Establishing a rabbit model with massive supraspinatus tendon defect for investigating scaffold-assisted tendon repair.

BACKGROUND: Shoulder pain and disability from rotator cuff tears remain challenging clinical problem despite advancements in surgical techniques and materials. To advance our understanding of injury progression and develop effective therapeutics using tissue engineering and regenerative medicine approaches, it is crucial to develop and utilize animal models that closely resemble the anatomy and display the pathophysiology of the human rotator cuff. Among various animal models, the rabbit shoulder defect model is particularly favored due to its similarity to human rotator cuff pathology. However, a standardized protocol for creating a massive rotator cuff defect in the rabbits is not well defined. Therefore, the objective of our study was to establish a robust and reproducible model of a rotator cuff defect to evaluate the regenerative efficacy of scaffolds. RESULTS: In our study, we successfully developed a rabbit model with a massive supraspinatus tendon defect that closely resembles the common rotator cuff injuries observed in humans. This defect involved a complete transection of the tendon, spanning 10 mm in length and encompassing its full thickness and width. To ensure stable scaffolding, we employed an innovative bridging suture technique that utilized a modified Mason-Allen suture as a structural support. Moreover, to assess the therapeutic effectiveness of the model, we utilized different scaffolds, including a bovine tendon extracellular matrix (ECM) scaffold and a commercial acellular dermal matrix (ADM) scaffold. Throughout the observation period, no scaffold damage was observed. Notably, comprehensive histological analysis demonstrated that the regenerative tissue in the tendon ECM scaffold group exhibited an organized and aligned fiber structure, indicating tendon-like tissue regeneration while the tissue in the ADM group showed comparatively less organization. CONCLUSIONS: This study presents a comprehensive description of the implemented procedures for the development of a highly reproducible animal model that induces massive segmental defects in rotator cuff tendons. This protocol can be universally implemented with alternative scaffolds to investigate extensive tendon defects and evaluate the efficacy of regenerative treatments. The application of our animal model offers a standardized and reproducible platform, enabling researchers to systematically evaluate, compare, and optimize scaffold designs. This approach holds significant importance in advancing the development of tissue engineering strategies for effectively repairing extensive tendon defects.

The application of platelet-rich plasma in the treatment of knee osteoarthritis: A literature review.

BACKGROUND: Primary knee osteoarthritis remains a difficult-to-control degenerative disease. With the rise in average life expectancy and the incidence of obesity, osteoarthritis has brought an increasing economic and physical burden on people. This article summarizes the latest understanding of platelet-rich plasma in the treatment of knee osteoarthritis, and reviews the economic issues of PRP. METHODS: The literatures in Pubmed, Embase, Cochrane library, Web-science and other databases were searched, and literature inclusion and exclusion criteria were formulated. According to the Cochrane systematic reviewer's manual, the included literatures were grouped, and qualitative descriptions and quantitative meta-analysis were performed. Continuous statistical methods were used to compare the effects and adverse effects of PRP before and after treatment, as well as between PRP and other conservative treatments. RESULTS: A total of 12 randomized controlled trials were included in this study. A total of 959 KOA patients (1070 knees) were enrolled and followed for 3-12 months. PRP total knee scores were significantly better than baseline at 1, 2, 3, 6 and 12 months after treatment (1 month: SMD = 0.60, P < 0.01; 2 months: SMD = 0.98, P < 0.01; 3 months: SMD = 1.16, P < 0.01; 6 months: SMD = 1.49, P < 0.01; 12 months: SMD = 1.47, P < 0.01). In terms of adverse reactions, PRP did not increase the risk of adverse events compared with HA (OR = 0.96, P = 0.85). CONCLUSIONS: Compared with many other treatment methods, intra-articular injection of PRP has been proven to be safe and effective to improve the quality of life of patients with KOA.

Long non-coding RNA MEG3 silencing and microRNA-214 restoration elevate osteoprotegerin expression to ameliorate osteoporosis by limiting TXNIP.

Studies have shown that long non-coding RNA (lncRNA) MEG3 plays a key role in osteoporosis (OP), but its regulatory mechanism is somewhat incompletely clear. Here, we intend to probe into the mechanism of MEG3 on OP development by modulating microRNA-214 (miR-214) and thioredoxin-interacting protein (TXNIP). Rat models of OP were established. MEG3, miR-214 and TXNIP mRNA expression in rat femoral tissues were detected, along with TXNIP, OPG and RANKL protein expression. BMD, BV/TV, Tb.N and Tb.Th in tissue samples were measured. Ca, P and ALP contents in rat serum were also determined. Primary osteoblasts were isolated and cultured. Viability, COL-I, COL-II and COL-Χ mRNA expression, PCNA, cyclin D1, OCN, RUNX2 and osteolix protein expresion, ALP content and activity, and mineralized nodule area of rat osteoblasts were further detected. Dual-luciferase reporter gene and RNA-pull down assays verified the targeting relationship between MEG3, miR-214 and TXNIP. MEG3 and TXNIP were up-regulated while miR-214 was down-regulated in femoral tissues of OP rats. MEG3 silencing and miR-214 overexpression increased BMD, BV/TV, Tb.N, Tb.Th, trabecular bone area, collagen area and OPG expression, and down-regulated RANKL of femoral tissues in OP rats. MEG3 silencing and miR-214 overexpression elevated Ca and P and reduced ALP in OP rat serum, elevated osteoblast viability, differentiation ability, COL-I and COL-Χ expression and ALP activity, and reduced COL-II expression of osteoblasts. MEG3 specifically bound to miR-214 to regulate TXNIP. MEG3 silencing and miR-214 overexpression promote proliferation and differentiation of osteoblasts in OP by down-regulating TXNIP, which further improves OP.

Mesenchymal stem cells plus bone repair materials as a therapeutic strategy for abnormal bone metabolism: Evidence of clinical efficacy and mechanisms of action implied.

The regeneration process of human bones is very complicated, the management and treatment of bone damage caused by diseases are the main problems faced by clinicians worldwide. It is known that cell-based stem cell therapy together with biomaterials is a fast-developing method of tissue regeneration. This review focuses on the different types and main characteristics of scaffolds and stem cells suitable for bone regeneration, and aims to provide a state-of-the-art description of the current treatment of common bone metabolism related diseases such as osteoarthritis, osteoporosis and osteosarcoma and the strategies based on stem cell biological scaffolds used in bone tissue engineering. This method may provide a new treatment option for the treatment of common bone metabolism-related diseases that cannot be cured by ordinary and routine applications. Three databases (PubMed, CNKI and Web of Science) search terms used to write this review are: "arthritis", "osteoporosis", "osteosarcoma", "bone tissue engineering", "mesenchymal stem cells", "materials", "bioactive scaffolds" and their combinations, and the most relevant studies are selected. As a conclusion, it needs to be emphasized that despite the encouraging results, further development is needed due to the need for more in-depth research, standardization of stem cell manufacturing processes, large-scale development of clinical methods for bone tissue engineering, and market regulatory approval. Although the research and application of tissue regeneration technology and stem cells are still in their infancy, the application prospect is broad and it is expected to solve the current clinical problems.

Citrate-based materials fuel human stem cells by metabonegenic regulation.

A comprehensive understanding of the key microenvironmental signals regulating bone regeneration is pivotal for the effective design of bioinspired orthopedic materials. Here, we identified citrate as an osteopromotive factor and revealed its metabonegenic role in mediating citrate metabolism and its downstream effects on the osteogenic differentiation of human mesenchymal stem cells (hMSCs). Our studies show that extracellular citrate uptake through solute carrier family 13, member 5 (SLC13a5) supports osteogenic differentiation via regulation of energy-producing metabolic pathways, leading to elevated cell energy status that fuels the high metabolic demands of hMSC osteodifferentiation. We next identified citrate and phosphoserine (PSer) as a synergistic pair in polymeric design, exhibiting concerted action not only in metabonegenic potential for orthopedic regeneration but also in facile reactivity in a fluorescent system for materials tracking and imaging. We designed a citrate/phosphoserine-based photoluminescent biodegradable polymer (BPLP-PSer), which was fabricated into BPLP-PSer/hydroxyapatite composite microparticulate scaffolds that demonstrated significant improvements in bone regeneration and tissue response in rat femoral-condyle and cranial-defect models. We believe that the present study may inspire the development of new generations of biomimetic biomaterials that better recapitulate the metabolic microenvironments of stem cells to meet the dynamic needs of cellular growth, differentiation, and maturation for use in tissue engineering.

MicroRNA-497 elevation or LRG1 knockdown promotes osteoblast proliferation and collagen synthesis in osteoporosis via TGF-ß1/Smads signalling pathway.

MicroRNAs (miRNAs) have been corroborated to engage in the process of cellular activities in osteoporosis. However, few researches have been conducted to expose the integrated role of miR-497, leucine-rich alpha-2-glycoprotein-1 (LRG1) and transforming growth factor beta 1 (TGF-ß1)/Smads signalling pathway in osteoporosis. Thereafter, the study is set out to delve into miR-497/LRG1/TGF-ß1/Smads signalling pathway axis in osteoporosis. Osteoporosis bone tissues and normal bone tissues were collected. Rat osteoporosis models were constructed via ovariectomy. Model rats were injected with restored miR-497 or depleted LRG1 to explore their roles in osteoporosis. Rat osteoblasts were extracted from osteoporosis rats and transfected with restored miR-497 or depleted LRG1 for further verification. MiR-497 and LRG1 expression in femoral head tissues and osteoblasts of osteoporosis rats were detected. TGF-ß1/Smads signalling pathway-related factors were detected. MiR-497 was poorly expressed while LRG1 was highly expressed and TGF-ß1/Smads signalling pathway activation was inhibited in osteoporosis. MiR-497 up-regulation or LRG1 down-regulation activated TGF-ß1/Smads signalling pathway, promoted collagen type 1 synthesis and suppressed oxidative stress in femoral head tissues in osteoporosis. MiR-497 restoration or LRG1 knockdown activated TGF-ß1/Smads signalling pathway, promoted viability and suppressed apoptosis of osteoblasts in osteoporosis. Our study suggests that miR-497 up-regulation or LRG1 down-regulation promotes osteoblast viability and collagen synthesis via activating TGF-ß1/Smads signalling pathway, which may provide a novel reference for osteoporosis treatment.

Application of mesenchymal stem cell exosomes and their drug-loading systems in acute liver failure.

Stem cell exosomes are nanoscale membrane vesicles released from stem cells of various origins that can regulate signal transduction pathways between liver cells, and their functions in intercellular communication have been recognized. Due to their natural substance transport properties and excellent biocompatibility, exosomes can also be used as drug carriers to release a variety of substances, which has great prospects in the treatment of critical and incurable diseases. Different types of stem cell exosomes have been used to study liver diseases. Due to current difficulties in the treatment of acute liver failure (ALF), this review will outline the potential of stem cell exosomes for ALF treatment. Specifically, we reviewed the pathogenesis of acute liver failure and the latest progress in the use of stem cell exosomes in the treatment of ALF, including the role of exosomes in inhibiting the ALF inflammatory response and regulating signal transduction pathways, the advantages of stem cell exosomes and their use as a drug-loading system, and their pre-clinical application in the treatment of ALF. Finally, the clinical research status of stem cell therapy for ALF and the current challenges of exosome clinical transformation are summarized.

Recurrent arthritis caused by Candida parapsilosis: a case report and literature review.

BACKGROUND: Candida arthritis is extremely rare and also represents a major challenge of diagnosis and treatment. Here we reported a rare case of recurrent arthritis caused by Candida parapsilosis. CASE PRESENTATION: A 56-year-old Chinese male suffered from recurrent pain and swelling in his right knee after several times of "small needle-knife" acupuncture and corticosteroid injection of the joint. Candida parapsilosis was cultured in his synovial fluid and identified by sequencing of its Internal Transcribed Spacer (ITS) gene. Here we present the radiological characteristics, arthroscopic pictures, and synovium pathology of this patient. Also, blood test and chemical analysis of his synovial fluid were listed as well as the ITS sequence of this Candida species identified. The patient underwent thorough arthroscopic debridement and then set on fluconazole 400 mg daily for 12 months. His symptoms resolved and no relapse was observed on the last follow-up. Additionally, a brief but comprehensive review of C. parapsilosis arthritis episodes from past to now were studied. CONCLUSION: With the detailed clinical information reported in this case and our literature review, we hope they would add to our knowledge of C. parapsilosis arthritis - its clinical settings, laboratory features, radiological characteristics, arthroscopic findings and experience of management.

Synovial macrophage M1 polarisation exacerbates experimental osteoarthritis partially through R-spondin-2.

OBJECTIVES: To investigate the roles and regulatory mechanisms of synovial macrophages and their polarisation in the development of osteoarthritis (OA). METHODS: Synovial tissues from normal patients and patients with OA were collected. M1 or M2-polarised macrophages in synovial tissues of patients with OA and OA mice were analysed by immunofluorescence and immunohistochemical staining. Mice with tuberous sclerosis complex 1 (TSC1) or Rheb deletion specifically in the myeloid lineage were generated and subjected to intra-articular injection of collagenase (collagenase-induced osteoarthritis, CIOA) and destabilisation of the medial meniscus (DMM) surgery to induce OA. Cartilage damage and osteophyte size were measured by Osteoarthritis Research Society International score and micro-CT, respectively. mRNA sequencing was performed in M1 and control macrophages. Mice and ATDC5 cells were treated with R-spondin-2 (Rspo2) or anti-Rspo2 to investigate the role of Rspo2 in OA. RESULTS: M1 but not M2-polarised macrophages accumulated in human and mouse OA synovial tissue. TSC1 deletion in the myeloid lineage constitutively activated mechanistic target of rapamycin complex 1 (mTORC1), increased M1 polarisation in synovial macrophages and exacerbated experimental OA in both CIOA and DMM models, while Rheb deletion inhibited mTORC1, enhanced M2 polarisation and alleviated CIOA in mice. The results show that promoting the macrophage M1 polarisation leads to exacerbation of experimental OA partially through secretion of Rspo2 and activation of ß-catenin signalling in chondrocytes. CONCLUSIONS: Synovial macrophage M1 polarisation exacerbates experimental CIOA partially through Rspo2. M1 macrophages and Rspo2 are potential therapeutic targets for OA treatment.

Comparison of the Wake-up Test and Combined TES-MEP and CSEP Monitoring in Spinal Surgery.

STUDY DESIGN: A retrospective clinical analysis. OBJECTIVE: The aim of this study was to compare the effectiveness of the wake-up test with that of combined monitoring of transcranial electrical stimulation motor evoked potentials (TES-MEP) and cortical somatosensory evoked potentials (CSEP) in spinal surgery. SUMMARY OF BACKGROUND DATA: TES-MEP/CSEP combined monitoring is being increasingly recognized as the ideal approach to detect spinal neurophysiological compromise during spinal surgery; however, as a result the merit of the wake-up test is now in doubt. MATERIALS AND METHODS: TES-MEP/CSEP combined monitoring was performed simultaneously in 426 patients who underwent spinal surgery at our department, and wake-up tests were conducted on 23 patients because of positive neurophysiological monitoring results with uncertain causes or persistent positive monitoring findings after all potential causes had been resolved. Preoperative and postoperative neurological examinations were performed as the gold standard to detect irreversible spinal function compromise. All data were collected to compare the efficiency of TES-MEP/CSEP combined monitoring with that of the wake-up test. RESULTS: Positive results of TES-MEP/CSEP combined monitoring were recorded in 64 cases. Among them, the positive monitoring findings agreed with the results of the neurological examination in 51 cases, and the monitoring results did not match that of neurological examination in 13 cases. No false-negative result was observed. The sensitivity of TES-MEP/CSEP monitoring was 100%, the specificity was 96.5%, and the Youden index was 0.965. Wake-up tests were conducted in 23 cases. In 8 patients the positive monitoring findings completely matched the postoperative neurological examination results. In contrast, in the other 15 cases with negative neurophysiological monitoring results, only 9 patients retained intact neurological function and 6 patients suffered compromised neurological function. The sensitivity of the wake-up test was 57.1%, the specificity was 100%, and the Youden index was 0.571. CONCLUSIONS: Combined TES-MEP and CSEP monitoring, with its high sensitivity and specificity, is an effective method for monitoring spinal function during surgery and should be the preferred choice. The wake-up test is a useful complementary method for monitoring because of its high specificity.

Application of Artificial Intelligence in Shoulder Pathology.

Artificial intelligence (AI) refers to the science and engineering of creating intelligent machines for imitating and expanding human intelligence. Given the ongoing evolution of the multidisciplinary integration trend in modern medicine, numerous studies have investigated the power of AI to address orthopedic-specific problems. One particular area of investigation focuses on shoulder pathology, which is a range of disorders or abnormalities of the shoulder joint, causing pain, inflammation, stiffness, weakness, and reduced range of motion. There has not yet been a comprehensive review of the recent advancements in this field. Therefore, the purpose of this review is to evaluate current AI applications in shoulder pathology. This review mainly summarizes several crucial stages of the clinical practice, including predictive models and prognosis, diagnosis, treatment, and physical therapy. In addition, the challenges and future development of AI technology are also discussed.

Biomimetic cryogel promotes the repair of osteoporotic bone defects through altering the ROS niche via down-regulating the ROMO1.

Osteoporosis is a systemic bone disease that is prone to fractures due to decreased bone density and bone quality, and delayed union or nonunion often occurs in osteoporotic fractures. Therefore, it is particularly important to develop tissue engineering materials to promote osteoporotic fracture healing. In this study, a series of biomimetic cryogels prepared from the decellularized extracellular matrix (dECM), methacrylate gelatin (GelMA), and carboxymethyl chitosan (CMCS) via unidirectional freezing, photo- and genipin crosslinking were applied for the regeneration of osteoporotic fractures. Specifically, dECM extracted from normal or osteoporotic rats was applied for the preparation of the cryogels, named as GC-Normal dECM or GC-OVX dECM, respectively. It was verified that the GC-Normal dECM demonstrated superior performance in promoting the proliferation of BMSCs isolated from osteoporotic rats (OVX-BMSCs), and the differentiation of OVX-BMSCs into osteoblasts both in vitro and in vivo. RNA sequencing and further verifications confirmed that GC-Normal dECM cryogel could scavenge the intracellular reactive oxygen species (ROS) in OVX-BMSCs to accelerate the regeneration of osteoporotic fracture by down-regulating the reactive oxygen species modulator 1 (Romo1). The results indicated that by regulating the ROS niche of OVX-BMSCs, biomimetic the GC-Normal dECM cryogel was expected to be a clinical candidate for repairing osteoporotic bone defects.

[Anatomical study of the limited osteotomy suture button fixation Latarjet procedure with coracoacromial ligament preservation].

Objective: To investigate the morphological characteristics of the glenohumeral joint (including the glenoid and coracoid) in the Chinese population and determine the feasibility of designing coracoid osteotomy based on the preoperative glenoid defect arc length by constructing glenoid defect models and simulating suture button fixation Latarjet procedure. Methods: Twelve shoulder joint specimens from 6 adult cadavers donated voluntarily were harvested. First, whether the coracoacromial ligament and conjoint tendon connected was anatomically observed and their intersection point was identified. The vertical distance from the intersection point to the coracoid, the maximum allowable osteotomy length starting from the intersection point, and the maximum osteotomy angle were measured. Next, the anteroinferior glenoid defect models of different degrees were randomly constructed. The arc length and area of the glenoid defect were measured. Based on the arc length of the glenoid defect of the model, the size of coracoid oblique osteotomy was designed and the actual length and angle of the coracoid osteotomy were measured. A limited osteotomy suture button fixation Latarjet procedure with the coracoacromial ligament and pectoralis minor preservation was performed and the position of coracoid block was observed. Results: All shoulder joint specimens exhibited crossing fibers between the coracoacromial ligament and the conjoint tendon. The vertical distance from the tip of the coracoid to the coracoid return point was 24.8-32.2 mm (mean, 28.5 mm). The maximum allowable osteotomy length starting from the intersection point was 26.7-36.9 mm (mean, 32.0 mm). The maximum osteotomy angle was 58.8°-71.9° (mean, 63.5°). Based on the anteroinferior glenoid defect model, the arc length of the glenoid defect was 22.6-29.4 mm (mean, 26.0 mm); the ratio of glenoid defect was 20.8%-26.2% (mean, 23.7%). Based on the coracoid block, the length of the coracoid osteotomy was 23.5-31.4 mm (mean, 26.4 mm); the osteotomy angle was 51.3°-69.2° (mean, 57.1°). There was no significant difference between the arc length of the glenoid defect and the length of the coracoid osteotomy ( P>0.05). After simulating the suture button fixation Latarjet procedure, the highest points of the coracoid block (suture loop fixation position) in all models located below the optimal center point, with the bone block concentrated in the anteroinferior glenoid defect position. Conclusion: The size of the coracoid is generally sufficient to meet the needs of repairing larger glenoid defects. The oblique osteotomy with preserving the coracoacromial ligament may potentially replace the traditional Latarjet osteotomy method.

Chitosan nanofibrous scaffold with graded and controlled release of ciprofloxacin and BMP-2 nanoparticles for the conception of bone regeneration.

The repair of bone defects using grafts is commonly employed in clinical practice. However, the risk of infection poses a significant concern. Tissue engineering scaffolds with antibacterial functionalities offer a better approach for bone tissue repair. In this work, firstly, two kinds of nanoparticles were prepared using chitosan to complex with ciprofloxacin and BMP-2, respectively. The ciprofloxacin complex nanoparticles improved the dissolution efficiency of ciprofloxacin achieving a potent antibacterial effect and cumulative release reached 95 % in 7 h. For BMP-2 complexed nanoparticles, the release time points can be programmed at 80 h, 100 h or 180 h by regulating the number of coating chitosan layers. Secondly, a functional scaffold was prepared by combining the two nanoparticles with chitosan nanofibers. The microscopic nanofiber structure of the scaffold with 27.28 m2/g specific surface area promotes cell adhesion, high porosity provides space for cell growth, and facilitates drug loading and release. The multifunctional scaffold exhibits programmed release function, and has obvious antibacterial effect at the initial stage of implantation, and releases BMP-2 to promote osteogenic differentiation of mesenchymal stem cells after the antibacterial effect ends. The scaffold is expected to be applied in clinical bone repair and graft infection prevention.

An Integrated Microcurrent Delivery System Facilitates Human Parathyroid Hormone Delivery for Enhancing Osteoanabolic Effect.

Human parathyroid hormone (1-34) (PTH) exhibits osteoanabolic and osteocatabolic effects, with shorter plasma exposure times favoring bone formation. Subcutaneous injection (SCI) is the conventional delivery route for PTH but faces low delivery efficiency due to limited passive diffusion and the obstruction of the vascular endothelial barrier, leading to prolonged drug exposure times and reduced osteoanabolic effects. In this work, a microcurrent delivery system (MDS) based on multimicrochannel microneedle arrays (MMAs) is proposed, achieving high efficiency and safety for PTH transdermal delivery. The internal microchannels of the MMAs are fabricated using high-precision 3D printing technology, providing a concentrated and safe electric field that not only accelerates the movement of PTH but also reversibly increases vascular endothelial permeability by regulating the actin cytoskeleton and interendothelial junctions through Ca2+-dependent cAMP signaling, ultimately promoting PTH absorption and shortening exposure times. The MDS enhances the osteoanabolic effect of PTH in an osteoporosis model by inhibiting osteoclast differentiation on the bone surface compared to SCI. Moreover, histopathological analysis of the skin and organs demonstrated the good safety of PTH delivered by MDS in vivo. In addition to PTH, the MDS shows broad prospects for the high-efficiency transdermal delivery of macromolecular drugs.

Citric Acid: A Nexus Between Cellular Mechanisms and Biomaterial Innovations.

Citrate-based biodegradable polymers have emerged as a distinctive biomaterial platform with tremendous potential for diverse medical applications. By harnessing their versatile chemistry, these polymers exhibit a wide range of material and bioactive properties, enabling them to regulate cell metabolism and stem cell differentiation through energy metabolism, metabonegenesis, angiogenesis, and immunomodulation. Moreover, the recent US Food and Drug Administration (FDA) clearance of the biodegradable poly(octamethylene citrate) (POC)/hydroxyapatite-based orthopedic fixation devices represents a translational research milestone for biomaterial science. POC joins a short list of biodegradable synthetic polymers that have ever been authorized by the FDA for use in humans. The clinical success of POC has sparked enthusiasm and accelerated the development of next-generation citrate-based biomaterials. This review presents a comprehensive, forward-thinking discussion on the pivotal role of citrate chemistry and metabolism in various tissue regeneration and on the development of functional citrate-based metabotissugenic biomaterials for regenerative engineering applications.

Microbial Tryptophan Metabolites Ameliorate Ovariectomy-Induced Bone Loss by Repairing Intestinal AhR-Mediated Gut-Bone Signaling Pathway.

Microbial tryptophan (Trp) metabolites acting as aryl hydrocarbon receptor (AhR) ligands are shown to effectively improve metabolic diseases via regulating microbial community. However, the underlying mechanisms by which Trp metabolites ameliorate bone loss via gut-bone crosstalk are largely unknown. In this study, supplementation with Trp metabolites, indole acetic acid (IAA), and indole-3-propionic acid (IPA), markedly ameliorate bone loss by repairing intestinal barrier integrity in ovariectomy (OVX)-induced postmenopausal osteoporosis mice in an AhR-dependent manner. Mechanistically, intestinal AhR activation by Trp metabolites, especially IAA, effectively repairs intestinal barrier function by stimulating Wnt/ß-catenin signaling pathway. Consequently, enhanced M2 macrophage by supplementation with IAA and IPA secrete large amount of IL-10 that expands from intestinal lamina propria to bone marrow, thereby simultaneously promoting osteoblastogenesis and inhibiting osteoclastogenesis in vivo and in vitro. Interestingly, supplementation with Trp metabolites exhibit negligible ameliorative effects on both gut homeostasis and bone loss of OVX mice with intestinal AhR knockout (VillinCreAhrfl/fl). These findings suggest that microbial Trp metabolites may be potential therapeutic candidates against osteoporosis via regulating AhR-mediated gut-bone axis.

DHTPY-Cu@ZOL-Enhanced Photodynamic Therapy: A Strategic Platform for Advanced Treatment of Drug-Resistant Bacterial Wound Infections.

Purpose: This research was to innovate a nanozyme-based therapeutic strategy that combines aggregation-induced emission (AIE) photosensitizers with copper nanozymes. This approach is designed to address the hypoxic conditions often found in bacterial infections and aims to boost the effectiveness of photodynamic therapy (PDT) by ensuring sufficient oxygen supply for reactive oxygen species (ROS) generation. Methods: Our approach involved the synthesis of dihydroxyl triphenyl vinyl pyridine (DHTPY)-Cu@zoledronic acid (ZOL) nanozyme particles. We initially synthesized DHTPY and then combined it with copper nanozymes to form the DHTPY-Cu@ZOL composite. The nanozyme's size, morphology, and chemical properties were characterized using various techniques, including dynamic light scattering, transmission electron microscopy, and X-ray photoelectron spectroscopy. We conducted a series of in vitro and in vivo tests to evaluate the photodynamic, antibacterial, and wound-healing properties of the DHTPY-Cu@ZOL nanozymes, including their oxygen-generation capacity, ROS production, and antibacterial efficacy against methicillin-resistant Staphylococcus aureus (MRSA). Results: The DHTPY-Cu@ZOL exhibited proficient H2O2 scavenging and oxygen generation, crucial for enhancing PDT in oxygen-deprived infection environments. Our in vitro analysis revealed a notable antibacterial effect against MRSA, suggesting the nanozymes' potential to disrupt bacterial cell membranes. Further, in vivo studies using a diabetic rat model with MRSA-infected wounds showed that DHTPY-Cu@ZOL markedly improved wound healing and reduced bacterial presence, underscoring its efficacy as a non-antibiotic approach for chronic infections. Conclusion: Our study suggests that DHTPY-Cu@ZOL is a highly promising approach for combating antibiotic-resistant microbial pathogens and biofilms. The biocompatibility and stability of these nanozyme particles, coupled with their improved PDT efficacy position them as a promising candidate for clinical applications.

Controlled-release hydrogel loaded with magnesium-based nanoflowers synergize immunomodulation and cartilage regeneration in tendon-bone healing.

Tendon-bone interface injuries pose a significant challenge in tissue regeneration, necessitating innovative approaches. Hydrogels with integrated supportive features and controlled release of therapeutic agents have emerged as promising candidates for the treatment of such injuries. In this study, we aimed to develop a temperature-sensitive composite hydrogel capable of providing sustained release of magnesium ions (Mg2+). We synthesized magnesium-Procyanidin coordinated metal polyphenol nanoparticles (Mg-PC) through a self-assembly process and integrated them into a two-component hydrogel. The hydrogel was composed of dopamine-modified hyaluronic acid (Dop-HA) and F127. To ensure controlled release and mitigate the "burst release" effect of Mg2+, we covalently crosslinked the Mg-PC nanoparticles through coordination bonds with the catechol moiety within the hydrogel. This crosslinking strategy extended the release window of Mg2+ concentrations for up to 56 days. The resulting hydrogel (Mg-PC@Dop-HA/F127) exhibited favorable properties, including injectability, thermosensitivity and shape adaptability, making it suitable for injection and adaptation to irregularly shaped supraspinatus implantation sites. Furthermore, the hydrogel sustained the release of Mg2+ and Procyanidins, which attracted mesenchymal stem and progenitor cells, alleviated inflammation, and promoted macrophage polarization towards the M2 phenotype. Additionally, it enhanced collagen synthesis and mineralization, facilitating the repair of the tendon-bone interface. By incorporating multilevel metal phenolic networks (MPN) to control ion release, these hybridized hydrogels can be customized for various biomedical applications.

Dynamic control of mTORC1 facilitates bone healing in mice.

Bone healing requires well-orchestrated sequential actions of osteoblasts and osteoclasts. Previous studies have demonstrated that the mechanistic target of rapamycin complex 1 (mTORC1) plays a critical role in the metabolism of osteoblasts and osteoclasts. However, the role of mTORC1 in bone healing remains unclear. Here, we showed that a dynamic change in mTORC1 activity during the process was essential for proper healing and can be harnessed therapeutically for treatment of bone fractures. Low mTORC1 activity induced by osteoblastic Raptor knockout or rapamycin treatment promoted osteoblast-mediated osteogenesis, thus leading to better bone formation and shorter bone union time. Rapamycin treatment in vitro also revealed that low mTORC1 activity enhanced osteoblast differentiation and maturation. However, rapamycin treatment affected the recruitment of osteoclasts to new bone sites, thus resulting in delayed callus absorption in bone marrow cavity. Mechanistically, decreased mTORC1 activity inhibited the recruitment of osteoclast progenitor cells to healing sites through a decrease in osteoblastic expression of monocyte chemoattractant protein-1, thus inhibiting osteoclast-mediated remodeling. Therefore, normal mTORC1 activity was necessary for bone remodeling stage. Furthermore, through the use of sustained-release materials at the bone defect, we confirmed that localized application of rapamycin in early stages accelerated bone healing without affecting bone remodeling. Together, these findings revealed that the activity of mTORC1 continually changed during bone healing, and staged rapamycin treatment could be used to promote bone healing.