Bioinspired Mild Photothermal Effect-Reinforced Multifunctional Fiber Scaffolds Promote Bone Regeneration.

Bone fractures are often companied with poor bone healing and high rates of infection. Early recruitment of mesenchymal stem cells (MSCs) is critical for initiating efficient bone repair, and mild thermal stimulation can accelerate the recovery of chronic diseases. Here, a bioinspired, staged photothermal effect-reinforced multifunctional scaffold was fabricated for bone repair. Uniaxially aligned electrospun polycaprolactone nanofibers were doped with black phosphorus nanosheets (BP NSs) to endow the scaffold with excellent near-infrared (NIR) responsive capability. Apt19S was then decorated on the surface of the scaffold to selectively recruit MSCs toward the injured site. Afterward, microparticles of phase change materials loaded with antibacterial drugs were also deposited on the surface of the scaffold, which could undergo a solid-to-liquid phase transition above 39 °C, triggering the release of payload to eliminate bacteria and prevent infection. Under NIR irradiation, photothermal-mediated up-regulation of heat shock proteins and accelerated biodegradation of BP NSs could promote the osteogenic differentiation of MSCs and biomineralization. Overall, this strategy shows the ability of bacteria elimination, MSCs recruitment, and bone regeneration promotion with the assistance of photothermal effect in vitro and in vivo, which emphasizes the design of a bioinspired scaffold and its potential for a mild photothermal effect in bone tissue engineering.

Role and mechanism of circular RNA circ_0050486 in regulating oxidized low-density lipoprotein-induced injury in endothelial cells.

BACKGROUND: Dysfunction of endothelial cells in the arterial vasculature is an essential contributor to the pathogenesis of atherosclerosis. Circular RNAs (circRNAs) exert important regulatory functions in endothelial cell dysfunction. Here, we explored the precise role and mechanism of circ_0050486 in regulating endothelial cell injury induced by oxidized low-density lipoprotein (ox-LDL). METHODS: Circ_0050486, microRNA (miR)-182-5p and myeloid differentiation primary response gene 88 (MyD88) were quantified by quantitative real-time PCR or western blot. Cell viability, proliferation and apoptosis were examined by MTS, 5-Ethynyl-2'-Deoxyuridine (EdU), and flow cytometry assays, respectively. Direct relationship between miR-182-5p and circ_0050486 or MYD88 was verified by dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. RESULTS: Circ_0050486 was upregulated in atherosclerosis serum and ox-LDL-treated human aortic endothelial cells (HAECs). Silencing of circ_0050486 suppressed HAEC injury induced by ox-LDL. Mechanistically, circ_0050486 targeted miR-182-5p, and the effects of circ_0050486 silencing were partially due to the upregulation of miR-182-5p. MYD88 was a direct target of miR-182-5p, and miR-182-5p-mediated inhibition of MYD88 attenuated ox-LDL-evoked HAEC injury. Circ_0050486 bound to miR-182-5p to regulate MYD88 expression. Additionally, the NF-κB signaling pathway was involved in the regulation of circ_0050486/miR-182-5p/MYD88 axis in ox-LDL-treated HAECs. CONCLUSION: Our study identifies the functional role of circ_0050486 in ox-LDL-induced endogenous cell injury and establishes a mechanism of circ_0050486 function by affecting MYD88 through competitively binding to shared miR-182-5p.

Hydrogel-based delivery of antimiR-221 enhances cartilage regeneration by endogenous cells.

Articular cartilage is frequently injured by trauma or osteoarthritis, with limited and inadequate treatment options. We investigated a new strategy based on hydrogel-mediated delivery of a locked nucleic acid microRNA inhibitor targeting miR-221 (antimiR-221) to guide in situ cartilage repair by endogenous cells. First, we showed that transfection of antimiR-221 into human bone marrow-derived mesenchymal stromal cells (hMSCs) blocked miR-221 expression and enhanced chondrogenesis in vitro. Next, we loaded a fibrin/hyaluronan (FB/HA) hydrogel with antimiR-221 in combination or not with lipofectamine carrier. FB/HA strongly retained functional antimiR-221 over 14 days of in vitro culture, and provided a supportive environment for cell transfection, as validated by flow cytometry and qRT-PCR analysis. Seeding of hMSCs on the surface of antimiR-221 loaded FB/HA led to invasion of the hydrogel and miR-221 knockdown in situ within 7 days. Overall, the use of lipofectamine enhanced the potency of the system, with increased antimiR-221 retention and miR-221 silencing in infiltrating cells. Finally, FB/HA hydrogels were used to fill defects in osteochondral biopsies that were implanted subcutaneously in mice. FB/HA loaded with antimiR-221/lipofectamine significantly enhanced cartilage repair by endogenous cells, demonstrating the feasibility of our approach and the need to achieve highly effective in situ transfection. Our study provides new evidence on the treatment of focal cartilage injuries using controlled biomaterial-mediated delivery of antimicroRNA for in situ guided regeneration.

Effect of age on biomaterial-mediated in situ bone tissue regeneration.

Emerging studies show the potential application of synthetic biomaterials that are intrinsically osteoconductive and osteoinductive as bone grafts to treat critical bone defects. Here, the biomaterial not only assists recruitment of endogenous cells, but also supports cellular activities relevant to bone tissue formation and function. While such biomaterial-mediated in situ tissue engineering is highly attractive, success of such an approach relies largely on the regenerative potential of the recruited cells, which is anticipated to vary with age. In this study, we investigated the effect of the age of the host on mineralized biomaterial-mediated bone tissue repair using critical-sized cranial defects as a model system. Mice of varying ages, 1-month-old (juvenile), 2-month-old (young-adult), 6-month-old (middle-aged), and 14-month-old (elderly), were used as recipients. Our results show that the bio-mineralized scaffolds support bone tissue formation by recruiting endogenous cells for all groups albeit with differences in an age-related manner. Analyses of bone tissue formation after 2 and 8 weeks post-treatment show low mineral deposition and reduced number of osteocalcin and tartrate-resistant acid phosphatase (TRAP)-expressing cells in elderly mice. STATEMENT OF SIGNIFICANCE: Tissue engineering strategies that promote tissue repair through recruitment of endogenous cells will have a significant impact in regenerative medicine. Previous studies from our group have shown that biomineralized materials containing calcium phosphate minerals can contribute to neo-bone tissue through recruitment and activation of endogenous cells. In this study, we investigated the effect of age of the recipient on biomaterial-mediated bone tissue repair. Our results show that the age of the recipient mouse had a significant impact on the quality and quantity of the engineered neo-bone tissues, in which delayed/compromised bone tissue formation was observed in older mice. These findings are in agreement with the clinical observations that age of patients is a key factor in bone repair.

Biomaterials for Enhancing CNS Repair.

The health of the central nervous system (CNS) does not only rely on the state of the neural cells but also on how various extracellular components organize cellular behaviors into proper tissue functions. Biomaterials have been valuable in restoring or augmenting the roles of extracellular components in the CNS in the event of injury and disease. In this review, we highlight how biomaterials have been enabling tools in important therapeutic strategies involving cell transplantation and drug/protein delivery. We further discuss advances in biomaterial design and applications that can potentially be translated into the CNS to provide unprecedented benefits.