Biodegradable elastic nanofibrous platforms with integrated flexible heaters for on-demand drug delivery

Abstract

Delivery of drugs with controlled temporal profiles is essential for wound treatment and regenerative medicine applications. For example, bacterial infection is a key challenge in the treatment of chronic and deep wounds. Current treatment strategies are based on systemic administration of high doses of antibiotics, which result in side effects and drug resistance. On-demand delivery of drugs with controlled temporal profile is highly desirable. Here, we have developed thermally controllable, antibiotic-releasing nanofibrous sheets. Poly(glycerol sebacate)- poly(caprolactone) (PGS-PCL) blends were electrospun to form elastic polymeric sheets with fiber diameters ranging from 350 to 1100 nm and substrates with a tensile modulus of approximately 4-8 MPa. A bioresorbable metallic heater was patterned directly on the nanofibrous substrate for applying thermal stimulation to release antibiotics on-demand. In vitro studies confirmed the platform's biocompatibility and biodegradability. The released antibiotics were potent against tested bacterial strains. These results may pave the path toward developing electronically controllable wound dressings that can deliver drugs with desired temporal patterns.

Figure 1

The principle of operation of the drug delivery system and a typical fabricated bandage with integrated heater and electronics. Thermo-responsive drug nanocarriers were embedded within nanofibers of the engineered mesh and released their payload upon temperature increase induced by the integrated flexible heater. A typical fabricated bandage with the miniaturized control electronics is shown on the right.

Figure 2

Fabrication of the elastic biodegradable nanofibrous drug delivery platform. (a) Schematic of the fabrication of the substrate by electrospinning (b,c) Representative SEM images of a typical nanofibrous substrate containing drug nanocarriers. (d) Size distribution of the generated particles in wet conditions measured by DLS. (e) TEM image of PEGylated chitosan nanoparticles which represented the spherical shape of nanoparticles and particles size. (f) Effects of nanocarriers on the Young’s modulus of the nanofibrous substrate containing 10% (w/w) of nanocarriers.

Figure 3

Characterization of the nanofibrous substrate containing nanocarriers and the engineered heater. (a,b) Representative images of a nanofibrous substrate with a biodegradable Zn heater deposited by RF sputtering. (c) Characterization of the zinc microheater, the resulting temperature as a function of applied voltage. (d) Degradation of zinc patterns over 24 days in aqueous solutions containing NaOH (2.5 mM). (e) Micrograph showing the hydrolysis of zinc patterns over 24 days. (f) Degradation of magnesium patterns over 4 h in aqueous solutions containing 2.5 mM NaOH. (g) A representative SEM image of a nanofibrous substrate heated to 38 °C for 1 h confirming the stability of the membranes at that temperature. (h) A representative SEM image of nanofibrous substrate heated to 50 °C for 1 h, showing melted, decomposed and deformed state.

Figure 4

Characterization of the release profile and biocompatibility of the engineered platform. (a) Effect of temperature on the intensity of the methylene blue release from the nanofibrous platform. (b) The spectrum of release rate of cefazolin from the nanofibrous drug delivery system at different temperatures. (c) Effect of temperature on the interfacial release rate of ceftriaxone from the nanofibrous drug delivery system. (d) Cyclic thermal stimulation at different temperatures for on-demand release of cefazolin. (e) Assessment of the effectiveness of the released drug against bacterial culture; occurrence of a clear inhibition zone around the mesh containing cefazolin at 38 °C (i) in comparison to the mesh without cefazolin (ii) and the mesh containing cefazolin without heater after 12 h (iii). (f,g) Effect of the released antibiotics on the number of CFUs in a bacteria solution after 24 h of culture; ceftriaxone against E. coli and cefazoline against S. areus. (h) Metabolic activity of human keratinocytes cultured in contact with the nanofibrous substrate with and without nanoparticles and the flexible heater (***p < 0.001). (i) Immunostaining against F-actin and cell nuclei (DAPI) confirming the normal morphology of the cells cultured in contact with the nanofibrous substrate.