Electrospinning Machine| A sandwich-like nanofibrous scaffold with macrophage phenotype transformation and myogenic differentiation for skeletal muscle regeneration

Trauma, infection, and tumor resection can cause muscle damage, even leading to loss of limb function, directly impacting patients' health and quality of life. Like other soft tissues, minor muscle injuries can typically self-repair. However, volumetric muscle loss (VML), where muscle mass loss exceeds 20%, cannot regenerate due to rapid fibrosis and scar tissue formation.

Recently, a collaborative study by Dr. Shue Jin, Prof. Zongke Zhou from West China Hospital, Sichuan University, and Researcher Jidong Li from Sichuan University was published in Bioactive Materials under the title "A sandwich-like nanofibrous scaffold with macrophage phenotype transformation and myogenic differentiation for skeletal muscle regeneration."

To address limitations in current muscle stem cell-based therapies (e.g., limited autologous cells and immune rejection of allogeneic cells), the team designed a triple-layer "sandwich-like" fibrous scaffold loaded with hyaluronic acid (HA). HA effectively activates quiescent muscle stem cells to initiate repair and stimulates pro-regenerative macrophage polarization, achieving immune reprogramming and ultimately enhancing skeletal muscle regeneration. This scaffold system, ingeniously coupling natural and synthetic polymers via structure and composition, enables a factor-free, cell-free muscle regeneration strategy. In vitro experiments and VML animal models validated its potential in promoting myogenesis, macrophage phenotype switching, and functional recovery.

Fig. 1. Schematic of HA-loaded sandwich scaffold fabrication and muscle repair.

This study proposes a cell-free and factor-free muscle injury treatment strategy utilizing only synthetic and natural polymers. The approach promotes skeletal muscle regeneration through two key mechanisms: mimicking muscle heterogeneous structure and activating macrophage phenotype transformation.

Fig. 2. Characterization of sandwich PGH scaffold.

The effects of aligned polycaprolactone (PCL) fibers on fibroblast morphology and C2C12 myogenic differentiation were investigated.The aligned layers guide cytoskeletal and nuclear remodeling to promote myocyte alignment, differentiation, and subsequent myotube formation.

Fig. 3. Aligned/random PCL fibers reshape cytoskeleton and nuclear deformation to regulate myogenesis.

Fig. 4. Mechanical properties of PGH scaffold.

Meanwhile, the study systematically investigated how gelatin incorporation influences the physicochemical properties of the fibrous scaffold, with particular emphasis on optimizing the gelatin-to-PCL ratio.

Fig. 5. Scaffold-mediated macrophage phenotype switching in vitro/in vivo.

Importantly, the hyaluronic acid (HA) encapsulated in the core-shell fibers plays a pivotal role in biological activation:

Fig. 6. TA VML model evaluating scaffold’s role in muscle regeneration.

Fig. 7. TA functional recovery at 4 weeks (gait analysis and grip strength).

The scaffold’s macrophage-modulating ability was assessed in vitro and in vivo. Finally, its regenerative potential was evaluated in a tibialis anterior (TA) VML model, with preliminary functional recovery assessed via gait analysis and grip strength at 4 weeks post-operation.

Original link: https://www.sciencedirect.com/science/article/pii/S2452199X2500194X