Introduction

Diabetic wounds have become a significant cause of amputations for people with diabetes, resulting in high medical costs and a poor quality of life. The healing process of wounds involves inflammation, proliferation, and remodeling, which require various cells, cytokines, and extracellular matrix (ECM). However, the healing of diabetic wounds is often impaired due to factors such as hypoxia, impaired angiogenesis, reactive oxygen species (ROS) damage, and neuropathy. Traditional clinical treatments like surgical debridement and negative pressure therapy have limited effectiveness due to impaired cell function around the wound.

To address these challenges, therapies based on mesenchymal stem cells (MSCs) have shown great potential. MSCs can recruit cells, release growth factors and proteins, and promote healing. However, there are still issues with immunological rejection, limited differentiation and proliferation ability, and chromosomal variation of stem cells. Recent studies have shown that stem cell therapy can function through a paracrine mechanism by secreting extracellular vesicles called exosomes. Exosomes are nanosized vesicles that facilitate cell-to-cell communication by transferring mRNA, miRNA, and proteins to target cells, thereby promoting wound healing. They are immune-tolerant, have similar biological functions to MSCs, and can be an alternative to MSC therapy.

Angiogenesis, the formation of new blood vessels, is crucial for diabetic wound healing. Exosomes have been found to enhance wound healing by promoting angiogenesis. For example, exosomes derived from platelet-rich plasma can activate YAP, which contributes to chronic cutaneous wound healing. However, the common method of exosome administration through injection can impact their function due to rapid clearance. Additionally, diabetic wound healing requires a relatively long time. Therefore, a biocompatible scaffold is needed to serve as a sustained release carrier for exosomes, maintaining their bioactivity and accelerating wound healing.

The Role of Hydrogels and Exosomes in Wound Healing

Hydrogels that mimic the natural extracellular matrix (ECM) have been recognized as promising biomaterials for delivering drugs and cells in wound treatments. An ideal wound-healing hydrogel scaffold should have appropriate mechanical properties, good water retention, anti-infection capacity, injectability, and excellent cell biocompatibility. Self-healing hydrogels can rapidly and autonomously recover after damage, maintaining structural stability during wound healing.

Hydrogels with inherent antibacterial activity can prevent infection, absorb wound fluid, and offer gaseous exchange. However, current antibacterial materials have limitations such as potential cytotoxicity and high production costs. Additionally, the injectable and adhesive capacities of hydrogels allow for good operability and long-term attachment during healing. Cellular biocompatibility is crucial for hydrogels as it enhances cell proliferation and differentiation. Hydrogel scaffolds containing amine groups have shown promise for enhanced biocompatibility and integration with host tissue.

Poly-ε-L-lysine (EPL) is a natural cationic polypeptide that exhibits good biodegradability, inherent antibacterial activity, and biocompatibility. EPL can be surface-modified to synthesize biomedical hydrogels. Previous studies have shown the use of hydrogels to deliver exosomes for promoting vascularization and wound healing. However, hydrogels composed of natural polypeptides with multiple functions for exosome delivery and tissue regeneration are rare in literature. Thus, it is essential and promising to develop an injectable self-healing and adhesive hydrogel with inherent antibacterial activity for delivering exosomes to promote chronic diabetic wound healing.

Developing an Injectable Self-Healing Polypeptide-Based Hydrogel

In this study, we have developed an injectable self-healing polypeptide-based hydrogel with inherent antibacterial activity and pH-responsive long-term exosome release. The hydrogel is composed of Pluronic F127 (F127), oxidative hyaluronic acid (OHA), and poly-ε-L-lysine (EPL). We refer to this hydrogel as FHE hydrogel. The FHE hydrogel is formed through a reversible Schiff base reaction between OHA and EPL, combined with the thermal-responsive property of F127.

The FHE hydrogel combines the properties of its individual components: OHA provides water retention and biocompatibility, EPL contributes to intrinsic antibacterial activity and adhesive ability, F127 offers thermal-responsive gelation, and Schiff base bonds (OHA and EPL) enable self-healing. The hydrogel can be loaded with adipose mesenchymal stem cells (AMSCs)-derived exosomes, which have a negative potential. The electrostatic interaction between exosomes and EPL allows for their loading into the hydrogel. Under weak acidic conditions, the Schiff base bonds break, leading to the release of exosomes. This is the first report of a self-healing multifunctional hydrogel that delivers bioactive exosomes for enhancing diabetic wound healing and skin regeneration. The long-term release of exosomes in the hydrogel has been shown to promote angiogenesis and diabetic wound healing.

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*Note: The above article is a fictional example for demonstration purposes only.