Hydrogels with tunable mechanical plasticity regulate endothelial cell outgrowth in vasculogenesis and angiogenesis.

The endothelial cell (EC) outgrowth in both vasculogenesis and angiogenesis starts with remodeling surrounding matrix and proceeds with the crosstalk between cells for the multicellular vasculature formation. The mechanical plasticity of matrix, defined as the ability to permanently deform by external traction, is pivotal in modulating cell behaviors. Nevertheless, the implications of matrix plasticity on cell-to-cell interactions during EC outgrowth, along with the molecular pathways involved, remain elusive. Here we develop a collagen-hyaluronic acid based hydrogel platform with tunable plasticity by using compositing strategy of dynamic and covalent networks. We show that although the increasing plasticity of the hydrogel facilitates the matrix remodeling by ECs, the largest tubular lumens and the longest invading distance unexpectedly appear in hydrogels with medium plasticity instead of the highest ones. We unravel that the high plasticity of the hydrogels promotes stable integrin cluster of ECs and recruitment of focal adhesion kinase with an overenhanced contractility which downregulates the vascular endothelial cadherin expression and destabilizes the adherens junctions between individual ECs. Our results, further validated with mathematical simulations and in vivo angiogenic tests, demonstrate that a balance of matrix plasticity facilitates both cell-matrix binding and cell-to-cell adherens, for promoting vascular assembly and invasion.

Novel Bioinspired Nerve Scaffold with High Synchrony between Biodegradation and Nerve Regeneration for Repair of Peripheral Nerve Injury.

The morphological structure reconstruction and functional recovery of long-distance peripheral nerve injury (PNI) are global medical challenges. Biodegradable nerve scaffolds that provide mechanical support for the growth and extension of neurites are a desired way to repair long-distance PNI. However, the synchrony of scaffold degradation and nerve regeneration is still challenging. Here, a novel bioinspired multichannel nerve guide conduit (MNGC) with topographical cues based on silk fibroin and ε-polylysine modification was constructed. This conduit (SF(A) + PLL MNGC) exhibited sufficient mechanical strength, excellent degradability, and favorable promotion of cell growth. Peripheral nerve repairing was evaluated by an in vivo 10 mm rat sciatic model. In vivo evidence demonstrated that SF(A) + PLL MNGC was completely biodegraded in the body within 4 weeks after providing sufficient physical support and guide for neurite extension, and a 10 mm sciatic nerve defect was effectively repaired without scar formation, indicating a high synchronous effect of scaffold biodegradation and nerve regeneration. More importantly, the regenerated nerve of the SF(A) + PLL MNGC group showed comparable morphological reconstruction and functional recovery to that of autologous nerve transplantation. This work proved that the designed SF(A) + PLL MNGC has potential for application in long-distance PNI repair in the clinic.

Electrospun Piezoelectric Scaffold with External Mechanical Stimulation for Promoting Regeneration of Peripheral Nerve Injury.

Safe and efficient provision of electrical stimulation (ES) for nerve repair and regeneration is a problem that needs to be addressed. In this study, a silk fibroin/poly(vinylidene fluoride-co-hexafluoropropylene)/Ti3C2Tx (SF/PVDF-HFP/MXene) composite scaffold with piezoelectricity was developed by electrospinning technology. MXene was loaded to the scaffold to enhance the piezoelectric properties (Output voltage reaches up to 100 mV), mechanical properties, and antibacterial activity. Cell experiments demonstrated piezoelectric stimulation under external ultrasonication for promoting the growth and proliferation of Schwann cells (SCs) cultured on this electrospun scaffold. Further in vivo study with rat sciatic nerve injury model revealed that the SF/PVDF-HFP/MXene nerve conduit could induce the proliferation of SCs, enhance the elongation of axon, and promote axonal myelination. Under the piezoelectric effect of this nerve scaffold, the rats with regenerative nerve exhibited a favorable recovery effect of motor and sensory function, indicating a safe and feasible method of using this SF/PVDF-HFP/MXene piezoelectric scaffold for ES provision in vivo.

ε-Poly-l-lysine-modified natural silk fiber membrane wound dressings with improved antimicrobial properties.

Many complex diseases, such as bacterial infections, frequently accompany cutaneous wound healing, adding to the difficulty of clinical wound management. Consequently, in addition to displaying strong biocompatibility and actively promoting wound healing, an optimal wound dressing should also possess antimicrobial qualities to address issues with bacterial infection. This paper developed natural silk fiber (SF) membranes (also known as a flat silk cocoon (FSC)) with antimicrobial properties as a dressing for skin wounds. By changing the spinning tools and environment of silkworm larvae, a novel natural SF membrane with a cocoon structure and controllable size was prepared. The functional SF membranes were obtained via a hot press process and grafted with ε-Poly-l-lysine (EPL). The results showed that the SF membrane dressing was adjustable in size with a similar structure to the extracellular matrix (ECM), displaying inherent mechanical properties, excellent antimicrobial qualities, and biocompatibility. In vivo experiments using a full-thickness skin defect model indicated that EPL-modified SF membranes significantly promoted the rate of wound healing, exhibiting thicker granulation tissue and higher collagen disposition than commercial dressings (Tegaderm™ film). Therefore, the excellent mechanical qualities and cytocompatibility of the antimicrobial EPL-modified SF membranes substantially promote their potential application as a chronic wound dressing.

Preparation and characterization of silk fibroin/polyethylene oxide nanofiber membranes with antibacterial activity.

Bacterial infection is among the most common diseases that threaten human health. Antibiotics are effective in treating bacterial infections. However, the overuse of antibiotics will lead to an increase in bacterial resistance. To reduce the overuse of antibiotics and improve the effective use of antibiotics through slow release, silk fibroin (SF)/polyethylene oxide (PEO) nanofiber membranes with different SF and PEO proportions were prepared by electrospinning. The ecofriendly solvent ethanol solution was used for electrospinning for better protection of antibiotic activity. The SEM showed that the surface of SF/PEO (2:8) and SF/PEO (3:7) was smoother and more uniform. With the increase of SF content, the thermal stability and hydrophilicity of SF/PEO nanofiber membranes were improved. The SF/PEO (3:7) nanofiber membrane had the best mechanical property and its maximum stress and strain were 4.6 1 ± 0.24 MPa and 16.36 ± 0.41%, respectively. Based on these good properties, SF/PEO (3:7) nanofiber membrane was chosen for loading and releasing gentamicin sulfate (GS). The fabricated (GS)/SF/PEO (3:7) nanofiber membrane exhibited good release efficiency and showed the good antibacterial activity against Staphylococcus aureus and Escherichia coli. These investigations indicated the GS/SF/PEO (3:7) nanofiber membrane (GS/SF/PEO) has a great potential for application in antibacterial materials.