Novel dopa-functionalized bioadhesives for internal medical applications
Date of Issue2018-11-13
School of Chemical and Biomedical Engineering
Bioadhesives, such as tissue adhesives, hemostatic agents, and tissue sealants, have gained increasing popularity in different areas of clinical operations. Currently, bioadhesives have been widely applied in diverse clinical medications, including chronic organ leak repair, bleeding complications reduction, as well as wound closure and epidermal grafting. Following the revolutionary advancements of medical technologies in the last three decades, diverse bioadhesive formulations have been developed based on different design principles and conjugation systems, some of which have even been proceeded into commercial products and can be easily obtained by anyone recently. Since bioadhesives may directly contact with the receivers’ intracorporeal tissue and organs, their safety has been considered the most important factor besides adhesive strength during the design and development processes. However, at the initial stage of bioadhesives’ development decades ago, a lot has been emphasized on the functionalities of the products, which were exactly the adhesives’ bonding strengths to adherent surfaces. Synthetic bioadhesives were largely developed with chemical-derived materials and organic solvents. Despite its excellent adhesive capability, they usually bring potential toxicities, irritations, or inflammatory effects to the patients’ internal health. Based on this concern, safe, biocompatible bioadhesive formulations based on human body-friendly backbone materials and gluing mechanisms are desired by both patients and clinical operators for better treatment outcomes and simpler operations. In the first instance, a double-crosslinking gluing mechanism was put forward for the first time by utilizing of two crosslinkers, namely rapid crosslinker and long term crosslinker. One study was based on this gluing system: double crosslinked tissue adhesive (DCTA). The gelatin-based tissue adhesive was adequately evaluated in vitro the gluing properties, the adhesive capabilities, and the cytocompatibility to be used in intracorporal environment. After this, the optimal dosage of the three components of DCTA was further finalized and evaluated for its potential as a practical tissue adhesive on a rat mastectomy model. The in vivo biocompatibility of DCTA after application was also tested in tissue level and in genetic level. However, although the DCTA was proved to have good mechanical properties and cytocompatibility, a low level of inflammatory reaction was detected during the in vivo biocompatibility assessment. The inflammatory reaction was considered come from the utilization of the long-term crosslinker, namely genipin. It is known that genipin would result in low-level acute toxicity although it would not cause severe harm to organisms. In the second instance, a new gluing mechanism was designed with the inspiration came from the anchor process of marine mussels in the marine environment. After introduction of catechol groups, the functionalized gluing macromer would be firstly stabilized by a fast crosslinker, namely Fe3+, followed by changing the gluing environment pH to alkalinity using a small amount of NaOH. During the gluing process, the bonding types were proved to vary spontaneously from non-covalent chelation to covalent intermolecular couplings, from weak to strong. Two studies were based on this gluing system: bovine serum albumin-based bioadhesive, and chondroitin sulfate-based bioadhesive. In the former study, an essential protein existed in blood, namely bovine serum albumin, was taken as the backbone material and developed into catechol functionalized bioadhesive. The properties of the newly developed formulation were subsequently tested both in vitro and in vivo, and its promising potential to be used as a multi-purpose bioadhesive for internal medical conditions were assessed with rat mastectomy and rat hemorrhaging liver models. Using the same gluing system in another study, a new formulation was developed from a polysaccharide, namely chondroitin sulfate. Both formulations were based on bio-derived materials, which were proved to have excellent biocompatibility and strong adhesive strength. In summary, the studies in this thesis adequately studied the nature phenomenon of the self-anchorage of marine mussels, and subtly transferred the principle from natural world to medical devices. The protein-based bioadhesive formulation was considered a promising internal bioadhesive for multiple medications. After further optimization and clinical trials, it will become a prospective medical adhesive to be used in practical clinical conditions in the future.