Date of Award
Doctor of Philosophy (PhD)
Karen J. L. Burg, Ph.D., Committee Co-Chair
Joel Corbett, Ph.D., Committee Co-Chair
Frank Alexis, Ph.D.
Ken Webb, Ph.D.
Jeremy Mercuri, Ph.D.
Over 100 million surgical incisions, 50 million traumatic wounds, and 20 million minor lacerations from cuts and grazes are treated globally each year. One study determined that globally internal and external wounds occur for 40% and 37% of cases respectively for a total of 111 million patients that were treated for wounds. The remaining 23% of patients were treated for minor lacerations and trauma in the emergency room. These wounds require immediate medical attention including pressure application, sutures, clips, tissue cautery, and/or topical hemostatic agents to cease hemorrhage or the exit of other bodily fluids. With blood flow ceased, wound approximation or sealant is used temporarily to close the wound until fresh tissue is formed.
There are several different approaches to close a wound with each lacking in one or more properties to achieve ideal wound healing. Tissue welding and cauterization are two methods employed; however, these methods result in the formation of necrotic tissue, which is undesirable. Sutures are the wound approximation gold standard due to their flexibility and ability to resist tensile forces, but they can result in complications such as bleeding from the holes created during the suturing application required to place them. Staples and tapes are common wound approximation devices, but unlike sutures, they lack the ability to resist large tensile forces. In addition to these mechanical closure devices, fibrin and thrombin based sealants have been employed to approximate or seal tissues. These biological sealants are very biocompatibility, but they also have a low mechanical strength especially as compared to the mechanical closure devices. This low strength has resulted in re-bleeding when this type of sealant was applied externally and also in cases when it was applied internally. In comparison, BioGlue®, a non-biological sealant has a high mechanical strength, but is limited by its poor biocompatibility. Alternatively, there have been advancements based on gecko and mussel adhesions (bioadhesion) in order to fabricate synthetic materials that mimic these naturally occurring dry and wet adhesives respectively. Studies have demonstrated that these materials have a great potential, but they still require additional research in order to render them clinically relevant for wound approximation.
Cyanoacrylate adhesives is another family of wound approximation and sealant devices. As a general overview, these materials are able to penetrate into tissue due to their liquid monomer form, rapidly polymerize due to their highly electrophilic nature, and then form bonds due to the interpenetrating networks formed. They have been fabricated in many varieties by differing the side chain for the adhesive monomer during its synthesis, blending additives into the adhesive, or mixing insoluble materials into the adhesive. A myriad of studies have demonstrated that these variations can control the properties of the adhesive in its monomer and polymer forms. Several of these properties include viscosity, mechanical strength and flexibility, polymerization rate and reaction temperature, degradation rate, and biocompatibility.
By controlling the side chain type and materials added to it, researchers are able to tailor cyanoacrylates for specific external and internal medical and industrial uses. These adhesives are well known for their typically successful external medical uses and industrial uses; however, their internal medical use has been slow to reach global use due to the heat released during the adhesives polymerization, and the cytotoxic formaldehyde byproduct released as the polymerized adhesive degrades. In order to overcome this issue, researchers commonly synthesize cyanoacrylates for internal use by attaching long alkane side chains (e.g. 2-octyl) to them. The resulting cyanoacrylate releases a lower amount of heat during its polymerization and minimal formaldehyde as it degrades; however, several studies have demonstrated that this degradation take years, if it degrades at all, which can result in a prolonged, chronic wound healing. Nevertheless, this material has excellent clinical usefulness when the specific cyanoacrylate types are used for their specific intended uses. There is therefore great potential to modulate the adhesive to improve its clinical usefulness.
The completed research presented in this dissertation focused on using this information to formulate cyanoacrylates with potentially improved clinical usefulness. The cyanoacrylates were improved through the addition of novel chemically active polyesters (rheological modifiers). Methoxypropyl cyanoacrylate was selected for this research due to its inclusion of a short alkoxy side chain resulting in a flexible, high strength bond as well as the adhesive’s proven biocompatibility. Poly(glycolide-cocaprolactone) polymers (PGCL) were synthesized as the polyesters for this research due to the fast degrading, low pH producing ability of glycolide and slow degrading, increased flexibility of ε-caprolactone. The combination of both fast and slow degrading monomers allows one specifically to control the polyester’s degradation rate and thus resulting pH level for the eluent. Based on these properties, it was hypothesized that mixing PGCL as an amorphous polymer into cyanoacrylate, polymerizing the cyanoacrylate, and then allowing the polycyanoacrylate to degrade in water or a phosphate buffered saline will allow the adhesive modifier contained within the polycyanoacrylate to also hydrolyze and self-modulate the pH of the surrounding environment to an acidic level. When a polycyanoacrylate degrades in an acidic instead of basic solution, then the formaldehyde levels released should be minimized, and the alcohol and cyanoacrylic acid released should be less toxic; thus, rendering the polycyanoacrylate potentially safer for internal use.
Garcia, Kyle Joseph, "Chemically Active Rheological Modifiers for the Improved Clinical Use of Cyanoacrylates" (2018). All Dissertations. 2707.