Adhesives might seem unlikely film stars, but they are well enough established in medical applications to feature on the big screen. Or so I noticed recently, when at home watching the movie "The Incredible Hulk". In it, the hero uses what looks like a cyanoacrylate formulation to stop his irradiated blood seeping from a wound and contaminating others.
Despite this recognition, concerns continue over cyanoacrylates' suitability for use in internal medicines.1 Meanwhile their main rival, fibrin glue, reproduces the last steps of natural clotting, making it biocompatible. However, it is expensive and can also trigger adverse reactions or even transmit viruses as it is derived from blood. Consequently researchers are developing hydrogel adhesives to - quite literally - fill the resulting gap.
Hydrogel adhesives are already familiar in medical applications as pressure sensitive adhesives (PSAs) used to secure bandages, transdermal drug-delivery (TDD) patches and medical devices. Historically, polyisobutylenes, polysiloxanes and polyacrylate PSAs have been used for this purpose. Yet ensuring they don't come off prematurely when they get wet with bodily fluids, or cause pain and leave difficult-to-remove residue when they are removed remains difficult.2 They also often trap water by the skin, which can lead to microbial contamination. By contrast, as hydrogels contain a large quantity of water they can tolerate bodily fluids, but their mechanical properties have typically been poor. Their strength can be boosted by end-capping a basic polyethylene oxide polymer with methacrylate groups.3 Formulators can then radically cross-link these unsaturated chain ends.
Researchers have also recently developed hydrogel adhesives that they say combine economy, painless, residue-free removal and air- and water-permeability, allowing water to move away from skin.4 The key lies in "depolymerizing" polysaccharide hydrocolloid gums like gum arabic and gum karaya, then stripping off their surface functional groups and cross-linking them with boric acid. The hydrogels have particularly high surface areas, and the increased contact with the skin surface improves adhesion and TDD performance. They also reputedly have adequate cohesiveness to provide excellent flexibility, strength and integrity, which in turn allows prolonged adhesion for single application or multiple repositioning.
Figure 1: Bond formation between PTFE or aluminum and hydrogel adhesives based on gum karaya that has been depolymerized, stripped of surface functional groups and crosslinked with boric acid with different degrees of crosslinking density (µ).
Beyond PSAs, hydrogel use in tissue sealants has been limited by too rapid gel times. Such tissue adhesive hydrogels mix an oxidized polysaccharide polymer, such as dextran or starch, with a polyamine dendrimer, such as polyether amines, poly-L-lysine, chitosan or amine-modified polyvinyl alcohols. Early formulations had gelled in as little as 10 seconds, which makes them difficult to use in internal surgery scenarios. For example, this doesn't allow enough time to apply adhesive around the entire circumference of the intestine to form a complete seal in intestinal anastomosis. Likewise, it doesn't suit minimally invasive procedures, such as laparoscopic surgery, where the mixture of components is delivered by means of a long tube.
But formulators have discovered additive chemicals that can not only control gelation time but also adhesive performance and degradation time.5 The added chemical, for example an amino acid, aminoalcohol, or peptide, interferes in the reaction between the oxidised polysaccharide and polyamine dendrimer. It forms a reversible bond to the two main components, slowing the rate of crosslinking reaction and results in a longer gelation time. Yet overall adhesive performance and degradation times may not be affected because the additive can be displaced later, leading to the normal level of crosslinking. Alternatively, molecules that irreversibly bond again decrease gelation time and reduce crosslink density, speeding degradation.
Figure 2: Structures of additives that can improve the performance of polyamine dendrimer/oxidized polysaccharide tissue adhesives
In stark contrast from gelation times of these adhesives, it often takes many hours at raised temperatures to dissolve oxidized dextran in water. But in this case aminoether additives can help. 6 In particular polyethylene glycol molecules that have reactive amines on one and inert methoxy groups on the other end dissolve dextrans in water in less than five minutes. Again, as well as reducing dissolution time, these additives again also shorten the time needed for the adhesive to degrade.
With formulators rapidly overcoming hydrogel adhesives' remaining weaknesses, if it's possible for medical adhesives become a household name, then these products are going to attract at least some of the spotlight.
What are the remaining performance areas that hydrogel medical adhesives are yet to deliver in?
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Webster, I.; West, P. J. in Polymeric Biomaterials, 2nd ed.; Dumitriu, S., Ed.; Marcel Dekker: New York, 2002; pp 703-737
Menon, V. P.; Cotton, J. D.; Spawn, T. D "Process for making pressure sensitive adhesive hydrogels", US Patent Application No. 20060122298, June 8, 2006
Nussinovitch, A; Manor Ben-Zion, O. "Depolymerized Polysaccharide-Based Hydrogel Adhesive and Methods of Use Thereof", US Patent Application No. 20110190401, August 4, 2011
Figuly, G. D.; Arthur, S. D.; Burch, R. R.; Lu, H. S. M. "Method For Preparing A Hydrogel Adhesive Having Extended Gelation Time and Decreased Degradation Time", US Patent Application No. 20100112063, May 6, 201
Wagman, M. E. "Method of Dissolving An Oxidized Polysaccharide in an Aqueous Solution", US Patent Application No. 20120094955, April 19, 2012