Chitosan@Puerarin hydrogel for accelerated wound healing in diabetic subjects by miR-29ab1 mediated inflammatory axis suppression.

Wound healing is one of the major global health concerns in patients with diabetes. Overactivation of pro-inflammatory M1 macrophages is associated with delayed wound healing in diabetes. miR-29ab1 plays a critical role in diabetes-related macrophage inflammation. Hence, inhibition of inflammation and regulation of miR-29 expression have been implicated as new points for skin wound healing. In this study, the traditional Chinese medicine, puerarin, was introduced to construct an injectable and self-healing chitosan@puerarin (C@P) hydrogel. The C@P hydrogel promoted diabetic wound healing and accelerated angiogenesis, which were related to the inhibition of the miR-29 mediated inflammation response. Compared to healthy subjects, miR-29a and miR-29b1 were ectopically increased in the skin wound of the diabetic model, accompanied by upregulated M1-polarization, and elevated levels of IL-1ß and TNF-α. Further evaluations by miR-29ab1 knockout mice exhibited superior wound healing and attenuated inflammation. The present results suggested that miR-29ab1 is essential for diabetic wound healing by regulating the inflammatory response. Suppression of miR-29ab1 by the C@P hydrogel has the potential for improving medical approaches for wound repair.

miR-29cb2 promotes angiogenesis and osteogenesis by inhibiting HIF-3α in bone.

Coordination between osteogenesis and angiogenesis is required for bone homeostasis. Here, we show that miR-29cb2 is a bone-specific miRNA and plays critical roles on angiogenesis-osteogenesis coupling during bone remodeling. Mice with deletion of miR-29cb2 exhibit osteopenic phenotypes and osteoblast impairment, accompanied by pronounced decreases in specific H vessels. The decrease in bone miR-29cb2 was associated with pathological ovariectomy stimuli. Mechanistically, hypoxia-inducible factor (HIF)-3α, as a target for miR-29cb2, inhibits HIF-1α activity by competitively bonding with HIF-1ß. Notably, miR-29cb2 in peripheral blood (PB) nearly is undetectable in sham and significantly increases in ovariectomy mice. Further evaluation from osteoporosis patients demonstrates similar signatures. ROC analysis shows miR-29cb2 in PB has higher sensitivity and specificity for diagnosing osteoporosis when compared with four clinical biomarkers. Collectively, these findings reveal that miR-29cb2 is essential for bone remodeling by inhibiting HIF-3α and elevated bone-specific miR-29cb2 in PB, which may be a promising biomarker for bone loss.

Strontium ranelate incorporated 3D porous sulfonated PEEK simulating MC3T3-E1 cell differentiation.

Polyetheretherketone (PEEK) has been used as an implant material because it has similar mechanical properties to natural bone. However, inferior osseointegration and bioinertness hamper the clinical application of PEEK. In this study, the surfaces of sulfonated three-dimensional (3D) PEEK porous structures were loaded with different concentrations of strontium ranelate, a compound commonly used in the treatment or prevention of osteoporosis by promoting bone formation and inhibiting bone resorption. Field-emission scanning electron microscopy was used to characterize the topography of the structures, elemental carbon, oxygen and strontium contents were measured by X-ray photoelectron spectroscopy, and surface zeta potentials and water-contact angle were also measured. The results indicated that strontium ranelate was successfully loaded onto the 3D porous structures. In vitro cellular results showed that strontium ranelate-treated sulfonated PEEK (SP-SR) strengthened the adhesion of MC3T3-E1 cells. The activity of alkaline phosphatase, collagen secretion and extracellular matrix mineralization deposition of MC3T3-E1 cells were also improved on the surface of SP-SR. These results indicate that SP-SR could serve a new implant candidate for surgical treatment.

Pravastatin regulates host foreign-body reaction to polyetheretherketone implants via miR-29ab1-mediated SLIT3 upregulation.

Host rejection to biomaterials can induce uncontrolled foreign-body reactions (FBR), resulting in a dense fibrous encapsulation that blocks mass transport and/or communication between the host and the implant. Adequate angiogenesis between the body and the implant has been implicated as a key regulator for overcoming FBR. Thus, approaches for stimulating neovascularization and/or suppressing FBR are under investigation. In this study, pravastatin (Pra) was loaded onto a 3D network surface of sulfonated polyetheretherketone (SP) to achieve superior local drug effects. The SP loaded with Pra (SP-Pra) promoted angiogenesis and mitigated FBR via miR-29 dependent SLIT3 upregulation in wild-type (WT) mice. miR-29a and miR-29b1 were significantly downregulated in the SP-Pra capsule compared to levels in the SP capsule, while SLIT3 and neovascularization were substantially upregulated in WT mice. However, the above effects presented in the WT mice were not detected in miR-29ab1 knockout mice which was generated by the CRISPR/Cas9 approach. Overall, the results suggest that miR-29 plays a critical role in reducing FBR to these implants by targeting SLIT3. Suppression of FBR by SP-Pra implants offers the potential to improve the performance of current medical devices.