Sophisticated Magneto-Mechanical Actuation Promotes In Situ Stem Cell Assembly and Chondrogenesis for Treating Osteoarthritis.

Abnormal mechanical loading often leads to the progressive degradation of cartilage and causes osteoarthritis (OA). Although multiple mechanoresponsive strategies based on biomaterials have been designed to restore healthy cartilage microenvironments, methods to remotely control the on-demand mechanical forces for cartilage repair pose significant challenges. Here, a magneto-mechanically controlled mesenchymal stem cell (MSC) platform, based on the integration of intercellular mechanical communication and intracellular mechanosignaling processes, is developed for OA treatment. MSCs loaded with antioxidative melanin@Fe3O4 magnetic nanoparticles (Magcells) rapidly assemble into highly ordered cell clusters with enhanced cell-cell communication under a time-varying magnetic field, which enables long-term retention and differentiation of Magcells in the articular cavity. Subsequently, via mimicking the gait cycle, chondrogenesis can be further enhanced by the dynamic activation of mechanical signaling processes in Magcells. This sophisticated magneto-mechanical actuation strategy provides a paradigm for developing mechano-therapeutics to repair cartilage in OA treatment.

Structural and Molecular Fusion MRI Nanoprobe for Differential Diagnosis of Malignant Tumors and Follow-Up Chemodynamic Therapy.

Enhanced imaging techniques using contrast agents enable high-resolution structural imaging to reveal space-occupying lesions but rarely provide detailed molecular information. To this end, we report a structural and molecular fusion magnetic resonance imaging (MRI) nanoprobe for differential diagnosis between benign and malignant tumors. This fusion nanoprobe, termed FFT NPs, follows a working mechanism involving a T1-/T2-weighted magnetic resonance tuning effect (MRET) between a magnetic Fe3O4 core and a paramagnetic Fe-tannic acid (Fe-TA) shell. The FFT NPs with an "always-on" inert T2 signal provide structural MRI (sMRI) contrast of tumors while affording an activated T1 signal in the presence of ATP, which is overproduced during the rapid growth of malignant tumors to enable molecular MRI (mMRI) of tumor lesions. We propose the use of the ratiometric mMRI:sMRI intensity to assist in the differential diagnosis of malignant 4T1 tumors from benign L929 fibroblast tumors. Furthermore, the dissociated FFT NPs were found to be able to catalyze H2O2 conversion in 4T1 tumors to generate excess reactive oxygen species (ROS) for chemodynamic therapy. The described fusion nanoprobe strategy enables the differential diagnosis of tumors from a combined spatial and molecular perspective with one-stop MRI imaging with potential applications in precision intervention.

An Engineered Bacteria-Hybrid Microrobot with the Magnetothermal Bioswitch for Remotely Collective Perception and Imaging-Guided Cancer Treatment.

Microrobots driven by multiple propelling forces hold great potential for noninvasively targeted delivery in the physiologic environment. However, the remotely collective perception and precise propelling in a low Reynold's number bioenvironment remain the major challenges of microrobots to achieve desired therapeutic effects in vivo. Here, we reported a biohybrid microrobot that integrated with magnetic, thermal, and hypoxia sensitivities and an internal fluorescent protein as the dual reporter of thermal and positioning signals for targeted cancer treatment. There were three key elements in the microrobotic system, including the magnetic nanoparticle (MNP)-loaded probiotic Escherichia coli Nissle1917 (EcN@MNP) for spatially magnetic and hypoxia perception, a thermal-logic circuit engineered into the bacteria to control the biosynthesis of mCherry as the temperature and positioning reporter, and NDH-2 enzyme encoded in the EcN for enhanced anticancer therapy. According to the fluorescent-protein-based imaging feedback, the microrobot showed good thermal sensitivity and active targeting ability to the tumor area in a collective manner under the magnetic field. The cancer cell apoptosis was efficiently triggered in vitro and in vivo by the hybrid microrobot coupled with the effects of magnetothermal ablation and NDH-2-induced reactive oxygen species (ROS) damage. Our study demonstrates that the biohybrid EcN microrobot is an ideal platform to integrate the physical, biological, and chemical properties for collective perception and propelling in targeted cancer treatment.

Multimodal Imaging-Guided Spatiotemporal Tracking of Photosensitive Stem Cells for Breast Cancer Treatment.

Stem cell therapy has shown great potential in treating a wide range of diseases including cancer. The real-time tracking of stem cells with high spatiotemporal resolution and stable imaging signals remains the bottleneck to evaluate and monitor therapeutic outcomes once transplanted into patients. Here, we developed a photosensitive mesenchymal stem cell (MSC) loaded with mesoporous silica-coated gold nanostars (MGNSs) integrated with indocyanine green for spatiotemporal tracking and imaging-guided photothermal therapy (PTT) in treating breast cancers. The MGNS served as a stable imaging probe with multifunctional properties for photoacoustic imaging (PAI), fluorescence imaging, and PT imaging. Owing to the excellent PT stability of MGNSs, long-term three-dimensional (3D) PAI was achieved to monitor stem cells in real time at the tumor site, while the tumor structure was imaged using 3D B-mode ultrasound imaging. PAI revealed that the photosensitive stem cells reached the widest distribution area at the tumor site post 24 h of intratumoral injection, which was further confirmed via two-dimensional (2D) PT and fluorescence imaging. With this optimal cell distribution window, in vivo studies showed that the photosensitive stem cells via both intratumoral and intravenous injections successfully inhibited breast cancer cell growth and decreased the tumor recurrence rate post PTT. Our results support that this photo-integrated platform with stable optical properties is promising to achieve real-time tracking and measure the cell distribution quantitatively with high spatiotemporal resolution for stem cell therapy.

Bioceramic Scaffolds with Antioxidative Functions for ROS Scavenging and Osteochondral Regeneration.

Osteoarthritis (OA) is a degenerative disease that involves excess reactive oxygen species (ROS) and osteochondral defects. Although multiple approaches have been developed for osteochondral regeneration, how to balance the biochemical and physical microenvironment in OA remains a big challenge. In this study, a bioceramic scaffold by 3D printed akermanite (AKT) integrated with hair-derived antioxidative nanoparticles (HNPs)/microparticles (HMPs) for ROS scavenging and osteochondral regeneration has been developed. The prepared bioscaffold with multi-mimetic enzyme effects, which can scavenge a broad spectrum of free radicals in OA, can protect chondrocytes under the ROS microenvironment. Importantly, the bioscaffold can distinctly stimulate the proliferation and maturation of chondrocytes due to the stimulation of the glucose transporter pathway (GLUT) via HNPs/HMPs. Furthermore, it significantly accelerated osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). In vivo results showed that the bioscaffold can effectively enhance the osteochondral regeneration compared to the unmodified scaffold. The work shows that integration of antioxidant and mechanical properties via the bioscaffold is a promising strategy for osteochondral regeneration in OA treatment.

The potential application of nanomaterials for ferroptosis-based cancer therapy.

Ferroptosis is a new type of programmed cell death, which is expected to become an important strategy of cancer treatment. Traditional strategies for inducing iron death are small molecule inducers based on biological agents. However, because of their poor water solubility, low cell targeting ability and fast metabolismin vivo, it is difficult for molecular drugs to play the long-acting role of ferroptosis induction. With the further study of ferroptosis and development of nanotechnology, nanomaterials have been proved to be more efficient drugs for inducing ferroptosis than those biological drugs. Therein, iron-based nanomaterials can directly release high concentrations of irons and increase reactive oxygen species levels in cells, which produce a better induction effect for ferroptosis. Whereas, it is challenging to differentiate nanoparticle-induced ferroptosis and traditional inducing strategies, elucidate the detailed mechanisms and further classify the synthetical methods of nanomaterials. For better guidance on the development of anticancer strategies, comprehensive summary of the latest developments of ferroptosis related nanomaterials, especially iron-based nanomaterials are in urgent need. In the paper, we summarized the main mechanisms of ferroptosis, highlighted the latest developments of nanomaterials for ferroptosis, and emphasized the advantages of iron-based nanomaterials for ferroptosis. The future prospect in this field was also discussed, paving the way for the related nanomaterials in the clinical cancer therapy.

Mn-containing bioceramics inhibit osteoclastogenesis and promote osteoporotic bone regeneration via scavenging ROS.

Osteoporosis is caused by an osteoclast activation mechanism. People suffering from osteoporosis are prone to bone defects. Increasing evidence indicates that scavenging reactive oxygen species (ROS) can inhibit receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclastogenesis and suppress ovariectomy-induced osteoporosis. It is critical to develop biomaterials with antioxidant properties to modulate osteoclast activity for treating osteoporotic bone defects. Previous studies have shown that manganese (Mn) can improve bone regeneration, and Mn supplementation may treat osteoporosis. However, the effect of Mn on osteoclasts and the role of Mn in osteoporotic bone defects remain unclear. In present research, a model bioceramic, Mn-contained ß-tricalcium phosphate (Mn-TCP) was prepared by introducing Mn into ß-TCP. The introduction of Mn into ß-TCP significantly improved the scavenging of oxygen radicals and nitrogen radicals, demonstrating that Mn-TCP bioceramics might have antioxidant properties. The in vitro and in vivo findings revealed that Mn2+ ions released from Mn-TCP bioceramics could distinctly inhibit the formation and function of osteoclasts, promote the differentiation of osteoblasts, and accelerate bone regeneration under osteoporotic conditions in vivo. Mechanistically, Mn-TCP bioceramics inhibited osteoclastogenesis and promoted the regeneration of osteoporotic bone defects by scavenging ROS via Nrf2 activation. These results suggest that Mn-containing bioceramics with osteoconductivity, ROS scavenging and bone resorption inhibition abilities may be an ideal biomaterial for the treatment of osteoporotic bone defect.

3D printing of Haversian bone-mimicking scaffolds for multicellular delivery in bone regeneration.

The integration of structure and function for tissue engineering scaffolds is of great importance in mimicking native bone tissue. However, the complexity of hierarchical structures, the requirement for mechanical properties, and the diversity of bone resident cells are the major challenges in constructing biomimetic bone tissue engineering scaffolds. Herein, a Haversian bone-mimicking scaffold with integrated hierarchical Haversian bone structure was successfully prepared via digital laser processing (DLP)-based 3D printing. The compressive strength and porosity of scaffolds could be well controlled by altering the parameters of the Haversian bone-mimicking structure. The Haversian bone-mimicking scaffolds showed great potential for multicellular delivery by inducing osteogenic, angiogenic, and neurogenic differentiation in vitro and accelerated the ingrowth of blood vessels and new bone formation in vivo. The work offers a new strategy for designing structured and functionalized biomaterials through mimicking native complex bone tissue for tissue regeneration.

Tumor microenvironment triggered biodegradation of inorganic nanoparticles for enhanced tumor theranostics.

Inorganic nanoparticles (NPs)-mediated tumor theranostics have attracted widespread attention due to their unique physicochemical properties, such as optical, electrical, magnetic, and thermal properties. In the past decade, great advancements have been made in inorganic NPs-associated drug delivery, multimodal tumor imaging, and tumor therapy. However, the potential toxicity of inorganic NPs due to their low biodegradability, background signals interference and treatment side effects limit their clinical application. Therefore, developing biodegradable and intelligent NPs is beneficial to avoid excessive metal ions deposition, specific tumor imaging and treatment. In this review, we summarize the recent advances in tumor microenvironment (TME)-triggered biodegradation of inorganic NPs accompanied by imaging signal amplification and the released ions-mediated tumor therapy. First, the feature characteristics of the TME are introduced, including mild acidity, hypoxia, overexpressed reactive oxygen species (ROS), glutathione (GSH), and enzymes et al.; then, the biodegradation of NPs in a TME-induced activation of imaging signals, such as magnetic resonance (MR) imaging and fluorescence imaging is described; furthermore, tumor therapies through "Fenton", "Fenton-like" reactions, and interference of biological effects in cells is presented. Finally, the challenges and outlook for improving the degradation efficiency, imaging, specificity and efficiency of tumor imaging and treatment are discussed.

Copper-incorporated bioactive glass-ceramics inducing anti-inflammatory phenotype and regeneration of cartilage/bone interface.

Osteoarthritis not only results in cartilage lesion, but also is accompanied with subchondral bone damage caused by the inflammatory response. It is of great significance to treat osteoarthritis by regulating the immune response. As copper (Cu) plays an essential role in immune response and anti-arthritis, a copper-incorporated bioactive glass-ceramics (Cu-BGC) may achieve the aim of healing cartilage lesion and reducing inflammatory response caused by osteoarthritis. We hypothesized that the Cu2+ released from Cu-BGC scaffolds may satisfy the requirements of cartilage regeneration and anti-arthritis. Methods: 3D-printing method was employed to prepare Cu-BGC scaffolds. The stimulating effect on the chondrocytes and macrophages cultured with Cu-BGC extracts was investigated. Furthermore, the in vivo regenerative effect of Cu-BGC scaffolds on osteochondral defects was studied. Results: The incorporation of Cu2+ into BGC considerably promoted the proliferation and maturation of chondrocytes, and induced macrophages shifting to anti-inflammatory phenotype. Histological analysis demonstrated that the Cu-BGC scaffolds meaningfully improved the regeneration of cartilage and elevated the recovery of the osteochondral interface as compared with the CTR and BGC groups. The potential mechanism is related to Cu2+ ions triggering the immune response of cartilage via activating HIF signaling pathway and inhibiting the inflammatory response in osteochondral tissue. Conclusion: These results demonstrated that Cu-BGC scaffolds significantly facilitated the regeneration of cartilage and osteochondral interface, as well as inhibited inflammatory response, which may prevent the development of osteoarthritis associated with osteochondral defects.

Advances of nanotechnology in osteochondral regeneration.

In the past few decades, nanotechnology has proven to be one of the most powerful engineering strategies. The nanotechnologies for osteochondral tissue engineering aim to restore the anatomical structures and physiological functions of cartilage, subchondral bone, and osteochondral interface. As subchondral bone and articular cartilage have different anatomical structures and the physiological functions, complete healing of osteochondral defects remains a great challenge. Considering the limitation of articular cartilage to self-healing and the complexity of osteochondral tissue, osteochondral defects are in urgently need for new therapeutic strategies. This review article will concentrate on the most recent advancements of nanotechnologies, which facilitates chondrogenic and osteogenic differentiation for osteochondral regeneration. Moreover, this review will also discuss the current strategies and physiological challenges for the regeneration of osteochondral tissue. Specifically, we will summarize the latest developments of nanobased scaffolds for simultaneously regenerating subchondral bone and articular cartilage tissues. Additionally, perspectives of nanotechnology in osteochondral tissue engineering will be highlighted. This review article provides a comprehensive summary of the latest trends in cartilage and subchondral bone regeneration, paving the way for nanotechnologies in osteochondral tissue engineering. This article is categorized under: Implantable Materials and Surgical Technologies > Nanomaterials and Implants Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Implantable Materials and Surgical Technologies > Nanotechnology in Tissue Repair and Replacement.

Bioactive scaffolds for osteochondral regeneration.

Treatment for osteochondral defects remains a great challenge. Although several clinical strategies have been developed for management of osteochondral defects, the reconstruction of both cartilage and subchondral bone has proved to be difficult due to their different physiological structures and functions. Considering the restriction of cartilage to self-healing and the different biological properties in osteochondral tissue, new therapy strategies are essential to be developed. This review will focus on the latest developments of bioactive scaffolds, which facilitate the osteogenic and chondrogenic differentiation for the regeneration of bone and cartilage. Besides, the topic will also review the basic anatomy, strategies and challenges for osteochondral reconstruction, the selection of cells, biochemical factors and bioactive materials, as well as the design and preparation of bioactive scaffolds. Specifically, we summarize the most recent developments of single-type bioactive scaffolds for simultaneously regenerating cartilage and subchondral bone. Moreover, the future outlook of bioactive scaffolds in osteochondral tissue engineering will be discussed. This review offers a comprehensive summary of the most recent trend in osteochondral defect reconstruction, paving the way for the bioactive scaffolds in clinical therapy. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: This review summaries the latest developments of single-type bioactive scaffolds for regeneration of osteochondral defects. We also highlight a new possible translational direction for cartilage formation by harnessing bioactive ions and propose novel paradigms for subchondral bone regeneration in application of bioceramic scaffolds.

3D printing of a lithium-calcium-silicate crystal bioscaffold with dual bioactivities for osteochondral interface reconstruction.

It is difficult to achieve self-healing outcoming for the osteochondral defects caused by degenerative diseases. The simultaneous regeneration of both cartilage and subchondral bone tissues is an effective therapeutic strategy for osteochondral defects. However, it is challenging to design a single type of bioscaffold with suitable ionic components and beneficial osteo/chondral-stimulation ability for regeneration of osteochondral defects. In this study, we successfully synthesized a pure-phase lithium calcium silicate (Li2Ca4Si4O13, L2C4S4) bioceramic by a sol-gel method, and further prepared L2C4S4 scaffolds by using a 3D-printing method. The compressive strength of L2C4S4 scaffolds could be well controlled in the range of 15-40 MPa when pore size varied from 170 to 400 µm. L2C4S4 scaffolds have been demonstrated to possess controlled biodegradability and good apatite-mineralization ability. At a certain concentration range, the ionic products from L2C4S4 significantly stimulated the proliferation and maturation of chondrocytes, as well as promoted the osteogenic differentiation of rBMSCs. L2C4S4 scaffolds simultaneously promoted the regeneration of both cartilage and subchondral bone as compared to pure ß-TCP scaffolds in rabbit osteochondral defects. These findings suggest that 3D-printed L2C4S4 scaffolds with such specific ionic combination, high mechanical strength and good degradability as well as dual bioactivities, represent a promising biomaterial for osteochondral interface reconstruction.

Intra-articular tracking of adipose-derived stem cells by chitosan-conjugated iron oxide nanoparticles in a rat osteoarthritis model.

Adipose-derived stem cells (ADSCs) hold great potential in cartilage tissue engineering due to their multipotency and ease of availability. MRI is an effective and noninvasive imaging approach to track cells and observe new tissue regeneration. It is essential to find a compatible and efficient imaging reagent without affecting the stemness of ADSCs. Herein, we developed chitosan-modified iron oxide nanoparticles (IO-CS) as the T 2 contrast reagent with good cell compatibility and high cellular uptake efficiency and used IO-CS for ADSC intra-articular imaging in a rat osteoarthritis (OA) model. TEM demonstrated the great morphology and size distribution of IO-CS nanoparticles with the size of 17 nm. Magnetization (29.4 emu per g) and MRI tests confirmed (R 2 of 184 mM-1 s-1) the feasibility of IO-CS nanoparticles as an MRI contrast reagent. In addition, the IO-CS nanoparticles showed good cellular compatibility and high labeling efficiency as compared to the commercial agent ferumoxytol. Moreover, incorporation of IO-CS nanoparticles did not alter the adipogenic, osteogenic and chondrogenic differentiation ability of ADSCs. Furthermore, the MRI transverse R 2 maps showed a persistence time of the IO-CS nanoparticles in ADSCs of 6 days in vitro. Then, we investigated the imaging capability of the IO-CS nanoparticle-labeled ADSCs in vivo with MRI for 5 weeks. The histological studies demonstrated the intra-articular biodistribution of the IO-CS nanoparticles, including in the cartilage superficial layer, synovial sublining layer, periosteum and bone marrow cavity. They provided systemic distribution information of the ADSCs in the OA rat model. In summary, we developed an accessible and effective T 2 imaging reagent with good biocompatibility and maintenance of the stemness of ADSCs. This showed the potential translational application of IO-CS nanoparticles as an MRI reagent in cartilage tissue engineering.

3D printing of Mo-containing scaffolds with activated anabolic responses and bi-lineage bioactivities.

When osteochondral tissues suffer from focal or degenerative lesions caused by trauma or disorders, it is a tough challenge to regenerate them because of the limited self-healing capacity of articular cartilage. In this study, a series of Mo-doped bioactive glass ceramic (Mo-BGC) scaffolds were prepared and then systematically characterized. The released MoO42- ions from 7.5Mo-BGC scaffolds played a vital role in regenerating articular cartilage and subchondral bone synchronously. Methods: The Mo-BGC scaffolds were fabricated through employing both a sol-gel method and 3D printing technology. SEM, EDS, HRTEM, XRD, ICPAES and mechanical strength tests were respectively applied to analyze the physicochemical properties of Mo-BGC scaffolds. The proliferation and differentiation of rabbit chondrocytes (RCs) and human bone mesenchymal stem cells (HBMSCs) cultured with dilute solutions of 7.5Mo-BGC powder extract were investigated in vitro. The co-culture model was established to explore the possible mechanism of stimulatory effects of MoO42- ions on the RCs and HBMSCs. The efficacy of regenerating articular cartilage and subchondral bone using 7.5Mo-BGC scaffolds was evaluated in vivo. Results: The incorporation of Mo into BGC scaffolds effectively enhanced the compressive strength of scaffolds owing to the improved surface densification. The MoO42- ions released from the 7.5Mo-BGC powders remarkably promoted the proliferation and differentiation of both RCs and HBMSCs. The MoO42- ions in the co-culture system significantly stimulated the chondrogenic differentiation of RCs and meanwhile induced the chondrogenesis of HBMSCs. The chondrogenesis stimulated by MoO42- ions happened through two pathways: 1) MoO42- ions elicited anabolic responses through activating the HIF-1α signaling pathway; 2) MoO42- ions inhibited catabolic responses and protected cartilage matrix from degradation. The in vivo study showed that 7.5Mo-BGC scaffolds were able to significantly promote cartilage/bone regeneration when implanted into rabbit osteochondral defects for 8 and 12 weeks, displaying bi-lineage bioactivities. Conclusion: The 3D-printed Mo-BGC scaffolds with bi-lineage bioactivities and activated anabolic responses could offer an effective strategy for cartilage/bone interface regeneration.

3D-printed scaffolds with bioactive elements-induced photothermal effect for bone tumor therapy.

For treatment of bone tumor and regeneration of bone defects, the biomaterials should possess the ability to kill tumor cells and regenerate bone defect simultaneously. To date, there are a few biomaterials possessing such dual functions, the disadvantages, however, such as long-term toxicity and degradation, restrict their application. Although bioactive elements have been incorporated into biomaterials to improve their osteogenic activity, there is no report about elements-induced functional scaffolds for photothermal tumor therapy. Herein, the elements (Cu, Fe, Mn, Co)-doped bioactive glass-ceramic (BGC) scaffolds with photothermal effect and osteogenic differentiation ability were prepared via 3D-printing method. Moreover, the photothermal anti-tumor effect and osteogenic activity of these scaffolds were systematically investigated. The prepared elements-doped scaffolds possessed excellent photothermal performance, which displayed a trend, 5Cu-BGC > 5Fe-BGC > 5Mn-BGC > 5Co-BGC, in this study. The final temperature of elements-doped scaffolds can be well controlled by altering the doping element categories, contents and laser power density. Additionally, the hyperthermia induced by 5Cu-BGC, 5Fe-BGC and 5Mn-BGC effectively killed tumor cells in vitro and inhibited tumor growth in vivo. More importantly, 5Fe-BGC and 5Mn-BGC scaffolds could promote rabbit bone mesenchymal stem cells (rBMSCs) adhesion, and the ionic products released from elements-doped scaffolds significantly stimulated the osteogenic differentiation of bone-forming cells. These results suggested that 5Fe-BGC and 5Mn-BGC scaffolds possessed promising potential for photothermal treatment of bone tumor and at the same time for stimulating bone regeneration, representing a smart strategy for the treatment of bone tumors by combining dual functional bioactive ions with tissue engineering scaffolds. STATEMENT OF SIGNIFICANCE: The major innovation of this study is that we fabricated the elements (Cu, Fe, Mn, Co)-doped bioactive scaffolds via 3D printing technique and found that they possess distinct photothermal performance and osteogenic differentiation ability. To the best of our knowledge, there is no report about elements-doped scaffolds for photothermal therapy of bone tumor. This is an important research advance by combining the photothermal effect and osteogenic differentiation activity of bioactive elements in the scaffold system for potential bone tumor therapy and bone reconstruction. We optimized the elements-doped scaffolds and found the photothermal effect of elements-doped scaffolds (5Cu-BGC, 5Fe-BGC, 5Mn-BGC) could effectively kill tumor cells in vivo. The photothermal performance of elements-doped scaffolds follows a trend: 5Cu-BGC > 5Fe-BGC > 5Mn-BGC > 5Co-BGC > BGC. Compared to traditional nano-sized photothermal agents, bioactive elements-induced functional scaffolds have better biosecurity and bioactivity. Furthermore, 5Fe-BGC and 5Mn-BGC scaffolds displayed excellent bone-forming activity by stimulating the osteogenic differentiation of bone-forming cells. The major significance of the study is that the elements-doped bioactive glass-ceramics (5Fe-BGC, 5Mn-BGC) have great potential to be used as bifunctional scaffolds for photothermal tumor therapy and bone regeneration, representing a smart strategy for the treatment of bone tumors by combining dual functional bioactive ions with tissue engineering scaffolds.

Bioactive Scaffolds for Regeneration of Cartilage and Subchondral Bone Interface.

The cartilage lesion resulting from osteoarthritis (OA) always extends into subchondral bone. It is of great importance for simultaneous regeneration of two tissues of cartilage and subchondral bone. 3D-printed Sr5(PO4)2SiO4 (SPS) bioactive ceramic scaffolds may achieve the aim of regenerating both of cartilage and subchondral bone. We hypothesized that strontium (Sr) and silicon (Si) ions released from SPS scaffolds play a crucial role in osteochondral defect reconstruction. Methods: SPS bioactive ceramic scaffolds were fabricated by a 3D-printing method. The SEM and ICPAES were used to investigate the physicochemical properties of SPS scaffolds. The proliferation and maturation of rabbit chondrocytes stimulated by SPS bioactive ceramics were measured in vitro. The stimulatory effect of SPS scaffolds for cartilage and subchondral bone regeneration was investigated in vivo. Results: SPS scaffolds significantly stimulated chondrocyte proliferation, and SPS extracts distinctly enhanced the maturation of chondrocytes and preserved chondrocytes from OA. SPS scaffolds markedly promoted the regeneration of osteochondral defects. The complex interface microstructure between cartilage and subchondral bone was obviously reconstructed. The underlying mechanism may be related to Sr and Si ions stimulating cartilage regeneration by activating HIF pathway and promoting subchondral bone reconstruction through activating Wnt pathway, as well as preserving chondrocytes from OA via inducing autophagy and inhibiting hedgehog pathway. Conclusion: Our findings suggest that SPS scaffolds can help osteochondral defect reconstruction and well reconstruct the complex interface between cartilage and subchondral bone, which represents a promising strategy for osteochondral defect regeneration.

3D Printing of Lotus Root-Like Biomimetic Materials for Cell Delivery and Tissue Regeneration.

Biomimetic materials have drawn more and more attention in recent years. Regeneration of large bone defects is still a major clinical challenge. In addition, vascularization plays an important role in the process of large bone regeneration and microchannel structure can induce endothelial cells to form rudimentary vasculature. In recent years, 3D printing scaffolds are major materials for large bone defect repair. However, these traditional 3D scaffolds have low porosity and nonchannel structure, which impede angiogenesis and osteogenesis. In this study, inspired by the microstructure of natural plant lotus root, biomimetic materials with lotus root-like structures are successfully prepared via a modified 3D printing strategy. Compared with traditional 3D materials, these biomimetic materials can significantly improve in vitro cell attachment and proliferation as well as promote in vivo osteogenesis, indicating potential application for cell delivery and bone regeneration.

Fabrication of photo-crosslinked chitosan- gelatin scaffold in sodium alginate hydrogel for chondrocyte culture.

Photo-crosslinked chitosan-gelatin scaffolds were fabricated and applied for chondrocyte culture in vitro. Photocurable methacryloyl chitosan was synthesized and characterized by FTIR and 1H NMR, respectively. Microstructure and mechanical properties of the chitosan-gelatin scaffold treated with or without EDC as crosslinking agent were analyzed by scanning electronic microscopy (SEM), compression and viscoelastic measurement. It is demonstrated that EDC-treated chitosan-gelatin scaffold possesses better porous structure and improved mechanical properties. Photo-crosslinked chitosan-gelatin scaffold could be further integrated in sodium alginate hydrogel using calcium chloride to support proliferation of chondrocytes for over 21 days and maintain spherical phenotype, as evaluated by AlamarBlue assay and SEM, respectively, implying that the chitosan-gelatin-hydrogel system exhibits great cyto-biocompatibility. Results of this study show that photo-crosslinked chitosan-gelatin scaffold in sodium alginate hydrogel is suited as a scaffold candidate for cartilage tissue engineering.