The Pursuit of the ‘Ideal’ Submucosal Injection

S K Sharma1, K Nakajima2, G Abdalla2, A Levin3, J F Cornhill1, J W Milsom1. 1Minimally Invasive New Technologies, Weill Cornell Medical College & New York Presbyterian Hospital, 2Section of Colon and Rectal Surgery, Weill Cornell Medical College & New York Presbyterian Hospital, 3Rockefeller University, New York


Traditional surgical methods for treating serious digestive diseases, such as colorectal cancer, although widely employed across the Western world, carry with them significant risks. The endoluminal approach describes the method of treating pathology, such as benign polyps, by methods such as Endoscopic Mucosal Resection (EMR) and Endoscopic Submucosal Dissection (ESD). In addition, collective therapeutic approaches such as Combined Endoscopic and Laparoscopic Surgery (CELS) may be used to overcome the limitations and challenges of EMR and ESD, whilst still obviating intestinal resection and anastomosis. Through injecting agents into the submucosal intestinal layer, we may improve the margin of safety, but this field is highly underdeveloped with Saline Solution (SS) being the primary submucosal injection agent (SMIA) used worldwide. Endoluminal ultrasonography has enabled higher levels of tissue discrimination and anatomical appreciation, and such a SMIAs ability to further enhance this feature is desirable.


The purpose of this study was to investigate the ability of twelve established and novel SMIAs – including normal saline, hyaluronic acid and thermo-sensitive polymers (TSP) – as well as some combinations of those agents, to create a durable submucosal cushion. In addition we assessed the SMIAs ability to change the ultrasonogaphic (US) characteristics.


Fresh ex-vivo calf rectum was used. One-millilitre of the twelve SMIA agents were injected into the submucosal space, ten times per SMIA. Height loss over one hour was measured as a proxy for the agents’ ability to create a durable submucosal cushion. Height loss for each solution was plotted and Area Under the Curve (AUC) analysis was undertaken by taking the best-fit line integral equation. Percentage of an ideal agent was then calculated. One-hundred percent being a SMIA that preserves it’s initial height over one hour. US views were also taken to assess the SMIAs ability to modulate anatomical appreciation (a BK medical ultrasound 800 system was used).


SS exhibited the worst maintenance of ideal agent height at 54% after 1 hour, followed by an aqueous solution of carboxymethylcellulose (55%). An equal combination of saline solution, hyaluronic acid and aqueous carboxymethylcellulose performed the best with 87% (p<0.01 compared to SS) maintenance of height, closely followed by TSP (86%, p<0.01). Using direct visual and grey scale analysis, a clear variation in an SMIAs ability to demarcate intestinal anatomical layers using ultrasound was demonstrated, with TSP appearing to readily separate the mucosal layer from deeper structures.


Novel and combination SMIAs yielded significantly superior results to SS, particularly with regards to persistent mucosal elevation – the most important feature of an SMIA. This factor combined with the possibilities of novel therapeutic agent seeding and auto-dissection (as seen in US analysis) makes TSP one of the most likely, ideal SMIAs. Interestingly, SMIAs that displayed poor individual outcomes, exhibited superior results when used in combination – likely due to synergistic chemical effects. Further studies are needed to build on these promising results and expand this under-developed field.

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