**1. Introduction**

Eosinophilic esophagitis (EoE) is an emerging chronic allergic disease characterized by eosinophilic infiltration of the esophageal mucosa [1,2]. The most common symptoms of EoE include dysphagia and food impaction in adolescents and adults, and abdominal pain, vomiting, heartburn, feeding intolerance, and failure to thrive in children. EoE represents a major healthcare burden as the estimated prevalence is at least 1 in 2000 Americans, and EoE-associated healthcare costs approach up to \$1.4 billion per year [3,4]. Because there are no FDA-approved medications for EoE, asthma preparations, such as a fluticasone (FTS) from an inhaler, have traditionally been swallowed rather than inhaled to coat the esophagus [5]. The European Medical Agency (EMA) has approved a dissolvable budesonide tablet (Jorveza) for both acute and a long-term treatment. While these treatment approaches can be effective [6–8], because the medication delivery does not target the esophagus, it leads to suboptimal outcomes and adherence [9]. Our prior data, however, suggest that increased esophageal dwell time of pharmacologic agents is closely associated with subsequent treatment response [10]. To address these limitations, we aimed to produce strategies to more rationally provide drug exposure to the esophagus. Herein, we report the development of two esophageal-specific drug delivery platforms, a drug-eluting string and a 3D-printed ring for local rapid or sustained release of FTS in the esophagus.

These two delivery devices shared a common rationale—to deliver medication to the esophagus. A drug-eluting string could be swallowed, allowing a sustained release of drug along the entire length of the esophagus, perhaps during an overnight dwell, rather than the usual one-time bolus from a swallowed medication. While the minimally invasive esophageal string test has been used to absorb inflammatory factors related to EoE and characterize disease activity [11–13], there are no reports of delivering medication to the esophagus in this manner. A recent report outlined how a membrane deployed from a capsule might also target drug delivery to the esophagus. [14]. Our research strategy involved developing a FTS-eluting string and showing a target release of 1 mg/day of fluticasone in vitro for 24 h period of time. Fluticasone was coated on the surface of the string via drug adsorption using a dip coating process [15–17]. Studies were conducted to determine drug loading, in vitro drug release kinetics, ex vivo PK, and in vivo safety and PK in a porcine model [18].

In our second approach, we developed rings that can be inserted in the proximal esophagus to provide a long-acting sustained delivery of fluticasone. Rings were fabricated using 3D printing with additive manufacturing (AM), which involves a process of transforming digital models into real objects by placing materials layer by layer [19–23]. Recently, this emerging technology has been widely applied in the fields of drug delivery [24], biomaterials [20,25,26], medical [27] and food industry [28], and customized consumer products [29]. There are a number of 3D printing methodologies available which differ in how the 2D layers of materials are deposited. These include stereolithography (SLA) [30], two-photon polymerization [31], selective laser sintering (SLS) [32], fused deposition modeling (FDM) [33], and laminated object manufacturing (LOM) [34]. Among the existing AM technologies, photopolymerization offers the advantage of using a variety of synthetic polymers that can be tailored to have a desired structural property [35–37]. A photoprintable system mainly consists of an initiating system, photopolymerizable monomer or oligomer, and a light absorber [38]. Photoinitiators provide the required energy to initiate the photopolymerization, and a suitable light absorber is usually added to have an effective control over cure-depth [39]. The final properties of the printed part can be tailored by changing the constituents of photocurable resin formulation [40]. Recent advances in photopolymerization-based 3D printing involves spatially controlled curing of a photopolymer by interacting with a digitally modulated UV or visible light beam, defined by layer profiles of an Standard Tessellation Language (STL) file [41]. The process involves projection of an array of light spots on the surface of the resin, and propagation of light within each illuminated voxel in direction of the beam. The thickness of the photopolymerized layer is dependent on the interaction of photopolymer and the incident

beam. In our system, we used digital light processing (DLP) projection as the method of illumination which has the advantages of high printing precision and fast printing speed [42]. 3D printing, which includes the ability to construct structures with complex geometries via computer-aided design (CAD) models, has opened the door for rapid and facile production of controlled drug release devices and polymer biomaterials [43–47].

In recent years, drug delivery devices have been developed to release medication at a controlled rate, and upon implantation, allow treatment without requiring oral or intravenous dosing [48–50]. We demonstrated in vitro that our novel 3D printed ring eluted fluticasone at a constant rate. All rings were fabricated using a variety of biocompatible photopolymerizable resin formulations, with various strategies of incorporating fluticasone in the ring device. Fluticasone-loaded rings were tested ex vivo and in vivo in the porcine model and showed high levels of fluticasone in the esophageal tissue in the ex vivo studies. To the best of our knowledge, these two approaches—the fluticasone-eluting string and ring—are among the first such esophageal-specific devices developed for the treatment of EoE. These promising results will need to be extended into disease models, with the ultimate goal of translating this technology into human disease.
