多重刺激響應性黑色二氧化鈦奈米複合物水凝膠於增強抗菌治療

Abstract

本研究提出黑色二氧化鈦（bTiO2）奈米複合物水凝膠，並將其應用於生醫領域。TiO2奈米粒子做為光聲敏劑，在超音波和光刺激下能夠生成活性氧物種（ROS）。然而，TiO2的能隙較窄，限制了其在近紅外光（NIR）下活化，且電子-電洞對的快速癒合也會降低ROS的生成效率。第一部分的研究，我們通過水熱法合成的bTiO2，展現了獨特的氧空缺特性，可顯著降低電子電洞對的癒合速率，進而增加ROS的生成，並且還顯示出卓越的光熱性能。在NIR照射下，bTiO2能有效地將光能轉換為熱能，導致局部溫度升高，進而對細菌產生破壞性影響。我們將bTiO2奈米粒子引入由葡聚醣醛（PDA）和葡聚醣肼（PDH）交聯形成的高分子水凝膠網絡中，並進一步將bTiO2進行表面氨基修飾（bTiO2@MS-NH2），透過亞胺鍵交聯強化奈米粒子與水凝膠間的界面。該修飾不僅顯著改善bTiO2的分散穩定性，亦提升水凝膠的機械強度，其壓縮模數達約 83 kPa，儲能模數約為 4500 Pa。經過綜合研究，含bTiO2的PDA/PDH奈米複合物水凝膠在超音波及近紅外光照射下，透過聲動力治療（SDT）、光動力治療（PDT）與光熱治療（PTT）三重機制作用，展現高達 99%以上的抗菌效率。第二部分的研究，我們進一步通過將bTiO2表面修飾為含有硫化銅（CuS）的CuS/bTiO2奈米粒子（CuSBT），有效促進電子從bTiO2的導帶轉移至CuS的導帶，進而抑制電子電洞對的癒合，提高了ROS的生成效率。為了增加水凝膠的ROS響應性能，我們將PDA與胱胺（Cystamine）通過亞胺鍵交聯，製備具備雙硫鍵的水凝膠。在此系統中，CuS/bTiO2同樣功能化為CuS/bTiO2＠MS-NH2（CuSBTN）奈米粒子，增強了奈米粒子與水凝膠之間的鍵結。當受到超音波刺激時，CuSBTN生成的ROS會攻擊水凝膠中的雙硫鍵，導致其斷裂並釋放出裝載的活性物質。綜合以上，這些bTiO2奈米複合物水凝膠系統具有外部刺激響應性，能提高ROS生成效率，並實現超音波誘導的控制釋放，為抗菌治療、藥物傳遞及生醫應用提供了更多潛力。

Titanium dioxide (TiO2)-based nanocomposite hydrogels are developed in this study for advanced biomedical applications. TiO2 nanoparticles act as sono-/photosensitizers capable of generating reactive oxygen species (ROS) under ultrasound and light stimulation. However, their narrow bandgap restricts activation to ultraviolet (UV) light, and the rapid recombination of electron-hole pairs reduces ROS generation efficiency. To overcome these limitations, we synthesize black TiO2 (bTiO2) through a hydrothermal method, which exhibits oxygen vacancies that significantly reduce electron-hole recombination and enhance ROS generation. In addition, bTiO2 demonstrates excellent photothermal conversion under near-infrared (NIR) irradiation, producing localized heating with antibacterial effects. To improve interfacial integration, bTiO2 nanoparticles are further functionalized with amino groups, enabling the formation of imine crosslinks with the polymer. This modification enhances nanoparticle dispersion and increases the compressive modulus of the hydrogel to ~83 kPa, with a storage modulus of ~4500 Pa, thereby strengthening the mechanical properties of the hydrogel network. A comparative analysis is conducted among bTiO₂-based hydrogels, white TiO₂-based hydrogels, and only polymeric network hydrogels to evaluate structural and functional performance differences. The bTiO2-based polydextran aldehyde (PDA)/polydextran hydrazine (PDH) nanocomposite hydrogels exhibit superior ROS generation and photothermal behavior under ultrasound and NIR light, resulting in over 99% antibacterial efficacy through the combined effects of sonodynamic therapy (SDT), photodynamic therapy (PDT), and photothermal therapy (PTT). In the second project, we further enhance ROS generation by modifying bTiO2 with copper sulfide (CuS), forming CuS/bTiO2 (CuSBT) nanoparticles. This configuration promotes electron transfer from bTiO2 to CuS, further minimizing electron-hole recombination. A disulfide bond-containing hydrogel is prepared through imine crosslinking between PDA and cystamine (Cys) to improve hydrogel responsiveness and controlled release. Upon ultrasound stimulation, ROS generated by CuS/bTiO2＠MS-NH2 (CuSBTN) cleave disulfide bonds within the hydrogel network, triggering the release of the encapsulated bioactive agent. Overall, these bTiO2-based nanocomposite hydrogel systems demonstrate excellent responsiveness to external stimuli, enhanced ROS generation, and ultrasound-triggered controlled release, offering significant potential for antibacterial therapy, drug delivery, and various biomedical applications.