Achieving robust underwater adhesion by bioadhesives remains a challenge due to interfacial water. Herein a coacervate-to-hydrogel strategy to enhance interfacial water repulsion and bulk adhesion of bioadhesives is reported. The polyethyleneimine/thioctic acid (PEI/TA) coacervate is deposited onto underwater substrates, which can effectively repel interfacial water and completely spread into substrate surface irregularities due to its liquid and water-immiscible nature. The physical interactions between coacervate and substrate can further enhance interfacial adhesion. Furthermore, driven by the spontaneous hydrophobic aggregation of TA molecules and strong electrostatic interaction between PEI and TA, the coacervate can turn into a hydrogel in situ within minutes without additional stimuli to develop enhanced matrix cohesion and robust bulk adhesion on diverse underwater substrates. Molecular dynamics simulations further reveal atomistic details of the formation and wet adhesion of the PEI/TA coacervate via multimode physical interactions. Lastly, it is demonstrated that the PEI/TA coacervate-derived hydrogel can effectively repel blood and therefore efficiently deliver the carried growth factors at wound sites, thereby enhancing wound healing in an animal model. The advantages of the PEI/TA coacervate-derived hydrogel including body fluid-immiscibility, strong underwater adhesion, adaptability to fit irregular target sites, and excellent biocompatibility make it a promising bioadhesive for diverse biomedical applications.

Aims Treatment for delayed wound healing resulting from peripheral vascular diseases and diabetic foot ulcers remains a challenge. A novel surgical technique named ‘tibial cortex transverse transport’ (TTT) has been developed for treating peripheral ischaemia, with encouraging clinical effects. However, its underlying mechanisms remain unclear. In the present study, we explored the potential biological mechanisms of TTT surgery using various techniques in a rat TTT animal model. Methods A novel rat model of TTT was established with a designed external fixator, and effects on wound healing were investigated. Laser speckle perfusion imaging, vessel perfusion, histology, and immunohistochemistry were used to evaluate the wound healing processes. Results Gross and histological examinations showed that TTT technique accelerated wound closure and enhanced the quality of the newly formed skin tissues. In the TTT group, haematoxylin and eosin (H&E) staining demonstrated a better epidermis and dermis recovery, while immunohistochemical staining showed that TTT technique promoted local collagen deposition. The TTT technique also benefited to angiogenesis and immunomodulation. In the TTT group, blood flow in the wound area was higher than that of other groups according to laser speckle imaging with more blood vessels observed. Enhanced neovascularization was seen in the TTT group with double immune-labelling of CD31 and α-Smooth Muscle Actin (α-SMA). The number of M2 macrophages at the wound site in the TTT group was also increased. Conclusion The TTT technique accelerated wound healing through enhanced angiogenesis and immunomodulation. Cite this article: Bone Joint Res 2022;11(4):189–199.

Fracture remains one of the most common traumatic conditions in orthopedic surgery. The use of mesenchymal stem cells (MSCs) to augment fracture repair is promising. Leucine‐rich repeat‐containing GPCR 5 (Lgr5), a transmembrane protein, has been identified as a novel adult stem cell marker in various organs and tissues. However, the roles of Lgr5 in MSCs are not fully understood. In this study, we investigated cellular functions of Lgr5 in MSCs and its potential implications in treating fracture. Lgr5‐overexpressing MSCs (MSCLgr5) were established in murine SV40 promoter–driven luciferase reporter MSC line through virus transfection. Results of real‐time quantitative PCR and Western blot analysis confirmed the increased expression of Lgr5 in MSCLgr5. MSCLgr5 exhibited increased osteogenic capacity, which may result from elevated expression of β‐catenin and phosphorylated ERK1/2 within the nuclear region of cells. In contrast, inhibition of Lgr5 expression decreased the osteogenic differentiation ability of MSCs, accompanied with increased mitochondrial fragmentation and reduced expression of β‐catenin. Local transplantation of MSCLgr5 at fracture sites accelerated fracture healing via enhanced osteogenesis and angiogenesis. MSCLgr5 stimulated the tube formation capacity of HUVECs in a Matrigel coculture system in vitro significantly. Taken together, results suggest that Lgr5 is implicated in the cellular processes of osteogenic differentiation of MSCs through regulation of Wnt and ERK signaling pathways and mitochondrial dynamics in fusion and fission. Inhibition of Lgr5 expression induced increased mitochondrial fragmentation and suppression of osteogenesis. MSCLgr5 exhibited enhanced therapeutic efficacy for fracture healing, which may serve as a superior cell source for bone tissue repair.—Lin, W., Xu, L., Pan, Q., Lin, S., Feng, L., Wang, B., Chen, S., Li, Y., Wang, H., Li, Y., Wang, Y., Lee, W. Y. W., Sun, D., Li, G. Lgr5‐overexpressing mesenchymal stem cells augment fracture healing through regulation of Wnt/ERK signaling pathways and mitochondrial dynamics. FASEB J. 33, 8565–8577 (2019). http://www.fasebj.org

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Objective: The present study is to characterize the role of long intergenic non-coding RNA, regulator of reprogramming (linc-ROR) in bone marrow mesenchymal stem cell (BMSCs) chondrogenesis, cartilage formation and OA development. Methods: Linc-ROR expression pattern in articular cartilage tissue sample from OA patients were studied by real-time PCR. Linc-ROR lentivirus mediated BMSCs were constructed. In vitro micromass cultured BMSCs chondrogenesis or in vivo MeHA hydrogel encapsulated BMSCs cartilage formation activity were studied. Linc-ROR associating miRNAs which repressed SOX9 expression were characterized by luciferase assay, real-time PCR and Western blot. Linc-ROR was co-transfected with miRNAs into BMSCs to study its rescue effect on SOX9 expression and chondrogenesis activity. Results: Linc-ROR was down-regulated in articular cartilage tissue from OA patients and was positively correlated with the expression level of SOX9 (R 2 ¼ 0.43). Linc-ROR expression was upregulated during BMSCs chondrogenesis. Linc-ROR ectopic expression significantly promoted in vitro BMSCs chondrogenesis and in vivo cartilage formation activities as revealed by safranin O, alcian blue and COL II staining. The mRNA expression level of chondrogenesis markers including COL II, SOX9 and ACAN were increased, and the hypertrophy markers MMP13 and COL X were decreased upon linc-ROR overexpression in BMSCs. Linc-ROR functioned as a miRNA sponge for miR-138 and miR-145. Both miR-138 and miR-145 suppressed BMSCs chondrogenesis activity and SOX9 expression, while co-expression of linc-ROR displayed a rescuing effect. Conclusions: Taken together, linc-ROR modulated BMSCs chondrogenesis differentiation and cartilage formation by acting as a competing endogenous RNA for miR-138 and miR-145 and activating SOX9 expression. Linc-ROR could be considered as a new diagnostic and therapeutic target for OA treatment.

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Background: Meniscal tears in the avascular region are thought to rarely heal and are a considerable challenge to treat. Although the therapeutic effects of a pulsed electromagnetic field (PEMF) have been extensively studied in a variety of orthopaedic disorders, the effect of a PEMF on meniscal healing has not been reported. Hypothesis: PEMF treatment would promote meniscal healing and prevent osteoarthritis progression. Study Design: Controlled laboratory study. Methods: A total of 72 twelve-week-old male Sprague-Dawley rats with full-thickness longitudinal medial meniscal tears in the avascular region were divided into 3 groups: control (Gcon), treatment with a classic signal PEMF (Gclassic), and treatment with a high–slew rate signal PEMF (GHSR). Macroscopic observation and histological analysis of the meniscus and articular cartilage were performed to evaluate the meniscal healing and progression of osteoarthritis. The synovium was harvested for histological and immunofluorescent analysis to evaluate the intra-articular inflammation. Meniscal healing, articular cartilage degeneration, and synovitis were quantitatively evaluated according to their scoring systems. Results: Dramatic degenerative changes of the meniscus and articular cartilage were noticed during gross observation and histological evaluation in Gcon at 8 weeks. However, the menisci in the 2 treatment groups were restored to normal morphology, with a smooth surface and shiny white color. Particularly, the HSR signal remarkably enhanced the fibrochondrogenesis and accelerated the remodeling process of the regenerated tissue. The meniscal healing scores of the PEMF treatment groups were significantly higher than those in Gcon at 8 weeks. Specifically, the HSR signal showed a significantly higher meniscal repair score than did the classic signal at week 8 ( P < .01). Additionally, the HSR signal significantly downregulated the secretion levels of interleukin 1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α) in the meniscus and synovium as compared with the control group. When compared with the 2 treatment groups, Gcon had significantly higher degeneration scores (Gcon vs Gclassic, P < .0001; Gcon vs GHSR, P < .0001). The HSR signal also exhibited significantly lower synovitis scores compared with the other two groups (Gcon vs Gclassic, P < .0001; Gclassic vs GHSR, P = .0002). Conclusion: A PEMF promoted the healing of meniscal tears in the avascular region and restored the injured meniscus to its structural integrity in a rat model. As compared with the classic signal, the HSR signal showed increased capability to promote fibrocartilaginous tissue formation and modulate the inflammatory environment, therefore protecting the knee joint from posttraumatic osteoarthritis development. Clinical Relevance: Adjuvant PEMF therapy may offer a new approach for the treatment of meniscal tears attributed to the enhanced meniscal repair and ameliorated osteoarthritis progression.

Background: Ischemic stroke is a leading cause of death and disability worldwide. However, the time window for quickly dissolving clots and restoring cerebral blood flow, using tissue plasminogen activator treatment is rather limited, resulting in many patients experiencing long-term functional impairments if not death. This study aims to determine the roles of cranial bone transport (CBT), a novel, effective, and simple surgical technique, in the recovery of ischemic stroke using middle cerebral artery occlusion (MCAO) rat model. Methods: CBT was performed by slowly sliding a bone segment in skull with a special frame and a speed of 0.25 mm/12 hours for 10 days following MCAO. Morris water maze, rotarod test, and catwalk gait analysis were used to study the neurological behaviors, and infarct area and cerebral flow were evaluated during CBT process. Immunofluorescence staining of CD31 and Nestin/Sox2 (sex determining region Y box 2) was performed to study the angiogenesis and neurogenesis. OVA-A647 (ovalbumin-Alexa Fluor 647) was intracisterna magna injected to evaluate the meningeal lymphatic drainage function. Results: CBT treatment has significantly reduced the ischemic lesions areas and improved the neurological deficits in MCAO rats compared with the rats in the control groups. CBT treatment significantly promoted angiogenesis and neurogenesis in the brain of MCAO rats. The drainage function of meningeal lymphatic vessels in MCAO rats was significantly impaired compared with normal rats. Ablation of meningeal lymphatic drainage led to increased neuroinflammation and aggravated neurological deficits and ischemic injury in MCAO rats. CBT treatment significantly improved the meningeal lymphatic drainage function and alleviated T-cell infiltration in MCAO rats. Conclusions: This study provided evidence for the possible mechanisms on how CBT attenuates ischemic stroke injury and facilitates rapid neuronal function recovery, suggesting that CBT may be an alternative treatment strategy for managing ischemic stroke.