Multifunctional microfluidic-directed polymer/hydrogel fabrics towards pH-responsive drug delivery, wound monitoring and wearable sensing

Skin acts as the largest organ of human body that undertakes several crucial tasks, such as safeguarding the inner body system, resistance to foreign harm, body thermoregulation and metabolism [1,2]. Once damaged by physical trauma, surgery, diabetes, or burns, the resulting chronic wound disrupts the functions of the skin, further imposing a serious burden on both patients and worldwide healthcare system [3]. According to researches, wound healing is a dynamic and complex biological process, which is frequently impeded by severe oxidative stress, persistent bacterial infection and excessive inflammation in the absence of an epithelial barrier [4]. The timely monitoring of changes caused by wound infections in wound microenvironment, such as pH [5], temperature [6], or blood glucose [7,8], may provide valuable insights for healthcare. Among these, wound pH has been recognized as a reliable indicator that is closely associated with the physiological and biochemical changes during wound healing process [9]. Generally, a weakly acidic pH value is presented in the healed and intact skin, while chronic wounds with serious bacterial infection and inflammation have an alkaline pH ranging from 7 to 9. Even worse, the alkaline environment facilitates the bacterial growth and proliferation, thereby aggravating wound infection and delaying wound healing [10]. Thus, the real-time pH monitoring of wound area aids in identifying the degree of wound healing and enables to timely adjust the therapeutic schedule. To date, a variety of pH-responsive biosensors have been developed as fast diagnostic tools by estimating wound pH values according to diverse protocols, such as fluorometric [11], colorimetric [12] and electrochemical [13] detection. Compared with other methods, visual colorimetric detection of pH change appears its superiority due to its no need of complex detection devices. The simple addition of pH-sensitive dyes may effectively confer colorimetric pH-responsive property to hydrogel dressings. Curcumin, a natural phenolic compound dye derived from the rhizomes of plants belonging to the ginger family, exhibits a distinct color change from yellow to red as the environment transitions from acidic to alkaline conditions. [14]. However, most reported researches have focused on the construction of curcumin-containing dressings through direct blending, where the inevitable release of curcumin may compromise the long-term stability and safety of the pH-responsive biosensors [15,16]. Therefore, it is essential to encapsulate and immobilize curcumin within hydrogel matrix while preserving its pH-responsive characteristic. Furthermore, the development of an effective chronic wound management platform that integrates real-time monitoring and on-site treatment of wound infections remains a major clinical challenge.

The ideal wound dressings should incorporate various functions including antibacterial and sterilization, reactive oxygen species (ROS) scavenging and microenvironment-regulated drug release [17,18]. Bacterial infection is commonly considered as a critical issue referring to posing certain impediments for wound healing [19]. Multiple‌ pathogenic bacteria proliferate at the wound site and subsequently generate toxins, which adversely impacts cell viability and triggers a local or even systemic inflammatory response. Another crucial factor associated with delayed wound repair is the elevated and sustained ROS resulted from aerobic metabolism and immune cells activation [20]. Excessive ROS can directly or indirectly induce oxidative stress, cause oxidative damage to cellular components and degrade extracellular matrix proteins, eventually leading to a robust inflammatory response in chronic non-healing wounds [21]. A prevalent approach to addressing infections involves the incorporation of antibiotics into wound dressings. Nevertheless, their prolonged use may raise the risk of drug resistance and systemic toxicity in public health. Epigallocatechin gallate (EGCG), a natural polyphenolic compound extracted from green tea, possesses diverse biological activities including antioxidation, antibacterial and anti-inflammation properties [22]. Notably, this typical natural antibacterial agent has been confirmed great promise in enhancing the broad-spectrum antimicrobial effectiveness against drug-resistant bacteria [23]. For examples, Tan et al. fabricated a pH-responsive EGCG-loaded wound dressing by electrospinning. This dressing demonstrated effective antioxidant, antibacterial and anti-biofilm performances for promoting wound healing [24]. Cao et al. reported the design of the natural gelatin-based hydrogel loaded with epigallocatechin gallate-grafted polylysine (EPL-EGCG) and resveratrol. This adhesion, antibacterial and antioxidant hydrogel exhibited outstanding hemostatic, anti-inflammatory and wound healing effects [25]. However, most of these EGCG-loaded platforms are non-intelligent, which lacks the ability of real-time supervising the constantly changed microenvironment during wound repair period, and meanwhile dynamically regulating antibacterial and antioxidative abilities as feedback.

Hydrogels have garnered considerable attention in intelligent dressings application owing to their tissue-like three-dimensional structure, structural self-adaptability, stimuli-responsive capability and biocompatibility [26,27]. However, the insufficient mechanical strength and unidimensional function render them unable to satisfy the actual requirements of the complex and dynamic microenvironment in wounds. Hydrogel-based composite systems with customizable microstructure and enhanced performances have emerged as a promising candidate, but difficult to be fabricated by traditional methods [28,29]. Microfluidic spinning technology (MST) offers a facile, efficient and controllable pathway for the construction of micro-nano fiber-based hydrogel composite materials featuring both manageable complex structure (such as core-shell, hollow, Janus, heterogenous and knotted structures) and multifunction integration [[30], [31], [32]]. Further assembling the fibers into fabrics may provide a viable means of realizing the production of intelligent hydrogel composite-based dressings [33]. Nevertheless, the transformation of 1D fibers to 2D fabrics mainly relies on the time-consuming and operationally intricate physical weaving process [34,35], which imposes restrictions on its practical use.

In this work, a straightforward strategy was developed to manufacture well-aligned hydrogel composite fabrics through the nonweaving assembly of self-healing core-shell polymer/hydrogel microfibers (Fig. 1). The microfibers were continuously produced by integrating microfluidic spinning with shear-flow-induced coating technology, followed by UV-triggered free radical polymerization. The core phase of polycaprolactone (PCL) functioned as frameworks to enhance the mechanical strength of fabrics. The shell phase of hydrogel provided functionalities appertaining to self-healing, self-adhesion, flexibility, swellability and pH responsiveness. Additionally, EGCG was incorporated into the core PCL phase. The fabricated fabrics performed long-term and pH-controllable drug release properties, implementing intelligence and effectiveness in ROS cleaning and antibacterial activity against Gram-positive Staphylococcus aureus (S. aureus) and Gram-negative Escherichia coli (E. coli). Simultaneously, the pH-responsive curcumin-loaded mesoporous microparticles were introduced into the hydrogel shell, thereby imparting the fabrics with the function of visually monitoring pH level in real-time. Moreover, the fabrics could serve as flexible wearable sensors for accurately detecting motions of patients. Overall, the exploitation of an integrated diagnostic and therapeutic hydrogel composite fabric presents an ingenious method for timely tracking and suppressing infection in wounds, which provides a basis for personalized, intelligent and precise wound theranostic tools.

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