Is the clavicla pro humero a reliable reconstruction for paediatric proximal humerus sarcomas?

PURPOSE: The proximal humeral reconstruction is challenging. This study aims to investigate the survival, function and complications of clavicla pro humero (CPH) for pediatric proximal humeral reconstruction. METHODS: A retrospective cohort study was conducted on eight patients (4 males, and 4 females) who underwent clavicla pro humero reconstruction between January 2009 and December 2020 in our institution. The average age was 10.4 ± 2.7 years (range, 6 to 14 years). The functional outcomes were assessed by the Musculoskeletal Tumor Society Score (MSTS-93), the Toronto Extremity Salvage Score (TESS), the American Shoulder and Elbow Surgeons (ASES) score and the range of motion (ROM) of the shoulder. The complications and overall survivorship of clavicla pro humero were recorded in the follow-up. RESULTS: The mean follow-up of all patients was 54.6 ± 23.9 months (range, 24 to 84 months) and 73.3 ± 8.5 months (range, 72 to 84 months) in all survivors. All patients had a bone union at an average of 3.8 months after the initial procedure. Only one patient had no complications in the follow-up. The most common complications were clavicle fracture (87.5%, 7/8), followed by pseudarthrosis (62.5%, 5/8), proximal clavicle osteolysis (37.5%, 3/8) and skin flap necrosis (12.5%, 1/8). The average MSTS-93 score was 79% (range, 73-86%), the average TESS was 82% (range, 76-86%) and the average ASES was 70% (68-73%), respectively. CONCLUSIONS: The clavicla pro humero procedure provides rapid bone union but has a high complication rate. Therefore, we do not recommend this technique as a routine surgical procedure for paediatric proximal humeral reconstruction when other methods are available. LEVEL OF EVIDENCE: level IV therapeutic study.

Giant cell tumor of bone at distal radius suffered more soft tissue recurrence and ultrasonography is effective to detect the soft tissue recurrence.

BACKGROUND: Soft tissue recurrence of giant cell tumor of bone (GCTB) is rare. This study aims to provide its prevalence, recurrent locations, risk factors, effective detection methods and a modified classification for this recurrence. METHODS: Patients with soft tissue recurrence after primary surgery for GCTB were screened from January 2003 to December 2022. General data, recurrence frequency, types according to an original classification (type-I: peripheral ossification; type-II: central ossification; type-III: without ossification), a modified classification with more detailed subtypes (type I-1: ≤ 1/2 peripheral ossification; type I-2: ≥ 1/2 peripheral ossification; type II-1: ≤ 1/2 central ossification; type II-2: ≥ 1/2 central ossification; type III: without ossification), locations, detection methods such as ultrasonography, X-ray, CT or MRI, Musculoskeletal Tumor Society (MSTS) scores were recorded. Multivariate regression analysis was conducted to identify risk factors for recurrence frequency. RESULTS: A total of 558 recurrent cases were identified from 2009 patients with GCTB. Among them, 32 were soft tissue recurrence. The total recurrence rate was 27.78% (558/2009). Soft tissue recurrence rate was 5.73% among 558 recurrent cases, and 1.59% among 2009 GCTB patients, respectively. After excluding one patient lost to follow-up, 10 males and 21 females with the mean age of 28.52 ± 9.93 (16-57) years were included. The definitive diagnosis of all recurrences was confirmed by postoperative pathology. The interval from primary surgery to the first recurrence was 23.23 ± 26.12 (2-27) months. Eight recurrences occurred from primary GCTB located at distal radius, followed by distal femur (6 cases). Recurrence occurred twice in 12 patients and 3 times in 7 patients. Twenty-seven recurrences were firstly detected by ultrasonography, followed by CT or X-ray (10 cases in each). Types at the first recurrence were 5 cases in type-I, 8 in type-II and 18 in type-III. According to the modified classification, 3 patients in type I-1, 2 in type I-2, 1 in type II-1, 7 in type II-2, and 18 in type III. The mean MSTS score was 26.62 ± 4.21 (14-30). Neither Campanacci grade nor recurrence type, modified classification and other characters, were identified as risk factors. CONCLUSIONS: Soft tissue recurrence of GCTB may recur for more than once and distal radius was the most common location of primary GCTB that would suffer a soft tissue recurrence. Ultrasonography was a useful method to detect the recurrence. Since no risk factors were discovered, a careful follow-up with ultrasonography was recommended.

Fabrication of a composite 3D-printed titanium alloy combined with controlled in situ drug release to prevent osteosarcoma recurrence.

Osteosarcoma is a malignant bone tumor occurring in adolescents. Surgery combined with adjuvant or neoadjuvant chemotherapy is the standard treatment. However, systemic chemotherapy is associated with serious side effects and a high risk of postoperative tumor recurrence, leading to a high amputation rate and mortality in cancer patients. Implant materials that can simultaneously repair large bone defects and prevent osteosarcoma recurrence are in urgent need. Herein, an intelligent system comprising 3D-printed titanium scaffold (TS) and pH-responsive PEGylated paclitaxel prodrugs was fabricated for bone defect reconstruction and recurrence prevention following osteosarcoma surgery. The drug-loaded implants exhibited excellent stability and biocompatibility for supporting the activity of bone stem cells under normal body fluid conditions and the rapid release of drugs in response to faintly acidic environments. An in vitro study demonstrated that five human osteosarcoma cell lines could be efficiently eradicated by paclitaxel released in an acidic microenvironment. Using mice models, we demonstrated that the drug-loaded TS can enable a pH-responsive treatment of postoperative tumors and effectively prevent osteosarcoma recurrence. Therefore, local implantation of this composite scaffold may be a promising topical therapeutic method to prevent osteosarcoma recurrence.

CD38-selective immuno-nano-DM1 conjugates for depleting multiple myeloma.

Multiple myeloma (MM) is a neoplasm of aberrant plasma cells and ranks second among hematologic malignancies. Despite a substantial improvement in clinical outcomes with advances in therapeutic modalities over the past two decades, MM remains incurable, necessitating the development of new and potent therapies. Herein, we engineered a daratumumab-polymersome-DM1 conjugate (DPDC) based highly potent and CD38-selective immuno-nano-DM1 toxin for depleting MM cells in vivo. DPDC with controllable daratumumab density and disulfide-linked DM1 is of small size (51-56 nm), with high stability and reduction-triggered DM1 release. D6.2PDC potently inhibited the proliferation of CD38-overexpressed LP-1 and MM.1S MM cells with IC50 values of 2.7 and 1.2 ng DM1 equiv. per mL, about 4-fold stronger than non-targeted PDC. Moreover, D6.2PDC effectively and safely depleted LP-1-Luc MM cells in an orthotopic mouse model at a low DM1 dosage of 0.2 mg kg-1, thus alleviating osteolytic bone lesion and extending the median survival by 2.8-3.5-fold compared to all controls. This CD38-selective DPDC provides a safe and potent treatment strategy for MM.

3D printing of bone and cartilage with polymer materials.

Damage and degeneration to bone and articular cartilage are the leading causes of musculoskeletal disability. Commonly used clinical and surgical methods include autologous/allogeneic bone and cartilage transplantation, vascularized bone transplantation, autologous chondrocyte implantation, mosaicplasty, and joint replacement. 3D bio printing technology to construct implants by layer-by-layer printing of biological materials, living cells, and other biologically active substances in vitro, which is expected to replace the repair mentioned above methods. Researchers use cells and biomedical materials as discrete materials. 3D bio printing has largely solved the problem of insufficient organ donors with the ability to prepare different organs and tissue structures. This paper mainly discusses the application of polymer materials, bio printing cell selection, and its application in bone and cartilage repair.

Recent Advances in Nano-Therapeutic Strategies for Osteoarthritis.

Osteoarthritis (OA) is the most common type of arthritis and the leading cause of disability globally. It tends to occur in middle age or due to an injury or obesity. OA occurs with the onset of symptoms, including joint swelling, joint effusion, and limited movement at a late stage of the disease, which leads to teratogenesis and loss of joint function. During the pathogenesis of this degenerative joint lesion, several local inflammatory responses are activated, resulting in synovial proliferation and pannus formation that facilitates the destruction of the bone and the articular cartilage. The commonly used drugs for the clinical diagnosis and treatment of OA have limitations such as low bioavailability, short half-life, poor targeting, and high systemic toxicity. With the application of nanomaterials and intelligent nanomedicines, novel nanotherapeutic strategies have shown more specific targeting, prolonged half-life, refined bioavailability, and reduced systemic toxicity, compared to the existing medications. In this review, we summarized the recent advancements in new nanotherapeutic strategies for OA and provided suggestions for improving the treatment of OA.

High efficacy of tetra-PEG hydrogel sealants for sutureless dural closure.

Advances in meticulous dural closure technique remain a great challenge for watertight dural closure in the aged society, because the cerebrospinal fluid (CSF) leakage after spinal surgery is often accompanied with the disgusting wound infection, meningitis and pseudomeningocele. Here, a tetra-poly (ethylene glycol) (PEG)-based hydrogel sealant is developed with collective advantages of facile operation, high safety, quick set time, easy injectability, favorable mechanical strength and powerful tissue adhesion for effective sutureless dural closure during the surgery procedure. Impressively, this tetra-PEG sealant can instantaneously adhere to the irregular tissue surfaces even in a liquid environment, and effectively prevent or block off the intraoperative CSF leakage for sutureless dural closure and dura regeneration. Together, this sutureless tetra-PEG adhesive can be utilized as a very promising alternative for high-efficient watertight dural closure of the clinical patients who incidentally or deliberately undergo the durotomy during the spinal surgery.

Multifunctional microcapsules: A theranostic agent for US/MR/PAT multi-modality imaging and synergistic chemo-photothermal osteosarcoma therapy.

Development of versatile theranostic agents that simultaneously integrate therapeutic and diagnostic features remains a clinical urgent. Herein, we aimed to prepare uniform PEGylated (lactic-co-glycolic acid) (PLGA) microcapsules (PB@(Fe3O4@PEG-PLGA) MCs) with superparamagnetic Fe3O4 nanoparticles embedded in the shell and Prussian blue (PB) NPs inbuilt in the cavity via a premix membrane emulsification (PME) method. On account of the eligible geometry and multiple load capacity, these MCs could be used as efficient multi-modality contrast agents to simultaneously enhance the contrasts of US, MR and PAT imaging. In-built PB NPs furnished the MCs with excellent photothermal conversion property and embedded Fe3O4 NPs endowed the magnetic location for fabrication of targeted drug delivery system. Notably, after further in-situ encapsulation of antitumor drug of DOX, (PB+DOX)@(Fe3O4@PEG-PLGA) MCs possessed more unique advantages on achieving near infrared (NIR)-responsive drug delivery and magnetic-guided chemo-photothermal synergistic osteosarcoma therapy. In vitro and in vivo studies revealed these biocompatible (PB+DOX)@(Fe3O4@PEG-PLGA) MCs could effectively target to the tumor tissue with superior therapeutic effect against the invasion of osteosarcoma and alleviation of osteolytic lesions, which will be developed as a smart platform integrating multi-modality imaging capabilities and synergistic effect with high therapy efficacy.

CMTM3 suppresses bone formation and osteogenic differentiation of mesenchymal stem cells through inhibiting Erk1/2 and RUNX2 pathways.

Osteoporosis, fracture, large-scale craniofacial defects and osteonecrosis are hot topics and are still underdiagnosed and undertreated in the clinic. It is urgent to understand the molecular mechanisms corresponding to the regulation of bone formation. CMTM3 (CKLF-like MARVEL transmembrane domain containing 3) connects the classic chemokine to the transmembrane 4 superfamily and plays an important role in intracellular vesicles transport, EGF receptor function maintenance and cancer development. However, its expression and function in bone remain unclear. In this paper, we found that the bone volume/total volume, trabecular number, trabecular thickness and bone surface area/bone volume of Cmtm3 KO mice increased significantly, and trabecular separation and trabecular pattern factor decreased in Cmtm3 KO mice compared with WT mice by microcomputed tomography. Moreover, the bone mineral content, bone mineral density, ultimate force and stiffness were also increased in Cmtm3 KO mice. Using in vitro analysis, we showed that CMTM3 expression decreases during the differentiation of hBMSCs to osteoblasts. Knockdown of CMTM3 promoted ALP and mineralization of hBMSCs and facilitated osteoblastic differentiation with increasing RUNX2 expression. However, overexpression of CMTM3 got the opposite results. These results proved that CMTM3 was essential for osteogenic differentiation. In addition, knockdown of CMTM3 enhanced p-Erk1/2, but had no significant effect on p-Akt or p-STAT3 in hBMSCs and MC3T3-E1 cells. Taken together, our results indicated that Erk1/2 and RUNX2 pathways mediated by CMTM3 were involved in the process of osteogenic differentiation, and CMTM3 might be a new potential target in the treatment of bone formation-related disease.

Practical strategy to construct anti-osteosarcoma bone substitutes by loading cisplatin into 3D-printed titanium alloy implants using a thermosensitive hydrogel.

Surgical resection and perioperative adjuvant chemotherapy-based therapies have improved the prognosis of patients with osteosarcoma; however, intraoperative bone defects, local tumour recurrence, and chemotherapy-induced adverse effects still affect the quality of life of patients. Emerging 3D-printed titanium alloy (Ti6Al4V) implants have advantages over traditional implants in bone repair, including lower elastic modulus, lower stiffness, better bone conduction, more bone in-growth, stronger mechanical interlocking, and lager drug-loading capacity by their inherent porous structure. Here, cisplatin, a clinical first-line anti-osteosarcoma drug, was loaded into Ti6Al4V implants, within a PLGA-PEG-PLGA thermo-sensitive hydrogel, to construct bone substitutes with both anti-osteosarcoma and bone-repair functions. The optimal concentrations of cisplatin (0.8 and 1.6 mg/mL) were first determined in vitro. Thereafter, the anti-tumour effect and biosafety of the cisplatin/hydrogel-loaded implants, as well as their bone-repair potential were evaluated in vivo in tumour-bearing mouse, and bone defect rabbit models, respectively. The loading of cisplatin reduced tumour volume by more than two-thirds (from 641.1 to 201.4 mm3) with negligible organ damage, achieving better anti-tumour effects while avoiding the adverse effects of systemic cisplatin delivery. Although bone repair was hindered by cisplatin loading at 4 weeks, no difference was observed at 8 weeks in the context of implants with versus without cisplatin, indicating acceptable long-term stability of all implants (with 8.48%-10.04% bone in-growth and 16.94%-20.53% osseointegration). Overall, cisplatin/hydrogel-loaded 3D-printed Ti6Al4V implants are safe and effective for treating osteosarcoma-caused bone defects, and should be considered for clinical use.

Three-dimensional-printed individualized porous implants: A new "implant-bone" interface fusion concept for large bone defect treatment.

Bone defect repairs are based on bone graft fusion or replacement. Current large bone defect treatments are inadequate and lack of reliable technology. Therefore, we aimed to investigate a simple technique using three-dimensional (3D)-printed individualized porous implants without any bone grafts, osteoinductive agents, or surface biofunctionalization to treat large bone defects, and systematically study its long-term therapeutic effects and osseointegration characteristics. Twenty-six patients with large bone defects caused by tumor, infection, or trauma received treatment with individualized porous implants; among them, three typical cases underwent a detailed study. Additionally, a large segmental femur defect sheep model was used to study the osseointegration characteristics. Immediate and long-term biomechanical stability was achieved, and the animal study revealed that the bone grew into the pores with gradual remodeling, resulting in a long-term mechanically stable implant-bone complex. Advantages of 3D-printed microporous implants for the repair of bone defects included 1) that the stabilization devices were immediately designed and constructed to achieve early postoperative mobility, and 2) that osseointegration between the host bone and implants was achieved without bone grafting. Our osseointegration method, in which the "implant-bone" interface fusion concept was used instead of "bone-bone" fusion, subverts the traditional idea of osseointegration.

A6 peptide-tagged, ultra-small and reduction-sensitive polymersomal vincristine sulfate as a smart and specific treatment for CD44+ acute myeloid leukemia.

Acute myeloid leukemia (AML) is a severe blood malignancy associated with a high relapse rate. The current clinical chemotherapy is typically perplexed with serious side effects. Here, A6 peptide-tagged, small and reduction-sensitive polymersomal vincristine sulfate (A6-cPS-VCR) is reported as a novel, smart and specific treatment for CD44 positive AML. A6-cPS-VCR stably loaded with 3.3 wt% VCR displays a size of ≈ 31 nm and pronounced selectivity toward CD44-overexpressed MV4-11 leukemia cells. Intriguingly, A6-cPS-VCR effectively represses the outgrowth of orthotopic MV4-11 AML in vivo, as revealed by significant reduction of leukemia burdens in the circulation, bone marrow, liver and spleen, and significantly extends the median survival time of MV4-11 AML-bearing mice. In addition to active targetability and therapeutic benefits, A6-cPS-VCR has the advantage of easy fabrication, rendering it potentially interesting for clinical translation.

Recent Advances of Magnetic Nanomaterials in Bone Tissue Repair.

The magnetic field has been proven to enhance bone tissue repair by affecting cell metabolic behavior. Magnetic nanoparticles are used as biomaterials due to their unique magnetic properties and good biocompatibility. Through endocytosis, entering the cell makes it easier to affect the physiological function of the cell. Once the magnetic particles are exposed to an external magnetic field, they will be rapidly magnetized. The magnetic particles and the magnetic field work together to enhance the effectiveness of their bone tissue repair treatment. This article reviews the common synthesis methods, the mechanism, and application of magnetic nanomaterials in the field of bone tissue repair.

Functionalization of 3D-printed titanium alloy orthopedic implants: a literature review.

Titanium alloy orthopedic implants produced by 3D printing combine the dual advantages of having a complex structure that cannot be manufactured by traditional techniques and the excellent physical and chemical properties of titanium and its alloys; they have been widely used in the field of orthopedics in recent years. The inherent porous structure of 3D-printed implants and the original modification processes for titanium alloys provide conditions for the functionalization of implants. To meet the needs of orthopedic surgeons and patients, functionalized implants with long-term stability and anti-infection or anti-tumor properties have been developed. The various methods of functionalization deserve to be summarized, compared and analyzed. Therefore, in this review, we will collect and discuss existing knowledge on the functionalization of 3D-printed titanium alloy orthopedic implants.

Sustainable release of vancomycin from micro-arc oxidised 3D-printed porous Ti6Al4V for treating methicillin-resistant Staphylococcus aureus bone infection and enhancing osteogenesis in a rabbit tibia osteomyelitis model.

Elimination of infection and enhancement of osteogenesis by orthopaedic implants are two critical factors in the treatment of complex bone infections. A prolonged and expensive procedure requiring two surgical steps and a 6-8-week period of joint immobilisation is utilised as a primary treatment for revision arthroplasty of an infected prosthesis, greatly affecting long-term patient care for the ageing population. Here, we evaluated the effects of vancomycin-loaded in micro-arc oxidised (MAO) three-dimensional (3D) printed porous Ti6Al4V scaffolds on osteogenesis. This system showed a high loading capacity and sustained vancomycin release kinetics, as demonstrated using high-performance liquid chromatography. In vivo, 0.1 mL of 108 colony forming units (CFU) methicillin-resistant Staphylococcus aureus was injected into the tibias of rabbits to induce severe osteomyelitis. Physical, haematological, radiographic, microbiological, and histopathological analyses were performed to evaluate the effects of treatment. Rabbits with vancomycin-loaded in MAO scaffolds showed the inhibition of bone infection and enhancement of osteogenesis, resulting in better outcomes than in the other groups. Overall, these findings demonstrated the potential of this 3D printed porous Ti6Al4V, with good osteogenesis and sustained vancomycin release properties, for application in the treatment of complex bone infections.

Progressive 3D Printing Technology and Its Application in Medical Materials.

Three-dimensional (3D) printing enables patient-specific anatomical level productions with high adjustability and resolution in microstructures. With cost-effective manufacturing for high productivity, 3D printing has become a leading healthcare and pharmaceutical manufacturing technology, which is suitable for variety of applications including tissue engineering models, anatomical models, pharmacological design and validation model, medical apparatus and instruments. Today, 3D printing is offering clinical available medical products and platforms suitable for emerging research fields, including tissue and organ printing. In this review, our goal is to discuss progressive 3D printing technology and its application in medical materials. The additive overview also provides manufacturing techniques and printable materials.

Role of miRNA-542-5p in the tumorigenesis of osteosarcoma.

Osteosarcoma, one of the most common malignant bone tumors, is characterized by a high rate of metastasis, and the survival rate of patients with metastatic osteosarcoma is poor. Previous studies have reported that miRNAs often regulate the occurrence and development of various tumors. In this work, we identified miRNA-542-5p as a critical miRNA in osteosarcoma by overlapping three Gene Expression Omnibus datasets, and then evaluated miRNA-542-5p expression profiles using Gene Expression Omnibus and Sarcoma-microRNA Expression Database. We used MISIM to investigate miRNAs correlated with miR-542 and identified potential target genes of miRNA-542-5p using miRWalk. Functional and pathway enrichment analyses were performed using The Database for Annotation, Visualization and Integrated Discovery. Protein-protein interaction was performed using Search Tool for the Retrieval of Interacting Genes and Cytoscape. We report that the relative level of miRNA-542-5p was significantly higher in osteosarcoma than in healthy bone. Expressions of hsa-miR-330 and hsa-miR-1202 were found to be strongly correlated with that of miR-542-5p. Furthermore, we identified a total of 514 down-regulated genes as possible targets of miR-542-5p. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis demonstrated that the putative target genes of miR-542-5p were most enriched in the cell-cycle process. The differentially expressed genes CDCA5, PARP12 and HSPD1 were found to be hub genes in protein-protein interaction networks. Finally, transfection of the osteosarcoma cell line U2OS with miR-542-5p mimics or inhibitor revealed that miR-542-5p can promote cell proliferation. In conclusion, our results suggest that miR-542-5p may promote osteosarcoma proliferation; thus, this miRNA may have potential as a biomarker for diagnosis and prognosis.

Improved osseointegration with rhBMP-2 intraoperatively loaded in a specifically designed 3D-printed porous Ti6Al4V vertebral implant.

Three-dimensional (3D)-printed porous Ti6Al4V implants are commonly used for reconstructing bone defects in the treatment of orthopaedic diseases owing to their excellent osteoconduction. However, to achieve improved therapeutic outcomes, the osteoinduction of these implants requires further improvement. The aim of this study was to investigate the combined use of recombinant human BMP-2 (rhBMP-2) with a 3D-printed artificial vertebral implant (3D-AVI) to improve the osteoinduction. Eight male Small Tail Han sheep underwent cervical corpectomy, and 3D-AVIs with or without loaded rhBMP-2 in cavities designed at the center were implanted to treat the cervical defect. Radiographic, micro-computed tomography, fluorescence labelling, and histological examination revealed that the osseointegration efficiency of the rhBMP-2 group was significantly higher than that of the blank control group. The biomechanical test results suggested that rhBMP-2 reduced the range of motion of the cervical spine and provided a more stable implant. Fluorescence observations revealed that the bone tissue grew from the periphery to the center of the 3D-AVIs, first growing into the pore space and then interlocking with the Ti6Al4V implant surface. Therefore, we successfully improved osseointegration of the 3D-AVI by loading rhBMP-2 into the cavity designed at the center of the Ti6Al4V implant, realizing earlier and more stable fixation of implants postoperatively in a simple manner. These benefits of rhBMP-2 are expected to expand the application range and reliability of 3D-printed porous Ti6Al4V implants and improve their therapeutic efficacy.

Injectable Hydrogels for Localized Cancer Therapy.

Traditional intravenous chemotherapy is relative to many systemic side effects, including myelosuppression, liver or kidney dysfunction, and neurotoxicity. As an alternative method, the injectable hydrogel can efficiently avoid these problems by releasing drugs topically at the tumor site. With advantages of localized drug toxicity in the tumor site, proper injectable hydrogel as the drug delivery system has become a research hotspot. Based on different types and stages of cancer, a variety of hydrogel drug delivery systems were developed, including thermosensitive, pH-sensitive, photosensitive, and dual-sensitive hydrogel. In this review, the latest developments of these hydrogels and related drug delivery systems were summarized. In summary, our increasing knowledge of injectable hydrogel for localized cancer therapy ensures us that it is a more durable and effective approach than traditional chemotherapy. Smart release system reacting to different stimuli at different time according to the micro-environment changes in the tumor site is a promising tendency for further studies.