Introduction: Bacterial infection affects the outcome of surgical procedures and the successful operation of implantable devices. It is also a key challenge in treatment of chronic and deep wounds. Current treatment strategies are based on systemic administration of high doses of antibiotics, which can result in severe side effects such as antibiotic resistance and other complications. Therefore, localized and on-demand delivery of antibiotics at the wound site is highly important [1]. The recent advancement of the field of flexible electronics has enabled manufacturing electrical systems on non-conventional substrate with novel capabilities. Here, we developed an elastic nanofibrous mesh by electrospinning of a poly(caprolactone)-poly(glycerol sebacate) blend that contained thermoresponsive nanocarriers loaded with antibiotics. A bioresorbable metallic heater was patterned directly on the nanofibrous substrate for applying thermal stimulation to release antibiotics on demand. The engineered platform was flexible and elastic and could form conformal contact with the surrounding tissues. Such system will pave the path towards developing smart wound dressing, which can sense the wound environment and deliver suitable drug treatment that promotes wound healing.
Materials and Methods: Thermo-responsive carriers were prepared from PEGylated Chitosan at 70 °C using ammonium persulfate as initiator. The mixture was then refluxed for 4 h in N2 atmosphere, the microgels were filtered, dialyzed against distilled water for 2 days, and freeze-dried. Nanocarriers were mixed with a solution of PGS and PCL (at the ratio of 1:1, the total polymer concentration at 20% w/v) in anhydrous chloroform: ethanol (9:1) mixture. An electrical field of 20 kV over a distance of 18 cm (the distance between the needle and the collector) was applied to create the nanofibrous substrate (Fig. 1a-c). Flexible heater was generated by screen printing of silver ink on the nanofibrous substrate.
Results and Discussion: Thermo-responsive drug nanocarriers with an average size of 90 nm were fabricated as described above and loaded with ceftriaxone and cefazolin. The morphology of the fabricated nanocarriers and the nanofibrous substrate is shown in Fig. 1d-f. These nanocarriers were mixed with prepolymer solution and then electrospun to form the nanofibrous construct (Fig.1b). To trigger these thermo-responsive nanocarriers, a flexible heater was sputtered on the substrate (Fig. 2a-c). The release of different drugs could be tuned by adjusting the substrate temperature (Fig. 2d,e). The release of methylene blue from the platform is shown as a function of the substrate temperature in Figure 2e. We also characterized the release of ceftriaxone as a function of temperature (Fig. 2e). The drug release profile was related to the applied heat and could be tuned accordingly. In addition, the effectiveness of the released antibiotics was confirmed using both disk diffusion test and colony counting assays (Fig. 3a-e).
Conclusions: A scalable elastic platform containing stimuli-responsive drug nanocarriers with integrated flexible heater was engineered. This drug delivery platform enabled us to tune the release profile of various drugs by adjusting the generated heat.
The authors declare no conflict of interests in this work. The financial support from the National Science Foundation (EFRI-1240443), the office of Naval Research Young National Investigator Award, and the National Institutes of Health (HL092836, DE019024, EB012597, AR057837, DE021468, HL099073, EB008392) is gratefully acknowledged.SB acknowledges funding from MIT-Italy program (ProgettoRocca) and Polimi International Fellowship (PIF).
References:
[1] A. Hassani Najafabadi, A. Tamayol, N. Annabi, M. Ochoa, P. Mostafalou, M. Akbari, M. Nikkhah, R. Rahimi, M.R. Dokmeci, S. Sonkusale, B. Ziaie, and A. Khademhosseini, “Biodegradable nanofibrous polymeric substrates for generating elastic and flexible electronics” Advanced Materials, 26, 5823-5830 (2014).