patch that can release drugs and growth factors on de-mand. The proposed platform paves the road towards developing “smart” flexible, drug delivery system. ACKNOWLEDGEMENTS

Financial support from the National Science Foundation (EFRI-1240443) is gratefully acknowledged. SB acknowledges funding from MIT-Italy program (Progetto Rocca).

REFERENCES [1] C.K. Sen, G.M. Gordillo, et al., “Human Skin Wounds: a Major and Snowballing Threat to Public

Health and the Economy” Wound Repair and Regeneration. 17(6), 763-71, 2009. [2] A.H. Najafabadi, A. Tamayol, et al., “Biodegradable Nanofibrous Polymeric Substrates for Generat-

ing Elastic and Flexible Electronics” Advanced Materials., doi: 10.1002/adma.201401537, 2014.

280  340  400  460  520  580  640  700  760  

24   26   28   30   32   34   36   38   40   42  

Particle  Diameter  

(um)  

Temperature  (C)  

R=0.01  R=0.02  R=0.03  

0  0,5  1  

1,5  2  

2,5  3  

27   29   31   33   35   37   39   41   43  Absorbance  (λ

=460nm

)  

Temperature  (ºC)  

Heating  

Cooling  

20  

40  

60  

80  

100  

0   10   20   30   40   50  

Accumulative  FITC-­‐

Dextran  Release  (%

)  

Time  (h)  

37C  25C  

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