Design and Formulation of Stimuli Responsive Surgical Materials

Abstract

Every year around the world approximately 14 million people undergo abdominal surgery. These operations while lifesaving for a multitude of diseases ranging from cancer to weight loss inducing gastric bypass, carry great intrinsic risks. These latter are associated with the leaking of digestive fluids through sutured or stapled reconnections which can vastly prolong recovery but also cause premature death. As such, anastomotic leakage is one of the most dreaded complications following abdominal surgery with reported incidence rates reaching values of up to 21% and an associated mortality of up to 27%. To deal with the prospects of leaks, surgeons and medical practitioners rely on a vast array of oftentimes insensitive, non-conclusive criteria to determine or infer the leaking of sutured reconnections. Such criteria can range from tachycardia, hyperthermia, oliguria to mental status of patients and more. In addition to these latter, the installation of semi-permanent drains within patients or the diversion of tissue to the exterior surface of the abdomen are commonplace. Furthermore, while great advancements in the fields of surgical adhesives have been observed during the last decades, currently employed surgical gold standards only poorly address the issue, especially since most commonly used fibrin glues fail due to insufficient adhesion and chemical instability. Τowards addressing these issues the following thesis proposes and demonstrates the development of novel abdominal cavity adhesives, that remain attached to target tissues even in the face of serious leaks. In addition, the materials presented are developed to allow the rapid and unambiguous assessment of the breaching of sutured reconnections, using readily available ultrasound sonography and as such for the first time present a suture support patch that can assist a surgeon in the management of a patient and their complications. Hence, the present work is introduced by a first chapter detailing the state of the art of surgical adhesives in addition to introducing the two key design principles followed in this project. Namely the design of sealant materials that can weather the digestive fluids of the abdominal cavity and the post-application leverage of surgical materials as diagnostic tools by surgeons. In chapter 2, a chemically highly resistive, leak-tight and mucoadhesive hydrogel sealant, is presented, that makes use of a novel mutually interpenetrating network that traverses hydrogel and tissue to remain grafted on tissue. The material prepared does not degrade and exhibits strong tissue adhesion even when exposed to enzymatically active intestinal fluid. The biocompatible hydrogel patch effectively seals anastomotic leaks in ex vivo intestinal models, greatly surpassing commercial sealants (time to patch-failure >24 hours compared to 5 minutes for commonly used Tachosil). As such, the developed adhesive patch paves the way for the application of both mechanically and chemically robust sealants suitable for the treatment and prevention of intestinal leaks. Stepping on the anchoring technology of the mutually interpenetrating network presented in chapter 2, the design of a layered sealant that not only seals but also allows for the unambiguous detection of leaks is demonstrated in chapter 3. The smart patch developed, in addition to strong tissue adhesion and sealing (under the most demanding of conditions), provides unique triggerable leak-detection capabilities based on non-invasive point-of-need ultrasound imaging. As such, this second-generation surgical sealant paves the way for suture support materials that not only seal but also offer disambiguation in cases of surgical leaks as well as straightforward, point-of-need, monitoring of patients after gastrointestinal surgery. In chapter 4 and with the successful incorporation of triggerably acoustic sensing elements into hydrogel adhesives the possibility of extending the applications of acrylic polymer systems for the management of gastrointestinal complications is explored. To that end the surface engineering of magnetic nanoflower nanoparticles prepared via surface initiated atom transfer radical polymerization (ATRP) of acrylate polymers is undertaken. The achievement of this latter gave rise to materials with unprecedented medically relevant multi-toxin removing capabilities, which given their potential were studied for their ion-exchanging and blood purification properties in anticipation for future incorporation and validation in the sealant patches either as toxin sinks and/or responsive imaging modalities. Taken together, the herein described work presents the development and design of adhesives that despite their contact with digestive fluids remain attached to various target tissues of the abdominal cavity and as a result can safeguard against leaks. The incorporation of triggerable echogenic elements capable of specifically detecting leaks of various digestive fluids in record times post suture breach paves the way for next generation sealants that not only seal but also unambiguously diagnose the source of complications.