Development of Mechanoresponsive Drug-Releasing, High Pressure Resisting Balloon Catheter via Nanostructure Control of Silk Fibroin

Cardiovascular disease is one of the most highest mortality diseases worldwide and is incurring enormous social costs. Drug-eluting balloon catheters(DEBs) are used in intervention procedures by destroying atherosclerotic plaque in blood vessels through angioplasty, inserting stents to maintain vascular expansion, and eluting drugs that prevent restenosis from damaged blood vessels. DEBs can effectively treat cardiovascular diseases, but still has some problems. The two main problems are rupture at high pressure and unwanted drug release during the insertion process. To overcome these problems, we aim to create a balloon catheter using a polymer with high toughness and mechanoresponsive drug release properties.<br/>In this study, we selected silk fibroin, which allows easy control of nanostructures and it’s morphology. Silk fibroin also possesses high biocompatibility, making it suitable for various medical applications such as sutures and bone regeneration, which makes it an ideal material for balloon catheters. The beta sheet structure is the most important factor contributing to the strong mechanical properties of silk fibroin, providing crystallinity to the silk. Beta sheet crystals not only strengthen the silk fibroin networks but also generate small molecule traps by inhibiting molecular mobility. When deformation occurs in silk fibroin with trapped small molecules, the pore size of the amorphous strands increases, allowing the trapped molecules to be released as free molecules. By controlling this crystallinity, we aim to endow silk fibroin with strong mechanical properties and mechanoresponsive drug release characteristics.<br/>To this end, we synthesized a hydrogen bond-inducing molecular template to interact with silk fibroin. Silk fibroin beta sheet crystals have numerous hydrogen bonding sites, which stack with each other and strengthen the silk fibroin network. In the denatured state of silk fibroin, the Gibbs free energy required to form beta sheet structures is too high, remaining a structure dominated by amorphous strands. With the hydrogen bonding template, silk fibroins are induced from chaotic amorphous structures to arranged structures, which leads to lower Gibbs-free energy required for the assembly to beta sheets, inducing rapid, enormous beta sheet formation. We synthesized poly(tetrahydrofuran) (PTHF) dimer with quaternary ammonium, which we call Template, which has abundant hydrogen bonding sites to induce silk fibroin self-assembly and antibacterial properties to prevent bacterial invasion during intervention. The Template diffused into the denatured silk fibroin and controlled the nanostructure during self-assembly. Via nanostructure control of silk fibroin with Template, we trapped deoxycholic acid, the plaque digesting drug molecule, into the silk fibroin crystalline network. When this silk fibroin balloon catheter expands, the pore size increases, the drug is released from the trap, and it is released through pressure, allowing the mechanoresponsive drug releases.<br/>Additionally, due to the hydrogen bonding attraction between silk fibroin and the Template, silk fibroin strands gather closely and become entangled with neighboring strands. When physical force is applied, these entangled strands undergo reptation, causing friction with each other in the entangled area and dissipating the applied force. Through this viscoelastic behavior, the silk fibroin balloon catheter can effectively resist deformation and rupture from inflation pressure.<br/>In summary, our study controlled the nanostructure of silk fibroin to enable mechanoresponsive drug release through beta sheet crystallinity, strengthen the network, and fabricate balloon catheter raw materials that resist high pressure through polymer strand entanglement. The development of the silk fibroin balloon catheter addresses the limitations of commercial DEBs, offering a promising strategy for more effective cardiovascular disease treatment.