**1. Introduction**

The market for global drug-delivery technologies is a multibillion-dollar industry, and there is a growing demand for drug-delivery devices in both developed and emerging economies (in part, driven by aging societies and rapid urbanization) [1,2]. The market for implantable medical devices is also a multibillion-dollar industry, with a similarly growing demand driven by the same factors (i.e., increasing geriatric populations and incidences of chronic diseases, coupled with the adoption of implantable medical devices) [3–5]. Medical devices are implanted in either hard tissues (e.g., orthopedic implants such as reconstructive joint replacements, dental implants, and spinal

implants) or soft tissues (e.g., intraocular lenses, or the skin). The successful integration of such devices is dependent on the availability of sterile surgical conditions, patient health, etc., and their implantation is most commonly coupled with a course of condition- and patient-specific drugs [6,7].

Drug-delivery systems can be engineered to deliver drugs at rates controlled by specific features of the systems, particularly their chemical composition (e.g., inorganic/organic components, molecular weights of their constituents, crosslinking density of polymers, etc.) and the inclusion of components that respond to chemical stimuli (e.g., enzymes, ions, or pH) or physical stimuli (e.g., electromagnetic fields, or temperature) [8–15].

Responsiveness to electric fields is an inherent property of electrically conducting materials (e.g., metals), and certain molecules respond to the application of electric fields by orienting their dipoles with the applied field, whereas other molecules can undergo redox reactions in response to electricity. An exciting class of electrically conducting materials is that of organic electronic materials (OEMs). Various types of OEMs exist, including fullerenes (bucky balls or nanotubes), graphene/graphene oxide, or conjugated polymers (e.g., polyaniline, polypyrrole, or polythiophene). Some OEMs are commercially available, and their properties can be tailored (through chemical modification or the generation of composites) to suit the delivery of various drugs [16,17].

While OEM-based nanoparticles have promise for simultaneous imaging and drug delivery (i.e., theranostic applications) [18,19], nanoparticles are not the only morphology of materials that OEMs can be processed into, and it is also possible to manufacture OEM-based films, fibers, foams, and hydrogels [20–24]. The morphologies of these alternative materials are under investigation for their inclusion into new versions of a variety of clinically translated electronic interfaces for the body (e.g., cardiac pacemakers, cochlear implants, retinal prostheses, and electrodes for deep brain stimulation), or indeed, electronic interfaces for the peripheral nervous system (e.g., for the control of the bladder) [20–24]. The clinically translated examples of electronic interfaces for the body are all currently metal-based (typically connected to batteries implanted at the same time), and the mechanical properties of these metals are markedly different from the soft tissues in which they are implanted (known as a mechanical mismatch). Mechanical mismatches lead to inflammatory responses and the formation of scar tissue around the electronic interface [23,24]. Mismatches can potentially be diminished by coating the surface of the metals with relatively soft OEM-based materials [24], or indeed, the delivery of anti-inflammatories from OEM-based materials [25]. Moreover, it is 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 [16,17,25,26].

Conjugated polymers have fascinating optoelectronic properties, and are consequently being developed for use in the electronic industry [27–30]. There is academic and industrial interest in their potential application in the biomedical industry for use as bioactuators, biosensors, drug-delivery devices, neural electrode coatings, or indeed, tissue scaffolds for tissue engineering [20–22,31]. Polyaniline, polypyrrole, and polythiophene derivatives are most commonly investigated for biomedical applications, and polyaniline- and polypyrrole-based systems were shown to be capable of delivery of a variety of drugs (including anions and, less frequently, cations) [16,17,25,26,32–36].

Prospects for the clinical translation of conjugated polymer-based drug-delivery systems are clearly dependent on their biocompatibility. Histological analyses of tissue in the vicinity of polypyrrole (PPY)-based materials implanted subcutaneously or intramuscularly in rats revealed immune cell infiltration comparable to Food and Drug Administration (FDA) approved poly(lactic-co-glycolic acid) [37], or FDA-approved poly( D,L-lactide-co-glycolide) [38]. Similarly low inflammatory responses were observed for PPY-based materials implanted at the interface of the coronary artery of rats after five weeks [39], or PPY-based sciatic-nerve guidance channels implanted in rats after eight weeks [40], and importantly, PPY-coated electrodes in rat brains after three or six weeks [41]. The implantation of poly(3,4-ethylenedioxythiophene) (PEDOT)-coated electrodes in rat brains resulted in a modest global tissue reaction of approximately the same magnitude as that for silicon

probes [42], whereas there was no observable immune response after one week for PEDOT-based materials implanted subcutaneously [43]. The implantation of polyaniline (PANI)-based materials implanted subcutaneously in rats showed low levels of inflammation after four [44], or 50 weeks [45]. We recognize that differences in individual studies (e.g., composition/structure of the materials, animal/tissue models, and the methods used to evaluate immune responses) present challenges when attempting to directly compare the results of each study; however, conjugated polymer-based biomaterials have levels of immunogenicity that are comparable to other FDA-approved biomaterials, and have prospects for clinical translation in the long term.

With a view to the long-term development of surface coatings for medical devices (e.g., neural electrodes) to diminish adverse reactions to their implantation in vivo, we report the use of conducting polymer-based coatings that enhance the delivery of drugs upon the application of an electrical potential. As a simple model system, we used polypyrrole (PPY) loaded with clinically relevant drugs (either an anti-inflammatory, dexamethasone phosphate (DMP), or an antibiotic, meropenem (MER)), as depicted in Figure 1. The rationale behind the delivery of DMP was to address problems of local tissue inflammation in the proximity of the materials, whereas the rationale behind the delivery of MER was to help diminish the potential for microbial infections in the proximity of materials that might be associated with the complicated surgical procedures necessary to implant electronic interfaces for the body. The films were characterized using microscopic, spectroscopic, and electrochemical techniques; the delivery of the drugs into a biomedically relevant buffer (phosphate-buffered saline, PBS) was studied in vitro, and the correlation between drug loading/release was correlated with the physical descriptors of the drugs. Such materials have prospects for the preparation of conformal electroactive coatings for implantable biomaterials.

**Figure 1.** The chemical structures of the substances studied herein: ( **A**) Polypyrrole (PPY); (**B**) dexamethasone phosphate (DMP); ( **C**) meropenem (MER).
