Activating Angiogenesis and Immunoregulation to Propel Bone Regeneration via Deferoxamine-Laden Mg-Mediated Tantalum Oxide Nanoplatform.

Vascularization and inflammation management are essential for successful bone regeneration during the healing process of large bone defects assisted by artificial implants/fillers. Therefore, this study is devoted to the optimization of the osteogenic microenvironment for accelerated bone healing through rapid neovascularization and appropriate inflammation inhibition that were achieved by applying a tantalum oxide (TaO)-based nanoplatform carrying functional substances at the bone defect. Specifically, TaO mesoporous nanospheres were first constructed and then modified by functionalized metal ions (Mg2+) with the following deferoxamine (DFO) loading to obtain the final product simplified as DFO-Mg-TaO. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) revealed that the product was homogeneously dispersed hollow nanospheres with large specific surface areas and mesoporous shells suitable for loading Mg2+ and DFO. The biological assessments indicated that DFO-Mg-TaO could enhance the adhesion, proliferation, and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). The DFO released from DFO-Mg-TaO promoted angiogenetic activity by upregulating the expressions of hypoxia-inducible factor-1 (HIF-1α) and vascular endothelial growth factor (VEGF). Notably, DFO-Mg-TaO also displayed anti-inflammatory activity by reducing the expressions of pro-inflammatory factors, benefiting from the release of bioactive Mg2+. In vivo experiments demonstrated that DFO-Mg-TaO integrated with vascular regenerative, anti-inflammatory, and osteogenic activities significantly accelerated the reconstruction of bone defects. Our findings suggest that the optimized DFO-Mg-TaO nanospheres are promising as multifunctional fillers to speed up the bone healing process.

Black phosphorus-incorporated novel Ti-12Mo-10Zr implant for multimodal treatment of osteosarcoma.

The repair and reconstruction of large bone defects after bone tumor resection is still a great clinical challenge. At present, orthopedic implant reconstruction is the mainstream treatment for repairing bone defects. However, according to clinical feedback, local tumor recurrence and nonunion of bone graft are common reasons leading to the failure of bone defect repair and reconstruction after bone tumor resection, which seriously threaten the physical and mental health of patients. On this basis, here the self-developed low modulus Ti-12Mo-10Zr alloy (TMZ) was chosen as substrate material. To improve its biological activity and osteointegration, calcium, oxygen, and phosphorus co-doped microporous coating was prepared on TMZ alloy by microarc oxidation (MAO). Then, black phosphorus (BP) nanosheets were incorporated onto MAO treated TMZ alloy to obtain multifunctional composites. The obtained BP-MAO-TMZ implant exhibited excellent photothermal effects and effective ablation of osteosarcoma cancer cells under the irradiation of 808 nm near infrared laser, while no photothermal or therapeutic effects were observed for TMZ alloy. Meanwhile, the structure/component bionic coating obtained after MAO treatment as well as the P-driven in situ biomineralization performance after incorporation of BP nanosheets endowed BP-MAO-TMZ implant with synergistic promoting effect on MC3T3-E1 osteoblasts' activity, proliferation and differentiation ability. This study is expected to provide effective clinical solutions for problems of difficult bone regeneration and tumor recurrence after tumor resection in patients with bone tumors and to solve a series of medical problems such as poor prognosis and poor postoperative quality of patients life with malignant bone tumors.

Propelling Multi-Modal Therapeutics of PEEK Implants through the Power of NO evolving Covalent Organic Frameworks (COFs).

The design and fabrication of NO-evolving core-shell nanoparticles (denoted as NC@Fe), comprised of BNN6-laden COF@Fe3 O4 nanoparticles, are reported. This innovation extends to the modification of 3D printed polyetheretherketone scaffolds with NC@Fe, establishing a pioneering approach to multi-modal bone therapy tailored to address complications such as device-associated infections and osteomyelitis. This work stands out prominently from previous research, particularly those relying on the use of antibiotics, by introducing a bone implant capable of simultaneous NO gas therapy and photothermal therapy (PPT). Under NIR laser irradiation, the Fe3 O4 NP core (photothermal conversion agent) within NC@Fe absorbs photoenergy and initiates electron transfer to the loaded NO donor (BNN6), resulting in controlled NO release. The additional heat generated through photothermal conversion further propels the NC@Fe nanoparticles, amplifying the therapeutic reach. The combined effect of NO release and PPT enhances the efficacy in eradicating bacteria over a more extensive area around the implant, presenting a distinctive solution to conventional challenges. Thorough in vitro and in vivo investigations validate the robust potential of the scaffold in infection control, osteogenesis, and angiogenesis, emphasizing the timeliness of this unique solution in managing complicated bone related infectious diseases.

Hollow Cobalt Sulfide Nanospheres with Highly Enzyme-like Antibacterial Activities to Accelerate Infected Wound Healing.

The emergence of nanozymes presents a promising alternative to antibiotics for reactive oxygen species-mediated broad-spectrum antimicrobial purposes, but nanozymes still face challenges of low therapeutic efficiency and poor biocompatibility. Herein, we creatively prepared a novel kind of hollow cobalt sulfide (CoS) nanospheres with a unique mesoporous structure that is able to provide numerous active sites for enzyme-like reactions. The results revealed that 50 µg/mL of CoS nanospheres exhibited strong peroxidase- and oxidase-like activities under physiological conditions with the assistance of a low concentration of hydrogen peroxide (H2O2, 100 µM) while possessing highly efficient GSH-depletion ability, which endowed CoS nanospheres with triple enzyme-like properties to combat bacterial infections. The in vitro experiments demonstrated that the CoS nanozyme displayed significant antibacterial effects against both Gram-positive Staphylococcus aureus (S. aureus) and Gram-negative Escherichia coli (E. coli). The in vivo implantation showed that the synthesized CoS effectively eliminated bacteria and promoted the recovery of infected wounds in rats while exhibiting a low cytotoxicity. This study provides a promising treatment strategy to accelerate infected wound healing.

Injectable mesoporous bioactive glass/sodium alginate hydrogel loaded with melatonin for intervertebral disc regeneration.

Intervertebral disc degeneration (IDD) is a major contributing factor to both lower back and neck pain. As IDD progresses, the intervertebral disc (IVD) loses its ability to maintain its disc height when subjected to axial loading. This failure in the weight-bearing capacity of the IVD is a characteristic feature of degeneration. Natural polymer-based hydrogel, derived from biological polymers, possesses biocompatibility and is able to mimic the structure of extracellular matrix, enabling them to support cellular behavior. However, their mechanical performance is relatively poor, thus limiting their application in IVD regeneration. In this study, we developed an injectable composite hydrogel, namely, Mel-MBG/SA, which is similar to natural weight-bearing IVD. Mesoporous bioactive glasses not only enhance hydrogels, but also act as carriers for melatonin (Mel) to suppress inflammation during IDD. The Mel-MBG/SA hydrogel further provides a mixed system with sustained Mel release to alleviate IL-1ß-induced oxidative stress and relieve inflammation associated with IDD pathology. Furthermore, our study shows that this delivery system can effectively suppress inflammation in the rat tail model, which is expected to further promote IVD regeneration. This approach presents a novel strategy for promoting tissue regeneration by effectively modulating the inflammatory environment while harnessing the mechanical properties of the material.

The Regulatory Effect of MicroRNA-101-3p on Disc Degeneration by the STC1/VEGF/MAPK Pathway.

Aims. Accumulating evidence reported that the microRNA (miRNA) took an important role in intervertebral disc degeneration (IDD). In this study, we revealed a novel miRNA regulatory mechanism in IDD. Main Methods. The miRNA microarray analyses of human degenerated and normal disc samples were employed to screen out the target miRNA. In vitro and in vivo experiments were conducted to verify the regulatory effect of miR-101-3p. Key Findings. The expression level of miR-101-3p was significantly decreased in the degenerated disc samples which were confirmed by qRT-PCR. Moreover, the miR-101-3p expression level was changed dynamically according to the disc degeneration grade. Upregulation of miR-101-3p expression level inhibited cell apoptosis. Furthermore, stanniocalcin-1 (STC1) was selected to be the target gene of miR-101-3p according to the bioinformatic algorithms. Mechanically, upregulation of miR-101-3p significantly decreased the expression of STC1, vascular endothelial growth factor (VEGF), and MAPK pathway expression levels. Therapeutically, in vivo experiment on IDD rat model illustrated that agomir-101-3p could effectively suspend IDD. Significance. Our findings demonstrated that miR-101-3p alleviated IDD process through the STC1/VEGF/MAPK pathway.

3D-Printed Multifunctional Polyetheretherketone Bone Scaffold for Multimodal Treatment of Osteosarcoma and Osteomyelitis.

In this work, we developed the first 3D-printed polyetheretherketone (PEEK)-based bone scaffold with multi-functions targeting challenging bone diseases such as osteosarcoma and osteomyelitis. A 3D-printed PEEK/graphene nanocomposite scaffold was deposited with a drug-laden (antibiotics and/or anti-cancer drugs) hydroxyapatite coating. The graphene nanosheets within the scaffold served as effective photothermal agents that endowed the scaffold with on-demand photothermal conversion function under near-infrared laser irradiation. The bioactive hydroxyapatite coating significantly boosted the stem cell proliferation in vitro and promoted new bone growth in vivo. The presence of antibiotics and anti-cancer drugs enabled eradication of drug-resistant bacteria and ablation of osteosarcoma cancer cells, the treatment efficacy of which can be further enhanced by on-demand laser-induced heating. The promising results demonstrate the strong potential of our multi-functional scaffold in applications such as bone defect repair and multimodal treatment of osteosarcoma and osteomyelitis.

3D Printed Multifunctional Ti6Al4V-Based Hybrid Scaffold for the Management of Osteosarcoma.

Osteosarcoma is a challenging bone disease which is commonly associated with critically sized bone defects and cancer recurrence. Here, we designed and developed a multifunctional, hierarchical structured bone scaffold which can meet the demanding requirements for osteosarcoma management. The 3D printed Ti6Al4V scaffold with hydrothermally induced TiO2/TiP coating can offer a unique photothermal conversion property for in vitro bone cancer ablation. The scaffold is also infused with drug-laden gelatin/hydroxyapatite nanocomposite, which provides the ideal porous structure for cell adhesion/bone ingrowth and promotes bone regeneration. The scaffold has been thoroughly characterized by SEM/EDX, TEM, XPS, XRD, TGA, and UV-vis, and its in vitro bone cancer ablation efficiency has been validated using MG-63 cells. The hybrid scaffold showed excellent biocompatibility, and its osteointegration function has been demonstrated using an animal model.

A novel posterior multiple screws distraction reducer system versus anterior release, posterior internal distraction, and subsequent spinal fusion for severe scoliosis.

PURPOSE: We previously reported anterior release, posterior internal distraction, and subsequent spinal fusion (ARPIDF) for the correction of severe scoliosis with a satisfactory correction rate. However, surgical procedures were completed in 2-3 stages. Here we compare Cobb angle of ≥90° in scoliosis correction between a novel posterior multiple screws distraction reducer (MSDR) system and ARPIDF. METHODS: Thirty-six patients with severe scoliosis treated by MSDR or ARPIDF (n = 18 in both groups). We retrospectively analyzed and compared outcome measures between the two groups over a minimum follow-up duration of 2 years. The following variables were compared between the two groups: age at surgery, sex, etiology, flexibility of the main thoracic curve, number of fused segments and screws, operation time, estimated blood loss, hospitalization time, follow-up duration, various radiological parameters, complication rate, and Scoliosis Research Society-30 score. RESULTS: There were no significant between-group differences with respect to age, sex, etiology, flexibility of the main thoracic curve, number of fused segments and screws, and follow-up duration. Further, there was no significant difference in terms of preoperative, postoperative, and final follow-up findings of the radiographic data. However, the ARPIDF group had longer operation and hospitalization times and greater blood loss. In the ARPIDF group, 4 patient developed complications (infection, intraoperative neuromonitoring changes, transient dyspnea); none of these events occurred in the MSDR group. CONCLUSION: The use of MSDR helped achieve greater scoliosis correction with a shorter operation time, lower blood loss, and lower complication rate than the use of ARPIDF. MSDR facilitates safer and easier correction of severe scoliosis without increasing surgical risk.

Comparative Study on 3D Printed Ti6Al4V Scaffolds with Surface Modifications Using Hydrothermal Treatment and Microarc Oxidation to Enhance Osteogenic Activity.

Titanium (Ti) and its alloys have been widely used in clinics as preferred materials for bone tissue repair and replacement. However, the lack of biological activity of Ti limits its clinical applications. Surface modification of Ti with bioactive elements has always been a research hotspot. In this study, to promote the osseointegration of Ti6Al4V (Ti64) implants, calcium (Ca), oxygen (O), and phosphorus (P) codoped multifunctional micro-nanohybrid coatings were prepared on a three-dimensional (3D) printed porous Ti64 surface by microarc oxidation (MAO) and a hydrothermal method (HT). The surface morphologies, chemical compositions, and surface/cell interactions of the obtained coatings were studied. In vitro experiments indicated that all hybrid coating-modified Ti64 implants could enhance protein adsorption and MC3T3 osteoblasts' activity, adhesion, and differentiation ability. In vivo experiments showed that the hybrid coating promoted early osseointegration. By comparison, microarc oxidation-treated Ti64 (M-Ti) has the best biological activity and the strongest ability of osseointegration. It provides important theoretical significance and potential application prospects for improving the biological activity of Ti implants.

Therapeutic effect of the injectable thermosensitive hydrogel loaded with SHP099 on intervertebral disc degeneration.

AIMS: Intervertebral disc (IVD) degeneration (IDD), a common musculoskeletal disease with limited self-healing ability, is challenging to treat. The development of innovative therapies to reverse IDD depends on the elucidation of its regulatory mechanisms. Therefore, the role of Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2) in the pathogenesis of IDD and the therapeutic effect of its small-molecule inhibitor, SHP099, were investigated. MATERIALS AND METHODS: The expression of SHP2 by nucleus pulposus (NP) cells in IVD was investigated in vitro and in vivo, and its molecular mechanism in IDD was explored using transfection technology. Injectable N-isopropylacrylamide-based thermosensitive hydrogels were synthesized for SHP099 delivery. KEY FINDINGS: SHP2 was highly expressed in degenerated IVDs, where its overexpression in NP cells inhibited the expression of Sry-related HMG box-9 (Sox9), leading to the decreased expression of key proteins (collagen II and aggrecan) and consequently to IDD. SHP099 reversed the degeneration of NP cells in vitro. Moreover, its administration in rats via the injectable thermosensitive hydrogel had a therapeutic effect on IDD. SIGNIFICANCE: Our results suggest that SHP2 is a key factor in IDD progression, and SHP099 inhibits both its expression and NP cell degeneration. Therefore, SHP099 delivery via injectable thermosensitive hydrogels is a potential treatment strategy for IDD.

MicroRNA-25-3p therapy for intervertebral disc degeneration by targeting the IL-1ß/ZIP8/MTF1 signaling pathway with a novel thermo-responsive vector.

BACKGROUND: MicroRNAs play important roles in intervertebral disc degeneration (IDD). The therapeutic effects of miRNA-25-3p on IDD and underlying mechanism are unclear. METHODS: Normal and degenerated nuclear pulposus (NP) tissue were collected. Primary NP cells were isolated and treated with different concentrations of interleukin-1ß (IL-1ß). IL-1ß treated NP cells were interfered with miRNA-25-3p. Associated proteins IL-1ß, ZIP8, MTF1, extracellular matrix (ECM) degrading enzymes MMP3, MMP13, ADAMTS5, ECM proteins type II collagen, aggrecan and MiRNA-25-3p were detected by western blotting or qRT-PCR method. Dual luciferase reporter assays were performed to determine potential targets MTF1 of miRNA-25-3p. In vitro miRNA-25-3p transfection efficiency of thermos-responsive vector was observed by fluorescence microscopy. Animal studies were conducted to observe the therapeutic effects of miRNA-25-3p mimic delivered by thermo-responsive vector. RESULTS: Compared with normal NP tissues, IL-1ß, ZIP8 and MTF1 significantly increased and miRNA-25-3p significantly decreased in degenerated tissues. IL-1ß promotes the expression of ZIP8 and nuclear translocation of MTF1 in NP cells. Ultimately, it promotes expression of ECM degrading enzymes and inhibits synthesis of ECM protein. MiRNA- 25-3p could inhibit the effects of IL-1ß and the expression of ECM degrading enzymes, and recover the expression of ECM protein. Further investigation showed MTF1 was a target protein of miRNA-25-3p. The thermo-responsive vector could effectively deliver miRNA-25-3p into NP cells. Animal studies demonstrated miRNA-25-3p delivered by the thermo-responsive vector can delay progression of IDD. CONCLUSIONS: The thermo-responsive vector delivering miRNA-25-3p could delay the progression of IDD by inhibiting IL-1ß-induced effects, and may be potential therapy for IDD in future.

[Research progress of hydrogel used for regeneration of nucleus pulposus in intervertebral disc degeneration].

OBJECTIVE: To summarize the research progress of hydrogels for the regeneration and repair of degenerative intervertebral disc and to investigate the potential of hydrogels in clinical application. METHODS: The related literature about the role of hydrogels in intervertebral disc degeneration especially for nucleus pulposus was reviewed and analyzed. RESULTS: Hydrogels share similar properties with nucleus pulposus, and it plays an important role in the regeneration and repair of degenerative intervertebral disc, which can be mainly applied in nucleus pulposus prosthesis, hydrogel-based cell therapy, non-cellular therapy, and tissue engineering repair. CONCLUSION: Hydrogels are widely used in the regeneration and repair of intervertebral disc, which provides a potential treatment for intervertebral disc degeneration.