Osteocytic signalling pathways as therapeutic targets for bone fragility.
Nature reviews. Endocrinology
Osteocytes are differentiated osteoblasts that become surrounded by matrix during the process of bone formation. Acquisition of the osteocyte phenotype is achieved by profound changes in gene expression that facilitate adaptation to the changing cellular environment and constitute the molecular signature of osteocytes. During osteocytogenesis, the expression of genes that are characteristic of the osteoblast are altered and the expression of genes and/or proteins that impart dendritic cellular morphology, regulate matrix mineralization and control the function of cells at the bone surface are ordely modulated. The discovery of mutations in human osteocytic genes has contributed, in a large part, to our understanding of the role of osteocytes in bone homeostasis. Osteocytes are targets of the mechanical force imposed on the skeleton and have a critical role in integrating mechanosensory pathways with the action of hormones, which thereby leads to the orchestrated response of bone to environmental cues. Current, therapeutic approaches harness this accumulating knowledge by targeting osteocytic signalling pathways and messengers to improve skeletal health.
10.1038/nrendo.2016.71
Four-dimensional bioprinting: Current developments and applications in bone tissue engineering.
Wan Zhuqing,Zhang Ping,Liu Yunsong,Lv Longwei,Zhou Yongsheng
Acta biomaterialia
Four-dimensional (4D) bioprinting, in which the concept of time is integrated with three-dimensional (3D) bioprinting as the fourth dimension, has currently emerged as the next-generation solution of tissue engineering as it presents the possibility of constructing complex, functional structures. 4D bioprinting can be used to fabricate dynamic 3D-patterned biological architectures that will change their shapes under various stimuli by employing stimuli-responsive materials. The functional transformation and maturation of printed cell-laden constructs over time are also regarded as 4D bioprinting, providing unprecedented potential for bone tissue engineering. The shape memory properties of printed structures cater to the need for personalized bone defect repair and the functional maturation procedures promote the osteogenic differentiation of stem cells. In this review, we introduce the application of different stimuli-responsive biomaterials in tissue engineering and a series of 4D bioprinting strategies based on functional transformation of printed structures. Furthermore, we discuss the application of 4D bioprinting in bone tissue engineering, as well as the current challenges and future perspectives. STATEMENTS OF SIGNIFICANCE: In this review, we have demonstrated the 4D bioprinting technologies, which integrate the concept of time within the traditional 3D bioprinting technology as the fourth dimension and facilitate the fabrications of complex, functional biological architectures. These 4D bioprinting structures could go through shape or functional transformation over time via using different stimuli-responsive biomaterials and a series of 4D bioprinting strategies. Moreover, by summarizing potential applications of 4D bioprinting in the field of bone tissue engineering, these emerging technologies could fulfill unaddressed medical requirements. The further discussions about future challenges and perspectives will give us more inspirations about widespread applications of this emerging technology for tissue engineering in biomedical field.
10.1016/j.actbio.2019.10.038
3D-printed bioceramic scaffolds: From bone tissue engineering to tumor therapy.
Ma Hongshi,Feng Chun,Chang Jiang,Wu Chengtie
Acta biomaterialia
Toward the aim of personalized treatment, three-dimensional (3D) printing technology has been widely used in bone tissue engineering owing to its advantage of a fast, precise, and controllable fabrication process. Conventional bioceramic scaffolds are mainly used for bone tissue engineering; however, there has been a significant change in the application of bioceramic scaffolds during the past several years. Therefore, this review focuses on 3D-printed bioceramic scaffolds with different compositions and hierarchical structures (macro, micro, and nano scales), and their effects on the mechanical, degradation, permeability, and biological properties. Further, this review highlights 3D-printed bioceramic scaffolds for applications extending from bone tissue regeneration to bone tumor therapy. This review emphasizes recent developments in functional 3D-printed bioceramic scaffolds with the ability to be used for both tumor therapy and bone tissue regeneration. Considering the challenges in bone tumor therapy, these functional bioceramic scaffolds have a great potential in repairing bone defects induced by surgery and kill the possibly residual tumor cells to achieve bone tumor therapy. Finally, a brief perspective regarding future directions in this field was also provided. The review not only gives a summary of the research developments in bioceramic science but also offers a new therapy strategy by extending multifunctions of traditional biomaterials toward a specific disease. STATEMENT OF SIGNIFICANCE:This review outlines the development tendency of 3D-printed bioceramic scaffolds for applications ranging from bone tissue regeneration to bone tumor therapy. Conventional bioceramic scaffolds are mainly used for bone tissue engineering; however, there has been a significant change in the application of bioceramic scaffolds during the past several years. Therefore, this review focuses on 3D-printed bioceramic scaffolds with different compositions and hierarchical structures (macro, micro, and nano scales), and their effects on the mechanical, degradation, permeability, and biological properties. Further, this review highlights 3D-printed bioceramic scaffolds for applications extending from bone tissue regeneration to bone tumor therapy. This review emphasizes recent developments in the functional 3D-printed bioceramic scaffolds with the ability to be used for both bone tumor therapy and bone tissue regeneration.
10.1016/j.actbio.2018.08.026
Multifunctional Nanomachinery for Enhancement of Bone Healing.
Advanced materials (Deerfield Beach, Fla.)
The visionary idea that RNA adopts nonbiological roles in today's nanomaterial world has been nothing short of phenomenal. These RNA molecules have ample chemical functionality and self-assemble to form distinct nanostructures in response to external stimuli. They may be combined with inorganic materials to produce nanomachines that carry cargo to a target site in a controlled manner and respond dynamically to environmental changes. Comparable to biological cells, programmed RNA nanomachines have the potential to replicate bone healing in vitro. Here, an RNA-biomineral nanomachine is developed, which accomplishes intrafibrillar and extrafibrillar mineralization of collagen scaffolds to mimic bone formation in vitro. Molecular dynamics simulation indicates that noncovalent hydrogen bonding provides the energy source that initiates self-assembly of these nanomachines. Incorporation of the RNA-biomineral nanomachines into collagen scaffolds in vivo creates an osteoinductive microenvironment within a bone defect that is conducive to rapid biomineralization and osteogenesis. Addition of RNA-degrading enzymes into RNA-biomineral nanomachines further creates a stop signal that inhibits unwarranted bone formation in tissues. The potential of RNA in building functional nanostructures has been underestimated in the past. The concept of RNA-biomineral nanomachines participating in physiological processes may transform the nanoscopic world of life science.
10.1002/adma.202107924
Angiogenesis and bone growth.
Gerber H P,Ferrara N
Trends in cardiovascular medicine
Vascularization of the growth plate region represents a key mechanism for the coupling of two fundamental processes determining the rate of bone growth, chondrogenesis (cartilage production) and osteogenesis (bone formation). Precise coupling is crucial during periods of rapid bone growth or fracture repair in adults, and changes in the balance might induce pathologic conditions such as osteoarthritis and ectopic bone formation. During the formation of the growth plates of long bones, there is a close and dynamic interaction between developing vascular structures and the cartilage, which is one of the least vascular tissues in the body. Recent experimental findings provide an explanation why the close proximity of cartilage and vasculature is mutually exclusive: vascular invasion of cartilage is associated with chondrocyte apoptosis and consequently, inhibition of angiogenesis in the growth plate delays chondrocyte cell death, resulting in a massive expansion in the number of hypertrophic cartilage cells in the growth plate. The fundamental importance of chondrocytes in the growth, development and repair of the skeleton has led to intense investigation of the mechanisms that regulate chondrocyte maturation and apoptosis.
10.1016/s1050-1738(00)00074-8
In situ silk fibroin-mediated crystal formation of octacalcium phosphate and its application in bone repair.
Han Fengxuan,Hu Yuanbin,Li Jiaying,Gong Jiawei,Guo Qianping,Zhu Caihong,Zhu Xuesong,Yang Huilin,Li Bin
Materials science & engineering. C, Materials for biological applications
The development of an ideal scaffold material is critical for the repair of bone defects. Being an important precursor of the mineralized matrix of bone tissue, octacalcium phosphate (OCP) has been considered a promising bone substitute. However, its application is largely limited due to the thermodynamical instability and poor processability of it. In this study, OCP was prepared by co-precipitation in the presence of small amount of silk fibroin (SF), which regulated the crystallization of OCP and led to the formation of SF-OCP complex. The diameters of OCP crystals in OCP, 0.1SF-OCP, 0.3SF-OCP and 1SF-OCP complexes were 489.0 ± 399.1 nm, 102.2 ± 50.7 nm, 94.7 ± 48.4 nm and 223.7 ± 167.6 nm, respectively. However, the shape of OCP crystals did not apparently change by the presence of SF. Further, porous SF/OCP composite scaffolds with pore size of 111.9 ± 33.1 μm were prepared, in which small crystals of SF-OCP complex were embedded in a SF matrix. MC3T3-E1 cells could attach and proliferate well on both the rugged surfaces and the pores of SF/OCP scaffolds, indicating their decent biocompatibility. Further, SF/OCP scaffolds markedly promoted bone regeneration in a rat calvarial critical-sized defect model. Both micro-CT and H&E characterizations showed that bone formation not only occurred around the scaffolds, but also penetrated into their center. Therefore, such SF/OCP composite scaffolds may have potential applications in bone tissue engineering.
10.1016/j.msec.2018.10.041
In vivo changes of nanoapatite crystals during bone reconstruction and the differences with native bone apatite.
Science advances
Hydroxyapatite (HA) plays an important role in clinical bone repair. However, it remains a challenge to accurately determine its changes during bone reconstruction and to identify its differences from native bone apatite. Here, terbium (Tb) doped uniform HA nanocrystals were implanted into bone tissue and compared with native bone apatite. These comparisons demonstrated the occurrence of compositional and structural alteration of the implanted HA nanocrystals, and their gradual degradation, during bone reconstruction. They also revealed notable differences between HA nanocrystals and bone apatite crystals in crystal size, distribution pattern, and state of existence in bone tissue. Although synthetic HA nanocrystals could osteointegrate with bone tissue, they still seemed to be treated as foreign material in this tissue and thus were gradually degraded. These findings can help to identify and rethink the function of synthetic apatite and bone apatite, which will benefit future design and application of biomimetic bone repair materials.
10.1126/sciadv.aay6484
Adverse Biological Effect of TiO₂ and Hydroxyapatite Nanoparticles Used in Bone Repair and Replacement.
Wang Jiangxue,Wang Liting,Fan Yubo
International journal of molecular sciences
The adverse biological effect of nanoparticles is an unavoidable scientific problem because of their small size and high surface activity. In this review, we focus on nano-hydroxyapatite and TiO₂ nanoparticles (NPs) to clarify the potential systemic toxicological effect and cytotoxic response of wear nanoparticles because they are attractive materials for bone implants and are widely investigated to promote the repair and reconstruction of bone. The wear nanoparticles would be prone to binding with proteins to form protein-particle complexes, to interacting with visible components in the blood including erythrocytes, leukocytes, and platelets, and to being phagocytosed by macrophages or fibroblasts to deposit in the local tissue, leading to the formation of fibrous local pseudocapsules. These particles would also be translocated to and disseminated into the main organs such as the lung, liver and spleen via blood circulation. The inflammatory response, oxidative stress, and signaling pathway are elaborated to analyze the potential toxicological mechanism. Inhibition of the oxidative stress response and signaling transduction may be a new therapeutic strategy for wear debris-mediated osteolysis. Developing biomimetic materials with better biocompatibility is our goal for orthopedic implants.
10.3390/ijms17060798
Fracture Healing in the Setting of Endocrine Diseases, Aging, and Cellular Senescence.
Endocrine reviews
More than 2.1 million age-related fractures occur in the United States annually, resulting in an immense socioeconomic burden. Importantly, the age-related deterioration of bone structure is associated with impaired bone healing. Fracture healing is a dynamic process which can be divided into four stages. While the initial hematoma generates an inflammatory environment in which mesenchymal stem cells and macrophages orchestrate the framework for repair, angiogenesis and cartilage formation mark the second healing period. In the central region, endochondral ossification favors soft callus development while next to the fractured bony ends, intramembranous ossification directly forms woven bone. The third stage is characterized by removal and calcification of the endochondral cartilage. Finally, the chronic remodeling phase concludes the healing process. Impaired fracture healing due to aging is related to detrimental changes at the cellular level. Macrophages, osteocytes, and chondrocytes express markers of senescence, leading to reduced self-renewal and proliferative capacity. A prolonged phase of "inflammaging" results in an extended remodeling phase, characterized by a senescent microenvironment and deteriorating healing capacity. Although there is evidence that in the setting of injury, at least in some tissues, senescent cells may play a beneficial role in facilitating tissue repair, recent data demonstrate that clearing senescent cells enhances fracture repair. In this review, we summarize the physiological as well as pathological processes during fracture healing in endocrine disease and aging in order to establish a broad understanding of the biomechanical as well as molecular mechanisms involved in bone repair.
10.1210/endrev/bnac008
A Wnt-mediated transformation of the bone marrow stromal cell identity orchestrates skeletal regeneration.
Matsushita Yuki,Nagata Mizuki,Kozloff Kenneth M,Welch Joshua D,Mizuhashi Koji,Tokavanich Nicha,Hallett Shawn A,Link Daniel C,Nagasawa Takashi,Ono Wanida,Ono Noriaki
Nature communications
Bone marrow stromal cells (BMSCs) are versatile mesenchymal cell populations underpinning the major functions of the skeleton, a majority of which adjoin sinusoidal blood vessels and express C-X-C motif chemokine ligand 12 (CXCL12). However, how these cells are activated during regeneration and facilitate osteogenesis remains largely unknown. Cell-lineage analysis using Cxcl12-creER mice reveals that quiescent Cxcl12-creER perisinusoidal BMSCs differentiate into cortical bone osteoblasts solely during regeneration. A combined single cell RNA-seq analysis demonstrate that these cells convert their identity into a skeletal stem cell-like state in response to injury, associated with upregulation of osteoblast-signature genes and activation of canonical Wnt signaling components along the single-cell trajectory. β-catenin deficiency in these cells indeed causes insufficiency in cortical bone regeneration. Therefore, quiescent Cxcl12-creER BMSCs transform into osteoblast precursor cells in a manner mediated by canonical Wnt signaling, highlighting a unique mechanism by which dormant stromal cells are enlisted for skeletal regeneration.
10.1038/s41467-019-14029-w
The role of magnesium ions in bone regeneration involves the canonical Wnt signaling pathway.
Hung Chu-Chih,Chaya Amy,Liu Kai,Verdelis Konstantinos,Sfeir Charles
Acta biomaterialia
Magnesium (Mg)-based implants have become of interest to both academia and the medical industry. The attraction largely is due to Mg's biodegradability and ability to enhance bone healing and formation. However, the underlying mechanism of how Mg regulates osteogenesis is still unclear. Based on our previous in vivo and molecular signaling work demonstrating the osteogenic effect of Mg, the current study aims to extend this work at the molecular level especially that we also observed and quantified mineral deposits in the bone marrow space in a rabbit ulna fracture model with Mg plates and screws. Histological analysis and quantitative results of micro-CT showed mineralized deposition and a significant increase in bone volume at 8 weeks and 16 weeks post-operative. These in vivo results led us to focus on studying the effect of Mg on human bone marrow stromal cells (hBMSCs). The data presented in this manuscript demonstrate the activation of the canonical Wnt signaling pathway in hBMSCs when treated with 10 mM Mg. With additional Mg present, the protein expression of active β-catenin was significantly increased to a level similar to that of the positive control. Immunocytochemistry and the increased expression of LEF1 and Dkk1, downstream target genes that are controlled directly by active β-catenin, demonstrated the protein translocation and the activation of transcription. Taken together, these data suggest that Mg induces an osteogenic effect in the bone marrow space by activating the canonical Wnt signaling pathway, which in turn causes BMSCs to differentiate toward the osteoblast lineage. STATEMENT OF SIGNIFICANCE: Magnesium (Mg)-based alloys are being studied to be used in the field of implantable medical devices due to its natural biodegradability and the potential ability to promote bone regeneration. Despite many in vivo studies that demonstrated an increased new bone growth by implanting Mg-based devices, the underlying mechanism of this effect is still unclear. In order to safely use Mg-based implants on human and better control the osteogenic effect, it is necessary to understand the corresponding cellular response in the targeted area. The present study provides the rationale to study Mg ions on bone marrow stromal cells and shows the activation of canonical Wnt signaling pathway that promotes osteogenesis by in vivo and in vitro approaches.
10.1016/j.actbio.2019.06.001
Bone regeneration in implant dentistry: Which are the factors affecting the clinical outcome?
Periodontology 2000
The key factors that are needed for bone regeneration to take place include cells (osteoprogenitor and immune-inflammatory cells), a scaffold (blood clot) that facilitates the deposition of the bone matrix, signaling molecules, blood supply, and mechanical stability. However, even when these principles are met, the overall amount of regenerated bone, its stability over time and the incidence of complications may significantly vary. This manuscript provides a critical review on the main local and systemic factors that may have an impact on bone regeneration, trying to focus, whenever possible, on bone regeneration simultaneous to implant placement to treat bone dehiscence/fenestration defects or for bone contouring. In the future, it is likely that bone tissue engineering will change our approach to bone regeneration in implant dentistry by replacing the current biomaterials with osteoinductive scaffolds combined with cells and mechanical/soluble factors and by employing immunomodulatory materials that can both modulate the immune response and control other bone regeneration processes such as osteogenesis, osteoclastogenesis, or inflammation. However, there are currently important knowledge gaps on the biology of osseous formation and on the factors that can influence it that require further investigation. It is recommended that future studies should combine traditional clinical and radiographic assessments with non-invasive imaging and with patient-reported outcome measures. We also envisage that the integration of multi-omics approaches will help uncover the mechanisms responsible for the variability in regenerative outcomes observed in clinical practice.
10.1111/prd.12518
Mgp High-Expressing MSCs Orchestrate the Osteoimmune Microenvironment of Collagen/Nanohydroxyapatite-Mediated Bone Regeneration.
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
Activating autologous stem cells after the implantation of biomaterials is an important process to initiate bone regeneration. Although several studies have demonstrated the mechanism of biomaterial-mediated bone regeneration, a comprehensive single-cell level transcriptomic map revealing the influence of biomaterials on regulating the temporal and spatial expression patterns of mesenchymal stem cells (MSCs) is still lacking. Herein, the osteoimmune microenvironment is depicted around the classical collagen/nanohydroxyapatite-based bone repair materials via combining analysis of single-cell RNA sequencing and spatial transcriptomics. A group of functional MSCs with high expression of matrix Gla protein (Mgp) is identified, which may serve as a pioneer subpopulation involved in bone repair. Remarkably, these Mgp high-expressing MSCs (MgpMSCs) exhibit efficient osteogenic differentiation potential and orchestrate the osteoimmune microenvironment around implanted biomaterials, rewiring the polarization and osteoclastic differentiation of macrophages through the Mdk/Lrp1 ligand-receptor pair. The inhibition of Mdk/Lrp1 activates the pro-inflammatory programs of macrophages and osteoclastogenesis. Meanwhile, multiple immune-cell subsets also exhibit close crosstalk between MgpMSCs via the secreted phosphoprotein 1 (SPP1) signaling pathway. These cellular profiles and interactions characterized in this study can broaden the understanding of the functional MSC subpopulations at the early stage of biomaterial-mediated bone regeneration and provide the basis for materials-designed strategies that target osteoimmune modulation.
10.1002/advs.202308986
Osteoblast-derived VEGF regulates osteoblast differentiation and bone formation during bone repair.
The Journal of clinical investigation
Osteoblast-derived VEGF is important for bone development and postnatal bone homeostasis. Previous studies have demonstrated that VEGF affects bone repair and regeneration; however, the cellular mechanisms by which it works are not fully understood. In this study, we investigated the functions of osteoblast-derived VEGF in healing of a bone defect. The results indicate that osteoblast-derived VEGF plays critical roles at several stages in the repair process. Using transgenic mice with osteoblast-specific deletion of Vegfa, we demonstrated that VEGF promoted macrophage recruitment and angiogenic responses in the inflammation phase, and optimal levels of VEGF were required for coupling of angiogenesis and osteogenesis in areas where repair occurs by intramembranous ossification. VEGF likely functions as a paracrine factor in this process because deletion of Vegfr2 in osteoblastic lineage cells enhanced osteoblastic maturation and mineralization. Furthermore, osteoblast- and hypertrophic chondrocyte-derived VEGF stimulated recruitment of blood vessels and osteoclasts and promoted cartilage resorption at the repair site during the periosteal endochondral ossification stage. Finally, osteoblast-derived VEGF stimulated osteoclast formation in the final remodeling phase of the repair process. These findings provide a basis for clinical strategies to improve bone regeneration and treat defects in bone healing.
10.1172/JCI82585
The tissue origin effect of extracellular vesicles on cartilage and bone regeneration.
Li Qi,Yu Huilei,Sun Muyang,Yang Peng,Hu Xiaoqing,Ao Yingfang,Cheng Jin
Acta biomaterialia
Direct implantation of mesenchymal stem cells (MSCs) for cartilage and bone tissue engineering faces challenges, such as immune rejection and loss of cellular viability or functionality. As nanoscale natural particles, exosomes or small extracellular vesicles (EVs) of MSCs have potential to circumvent these problems. It is significant to investigate the impact of the tissue origin of MSCs on the therapeutic bioactivity of their corresponding EVs for cartilage and bone regeneration. Here, rat MSCs isolated from the adipose, bone marrow, and synovium are cultured to obtain their corresponding EVs (ADSC-EVs, BMSC-EVs, and SMSC-EVs, respectively). The ADSC-EVs stimulate the migration, proliferation, and chondrogenic and osteogenic differentiation of BMSCs in vitro as well as cartilage and bone regeneration in a mouse model more than the BMSC-EVs or SMSC-EVs. Proteomics analysis reveals that the tissue origin contributes to the distinct protein profiles among the three types of EVs, which induced cartilage and bone regenerative capacities by potential mechanisms of regulating signaling pathways including focal adhesion, ECM-receptor interaction, actin cytoskeleton, cAMP, and PI3K-Akt signaling pathways. Consequently, these findings provide insight that the adipose may be a superior candidate in EV-based nanomedicine for cartilage and bone regeneration. STATEMENT OF SIGNIFICANCE: Extracelluar vesicles (EVs) of mesenchymal stem cells (MSCs) have been considered as a promising approach in cartilage and bone tissue engineering. In this study, for the first time, we investigated the tissue origin effect of EVs on chondrogenesis and osteogenesis of MSCs in vitro and in vivo. The results demonstrated that EVs of adipose-derived MSCs showed the most efficiency. Meanwhile, protein proteomics revealed the potential mechanisms. We provide a novel evidence that the adipose is a superior reservoir in EV-based nanotechnologies and biomaterials for cartilage and bone regeneration.
10.1016/j.actbio.2021.02.039
Electrical stimulation of piezoelectric BaTiO3 coated Ti6Al4V scaffolds promotes anti-inflammatory polarization of macrophages and bone repair via MAPK/JNK inhibition and OXPHOS activation.
Biomaterials
Bone regeneration is a highly synchronized process that requires multiple biochemical, bioelectrical, mechanical, and other physiological cues. The restoration and delivery of electrical cues locally through piezoelectric materials have been demonstrated to facilitate osteogenesis in vitro and bone repair in vivo. However, the underlying mechanism by which piezoelectric stimulation promotes osteogenesis and bone repair remains unclear yet, limiting the design and clinical application of piezoelectric materials for bone repair. Herein, a piezoelectric BaTiO3/Ti6Al4V (BT/Ti) scaffold was prepared by hydrothermal synthesis of a uniform BaTiO3 layer on three dimensionally printed Ti6Al4V scaffold. The BT/Ti scaffolds exhibited piezoelectricity and favorable biocompatibility with RAW264.7 macrophages after polarization. In vitro results demonstrated that the piezoelectric effects of the poled BT/Ti scaffolds promoted M2 polarization of macrophages and immunoregulatory osteogenesis of MC-3T3 osteoblasts. In a subcutaneous implantation model, a higher proportion of CD68 CD206 M2 macrophages was observed in the tissues around the poled BT/Ti scaffolds under low intensity pulsed ultrasound (LIPUS) stimulation. Improvements in macrophage M2 polarization and bone regeneration were further identified in a sheep cervical corpectomy model. RNA sequencing and mechanistic investigation revealed that the piezoelectric BT/Ti (poled) scaffolds inhibited the inflammatory MAPK/JNK signaling cascade and activated oxidative phosphorylation (OXPHOS) and ATP synthesis in macrophages. Collectively, our study provides a promising method for regulating the immune microenvironment and enhancing bone regeneration using polarized piezoelectric BT/Ti scaffolds.
10.1016/j.biomaterials.2022.121990
A Logic-Based Diagnostic and Therapeutic Hydrogel with Multistimuli Responsiveness to Orchestrate Diabetic Bone Regeneration.
Li Dize,Chen Kaiwen,Tang Han,Hu Shanshan,Xin Liangjing,Jing Xuan,He Qingqing,Wang Si,Song Jinlin,Mei Li,Cannon Richard D,Ji Ping,Wang Huanan,Chen Tao
Advanced materials (Deerfield Beach, Fla.)
The regeneration of diabetic bone defects remains challenging as the innate healing process is impaired by glucose fluctuation, reactive oxygen species (ROS), and overexpression of proteinases (such as matrix metalloproteinases, MMPs). A "diagnostic" and therapeutic dual-logic-based hydrogel for diabetic bone regeneration is therefore developed through the design of a double-network hydrogel consisting of phenylboronic-acid-crosslinked poly(vinyl alcohol) and gelatin colloids. It exhibits a "diagnostic" logic to interpret pathological cues (glucose fluctuation, ROS, MMPs) and determines when to release drug in a diabetic microenvironment and a therapeutic logic to program different cargo release to match immune-osteo cascade for better tissue regeneration. The hydrogel is also shown to be mechanically adaptable to the local complexity at the bone defect. Furthermore, the underlying therapeutic mechanism is elucidated, whereby the logic-based cargo release enables the regulation of macrophage polarization by remodeling the mitochondria-related antioxidative system, resulting in enhanced osteogenesis in diabetic bone defects. This study provides critical insight into the design and biological mechanism of dual-logic-based tissue-engineering strategies for diabetic bone regeneration.
10.1002/adma.202108430
Biomaterial-induced pathway modulation for bone regeneration.
Biomaterials
Embryogenic developmental processes involve a tightly controlled regulation between mechanical forces and biochemical cues such as growth factors, matrix proteins, and cytokines. This interplay remains essential in the mature body, with aberrant pathway signaling leading to abnormalities such as atherosclerosis in the cardiovascular system, inflammation in tendon tissue, or osteoporosis in the bone. The aim of bone regenerative strategies is to develop tools and procedures that will harness the body's own self-repair ability in order to successfully regenerate even very large and complex bone defects and restore normal function. To achieve this, understanding pathways that govern processes of progenitor differentiation towards the osteogenic lineages, their phenotypical maintenance, and the construction of functional bone tissue is imperative to subsequently develop regenerative therapies that mimic these processes. While a body of literature exists that describes how biochemical stimuli guide cell behavior in the culture dish, due to the lack of an appropriate mechanical environment, these signals are often insufficient or inappropriate for achieving a desirable response in the body. Moreover, bone regenerative therapies rarely rely on a biochemical stimulus, such as a growth factor alone, and instead often comprise a carrier biomaterial that introduces a very different microenvironment from that of a cell culture dish. Therefore, in this review, we discuss which biomaterials elicit or influence pathways relevant for bone regeneration and describe mechanisms behind these effects, with the aim to inspire the development of novel, more effective bone regenerative therapies.
10.1016/j.biomaterials.2022.121431
Current Advances in Immunomodulatory Biomaterials for Bone Regeneration.
Lee Jinkyu,Byun Hayeon,Madhurakkat Perikamana Sajeesh Kumar,Lee Sangmin,Shin Heungsoo
Advanced healthcare materials
Biomaterials with suitable surface modification strategies are contributing significantly to the rapid development of the field of bone tissue engineering. Despite these encouraging results, utilization of biomaterials is poorly translated to human clinical trials potentially due to lack of knowledge about the interaction between biomaterials and the body defense mechanism, the "immune system". The highly complex immune system involves the coordinated action of many immune cells that can produce various inflammatory and anti-inflammatory cytokines. Besides, bone fracture healing initiates with acute inflammation and may later transform to a regenerative or degenerative phase mainly due to the cross-talk between immune cells and other cells in the bone regeneration process. Among various immune cells, macrophages possess a significant role in the immune defense, where their polarization state plays a key role in the wound healing process. Growing evidence shows that the macrophage polarization state is highly sensitive to the biomaterial's physiochemical properties, and advances in biomaterial research now allow well controlled surface properties. This review provides an overview of biomaterial-mediated modulation of the immune response for regulating key bone regeneration events, such as osteogenesis, osteoclastogenesis, and inflammation, and it discusses how these strategies can be utilized for future bone tissue engineering applications.
10.1002/adhm.201801106
N2-Polarized Neutrophils Guide Bone Mesenchymal Stem Cell Recruitment and Initiate Bone Regeneration: A Missing Piece of the Bone Regeneration Puzzle.
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
The role of neutrophils in bone regeneration remains elusive. In this study, it is shown that intramuscular implantation of interleukin-8 (IL-8) (commonly recognized as a chemotactic cytokine for neutrophils) at different levels lead to outcomes resembling those of fracture hematoma at various stages. Ectopic endochondral ossification is induced by certain levels of IL-8, during which neutrophils are recruited to the implanted site and are N2-polarized, which then secrete stromal cell-derived factor-1α (SDF-1α) for bone mesenchymal stem cell (BMSC) chemotaxis via the SDF-1/CXCR4 (C-X-C motif chemokine receptor 4) axis and its downstream phosphatidylinositol 3'-kinase (PI3K)/Akt pathway and β-catenin-mediated migration. Neutrophils are pivotal for recruiting and orchestrating innate and adaptive immunocytes, as well as BMSCs at the initial stage of bone healing and regeneration. The results in this study delineate the mechanism of neutrophil-initiated bone regeneration and interaction between neutrophils and BMSCs, and innate and adaptive immunities. This work lays the foundation for research in the fields of bone regenerative therapy and biomaterial development, and might inspire further research into novel therapeutic options.
10.1002/advs.202100584
Guided bone regeneration: materials and biological mechanisms revisited.
Elgali Ibrahim,Omar Omar,Dahlin Christer,Thomsen Peter
European journal of oral sciences
Guided bone regeneration (GBR) is commonly used in combination with the installment of titanium implants. The application of a membrane to exclude non-osteogenic tissues from interfering with bone regeneration is a key principle of GBR. Membrane materials possess a number of properties which are amenable to modification. A large number of membranes have been introduced for experimental and clinical verification. This prompts the need for an update on membrane properties and the biological outcomes, as well as a critical assessment of the biological mechanisms governing bone regeneration in defects covered by membranes. The relevant literature for this narrative review was assessed after a MEDLINE/PubMed database search. Experimental data suggest that different modifications of the physicochemical and mechanical properties of membranes may promote bone regeneration. Nevertheless, the precise role of membrane porosities for the barrier function of GBR membranes still awaits elucidation. Novel experimental findings also suggest an active role of the membrane compartment per se in promoting the regenerative processes in the underlying defect during GBR, instead of being purely a passive barrier. The optimization of membrane materials by systematically addressing both the barrier and the bioactive properties is an important strategy in this field of research.
10.1111/eos.12364