Acoustic Sensing and Ultrasonic Drug Delivery in Multimodal Theranostic Capsule Endoscopy

Abstract

Video capsule endoscopy (VCE) is now a clinically accepted diagnostic modality in which miniaturized technology, an on-board power supply and wireless telemetry stand as technological foundations for other capsule endoscopy (CE) devices. However, VCE does not provide therapeutic functionality, and research towards therapeutic CE (TCE) has been limited. In this paper, a route towards viable TCE is proposed, based on multiple CE devices including important acoustic sensing and drug delivery components. In this approach, an initial multimodal diagnostic device with high-frequency quantitative microultrasound that complements video imaging allows surface and subsurface visualization and computer-assisted diagnosis. Using focused ultrasound (US) to mark sites of pathology with exogenous fluorescent agents permits follow-up with another device to provide therapy. This is based on an US-mediated targeted drug delivery system with fluorescence imaging guidance. An additional device may then be utilized for treatment verification and monitoring, exploiting the minimally invasive nature of CE. While such a theranostic patient pathway for gastrointestinal treatment is presently incomplete, the description in this paper of previous research and work under way to realize further components for the proposed pathway suggests it is feasible and provides a framework around which to structure further work.

Keywords: USCE; UmTDD; acoustic sensing; capsule endoscopy; endoscopy; gastrointestinal; targeted drug delivery; theranostics; ultrasonic drug delivery; ultrasound.

Figure 1

Schematic of the proposed patient pathway.

Figure 2

Sequencing for the digital segmentation of the heterogeneous tissue samples to isolate the mucosa/submucosa. All images are shown with the superficial layer towards the top of the image. (a) Original ultrasound image (b) Initial threshold mask (c) Processed mask (d) segmented image.

Figure 3

48 MHz microultrasound scan of ex vivo porcine esophageal tissue. Tissues layers can be distinguished as (a) mucosa, (b) submucosa and (c) muscularis propria and serosa.

Figure 4

Increase in acoustic impedance as a function of segmented tissue thickness. Error bars show standard deviation across the full 30 mm scan for each sample.

Figure 5

Backscattering coefficients for each digitally segmented tissue sample as a function of sample. Error bars show standard deviation across the full 30 mm of each scan.

Figure 6

(a) Block diagram of fluorescence-imaging capsule and (b) final manufactured test capsule, Ø 16 mm. [8].

Figure 7

(a) CAD cross section of the miniature focused-US transducer with PZ54 bowl, backing layer, interconnects and casing. (b) Micro ScoutCam imaging camera 1.2 mm in diameter, 5 mm in length, tethered. Camera passes through illumination board with four LEDs mounted on a PCB with diameter 8 mm. (c) CAD cross section of the capsule with components included. All components are confocal and the US beam and therapeutic agents are indicated in the drawing. The capsule has diameter D_cap = 10 mm and length L_cap = 30 mm.

Figure 8

(a) Piezoceramic material was placed face down on a flat glass surface. (b) An additively-manufactured casing was placed over the piezoceramic material, ensuring they were coaxial. (c) Electrical interconnect was attached to the rear surface of the piezoceramic using Ag-loaded epoxy. (d) Glass microbubble-loaded epoxy was added to the rear surface of the piezoceramic and cured in an oven for 15 min at 70 °C. (e) A hole was drilled through the backing layer a 1 mm dia. drill bit. (f) The delivery channel was run through the central hole in the piezoceramic and out an outlet in the side of the casing. (g) The central pin on the surface mount SMA connector was attached to the electrical interconnect on the rear surface of the transducer using Ag-loaded epoxy. The SMA connector fit into grooves in the additively-manufactured casing and was secured using epoxy. (h) The electrical ground connection was attached from the outside of the SMA connector to the front face of the piezoceramic material using Ag-loaded epoxy. The ground connection runs along the outside of the transducer casing. Gaps in the transducer were sealed with epoxy to waterproof the transducer. (i) CAD model of the fully fabricated transducer showing piezoceramic, delivery channel, casing and SMA connector.

Figure 9

Insonation system comprising three axis translation stages, syringe pump, signal generator (off screen), cell plate holder, control program, and miniature focused US transducer.

Figure 10

Effect of TER on small bowel model. MB-only samples were unaffected. Ultrasound-only samples had an average drop of 2.94% from initial TER. Samples exposed to ultrasound with MBs present had an average drop of 5.52% from the starting value.