Additive Manufacturing of Drug-Eluting Multilayer Biodegradable Films

Abstract

Drug-eluting films made of bioresorbable polymers are a widely used tool of modern personalized medicine. However, most currently existing methods of producing coatings do not go beyond the laboratory, as they have low encapsulation efficiency and/or difficulties in scaling up. The PLACE (Printed Layered Adjustable Cargo Encapsulation) technology proposed in this article uses an additive approach for film manufacturing. PLACE technology is accessible, scalable, and reproducible in any laboratory. As a demonstration of the technology capabilities, we fabricated layered drug-eluting polyglycolic acid films containing different concentrations of Cefazolin antibiotic. The influence of the amount of loaded drug component on the film production process and the release kinetics was studied. The specific loading of drugs was significantly increased to 200-400 µg/cm² while maintaining the uniform release of Cefazolin antibiotic in a dosage sufficient for local antimicrobial therapy for 14 days. The fact that the further increase in the drug amount results in the crystallization of a substance, which can lead to specific defects in the cover film formation and accelerated one-week cargo release, was also shown, and options for further technology development were proposed.

Keywords: 3D printing; additive manufacturing; biopolymers; drug-eluting coatings; polymer films; zero-order release.

Figure A1

Absorbtion spectra (a) and calibration plots (b) for Cefazolin.

Figure 1

The design of the PLACE approach. (a) Mixing of the drug-containing matrix, (b) film fabrication pathway, and freestanding ready-to-use film (c).

Figure 2

Simplified process of DEFs production. (a) Template-based methods, (b) DEFs represented as array of microcontainers filled with drugs and sealed between two polymer films, (c) direct drug deposition approach and SEM image of drug deposited onto flat PLA film as separate piles using the PDMS stamp-assisted transfer method; scale bar 100 µm [21].

Figure 3

(a) Commercial 3D printer upgraded to use for drug gel printing, syringe extruder 3D model (b) and a complex shape print example (c).

Figure 4

Selection of parameters for PVA gel preparation. (a) Print defects when using 6 wt % PVA solution; line width on a straight section (b) and on turns (c) using 9 wt % PVA solution; the dependence of the dynamic viscosity of PVA on the concentration (d).

Figure 5

Large-area multilayered film under UV light (a), its optical image (b) and SEM image of cross-section (c).

Figure 6

(a) Cefazolin-containing film sample, SEM images of its edge (b,c) and of cover film-coated drug surface (d).

Figure 7

(a) Prolonged release profiles of Cefazolin from films prepared with various drug load (100/200/400 mg per 1 mL of PVA matrix). (b–d) SEM image for the surface of uncoated drug strips for Cef100, Cef200 and Cef400 samples, respectively.

Figure 8

Prolonged release daily profile of Cef100 series. Minimum Inhibitory Concentration (MIC) for MSSA is shown as a red dashed line.