Osteoporotic osseointegration: therapeutic hallmarks and engineering strategies.

Osteoporosis is a systemic skeletal disease caused by an imbalance between bone resorption and formation. Current treatments primarily involve systemic medication and hormone therapy. However, these systemic treatments lack directionality and are often ineffective for locally severe osteoporosis, with the potential for complex adverse reactions. Consequently, treatment strategies using bioactive materials or external interventions have emerged as the most promising approaches. This review proposes twelve microenvironmental treatment targets for osteoporosis-related pathological changes, including local accumulation of inflammatory factors and reactive oxygen species (ROS), imbalance of mitochondrial dynamics, insulin resistance, disruption of bone cell autophagy, imbalance of bone cell apoptosis, changes in neural secretions, aging of bone cells, increased local bone tissue vascular destruction, and decreased regeneration. Additionally, this review examines the current research status of effective or potential biophysical and biochemical stimuli based on these microenvironmental treatment targets and summarizes the advantages and optimal parameters of different bioengineering stimuli to support preclinical and clinical research on osteoporosis treatment and bone regeneration. Finally, the review addresses ongoing challenges and future research prospects.

Burden evaluation and prediction of osteoarthritis and site-specific osteoarthritis coupled with attributable risk factors in China from 1990 to 2030.

OBJECTIVE: This study aimed to estimate and predict the burden of osteoarthritis (OA) and site-specific OA (hip, knee, hand, and others) from 1990 to 2030 and their attributable risk factors in China. METHOD: Data were obtained from the Global Burden of Diseases 2019. The burden was estimated by analyzing the trends of prevalence, incidence, and disability-adjusted life years (DALY). Population attributable risk (PAR) was calculated to assess the impact of high body mass index (BMI). The prediction from 2020 to 2030 was implemented by Bayesian age-period-cohort analysis. RESULTS: In China, prevalent cases, DALY, and incident cases of OA increased to 132.81 million, 4.72 million, and 10.68 million, respectively. Age-standardized rates (ASRs) of prevalence, DALYs, and incidence increased for OA and site-specific OA, especially for hip OA. Site-specific OA showed different susceptible peaking ages, and the burden for those over 50 years old became serious. Female preference existed in the trends for knee OA but not in those for hip, hand, and other OA. PARs of high BMI continued to increase, impacting knee OA more than hip OA and showing female preference. In the next decade, incident cases for OA and site-specific OA will continue to increase, despite that the ASR of OA incidence will decrease. CONCLUSIONS: OA and site-specific OA remain huge public health challenges in China. The burden of OA and site-specific OA is increasing, especially among people over 50 years old. Health education, exercise, and removing modifiable risk factors contribute to alleviate the growing burden. Key Points • In China, the burden of osteoarthritis and site-specific osteoarthritis (hip, knee, hand, and others) as well as the Risk Factor (high body mass index) increased greatly from 1990 to 2019. • It is estimated that incident cases for OA and site-specific OA will continue to increase, despite that the ASR of OA incidence will decrease.

A parathyroid hormone related supramolecular peptide for multi-functionalized osteoregeneration.

Supramolecular peptide nanofiber hydrogels are emerging biomaterials for tissue engineering, but it is difficult to fabricate multi-functional systems by simply mixing several short-motif-modified supramolecular peptides because relatively abundant motifs generally hinder nanofiber cross-linking or the formation of long nanofiber. Coupling bioactive factors to the assembling backbone is an ideal strategy to design multi-functional supramolecular peptides in spite of challenging synthesis and purification. Herein, a multi-functional supramolecular peptide, P1R16, is developed by coupling a bioactive factor, parathyroid hormone related peptide 1 (PTHrP-1), to the basic supramolecular peptide RADA16-Ⅰ via solid-phase synthesis. It is found that P1R16 self-assembles into long nanofibers and co-assembles with RADA16-Ⅰ to form nanofiber hydrogels, thus coupling PTHrP-1 to hydrogel matrix. P1R16 nanofiber retains osteoinductive activity in a dose-dependent manner, and P1R16/RADA16-Ⅰ nanofiber hydrogels promote osteogenesis, angiogenesis and osteoclastogenesis in vitro and induce multi-functionalized osteoregeneration by intramembranous ossification and bone remodeling in vivo when loaded to collagen (Col) scaffolds. Abundant red blood marrow formation, ideal osteointegration and adapted degradation are observed in the 50% P1R16/Col scaffold group. Therefore, this study provides a promising strategy to develop multi-functional supramolecular peptides and a new method to topically administrate parathyroid hormone or parathyroid hormone related peptides for non-healing bone defects.

A Novel PTH-Related Peptide Combined With 3D Printed Macroporous Titanium Alloy Scaffold Enhances Osteoporotic Osseointegration.

Previous parathyroid hormone (PTH)-related peptides (PTHrPs) cannot be used to prevent implant loosening in osteoporosis patients due to the catabolic effect of local sustained release. A novel PTHrP (PTHrP-2) that can be used locally to promote osseointegration of macroporous titanium alloy scaffold (mTAS) and counteract implant slippage in osteoporosis patients is designed. In vitro, PTHrP-2 enhances the proliferation, adhesion, and osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) within the mTAS. Further, it promotes proliferation, migration, angiogenesis-related protein expression, and angiogenesis in human umbilical vein endothelial cells (HUVECs). Compared to PTH(1-34), PTHrP-2 can partially weaken the osteoclast differentiation of RAW 264.7 cells. Even in an oxidative stress microenvironment, PTHrP-2 safeguards the proliferation and migration of BMSCs and HUVECs, reduces reactive oxygen species generation and mitochondrial damage, and partially preserves the angiogenesis of HUVECs. In the Sprague-Dawley (SD) rat osteoporosis model, the therapeutic benefits of PTHrP-2-releasing mTAS (mTASP2 ) and ordinary mTAS implanted for 12 weeks via micro-CT, sequential fluorescent labeling, and histology are compared. The results demonstrate that mTASP2 exhibits high bone growth rate, without osteophyte formation. Consequently, PTHrP-2 exhibits unique local synthesis properties and holds the potential for assisting the osseointegration of alloy implants in osteoporosis patients.

Zn-Sr-sintered true bone ceramics enhance bone repair and regeneration.

Bone defects are one of the toughest challenges faced by orthopedic surgeons worldwide, especially at critical sizes, which are caused by severe trauma, malignancy, or congenital disease. The ideal bone tissue-engineered scaffold for bone regeneration is the one that has good osteoconductivity, osteoinductivity, pore structure, and antibacterial properties. Metal ions have been recognized in recent years to be essential regulators of bone metabolism, and they are widely used for bone tissue engineering. In particular, zinc ions are of interest because of their ideal biocompatibility, osteogenesis-promoting properties, and antibacterial properties. Moreover, the dual role of strontium (Sr) in promoting osteogenesis and inhibiting osteolysis provides academic support for Zn-Sr co-doped scaffolds. Based on true bone ceramics (TBC), Zn-Sr-sintered scaffolds with good pore structures were prepared using immersion-calcination. The biocompatibility, cell adhesion, osteogenic properties, and antibacterial activity of Zn-Sr-sintered TBC scaffolds in bone marrow mesenchymal stem cells (BMSCs) are superior to those of control TBC scaffolds. The Zn-Sr-sintered TBC scaffold was used to repair rat cranial defects. Its good in vivo repair performance was confirmed by osseointegration and inward bone growth compared with that of the control TBC scaffold. Zn0.25Sr0.20-TBC is an ideal material for bone repair because of its good biocompatibility and favorable in vitro osteogenic properties.

"Smart" Stimuli-responsive Injectable Gels for Bone Tissue Engineering Application.

Bone grafting, as the current gold-standard for large scaled bone damage of various causes, has faced challenges from both the source and appliance. Emerging new tissue engineering substitutes are demonstrating more options and possibilities, with their improved biocompatibility, accessibility, and customizable function. Amongst them, injectable gels (IGs) are a class of gel material displaying astonishing non-invasive properties and surgical viability. While possessing responsiveness toward specific stimuli, they change their physical form in vivo, thus serving as wonderful biomaterials and drug delivery systems. In this review, the mechanics of stimuli-responsive IGs developed during the past decade are illustrated. Two branches of crosslinked gels - co-valent and non-covalent crosslinked IGs and their composition and customization are introduced. In conclusion, the present trend in bone tissue engineering research is summarized and made an outlook for future. It is hoped that this comprehensive review can provide a proper reference for the development of new IGs.

Exosome-Hydrogel System in Bone Tissue Engineering: A Promising Therapeutic Strategy.

Exosomes, as messengers of cell-to-cell communication, have many functional properties similar to those of their derived cells. Because they contain a large number of bioactive components that regulate recipient cell behavior, they are inanimate and do not require external maintenance or assistance. Various cell-derived exosomes are involved in many physiological processes of bone tissue repair. Hydrogels are widely used as scaffolding materials for bone tissue repair because their 3D network structure resembles the natural extracellular matrix. Moreover, their material properties and biological functions are adjustable. Exosomes can be delivered directly to the bone tissue damage site by hydrogel, and their duration of action in vivo can be prolonged by slow release. Therefore, the exosome-loaded hydrogel (Exo-Gel) system is a promising material for bone tissue engineering. In this study, the progress of the application of Exo-Gel in bone tissue repair and the improvement strategies, problems and research prospects of the current exosomes and hydrogels that have been applied to the Exo-Gel system for bone tissue repair are reviewed.

Antimicrobial peptides for bone tissue engineering: Diversity, effects and applications.

Bone tissue engineering has been becoming a promising strategy for surgical bone repair, but the risk of infection during trauma repair remains a problematic health concern worldwide, especially for fracture and infection-caused bone defects. Conventional antibiotics fail to effectively prevent or treat bone infections during bone defect repair because of drug-resistance and recurrence, so novel antibacterial agents with limited resistance are highly needed for bone tissue engineering. Antimicrobial peptides (AMPs) characterized by cationic, hydrophobic and amphipathic properties show great promise to be used as next-generation antibiotics which rarely induce resistance and show potent antibacterial efficacy. In this review, four common structures of AMPs (helix-based, sheet-based, coil-based and composite) and related modifications are presented to identify AMPs and design novel analogs. Then, potential effects of AMPs for bone infection during bone repair are explored, including bactericidal activity, anti-biofilm, immunomodulation and regenerative properties. Moreover, we present distinctive applications of AMPs for topical bone repair, which can be either used by delivery system (surface immobilization, nanoparticles and hydrogels) or used in gene therapy. Finally, future prospects and ongoing challenges are discussed.

Supramolecular Peptide Nanofiber Hydrogels for Bone Tissue Engineering: From Multihierarchical Fabrications to Comprehensive Applications.

Bone tissue engineering is becoming an ideal strategy to replace autologous bone grafts for surgical bone repair, but the multihierarchical complexity of natural bone is still difficult to emulate due to the lack of suitable biomaterials. Supramolecular peptide nanofiber hydrogels (SPNHs) are emerging biomaterials because of their inherent biocompatibility, satisfied biodegradability, high purity, facile functionalization, and tunable mechanical properties. This review initially focuses on the multihierarchical fabrications by SPNHs to emulate natural bony extracellular matrix. Structurally, supramolecular peptides based on distinctive building blocks can assemble into nanofiber hydrogels, which can be used as nanomorphology-mimetic scaffolds for tissue engineering. Biochemically, bioactive motifs and bioactive factors can be covalently tethered or physically absorbed to SPNHs to endow various functions depending on physiological and pharmacological requirements. Mechanically, four strategies are summarized to optimize the biophysical microenvironment of SPNHs for bone regeneration. Furthermore, comprehensive applications about SPNHs for bone tissue engineering are reviewed. The biomaterials can be directly used in the form of injectable hydrogels or composite nanoscaffolds, or they can be used to construct engineered bone grafts by bioprinting or bioreactors. Finally, continuing challenges and outlook are discussed.

Mesenchymal Stem Cell-Immune Cell Interaction and Related Modulations for Bone Tissue Engineering.

Critical bone defects and related delayed union and nonunion are still worldwide problems to be solved. Bone tissue engineering is mainly aimed at achieving satisfactory bone reconstruction. Mesenchymal stem cells (MSCs) are a kind of pluripotent stem cells that can differentiate into bone cells and can be used as one of the key pillars of bone tissue engineering. In recent decades, immune responses play an important role in bone regeneration. Innate immune responses provide a suitable inflammatory microenvironment for bone regeneration and initiate bone regeneration in the early stage of fracture repair. Adaptive immune responses maintain bone regeneration and bone remodeling. MSCs and immune cells regulate each other. All kinds of immune cells and secreted cytokines can regulate the migration, proliferation, and osteogenic differentiation of MSCs, which have a strong immunomodulatory ability to these immune cells. This review mainly introduces the interaction between MSCs and immune cells on bone regeneration and its potential mechanism, and discusses the practical application in bone tissue engineering by modulating this kind of cell-to-cell crosstalk. Thus, an in-depth understanding of these principles of bone immunology can provide a new way for bone tissue engineering.

Strategies of Macrophages to Maintain Bone Homeostasis and Promote Bone Repair: A Narrative Review.

Bone homeostasis (a healthy bone mass) is regulated by maintaining a delicate balance between bone resorption and bone formation. The regulation of physiological bone remodeling by a complex system that involves multiple cells in the skeleton is closely related to bone homeostasis. Loss of bone mass or repair of bone is always accompanied by changes in bone homeostasis. However, due to the complexity of bone homeostasis, we are currently unable to identify all the mechanisms that affect bone homeostasis. To date, bone macrophages have been considered a third cellular component in addition to osteogenic spectrum cells and osteoclasts. As confirmed by co-culture models or in vivo experiments, polarized or unpolarized macrophages interact with multiple components within the bone to ensure bone homeostasis. Different macrophage phenotypes are prone to resorption and formation of bone differently. This review comprehensively summarizes the mechanisms by which macrophages regulate bone homeostasis and concludes that macrophages can control bone homeostasis from osteoclasts, mesenchymal cells, osteoblasts, osteocytes, and the blood/vasculature system. The elaboration of these mechanisms in this narrative review facilitates the development of macrophage-based strategies for the treatment of bone metabolic diseases and bone defects.

Biophysical Stimuli as the Fourth Pillar of Bone Tissue Engineering.

The repair of critical bone defects remains challenging worldwide. Three canonical pillars (biomaterial scaffolds, bioactive molecules, and stem cells) of bone tissue engineering have been widely used for bone regeneration in separate or combined strategies, but the delivery of bioactive molecules has several obvious drawbacks. Biophysical stimuli have great potential to become the fourth pillar of bone tissue engineering, which can be categorized into three groups depending on their physical properties: internal structural stimuli, external mechanical stimuli, and electromagnetic stimuli. In this review, distinctive biophysical stimuli coupled with their osteoinductive windows or parameters are initially presented to induce the osteogenesis of mesenchymal stem cells (MSCs). Then, osteoinductive mechanisms of biophysical transduction (a combination of mechanotransduction and electrocoupling) are reviewed to direct the osteogenic differentiation of MSCs. These mechanisms include biophysical sensing, transmission, and regulation. Furthermore, distinctive application strategies of biophysical stimuli are presented for bone tissue engineering, including predesigned biomaterials, tissue-engineered bone grafts, and postoperative biophysical stimuli loading strategies. Finally, ongoing challenges and future perspectives are discussed.

[Local administration of parathyroid hormone and parathyroid hormone-related peptides for bone tissue engineering].

Parathyroid hormone (PTH) exerts multiple effects such as regulating bone remodeling, promoting angiogenesis, etc., and it is an active factor with great application potential for bone repair. In recent years, with the development of scaffold material loading strategies and parathyroid hormone-related peptides (PTHrPs), in situ loading of PTH or PTHrPs on scaffold materials to promote bone defect healing gradually becomes possible. Based on the current status and challenges of intermittent PTH (iPTH) for bone tissue engineering, the review summarizes the in-situ application strategies of PTH and the construction of PTHrPs as well as current problems and further directions in this field, with a view to propel the clinical application of scaffold materials loaded with PTH or PTHrPs in situ.

Exosome: Function and Application in Inflammatory Bone Diseases.

In the skeletal system, inflammation is closely associated with many skeletal disorders, including periprosthetic osteolysis (bone loss around orthopedic implants), osteoporosis, and rheumatoid arthritis. These diseases, referred to as inflammatory bone diseases, are caused by various oxidative stress factors in the body, resulting in long-term chronic inflammatory processes and eventually causing disturbances in bone metabolism, increased osteoclast activity, and decreased osteoblast activity, thereby leading to osteolysis. Inflammatory bone diseases caused by nonbacterial factors include inflammation- and bone resorption-related processes. A growing number of studies show that exosomes play an essential role in developing and progressing inflammatory bone diseases. Mechanistically, exosomes are involved in the onset and progression of inflammatory bone disease and promote inflammatory osteolysis, but specific types of exosomes are also involved in inhibiting this process. Exosomal regulation of the NF-κB signaling pathway affects macrophage polarization and regulates inflammatory responses. The inflammatory response further causes alterations in cytokine and exosome secretion. These signals regulate osteoclast differentiation through the receptor activator of the nuclear factor-kappaB ligand pathway and affect osteoblast activity through the Wnt pathway and the transcription factor Runx2, thereby influencing bone metabolism. Overall, enhanced bone resorption dominates the overall mechanism, and over time, this imbalance leads to chronic osteolysis. Understanding the role of exosomes may provide new perspectives on their influence on bone metabolism in inflammatory bone diseases. At the same time, exosomes have a promising future in diagnosing and treating inflammatory bone disease due to their unique properties.

Parathyroid hormone and its related peptides in bone metabolism.

Parathyroid hormone (PTH) is an 84-amino-acid peptide hormone that is secreted by the parathyroid gland. It has different administration modes in bone tissue through which it promotes bone formation (intermittent administration) and bone resorption (continuous administration) and has great potential for application in sbone defect repair. PTH regulates bone metabolism by binding to PTH1R. PTH plays an osteogenic role by acting directly on mesenchymal stem cells, cells with an osteoblastic lineage, osteocytes, and T cells. It also participates as an osteoclast by indirectly acting on osteoclast precursor cells and osteoclasts and directly acting on T cells. In these cells, PTH activates the Wnt signaling, cAMP/PKA, cAMP/PKC, and RANKL/RANK/OPG pathways and other signaling pathways. Although PTH(1-34), also known as teriparatide, has been used clinically, it still has some disadvantages. Developing improved PTH-related peptides is a potential solution to teriparatide's shortcomings. The action mechanism of these PTH-related peptides is not exactly the same as that of PTH. Thus, the mechanisms of PTH and PTH-related peptides in bone metabolism were reviewed in this paper.

The effect of estrogen in coronavirus disease 2019.

The outcomes of coronavirus disease 2019 (COVID-19) vary between men and women. Some statistical reports have shown that men have a higher risk of developing COVID-19 and suffer from worse outcomes than females. Although there are many factors that can explain the high prevalence of COVID-19 in men, such as lifestyle habits and the different profile of comorbidities among sexes, the distinctions between male and female immune systems cannot be ignored. It has been sufficiently shown that sex differences have a critical influence on the shaping of immune response, which then leads to different pathogenesis in infectious diseases. Compared with males, females typically have a more effective innate and adaptive immune response to viral infections in COVID-19. What's more, there is a growing body of evidence showing that estrogen exerts an effect on the regulation of immune response. This article examines the effect and mechanism of estrogen on COVID-19.

Noninvasive Identification of Immune-Related Biomarkers in Hepatocellular Carcinoma.

Primary liver carcinoma is one of the most common malignant tumors with a poor prognosis. This study aims to uncover the potential mechanisms and identify core biomarkers of hepatocellular carcinoma (HCC). The HCC gene expression profile GSE49515 was chosen to analyze the differentially expressed genes from purified RNA of peripheral blood mononuclear cells, including 10 HCC patients and 10 normal individuals. GO and KEGG pathway analysis and PPI network were used, and the enrichment of the core genes out of 15 hub genes was evaluated using GEPIA and GSEA, respectively. We employed flow cytometry to count mononuclear cells to verify our opinions. In this analysis, 344 DEGs were captured, including 188 upregulated genes and 156 downregulated genes; besides that, 15 hub genes were identified. GO analysis and KEGG analysis showed the DEGs were particularly involved in immune response, antigen processing and presentation, and infection and inflammation. The PPI network uncovered 2 modules were also mainly involved in immune response. In conclusion, our analysis disclosed the immune subversion was the major signature of HCC associated closely with JUN, VEGFA, TNFSF10, and TLR4, which could be novel noninvasive biomarkers in peripheral blood and targets for early diagnosis and therapy of HCC.