Porous nanofibrous dressing enables mesenchymal stem cell spheroid formation and delivery to promote diabetic wound healing

Abstract

Delayed and nonhealing of diabetic wounds imposes substantial economic burdens and physical pain on patients. Mesenchymal stem cells (MSCs) promote diabetic wound healing. Particularly when MSCs aggregate into multicellular spheroids, their therapeutic effect is enhanced. However, traditional culture platforms are inadequate for the efficient preparation and delivery of MSC spheroids, resulting in inefficiencies and inconveniences in MSC spheroid therapy. In this study, a three-dimensional porous nanofibrous dressing (NFD) is prepared using a combination of electrospinning and homogeneous freeze-drying. Using thermal crosslinking, the NFD not only achieves satisfactory elasticity but also maintains notable cytocompatibility. Through the design of its structure and chemical composition, the NFD allows MSCs to spontaneously form MSC spheroids with controllable sizes, serving as MSC spheroid delivery systems for diabetic wound sites. Most importantly, MSC spheroids cultured on the NFD exhibit improved secretion of vascular endothelial growth factor, basic fibroblast growth factor, and hepatocyte growth factor, thereby accelerating diabetic wound healing. The NFD provides a competitive strategy for MSC spheroid formation and delivery to promote diabetic wound healing.

1. Introduction

In recent years, the prevalence of diabetes has increased annually, posing a global public health problem [1]. The worldwide prevalence of diabetes among individuals aged 20-79 years is predicted to be 12.2% in 2045 [2]. A wound that fails to heal for more than 90 days is considered a chronic wound [3]. Chronic wounds are common complications of diabetes that do not heal for long periods; therefore, they often carry the risk of amputation [4]. When chronic wounds appear on the feet of patients with diabetes mellitus, the risk of amputation is approximately 155 times higher than that in individuals without diabetes [5]. The traditional treatment strategies for diabetic wounds include topical dressings, pressure-relieving support, and antimicrobial treatment; however, the treatment effect is unsatisfactory and may cause secondary damage [6]. Therefore, there is an urgent need to develop advanced strategies for the effective treatment of diabetic wounds.

Owing to their multipotency and self-renewal capacity, mesenchymal stem cells (MSCs) replace damaged cells or tissues as well as accelerate wound healing by secreting a variety of growth factors [7]. MSCs can be dispersed or aggregated into multicellular spheroids to promote wound healing. Compared with dispersive MSCs, MSC spheroids have improved cell survival and overall function, providing new opportunities and broad prospects for diabetic wound healing [8,9]. Traditional MSC spheroid therapy requires two steps: MSC spheroid formation and delivery [10,11]. In this strategy, MSC spheroid formation depends on various culture platforms, such as spinner flasks, forced floats, and hanging drops [12,13]. Once MSC spheroids are formed, they must be transferred to the biomaterials that serve as carriers. However, this strategy is inefficient and is accompanied by the risk of losing spheroid function and activity. Therefore, the development of biomaterials capable of forming and delivering MSC spheroids is of considerable importance for MSC therapy.

The structure and chemical composition of biomaterials affect cell behavior [14,15]. When biomaterials possess a stereoscopic three-dimensional (3D) structure and exhibit lower cell adhesion than intercellular adhesion, dispersed cells tend to aggregate on the biomaterials to form multicellular spheroids [16,17]. Owing to its flexible structural design and chemical composition, electrospinning has attracted great attention in the field of biomaterials [18,19]. Additionally, electrospun nanofibers have many outstanding advantages, such as extracellular matrix-like structures, a large specific surface area, and high porosity, which support nutrient transport, cell survival, and cell communication [20]. Various nanofibers with 3D structures have been developed and used as biomaterials, providing new opportunities for stem cell therapy.