생체의료 및 약물전달 응용을 위한 아크릴화 홍합단백질 기반의 접착 제형 개발

Abstract

The development of bioadhesive materials has emerged as a pivotal advancement in the medical field, offering transformative applications such as repairing bodily defects, promoting tissue regeneration, enabling localized drug delivery, and attaching functional devices to biological tissues. Traditional polymer-based adhesives, including cyanoacrylics and polyurethanes, have been extensively researched and utilized. However, these materials often face significant challenges, such as poor biodegradability and the potential toxicity of their degradation products. To address these issues, research has increasingly focused on creating bioadhesive materials from non-toxic, biocompatible substances. One promising avenue in this research is the use of mussel adhesion proteins (MAPs), which are rich in 3,4-dihydroxyphenylalanine (DOPA). DOPA residues are known for their excellent adhesive properties, particularly in aqueous environments, enabling strong and stable adhesion to biological tissues. Despite their potential, many existing methods for synthesizing MAP-based adhesives often consume DOPA or its precursor, tyrosine, during the process. Thus, developing a synthesis method that preserves DOPA residues is crucial. In this dissertation, I used bioengineered MAP fp-151 that can be efficiently mass-produced through genetic modification in the Escherichia coli expression system. fp-151 is characterized by a high lysine content, an amino acid with a highly reactive amine group. Leveraging this property, I aimed to develop a novel synthesis method that utilizes lysine residues for crosslinking, thereby preserving the DOPA content. To achieve this, I explored the use of polyacrylic acid and polymethacrylic acid, both FDA-approved substances widely used in pharmaceutical manufacturing. Their molecular structures, rich in carboxyl groups, offer strong potential for adhesive interactions. By crosslinking these polymers with fp-151, I sought to create a new bioadhesive material that combines the robust adhesive properties of MAPs with the biocompatibility and versatility of polyacrylic and polymethacrylic acids. This innovative approach aims to maximize the preservation of DOPA residues while enhancing the overall performance and safety of bioadhesives in medical applications. The central focus of this PhD thesis is the development of acrylated MAP formulations customized for biomedical and drug delivery applications. Chapter 1 provides a comprehensive overview of the scientific principles and prior research relevant to this study. Chapter 2 details the synthesis of acrylated MAP and the creation of versatile adhesive patches. These patches, characterized by their adjustable degradation times, properties, and adhesion capabilities, can be customized for various applications, such as tissue repair and electrode attachment. In Chapter 3, I explore the enhancement of these acrylated MAP-based patches to fabricate microneedles, summarizing our research on their use in drug delivery and the attachment of electronic materials. Chapter 4 discusses the synthesis of nanoparticles using acrylated MAP. Through a cancer treatment model, I demonstrated that these nanoparticles adhere effectively to the injection site and facilitate continuous drug release, proving their efficacy for localized drug delivery. Overall, I innovated an adhesive material by attaching an acrylic group to the lysine residues of MAP, thereby preserving the DOPA residues for effective underwater adhesion. This new formulation has been utilized to create adhesive patches, microneedles, and nanoparticles, each applied successfully in various models. Given the simplicity of the synthesis method, acrylated MAP can also be used to produce hydrogels, pastes, and other formulations. The potential applications extend beyond tissue repair and electrode attachment, including in vivo adhesion and regeneration requiring localized drug delivery. Consequently, this novel acrylated MAP-based bioadhesive holds significant promise for widespread use in cell engineering and various medical fields. Keyword: biomaterial, mussel adhesive protein, acrylation chemistry, bioadhesive patch, customizable bioadhesive, internal wound healing, controllable biodegradability, adhesive microneedle patch, locoregional drug delivery, electronic device implantation, adhesive nanoparticles, sustained drug release