**3. Discussion**

Films of PPY loaded with an anionic drug (either DMP or MER, see Figure 1) were deposited onto the surface of ITO-coated glass electrodes via electropolymerization, yielding films where the positive charges on the backbone of the polypyrrole were counterbalanced by the presence of the anionic dopants from the electrolyte during the electropolymerization reaction (in this case, one of the anionic drugs, DMP or MER). PPY films prepared via electropolymerization on flat electrodes typically display cauliflower-like morphologies [16,46].

Clearly, surface morphologies and surface-area-to-volume ratios of materials used for drug delivery play an important role in the rate of release of the payloads, and it was observed that mass transport from PPY films with low surface-area-to-volume ratios (e.g., the cauliflower-like morphology) released drugs more slowly than materials with high surface-area-to-volume ratios (e.g., nanowire-like PPY) [16,46,59].

The films were observed to be somewhat imperfect with cracks and inhomogeneities observable (visually or via SEM), and they occasionally delaminated from the underlying ITO electrode. Such problems (i.e., cracks/inhomogeneities and delamination) may be solved using alternative materials for the underlying electrode (e.g., gold, glassy carbon, etc.); through the use of composites, wherein the polymeric dopant forms an interpenetrating network with the conducting polymer binding them together [60–63], or through the development of heat/solution processable electroactive block copolymers, in which one block is electroactive and the other block is heat/solvent responsive [64,65]. Analysis via spectroscopy (EDX, FTIR, and UV-vis), XRD, and electrochemical techniques (CV and EIS) confirmed the presence of the drugs in the films, and subtle differences in the packing of the PPY chains in the films in the presence of each drug. Interestingly, measurements of the total mass of the drug in the films revealed differences in loading, with DMP-doped PPY films containing 12 wt % of DMP, and MER-doped PPY films containing 4 wt % of MER. The physical descriptors for DMP and MER (Table 1) offered an explanation as to why this was observed: the dipole of DMP was lower than that of MER (1.7033 vs. 9.2305, respectively), as was the number of hydrogen-bond acceptors (8 vs. 9, respectively) and hydrogen-bond donors (5 vs. 7, respectively). Furthermore, the LogP of DMP was higher than that of MER (1.2640 vs. −0.5960, respectively). Consequently, the more hydrophobic drug (DMP) was more readily loaded into the hydrophobic PPY matrix than the hydrophilic MER.

For both DMP-doped and MER-doped films, the drugs were observed to passively diffuse from the films, as is the norm for drug-loaded polymers. The passive diffusion of DMP from the films was ca. 10–15% of the total DMP content of the films over the course of the experiment, whereas the passive diffusion of MER from the films was ca. 10–30% of the total MER content of the films over the course of the experiment.

The application of a reducing potential of 0.6 V (for 30 s) to the drug-loaded PPY films resulted in the proactive release of the anionic drug from the films, and rest periods (10.5 min) between the applications of electrical potential offered opportunities for re-doping by other anions (either the anionic drug, or anions from the PBS buffer: H2PO4− and HPO4<sup>2</sup><sup>−</sup>, and Cl−). We observed the amount of drug released from the electrically stimulated films (including the rest period) to be higher than that for the passive control samples at each time point measured (every 11 min). For the DMP-doped films (Figure 9B), there was an increase of ca. 10–15% in the amount of drug released at various time points; whereas for the MER-doped films (Figure 9C), there was an increase of ca. 15–30% in the amount of drug released at various time points after electrical stimulation. The differences in the in vitro release behavior observed for DMP and MER, despite their close molecular weights, could be attributed to differences in their physical descriptors (such as the dipole moment, total number of hydrogen-bond donors and acceptors present, molecular flexibility, LogP, and molecular globularity), which confirmed MER to be more hydrophilic and polar than DMP, rendering MER easier to release via diffusion from the PPY matrix, and therefore, more responsive to electrical stimuli (Table 1) [66].

The clinically translated examples of electronic interfaces for the body are all currently metal-based. The mechanical properties of these metals are markedly different from the soft tissues in which they are implanted. This mechanical mismatch leads to inflammatory responses and the formation of scar tissue around the electronic interface. A topic of intense current research interest is the development of soft conductive OEM-based coatings for the surface of the metal electrodes, and it is attractive to be able to deliver bioactive substances from the electrode coating (e.g., anti-inflammatories such as DMP). It is also noteworthy that the surgical procedures necessary to implant such devices are complex, and problems associated with microbial infections in the proximity of these devices can potentially be addressed through the delivery of antimicrobials (e.g., MER) from the surface coatings. The release of the clinically relevant drugs (DMP or MER) loaded into the PPY films was observed to be enhanced by the application of an electrochemical stimulus, thereby demonstrating proof of concept that such materials may form a useful conformal coating on the surface of implantable medical devices, potentially diminishing adverse reactions to their implantation in vivo [16,24,60].

### **4. Materials and Methods**
