Natural bone is a mineralized biological material, which serves a supportive and protective framework for the body, stores minerals for metabolism, and produces blood cells nourishing the body. Normally, bone has an innate capacity to heal from damage. However, massive bone defects due to traumatic injury, tumor resection, or congenital diseases pose a great challenge to reconstructive surgery. Scaffold-based tissue engineering (TE) is a promising strategy for bone regenerative medicine, because biomaterial scaffolds show advanced mechanical properties and a good degradation profile, as well as the feasibility of controlled release of growth and differentiation factors or immobilizing them on the material surface. Additionally, the defined structure of biomaterial scaffolds, as a kind of mechanical cue, can influence cell behaviors, modulate local microenvironment and control key features at the molecular and cellular levels. Recently, nano/micro-assisted regenerative medicine becomes a promising application of TE for the reconstruction of bone defects. For this reason, it is necessary for us to have in-depth knowledge of the development of novel nano/micro-based biomaterial scaffolds. Thus, we herein review the hierarchical structure of bone, and the potential application of nano/micro technologies to guide the design of novel biomaterial structures for bone repair and regeneration.

Effect of the nano/microscale structure of biomaterial scaffolds on bone regeneration

Immune reactions play important roles in determining the in vivo fate of bone substitute materials, either in new bone formation or inflammatory fibrous tissue encapsulation. The paradigm for the development of bone substitute materials has been shifted from inert to immunomodulatory materials, emphasizing the importance of immune cells in the material evaluation. Macrophages, the major effector cells in the immune reaction to implants, are indispensable for osteogenesis and their heterogeneity and plasticity render macrophages a primer target for immune system modulation. However, there are very few reports about the effects of macrophages on biomaterial-regulated osteogenesis. In this study, we used b-tricalcium phosphate (b-TCP) as a model biomaterial to investigate the role of macrophages on the material stimulated osteogenesis. The macrophage phenotype switched to M2 extreme in response to b-TCP extracts, which was related to the activation of calcium-sensing receptor (CaSR) pathway. Bone morphogenetic protein 2 (BMP2) was also significantly upregulated by the b-TCP stimulation, indicating that macrophage may participate in the b-TCP stimulated osteogenesis. Interestingly, when macrophageconditioned b-TCP extracts were applied to bone marrow mesenchymal stem cells (BMSCs), the osteogenic differentiation of BMSCs was significantly enhanced, indicating the important role of macrophages in biomaterial-induced osteogenesis. These findings provided valuable insights into the mechanism of material-stimulated osteogenesis, and a strategy to optimize the evaluation system for the in vitro osteogenesis capacity of bone substitute materials.

Osteogenic differentiation of bone marrow MSCs by β-tricalcium phosphate stimulating macrophages via BMP2 signalling pathway

Exploring innovative solutions to improve the healthcare of the aging and diseased population continues to be a global challenge. Among a number of strategies toward this goal, tissue engineering and regenerative medicine (TERM) has gradually evolved into a promising approach to meet future needs of patients. TERM has recently received increasing attention in Asia, as evidenced by the markedly increased number of researchers, publications, clinical trials, and translational products. This review aims to give a brief overview of TERM development in Asia over the last decade by highlighting some of the important advances in this field and featuring major achievements of representative research groups. The development of novel biomaterials and enabling technologies, identification of new cell sources, and applications of TERM in various tissues are briefly introduced. Finally, the achievement of TERM in Asia, including important publications, representative discoveries, clinical trials, and examples of commercial products will be introduced. Discussion on current limitations and future directions in this hot topic will also be provided.

Tissue Engineering and Regenerative Medicine: Achievements, Future, and Sustainability in Asia.

Switching macrophages from a pro-tumor type to an anti-tumor state is a promising strategy for cancer immunotherapy. Existing agents, many derived from bacterial components, have safety or specificity concerns. Here, we postulate that the structures of the bacterial signals can be mimicked by using non-toxic biomolecules of simple design. Based on bioactivity screening, we devise a glucomannan polysaccharide with acetyl modification at a degree of 1.8 (acGM-1.8), which specifically activates toll-like receptor 2 (TLR2) signaling and consequently induces macrophages into an anti-tumor phenotype. For acGM-1.8, the degree of acetyl modification, glucomannan pattern, and acetylation-induced assembly are three crucial factors for its bioactivity. In mice, intratumoral injection of acGM-1.8 suppresses the growth of two tumor models, and this polysaccharide demonstrates higher safety than four classical TLR agonists. In summary, we report the design of a new, safe, and specific TLR2 agonist that can generate macrophages with strong anti-tumor potential in mice.

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A toll-like receptor agonist mimicking microbial signal to generate tumor-suppressive macrophages.

Achieving satisfactory reconstruction of bone remains an important goal in orthopedic and dental conditions such as bone trauma, osteoporosis, arthritis, osteonecrosis, and periodontitis. Appropriate temporal and spatial differentiation of mesenchymal stem cells (MSCs) is essential for postnatal bone regeneration. Additionally, an acute inflammatory response is crucial at the onset of bone repair, while an adaptive immune response has important implications during late bone remodeling. Various reports have indicated bidirectional interactions between MSCs and inflammatory cells or molecules. For example, inflammatory cells can recruit MSCs, direct their migration and differentiation, so as to exert anabolic effects on bone repair. Furthermore, both pro-inflammatory and anti-inflammatory cytokines can regulate MSCs properties and subsequent bone regeneration. MSCs have demonstrated highly immunosuppressive functions, such as inhibiting the differentiation of monocytes/hematopoietic precursors and suppressing the secretion of pro-inflammatory cytokines. This review emphasizes the important interactions between inflammatory stimuli, MSCs, and bone regeneration as well as the underlying regulatory mechanisms. Better understanding of these principles will provide new opportunities for promoting bone regeneration and the treatment of bone loss associated with immunological diseases.

Inflammation, mesenchymal stem cells and bone regeneration

Modulating macrophage activities to promote endogenous bone regeneration: Biological mechanisms and engineering approaches

Modulating the phenotype of host macrophages to enhance osteogenesis in MSC-laden hydrogels: Design of a glucomannan coating material

Bioactive coating on bone and dental implants is widely used to increase their integration with the host tissue, with millions of implantations performed globally each year. Numerous coating strategies focus on creating a cell-adhesive surface by employing bone matrix components, but insufficient integration and its associated complications remain a substantial clinical challenge. Designing an implant coating to more comprehensively promote healing while appropriately modulating host immune response is still an unfulfilled promise. This study reports the development of a polysaccharide coating that can improve osseointegration by targeting and regulating inflammatory activity at the implant surface. Zymosan-a fungal component-is screened and covalently grafted onto titanium (Ti) substrates. The zymosan coating specifically stimulates macrophages through toll-like receptors into a proregenerative phenotype, which produces abundant osteogenic/angiogenic cytokines to enhance osteogenic activities locally. Further assessment in a rat femur condyle defect indicates that zymosan coated at a medium dose (0.1 mu g mm(-2)) remarkably increases the integration of Ti column with bone tissue, causing no abnormality to the host. This is the first demonstration that modulating inflammation with an immunoactive coating material can promote bone-implant integration, which may inspire new strategies for the design of bone and dental implants.

Yuchen Shi

Papers

Modulating macrophage activities to promote endogenous bone regeneration: Biological mechanisms and engineering approaches

Modulating the phenotype of host macrophages to enhance osteogenesis in MSC-laden hydrogels: Design of a glucomannan coating material

Fungal Component Coating Enhances Titanium Implant‐Bone Integration

An ortho-aldehyde modified probe to image thiols in living cells with enhanced selectivity

Bioactive Coatings: Fungal Component Coating Enhances Titanium Implant‐Bone Integration (Adv. Funct. Mater. 46/2018)