MiR-21 regulating PVT1/PTEN/IL-17 axis towards the treatment of infectious diabetic wound healing by modified GO-derived biomaterial in mouse models.

BACKGROUND: Diabetic foot ulcer (DFU), persistent hyperglycemia and inflammation, together with impaired nutrient and oxygen deficiency, can present abnormal angiogenesis following tissue injury such that these tissues fail to heal properly. It is critical to design a new treatment method for DFU patients with a distinct biomechanism that is more effective than current treatment regimens. METHOD: Graphene oxide (GO) was combined with a biocompatible polymer as a kind of modified GO-based hydrogel. The characterization of our biomaterial was measured in vitro. The repair efficiency of the biomaterial was evaluated in the mouse full-skin defect models. The key axis related to diabetic wound (DW) was identified and investigated using bioinformatics analyses and practical experiments. RESULT: In the study, we found that our modified GO-based wound dressing material is a promising option for diabetic wound. Secondly, our biomaterial could enhance the secretion of small EVs (sEVs) with more miR-21 by adipose-derived mesenchymal stem cells (AD-MSCs). Thirdly, the PVT1/PTEN/IL-17 axis was found to be decreased to promote DFU wound healing by modifying miR-21 with the discovery of PVT1 as a critical LncRNA by bioinformatics analysis and tests. CONCLUSION: These findings could aid in the development of clinical care strategies for DFU wounds.

Platelet-Rich Plasma-Loaded Poly(d,l-lactide)-Poly(ethylene glycol)-Poly(d,l-lactide) Hydrogel Dressing Promotes Full-Thickness Skin Wound Healing in a Rodent Model.

Traditional therapeutic methods for skin wounds have many disadvantages, and new wound dressings that can facilitate the healing process are thus urgently needed. Platelet-rich plasma (PRP) contains multiple growth factors (GFs) and shows a significant capacity to heal soft tissue wounds. However, these GFs have a short half-life and deactivate rapidly; we therefore need a sustained delivery system to overcome this shortcoming. In this study, poly(d,l-lactide)-poly(ethylene glycol)-poly(d,l-lactide) (PDLLA-PEG-PDLLA: PLEL) hydrogel was successfully created as delivery vehicle for PRP GFs and was evaluated systematically. PLEL hydrogel was injectable at room temperature and exhibited a smart thermosensitive in situ gel-formation behavior at body temperature. In vitro cell culture showed PRP-loaded PLEL hydrogel (PRP/PLEL) had little cytotoxicity, and promoted EaHy926 proliferation, migration and tube formation; the factor release assay additionally indicated that PLEL realized the controlled release of PRP GFs for as long as 14 days. When employed to treat rodents' full-thickness skin defects, PRP/PLEL showed a significantly better ability to raise the number of both newly formed and mature blood vessels compared to the control, PLEL and PRP groups. Furthermore, the PRP/PLEL-treated group displayed faster wound closure, better reepithelialization and collagen formation. Taken together, PRP/PLEL provides a promising strategy for promoting angiogenesis and skin wound healing, which extends the potential of this dressing for clinical application.

Thermosensitive Hydrogel Incorporating Prussian Blue Nanoparticles Promotes Diabetic Wound Healing via ROS Scavenging and Mitochondrial Function Restoration.

Diabetic foot ulcer is a serious complication in diabetes patients, imposing a serious physical and economic burden to patients and to the healthcare system as a whole. Oxidative stress is thought to be a key driver of the pathogenesis of such ulcers. However, no antioxidant drugs have received clinical approval to date, underscoring the need for the further development of such medications. Hydrogels can be applied directly to the wound site, wherein they function to prevent infection and maintain local moisture concentrations, in addition to serving as a reservoir for the delivery of a range of therapeutic compounds with the potential to expedite wound healing in a synergistic manner. Herein, we synthesized Prussian blue nanoparticles (PBNPs) capable of efficiently scavenging reactive oxygen species (ROS) owing to their ability to mimic the activity of catalase (CAT), peroxidase (POD), and superoxide dismutase (SOD). In the context of in vitro oxidative stress, these PBNPs were able to protect against cytotoxicity, protect mitochondria from oxidative stress-related damage, and restore nuclear factor erythroid 2-related factor 2 (NRF2)/heme oxygenase-1 (HO-1) pathway activity. To expand on these results in an in vivo context, we prepared a thermosensitive poly (d,l-lactide)-poly(ethylene glycol)-poly(d,l-lactide) (PDLLA-PEG-PDLLA) hydrogel (PLEL)-based wound dressing in which PBNPs had been homogenously incorporated, and we then used this dressing as a platform for controlled PBNP release. The resultant PBNPs@PLEL wound dressing was able to improve diabetic wound healing, decrease ROS production, promote angiogenesis, and reduce pro-inflammatory interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels within diabetic wounds. Overall, our results suggest that this PBNPs@PLEL platform holds great promise as a treatment for diabetic foot ulcers.

Small extracellular vesicles in combination with sleep-related circRNA3503: A targeted therapeutic agent with injectable thermosensitive hydrogel to prevent osteoarthritis.

Osteoarthritis (OA), characterized by chondrocyte apoptosis and disturbance of the balance between catabolism and anabolism of the extracellular matrix (ECM), is the most common age-related degenerative joint disease worldwide. As sleep has been found to be beneficial for cartilage repair, and circular RNAs (circRNAs) have been demonstrated to be involved in the pathogenesis of OA, we performed RNA sequencing (RNA-seq), and found circRNA3503 was significantly increased after melatonin (MT)-induced cell sleep. Upregulation of circRNA3503 expression completely rescued the effects of interleukin-1ß (IL-1ß), which was used to simulate OA, on apoptosis, ECM degradation- and synthesis-related genes. Mechanistically, circRNA3503 acted as a sponge of hsa-miR-181c-3p and hsa-let-7b-3p. Moreover, as we previously showed that small extracellular vesicles (sEVs) derived from synovium mesenchymal stem cells (SMSCs) can not only successfully deliver nucleic acids to chondrocytes, but also effectively promote chondrocyte proliferation and migration, we assessed the feasibility of sEVs in combination with sleep-related circRNA3503 as an OA therapy. We successfully produced and isolated circRNA3503-loaded sEVs (circRNA3503-OE-sEVs) from SMSCs. Then, poly(D,l-lactide)-b-poly(ethylene glycol)-b-poly(D,l-lactide) (PDLLA-PEG-PDLLA, PLEL) triblock copolymer gels were used as carriers of sEVs. Through in vivo and in vitro experiments, PLEL@circRNA3503-OE-sEVs were shown to be a highly-effective therapeutic strategy to prevent OA progression. Through multiple pathways, circRNA3503-OE-sEVs alleviated inflammation-induced apoptosis and the imbalance between ECM synthesis and ECM degradation by acting as a sponge of hsa-miR-181c-3p and hsa-let-7b-3p. In addition, circRNA3503-OE-sEVs promoted chondrocyte renewal to alleviate the progressive loss of chondrocytes. Our results highlight the potential of PLEL@circRNA3503-OE-sEVs for preventing OA progression.

Well-dispersed platelet lysate entrapped nanoparticles incorporate with injectable PDLLA-PEG-PDLLA triblock for preferable cartilage engineering application.

Platelet lysate (PL) as a cost-effective cocktail of growth factors is an emerging ingredient in regenerative medicine, especially in cartilage tissue engineering. However, most studies fail to pay attention to PL's intrinsic characteristics and incorporate it directly with scaffolds or hydrogels by simple mixture. Currently, the particle size distribution of PL was determined to be scattered. Directly introducing PL into a thermosensitive poly(d,l-lactide)-poly(ethylene glycol)-poly(d,l-lactide) (PLEL) hydrogel disturbed its sol-gel transition. Electrostatic self-assembly heparin (Hep) and ε-poly-l-lysine (EPL) nanoparticles (NPs) were fabricated to improve the dispersity of PL. Such PL-NPs-incorporated PLEL gels retained the initial gelling capacity and showed a long-term PL-releasing ability. Moreover, the PL-loaded composite hydrogels inhibited the inflammatory response and dedifferentiation of IL-1ß-induced chondrocytes. For in vivo applications, the PLEL@PL-NPs system ameliorated the early cartilage degeneration and promoted cartilage repair in the late stage of osteoarthritis. RNA sequencing analysis indicated that PL's protective effects might be associated with modulating hyaluronan synthase 1 (HAS-1) expression. Taken together, these results suggest that well-dispersed PL by Hep/EPL NPs is a preferable approach for its incorporation into hydrogels and the constructed PLEL@PL-NPs system is a promising cell-free and stepwise treatment option for cartilage tissue engineering.

Sunitinib microspheres based on [PDLLA-PEG-PDLLA]-b-PLLA multi-block copolymers for ocular drug delivery.

Sunitinib is a multi-targeted receptor tyrosine kinase (RTK) inhibitor that blocks several angiogenesis related pathways. The aim of this study was to develop sunitinib-loaded polymeric microspheres that can be used as intravitreal formulation for the treatment of ocular diseases. A series of novel multi-block copolymers composed of amorphous blocks of poly-(D,L-lactide) (PDLLA) and polyethylene glycol (PEG) and of semi-crystalline poly-(L-lactide) (PLLA) blocks were synthesized. Sunitinib-loaded microspheres were prepared by a single emulsion method using dichloromethane as volatile solvent and DMSO as co-solvent. SEM images showed that the prepared microspheres (∼ 30 µm) were spherical with a non-porous surface. Sunitinib-loaded microspheres were studied for their degradation and in-vitro release behavior. It was found that increasing the percentage of amorphous soft blocks from 10% to 30% accelerated the degradation of the multi-block copolymers. Sunitinib microspheres released their cargo for a period of at least 210 days by a combination of diffusion and polymer erosion. The initial burst (release in 24h) and release rate could be tailored by controlling the PEG-content of the multi-block copolymers. Sunitinib-loaded microspheres suppressed angiogenesis in a chicken chorioallantoic membrane (CAM) assay. These microspheres therefore hold promise for long-term suppression of ocular neovascularization.