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

‘Repair’ Treg Cells in Tissue Injury

Studies in mice and humans have elucidated an important role for Tregs in promoting tissue repair and restoring tissue integrity. Emerging evidence has revealed that Tregs promoted wound healing and repair processes at multiple tissue sites, such as the heart, liver, kidney, muscle, lung, bone and central nervous system. The localization of repair Tregs in the lung, muscle and liver exhibited unique phenotypes and functions. Epidermal growth factor receptor, amphiregulin, CD73/CD39 and keratinocyte growth factor are important repair factors that are produced or expressed by repair Tregs; these factors coordinate with parenchymal cells to limit injury and promote repair. In addition, repair Tregs can be modulated by IL-33/ST2, TCR signals and other cytokines in the context of injured microenvironment cues. In this review, we provide an overview of the emerging knowledge about Treg-mediated repair in damaged tissues and organs

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

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

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

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

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