Therapy using implanted organic bioelectronics

Abstract

Many drugs provide their therapeutic action only at specific sites in the body, but are administered in ways that cause the drug's spread throughout the organism. This can lead to serious side effects. Local delivery from an implanted device may avoid these issues, especially if the delivery rate can be tuned according to the need of the patient. We turned to electronically and ionically conducting polymers to design a device that could be implanted and used for local electrically controlled delivery of therapeutics. The conducting polymers in our device allow electronic pulses to be transduced into biological signals, in the form of ionic and molecular fluxes, which provide a way of interfacing biology with electronics. Devices based on conducting polymers and polyelectrolytes have been demonstrated in controlled substance delivery to neural tissue, biosensing, and neural recording and stimulation. While providing proof of principle of bioelectronic integration, such demonstrations have been performed in vitro or in anesthetized animals. Here, we demonstrate the efficacy of an implantable organic electronic delivery device for the treatment of neuropathic pain in an animal model. Devices were implanted onto the spinal cord of rats, and 2 days after implantation, local delivery of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) was initiated. Highly localized delivery resulted in a significant decrease in pain response with low dosage and no observable side effects. This demonstration of organic bioelectronics-based therapy in awake animals illustrates a viable alternative to existing pain treatments, paving the way for future implantable bioelectronic therapeutics.

Keywords: Drug delivery; Organic bioelectronics; conducting polymers; in vivo; neuropathic pain; polyelectrolytes; spinal cord; therapeutic.

Fig. 1. The implantable OEIP and its spinal target.

(A) Photograph of the device. (B) Schematic illustration: electrical connection (left); reservoir with internal electrode (center); delivery channel and outlets (right). Total length 120 mm; reservoir diameter 6 mm, length 60 mm; delivery tip width 1.2 mm, length 40 mm, thickness about 0.2 mm. (C) Depiction of the four outlets aligned with the sites where the sciatic nerve bundles enter the spinal cord [reused with permission from (24)]. The figure shows a human spinal cord, but the roots L3-L6 refer to the root levels of a rat spinal cord.

Fig. 2. Geometry of the implantable device.

(Left) The pattern of the delivery channel leading from the reservoir out to the four delivery points (ends of the “fingers”). Dimensions are given in micrometers. (Right) A simplified equivalent circuit. R_L > R_D > R_G ≫ R_E, where R_E represents the ionic resistance of the electrolyte and counter electrode.

Fig. 3. Demonstration of simultaneous delivery using pH.

(A and B) Microscope images of the delivery tip (A) before and (B) during delivery of H⁺. The dashed lines indicate the edge of the encapsulation, defining the delivery points. The scale bar refers to both (A) and (B). The clouds of lower pH can be seen as the red regions at the delivery tips. (C) Approximate pH profiles at the four delivery tips. The change in pH shows the highly localized regions of lower pH.

Fig. 4. Therapeutic effect of GABA delivery in vivo.

(A) WT as a function of time for OEIP delivery of GABA at two delivery rates and H⁺ control delivery. The asterisks indicate significance of multiple comparisons between all three traces. P = 0.0024, 0.0014, 0.0286, 0.0002, 0.0113, and 0.0002 for 45, 60, 75, 90, 105, and 120 min, respectively. (B) WT as a function of delivered therapeutic. P = 0.0303, 0.0079, 0.019, 0.0179, 0.0079, and 0.0286 for 3.6, 4.5, 5.4, 6.3, 7.2, and 9.1 mC, respectively. Data in both (A) and (B) are represented as means ± SEM.