(T1330-07-45) Tailored Sodium Alginate-Based Hydrogel System for Submucosal Lifting: A Breakthrough in Endoscopic Mucosal Resection and Submucosal Dissection

Purpose: Submucosal lifting agents are indispensable in endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD), as they create a protective cushion buffer between gastrointestinal lesions and the muscularis propria, thereby reducing the risk of thermal injury and mechanical perforation while promoting complete lesion excision^1,2. Although commercially available mucosal lifting agents such as Eleview^®, EverLift^®, BlueBoost^TM, ORISE™ gel, LiftUp^®, EndoClot SIS and Liftal^® K have improved procedural safety, however, each has inherent limitations such as transient duration of lift (more significant), staining artifacts, challenges in injection, substantial cost, and potential for histological misinterpretation³. Conventional agents, including saline and starch-based solutions, continue to be commonly utilized; however, they provide only temporary elevation, which needs reinjection again and again⁴. The advancing domain of lifting agents highlights the pressing requirement for alternatives that are not only safer but also offer enhanced durable lift and cost-effectiveness. In this study, we formulated and refined an innovative hydrogel based on sodium alginate, fortified with biocompatible methylene blue, which provides improved lesion visualization, prolonged elevation, and superior manipulability. Through iterative in vitro formulation, ex vivo performance testing, and in vivo validation using a porcine model, the hydrogel exhibited optimal physical and chemical characteristics including viscosity, osmolarity, and pH resulting in improved injectability, prolonged lift, which was easy to snare, and biocompatibility. Comparative evaluations against existing commercial agents established this formulation as a promising candidate for next generation lifting solutions in endoscopic resection procedures.

Methods: The medium viscosity sodium alginate from different sources, namely, Pronova UP MVG (IFF N&H Norway AS) and VIVAPHARM^® Alginate PHU 175 (JRS Pharma) in varying concentrations such as 0.6 %, 0.8% and 1% w/v was dissolved in PBS (0.8X, pH 6.5) and methylene blue was added to the clear Na alginate solution for enhanced visualization. The optimized 1% w/v formulation was lyophilized for stability and reconstituted prior to use, exhibiting rapid solubility within one minute. The viscosity of sodium alginate solution was measured before and after lyophilization and reconstitution concerning shear rate and shear stress using the Rheometer. Further, comprehensive in vitro characterization included detailed assessments of pH, osmolarity and color metrics using CIE Lab standards. Moreover, physical stability under accelerated condition (40 °C/70% RH) was evaluated over 6 months. Overall, a detailed analysis was performed on the rheological characteristics, pH, osmolarity, color metrics as well as lyophilization and reconstitution of Na alginate solution. Finally optimized Na alginate lifting gels were compared in detail to the commercially available lifting agents in terms of viscosity, pH, osmolarity, injectability, prolonged lift, how easy to snare, and biocompatibility through iterative in vitro formulation characterization, ex vivo performance testing, and in vivo validation using a porcine model. Then Data analysis was performed in order to correlate the best set of physical and chemical properties, e.g. viscosity for lifting gel performance using MATLAB R2024b (The MathWorks, Inc., Natick, MA, USA) and PLS toolbox 9.5 (R9.5) (Eigenvector Research, Inc., Wenatchee, WA, USA).

Results: The rheological characterization of Na alginate-based lifting hydrogels revealed that as the shear rate increased from 0.1 to 1000 1/s, it showed shear thinning (Figure 1). Also, the initial viscosity of Na alginate-based lifting gels was found significantly higher at lower shear rates than commercially available lifting agents and then viscosity decreased significantly with the increase in shear rates. Overall, the lifting gels demonstrated desirable shear-thinning behavior, physiological pH, optimal osmolarity, and a vivid blue hue. More importantly, lyophilized sodium alginate gels stored under accelerated conditions maintained consistent physicochemical properties over time, with no significant changes in viscosity at both room (25 °C) and physiological (37 °C) temperatures, aside from a slight, expected temperature-dependent decrease at 37 °C (Figure 2). Across all timepoints (t0, 1 month, and 6 months), the gels reconstituted quickly (60–90 seconds), retained their clear blue appearance, stable pH (~6.5), and osmolarity (265–275 mOsm/kg), underscoring their robust stability under stress conditions. Ex vivo testing on porcine gastric tissue evaluated lift height retention and cushion circumference using standard metrics and endoscopic tools (Figure 3). Our formulation consistently provided sustained submucosal elevation even after 60 minutes compared to commercial agents and controls. In vivo studies in swine further validated its injectability, efficacy, and safety, with submucosal cushions persisting at 45 minutes and no adverse tissue reactions observed at 72 hour and 3 months follow-up. The gel’s performance positions it as a promising alternative, longer lasting, and visually enhanced submucosal lifting in EMR and ESD procedures.

Conclusion: In summary, by integrating viscous and osmotic characteristics, this Na alginate based innovative lifting gel has exhibited excellent efficacy in in vitro, ex vivo, and in vivo models surpassing traditional agents such as saline, starch, and commercially available gels. By tackling significant challenges associated with current lifting gel solutions, our formulation establishes a new standard in submucosal lifting, offering safer, more efficient, and highly versatile performance in the context of endoscopic resection.

References: 1. Castro R, Libânio D, Pita I, Dinis-Ribeiro M. Solutions for submucosal injection: What to choose and how to do it. World J Gastroenterol. 2019 Feb 21;25(7):777-788. doi: 10.3748/wjg.v25.i7.777. PMID: 30809079; PMCID: PMC6385015.
2. Uraoka T, Saito Y, Yamamoto K, Fujii T. Submucosal injection solution for gastrointestinal tract endoscopic mucosal resection and endoscopic submucosal dissection. Drug Des Devel Ther. 2009 Feb 6;2:131-8. doi: 10.2147/dddt.s3219. PMID: 19920900; PMCID: PMC2761197.
3. Olivas AD, Setia N, Weber CR, Xiao SY, Villa E, Chapman CG, Siddiqui UD, Waxman I, Hart J, Alpert L. Histologic changes caused by injection of a novel submucosal lifting agent for endoscopic resection in GI lesions. Gastrointest Endosc. 2021 Feb;93(2):470-476. doi: 10.1016/j.gie.2020.06.056. Epub 2020 Jun 25. PMID: 32593688.
4. Coronel, Emmanuel. A new kid on the “bloc”? A case for another submucosal injection agent for endoscopic resection of early gastric neoplasms. Gastrointestinal Endoscopy, Volume 100, Issue 1, 46 – 48
5. Lee KY, Mooney DJ. Alginate: properties and biomedical applications. Prog Polym Sci. 2012 Jan;37(1):106-126. doi: 10.1016/j.progpolymsci.2011.06.003. PMID: 22125349; PMCID: PMC3223967

Acknowledgements: We acknowledge Origin Endoscopy and Maryland Innovation Initiative (MII) for funding this project. VSA and SWH are Co-founders of Origin Endoscopy LLC.


Figure 1: [A], [B] Graphs represent the rheological properties of the Na alginate (source: Sigma) solution of different concentrations, namely, 0.6%, 0.8%, and 1% in PBS of pH 6.5 measured at 25 °C and 37 °C as a function of shear rate and shear stress using Rheometer with 40 mm 1º cone. [C] and [D] Graphs represent viscosity of the Na alginate (source: Sigma) solution of different concentrations, namely, 0.6%, 0.8%, and 1%as a function of shear rate at 25 °C and 37 °C using Rheometer with 40 mm 1º cone. Empty symbols, up curve; closed symbols, down curve. graphs pH and osmolarity of Na alginate-based lifting gels in comparison to ORISE lifting gels (n=3).


Figure 2: Lyophilization of injectable gel to obtain lyophilized cake to prolong stability of injectable gel and reconstitution in liquid prior to the procedure within a minute. Stability study of lyophilized reconstituted 1% Na alginate (Pronova UP MVG) lifting gel stored under accelerated condition (40 °C/75%RH) at t0 (initial), t1 (1 month) and t2 (6 months). Graphs showing the rheological properties of reconstituted 1% w/v MVG-based lifting gel at t0 (initial), 1 month and 6 months of storage at °40 C/75% RH as a function of shear rate vs shear stress as evaluated using rheometer at [A] 25 °C and [B] 37 °C. For these graphs, the curvature indicated non-Newtonian behavior. Viscosity profile during upcurve and downcurve of reconstituted 1% w/v MVG-based lifting gel at t0 (initial), 1 month and 6 months of storage at °40 C/75% RH [C] 25 °C and [D] 37 °C. Data points with error bars represent mean ± standard deviations (n=3).


Figure 3: Evaluation of the feasibility of injection of lifting gel using an endoscopy injection needle in the porcine gastrointestinal tissue. [A] Lifting gel depots are created, and cushion height is measured. [B]Following dissection presence of an intact submucosal depot is noted. In vivo experiment evaluating the presence of submucosal cushion for at least 45 minutes when injected in live porcine gastrointestinal tissue. [C] and [D] Graphs demonstrating the percentage difference in height and breadth of the depot, 45 minutes after injection of the agent. This demonstrates the greater efficacy of the Na alginate-based lifting gel in maintaining a stable depot in comparison to available marketed products. Columns with error bars represent mean ± standard deviations (n=3–4). [E] Graphs representing the cushion height decrease percent and [F] Cushion breadth increase percent after 15 min, 30 min and 45 min. Data points with error bards represent mean ± standard deviations (n=3–4).