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Hydroxyapatite (HA), a commonly used material for bone repair, can enhance its biological properties through the modulation of its crystallinity. Exploring the variations in physicochemical and biological properties associated with different degrees of crystallinity is crucial for advancing the applications of HA. In this study, stoichiometric nano-apatite precursors were initially synthesized using chemical precipitation. Subsequently, four groups of HA ceramics with varying degrees of crystallinity (24 %, 42 %, 72 %, 100 %) were produced by adjusting the calcination temperature, as confirmed through comprehensive characterizations. A systematic investigation was then conducted to examine the impact of crystallinity on the physicochemical, cytological, and in vivo osteogenic properties of HA ceramics, elucidating the influence of crystallinity on the osteogenic potential of HA. Results indicated that higher crystallinity in HA ceramics enhanced mechanical strength and hardness while reducing surface roughness, hydrophilicity, and protein affinity. Cytological studies revealed that decreased crystallinity led to lower cell proliferation rates but facilitated cell adhesion, spreading, and increased expression of osteogenic genes. Moreover, cell experiments with extracts further supported the significant role of surface properties of HA ceramics in modulating cell behavior. In vivo osteogenic assays demonstrated that reduced crystallinity notably stimulated new bone formation. Overall, by integrating the results of in vitro and in vivo experiments, it can be concluded that reducing the crystallinity of HA ceramics, the biological properties of HA ceramics can be significantly enhanced while maintaining a certain level of mechanical strength, such as HA2 group (42 % crystallinity). This study highlights the substantial impact of crystallinity and surface characteristics of HA ceramics on cell behavior, offering valuable insights and strategies for enhancing and optimizing bone repair materials in future applications. [ABSTRACT FROM AUTHOR]

Bone extracellular matrix (ECM) has been shown to mimic aspects of the tissue's complex microenvironment, suggesting its potential role in promoting bone repair. However, current ECM-based therapies suffer from limitations such as inefficient scale-up, lack of mechanical integrity, and sub-optimal efficacy. Here, we fabricated hydrogels from decellularized ECM (dECM) from wild type (WT) and thrombospondin-2 knock-out (TSP2KO) mouse bones. TSP2KO bone ECM hydrogel was found to have distinct mechanical properties and collagen fibril assembly from WT. Furthermore, TSP2KO hydrogel promoted mesenchymal stem cell (MSC) attachment, spreading, and invasion in vitro. Similarly, it promoted formation of tube-like structures by human umbilical vein endothelial cells (HUVECs). When applied to a murine calvarial defect model, TSP2KO hydrogel enhanced repair, in part, due to increased angiogenesis. Our study suggests the pro-angiogenic therapeutic potential of TSP2KO bone ECM hydrogel in bone repair. The study describes the first successful preparation of a novel hydrogel made from decellularized bones from wild-type mice and mice lacking thrombospondin-2 (TSP2). Hydrogels from TSP2 knock-out (TSP2KO) bones have unique characteristics in structure and biomechanics. These gels interacted well with cells in vitro and helped repair damaged bone in a mouse model. Therefore, TSP2KO bone-derived hydrogel has translational potential for accelerating repair of bone defects that are otherwise difficult to heal. This study not only creates a new material with promise for accelerated healing, but also validates tunability of native biomaterials by genetic engineering. [Display omitted] [ABSTRACT FROM AUTHOR]

The cell (plasma) membrane is enriched with numerous receptors, ligands, enzymes, and phospholipids that play important roles in cell-cell and cell-extracellular matrix interactions governing, for instance, tissue development and repair. We previously showed that plasma membrane nanofragments (PMNFs) act as nucleation sites for bone formation in vivo , and induce in vitro mineralization within 1 day. In this study, we optimized the methods for generating, isolating, and applying PMNFs as a cell-free therapeutic to expedite bone defect repair. The PMNFs were isolated from different mouse cell lines (chondrocytes, osteoblasts, and fibroblasts), pre-conditioned, lyophilized, and subsequently transplanted into 2 mm critical-sized calvarial defects in mice (n = 75). The PMNFs from chondrocytes, following a 3-day pre-incubation, significantly accelerated bone repair within 2 weeks, through a coordinated attraction of macrophages, endothelial cells, and osteoblasts to the healing site. In vitro experiments confirmed that PMNFs enhanced cell adhesion. Comparison of the PMNF efficacy with phosphatidylserine, amorphous calcium phosphate (ACP), and living cells confirmed the unique ability of PMNFs to promote accelerated bone repair. Importantly, PMNFs promoted nearly complete integration of the regenerated bone with native tissue after 6 weeks (% non-integrated bone area = 15.02), contrasting with the partial integration (% non-integrated bone area = 56.10; p < 0.01, Student's test) with transplantation of ACP. Vickers microhardness tests demonstrated that the regenerated bone after 6 weeks (30.10 ± 1.75) exhibited hardness similar to native bone (31.07 ± 2.46). In conclusion, this is the first study to demonstrate that cell membrane can be a promising cell-free material with multifaceted biofunctional properties that promote accelerated bone repair. • For the first time, the cell (plasma) membrane is used as material for bone repair. • The plasma membrane from chondrocytes promoted rapid bone repair within 2 weeks, with complete integration of the newly formed bone with the surrounding native tissue. • The plasma membrane from chondrocytes presented multifaceted effects, strongly promoting the attraction of macrophages, endothelial cells and osteoblasts to the healing site. [Display omitted] [ABSTRACT FROM AUTHOR]

The demand for novel tissue grafting and regenerative wound care biomaterials is growing as traditional options often fall short in biocompatibility, functional integration with human tissue, associated cost(s), and sustainability. Salmon aquaculture generates significant volumes of waste, offering a sustainable opportunity for biomaterial production, particularly in osteo-conduction/-induction, and de novo clinical/surgical bone regeneration. Henceforth, this study explores re-purposing salmon waste through a standardized pre-treatment process that minimizes the biological waste content, followed by a treatment stage to remove proteins, lipids, and other compounds, resulting in a mineral-rich substrate. Herein, we examined various methods—alkaline hydrolysis, calcination, and NaOH hydrolysis—to better identify and determine the most efficient and effective process for producing bio-functional nano-sized hydroxyapatite. Through comprehensive chemical, physical, and biological assessments, including Raman spectroscopy and X-ray diffraction, we also optimized the extraction process. Our modified and innovative alkaline hydrolysis–calcination method yielded salmon-derived hydroxyapatite with a highly crystalline structure, an optimal Ca/P ratio, and excellent biocompatibility. The attractive nano-scale cellular/tissular properties and favorable molecular characteristics, particularly well-suited for bone repair, are comparable to or even surpass those of synthetic, human, bovine, and porcine hydroxyapatite, positioning it as a promising candidate for use in tissue engineering, wound healing, and regenerative medicine indications. [ABSTRACT FROM AUTHOR]

The development of hydroxyapatite (HAp) and polyether ether ketone (PEEK) biocomposites has been extensively studied for bone repair applications due to the synergistic properties of the involved materials. In this study, we aimed to develop HAp/PEEK biocomposites using high-energy ball milling, with HAp concentrations (20%, 40%, and 60% w/v) in PEEK, to evaluate their physicochemical, mechanical, cytotoxicity, and antimicrobial properties for potential applications in Tissue Engineering (TE). The biocomposites were characterized by structure, morphology, apparent porosity, diametral compression strength, cytotoxicity, and antimicrobial activity. The study results demonstrated that the HAp/PEEK biocomposites were successfully synthesized. The C2 biocomposite, containing 40% HAp, stood out due to the optimal distribution of HAp particles in the PEEK matrix, resulting in higher compression strength (246 MPa) and a homogeneous microstructure. It exhibited antimicrobial activity against Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli, with no cytotoxicity observed. These properties make the C2 biocomposite promising for regenerative medicine applications, combining mechanical strength, bioactivity, and biocompatibility. [ABSTRACT FROM AUTHOR]

Biometal ions are crucial in the structure and function of living organisms and have extensively been employed to promote bone tissue regeneration. Nevertheless, the biological functions of biometal ions and the underlying mechanisms responsible for their pro-regenerative effects remain incompletely understood, since bone repair is an intricate physiological process involving multiple cell types and signals. Recent accomplishments in the osteoimmunological field have revealed the momentous involvement of the immune system in mediating the therapeutic effects of biometal ions. The inflammatory factors secreted by immune cells contribute to bone cell migration, activation, and proliferation. This review summarizes the immune system and its constituent cells, followed by the current perspective on immunomodulation during bone healing. Next, the physicochemical and physiological properties of various biometal ions, including lithium, sodium, potassium, magnesium, calcium, strontium, vanadium, iron, cobalt, copper, and zinc, are thoroughly reviewed. In addition, the interactions between biometal ions, immune cells, and bone tissue are discussed, aiming to provide insights into the prospective development of novel approaches to bone tissue regeneration by harnessing the therapeutic potential of these biometal ions. [ABSTRACT FROM AUTHOR]

The aim of this study was to verify the effectiveness of attenuated total reflectance‐fourier transform infrared (ATR‐FTIR) spectroscopy in the characterization of bone repair in mandibular osteotomy using erbium, chromium‐doped yttrium, scandium, gallium and garnet (Er,Cr:YSGG) laser and multilaminate drill on each side. Two mandible bone fragments were removed from 30 rabbits, and the process of bone repair was studied immediately, 3, 7, 15, 21, and 28 days after the surgery. The histological analysis allowed detecting differences in the early stages of tissue repair after bone cutting performed with the Er,Cr:YSGG laser or multilaminate drill. The ATR‐FTIR spectroscopy technique was sensitive to changes in the organic content of bone tissue repair process. [ABSTRACT FROM AUTHOR]

BACKGROUND: Bone has bioelectric effects. However, bone defects can lead to loss of endogenous bioelectricity in bone. The implantation of bone tissue engineering scaffolds with bioelectric effect into bone defects will replenish the missing electrical signals and accelerate the repair of bone defects. OBJECTIVE: To introduce the bioelectric effect of bone tissue and expound the repair effect of electrical stimulation on bone defects, summarize the research progress of bioelectric effect applied to bone tissue engineering, in order to provide new ideas for the research of bone tissue engineering. METHODS: Relevant articles were searched on CNKI, WanFang, PubMed, Web of Science and ScienceDirect databases, using “bioelectrical effect, bioelectrical materials, electrical stimulation, bone tissue engineering, bone scaffold, bone defect, bone repair, osteogenesis” as the English and Chinese search terms. Finally, 87 articles were included for analysis. RESULTS AND CONCLUSION: (1) Bioelectrical effect combined with ex vivo electrical stimulation to design bone tissue engineering scaffolds is an ideal and feasible approach, and the main materials involved include metallic materials, graphene materials, natural bio-derived materials, and synthetic biomaterial. At present, the most widely used conductive material is graphene material, which benefits from its super conductivity, large specific surface area, good biocompatibility with cells and bones, and excellent mechanical properties. (2) Graphene materials are mainly introduced into the scaffold as modified materials to enhance the conductivity of the overall scaffold, while its large surface area and rich functional groups can promote the loading and release of bioactive substances. (3) However, there are still some major challenges to overcome for bioelectrically effective bone tissue engineering scaffolds: not only electrical conductivity but also the overall performance of the bracket needs to be considered; lack of uniform, standardized preparation of bioelectrically effective bone tissue engineering scaffolds; extracorporeal electrical stimulation intervention systems are not yet mature enough; lack of individualized guidance on stent selection to enable the selection and design of the most appropriate stent for patients with different pathologies. (4) When designing conductive scaffolds, researchers have to deeply consider the comprehensive effects of the scaffolds, such as biocompatibility, mechanical properties, and biodegradability. This combination of properties can be achieved by combining multiple materials. (5) Beyond that, clinical translation should be the ultimate consideration for conductive stent design. On the basis of evaluating the safe current threshold for electrical stimulation to act on the human body and facilitate the repair of bone defects, animal experiments as well as basic experiments are designed and then applied to the clinic to achieve the ultimate goal of applying bioelectrical effect bone tissue engineering scaffolds in the clinic. [ABSTRACT FROM AUTHOR]

Due to the limited supply of autologous bone grafts, there is a need to develop more bone matrix materials to repair bone defects. Xenograft bone is expected to be used for clinical treatment due to its exact structural similarity to natural bone and its high biocompatibility. In this study, decellularized antler cancellous bone matrix (DACB) was first prepared, and then the extent of decellularization of DACB was verified by histological staining, which demonstrated that it retained the extracellular matrix (ECM). The bioactivity of DACB was assessed using C3H10T1/2 cells, revealing that DACB enhanced cell proliferation and facilitated cell adhesion and osteogenic differentiation. When evaluated by implanting DACB into nude mice, there were no signs of necrosis or inflammation in the epidermal tissues. The bone repair effect of DACB was verified in vivo using sika deer during the antler growth period as an animal model, and the molecular mechanisms of bone repair were further evaluated by transcriptomic analysis of the regenerated tissues. Our findings suggest that the low immunogenicity of DACB enhances the production of bone extracellular matrix components, leading to effective osseointegration between bone and DACB. This study provides a new reference for solving bone defects. [ABSTRACT FROM AUTHOR]

Postoperative pain is a major clinical problem imposing a significant burden on patients and society. In a survey 2 years after orthopedic surgery, 57%of patients reported persisting postoperative pain. However, only limited progress has been made in the development of safe and effective therapies to prevent the onset and chronification of pain after orthopedic surgery. We established a tibial fracturemouse model that recapitulates clinically relevant orthopedic trauma surgery, which causes changes in neuropeptide levels in dorsal root ganglia and sustained neuroinflammation in the spinal cord. Here, we monitored extended pain behavior in this model, observing chronic bilateral hindpaw mechanical allodynia in both male and female C57BL/6J mice that persisted for .3 months after surgery. We also tested the analgesic effects of a novel, minimally invasive, bioelectronic approach to percutaneously stimulate the vagus nerve (termed percutaneous vagus nerve stimulation [pVNS]). Weekly pVNS treatment for 30 minutes at 10 Hz for 3 weeks after the surgery strongly reduced pain behaviors comparedwith untreated controls. Percutaneous vagus nerve stimulation also improved locomotor coordination and accelerated bone healing. In the dorsal root ganglia, vagal stimulation inhibited the activation of glial fibrillary acidic protein-positive satellite cells but without affectingmicroglial activation. Overall, these data provide novel evidence supportive of theuseof pVN Stop revent post operative pain and inform translational studies to test antinociceptive effects of bioelectronic medicine in the clinic. [ABSTRACT FROM AUTHOR]

Aim: To assess the efficacy of heterologous fibrin biopolymer (HFB) in promoting alveolar bone healing after tooth extraction in rats. Materials and Methods: The upper right incisors of 48 Wistar rats were extracted. Toothless sockets were filled with HFB (HFBG, n = 24) or blood clot (BCG, n = 24). The tooth extraction sites were subjected to micro‐computed tomography (micro‐CT), histological, histomorphometric and immunohistochemical (for Runt‐related transcription factor 2/Runx2 and tartrate‐resistant acid phosphatase/TRAP) analyses on days 0, 7, 14 and 42 after extraction. Results: Socket volume remained similar between days 0 and 14 (69 ± 5.4 mm3), except in the BCG on day 14, when it was 10% lower (p =.043). Although the number of Runx2+ osteoblasts was high and similar in both groups (34 × 102 cells/mm2), the HFBG showed lower inflammatory process and osteoclast activity than BCG at 7 days. On day 14, the number of Runx2+ osteoblasts remained high and similar to the previous period in both groups. However, osteoclast activity increased. This increase was 55% lower in the HFBG than BCG. In the BCG, the presence of an inflammatory process and larger and numerous osteoclasts on day 14 led to resorption of the alveolar bone ridge and newly formed bone. On day 42, numbers of Runx2+ osteoblast and TRAP+ osteoclasts decreased dramatically in both groups. Although the BCG exhibited a more mature cortical bone formation, it exhibited a higher socket reduction (28.3 ± 6.67%) and smaller bone volume (37 ± 5.8 mm3) compared with HFBG (socket reduction of 14.8 ± 7.14% and total bone volume of 46 ± 5.4 mm3). Conclusions: HFB effectively suppresses osteoclast activity and reduces alveolar bone resorption compared with blood clot, thus preventing three‐dimensional bone loss, particularly during the early healing period. HFB emerges as a promising biopharmaceutical material for enhancing healing processes after tooth extraction. [ABSTRACT FROM AUTHOR]

Structural alteration of synthetic implants aims to achieve better bioactivity, higher cellular response, and regulated degradability, all of which are critical criteria for a biomaterial to serve as a graft in bone regeneration. The aim of this work was to synthesize silicon-substituted hydroxyapatite and test its bioactivity in simulated body fluid (SBF) by proving the use of sodium metasilicate (Na2SiO3.9H2O) as an affordable precursor of silica. Thus, the study evaluated the in vitro bone-bonding capacity of hydroxyapatite (Ca10(PO4)6(OH)2) (HA) substituted with silicate ion (Ca10(PO4)6−x(SiO4)x(OH)2−x; SixHA). The SixHA with x = 0.4 was synthesized by utilizing a wet precipitation method with sodium metasilicate as a low-cost silica alternative for alkoxysilane precursors. The SixHA was then examined for properties such as morphology, elemental composition, phase composition, and the nature of chemical bonds using scanning electron microscopy (SEM), energy dispersive X-ray analysis (EDX), X-ray diffractometry (XRD), and Fourier transformed infrared spectroscopy (FTIR), respectively. An in vitro bioactivity experiment was also carried out by incubating the SixHA in simulated body fluid (SBF) at 36.5 ◦C for 7 and 14 days. The obtained results revealed the substitution of SiO44− for some PO4 3− groups in the hydroxyapatite structure. The SixHA nucleated more apatite crystals on its surface and demonstrated some degradability during the periods of immersion in SBF. The characteristics of the SixHA imply that it could be used as a graft in bone restoration applications, thus signifying that sodium metasilicate could serve as an economic silica source for silicon-substituted hydroxyapatite production. [ABSTRACT FROM AUTHOR]

Objective To study the effect of the combinational use of miR-34a-functionalized Bio-Oss® bone powder with transglutaminase crosslinked gelatin (Col-Tgel) on the osteoblastic differentiation of bone marrow mesenchymal stem cells (BMSCs) and bone defect healing after irradiation. Methods The experiment was approved by the Animal Ethics Committee. BMSCs were isolated from the bone marrow of 2-week-old Sprague-Dawley (SD) rats and identified. After reaching 80% confluence, BMSCs were irradiated with 2 Gy of X-ray radiation to establish a radiation-damaged BMSC model for further experimentation. 2.5 μL or 5 μL of Col-Tgel was mixed with 10 mg of Bio-Oss® (P) to prepare PG-2.5 and PG-5. The optimal proportion of Bio-Oss® (P) and Col-Tgel was determined through in vitro and in vivo experiments. Cy3-labeled agomiR-34a, agomiR-34a, or agomiR NC was mixed with lipofectamine 2000 and added to 10 mg of Bio-Oss® (P). The mixtures were lyophilized, and 2.5 μL Col-Tgel was added to each group of lyophilized Bio-Oss®/lipofectamine/miRNA complexes or to 10 mg of Bio-Oss® to obtain PG-Cy3-miR-34a, PG-miR-34a, PG-miR NC, and PG. Irradiated BMSCs were cocultured with PG-Cy3-miR-34a to evaluate cellular uptake of Cy3-agomiR-34a using confocal microscopy. Then, irradiated BMSCs were cocultured with PG-miR-34a, PG-miR NC, and PG. The expression of miR-34a was tested by RT-qPCR and cell proliferation was tested by CCK-8 assay. After 14 days of osteogenic induction, the mRNA expression of Runt-related transcription factor 2 (Runx2), alkaline phosphatase (ALP), and osteocalcin (OCN) was tested by RT-qPCR. The bilateral tibias of 8-week-old SD rats were irradiated with a single dose of 15 Gy of X-ray radiation. Three weeks later, tibial defects with a diameter of 3 mm and a depth of 2 mm were created 2-3 mm below the epiphyseal line in the tibial metaphysis. The composite bone substitute materials of PG-miR-34a, PG-miR NC, and PG were implanted into the defect area. Eight weeks after implantation, the tibias were harvested and evaluated for bone regeneration using micro-CT analysis and HE staining. Results The results demonstrated that 2 Gy irradiation adversely affected the osteogenic differentiation capacity of BMSCs, evidenced by the decreased ALP staining and number of mineralized nodules stained with Alizarin red in the irradiated group compared to the non-irradiated group. The composite material consisting of 10 mg Bio-Oss® and 2.5 μL Col-Tgel exhibited good osteogenic induction capability and handling properties and was used for subsequent experiments. The PG-Cy3-miR-34a could deliver the loaded Cy3-agomiR-34a into irradiated BMSCs. PG-miR-34a enhanced the expression of miR-34a in irradiated BMSCs without affecting cell proliferation. PG-miR-34a significantly upregulated the expression of osteogenic-related genes, including Runx2, ALP, and OCN. In the experiment of bone defect healing in irradiated tibias, micro-CT analysis showed that PG-miR-34a group had a higher bone volume in the bone defect area compared to other groups. The HE staining results also confirmed that implantation of PG-miR-34a can promote the healing of bone defects in irradiated tibias. Conclusion The combinational use of miR-34a-functionalized Bio-Oss® bone powder with Col-Tgel could promote the osteogenic differentiation of irradiated BMSCs and enhance bone regeneration in irradiated bone defects.

Diabetes mellitus (DM) is a chronic metabolic disorder that can affect the balance of bone metabolism and bone microenvironment, leading to impaired fracture healing. There are several underlying mechanisms which contributing to the impaired diabetic bone microenvironment such as hyperglycemia, the production of advanced glycation end products (AGEs), inflammation, and oxidative stress, etc. Recent studies have achieved great progress in developing novel smart biomaterials in improving the diabetic bone microenvironment to promote diabetic fracture healing. In this paper, we reviewed the mechanisms on DM-induced impaired fracture healing. Meanwhile, we also summarized the smart biomaterials used to improve the local microenvironment of diabetic fractures healing, which provides a novel perspective for the future treatment of fractures in diabetic patients.

Isotretinoin is an oral medication commonly utilized to treat severe acne. It belongs to the class of retinoids and is a synthetic form of vitamin A. Possible changes in bone tissue associated with the systemic administration of Isotretinoin for long periods and in high doses, such as hypercalcemia, osteopenia, diffuse hyperostosis, or even skeletal deformities, are reported in scientific studies. The objective of this literature review was to analyze the available scientific literature on the systemic administration of Isotretinoin and its effects on bone tissue. To this end, articles that demonstrate effects of Isotretinoin on bone metabolism, bone mineral density, bone formation, and resorption, in addition to possible changes generated in this tissue were considered valid for inclusion in this literature review. The search for articles that fit the premise of this work was carried out in the PubMed/MEDLINE database. In a preliminary search, 85 articles were obtained; after in-depth investigation and checking of the inclusion and exclusion criteria, 21 articles were selected, with 17 articles reporting the effect of systemic administration of Isotretinoin in humans and four articles analyzing the effect generated by this substance systemically administrated in animals, more specifically in rats. After analyzing the selected articles, it was possible to observe several reports on hyperostosis or even changes in the formation of bone structures in human patients. Concerning animals, the largest number of studies addressed the changes caused in the formation or development of bone structures by the systemic administration of Isotretinoin. From the current analyses, and given the wide use of Isotretinoin, it is necessary to know its viability and influence on tissues. Its clinical efficacy seems to overcome any of the skeletal side effects observed; however, more studies are necessary to properly evaluate and prove the effects generated on bone tissues as well as other structures.

Implant materials with micro/nanostructures bear a closer resemblance with the features of natural bone, which influences the wettability, bone differentiation, and vascularization of materials. However, it is still technically challenging to design the inner wall and surface micro/nanostructures on macroporous bioceramics due to their brittleness. In this work, micro/nanostructured composites with Si3N4 whiskers as a framework, and the (inner) surface covered with SiC nanowires were prepared, denoted as SiC‐nw@Si3N4‐w bioceramics. The synthesis, adopting the green chemistry concept, was utilized from environmental products (carbon evaporated in the furnace at high temperature) and reaction impurities (carbon obtained by polymer pyrolysis and silicon obtained by Si3N4 decomposition) to synthesize SiC nanowires via a vapor‐solid growth mechanism. The prepared SiC‐nw@Si3N4‐w bioceramics have potential applications in bone repair due to their cell adhesion and proliferation. [ABSTRACT FROM AUTHOR]

Creating interconnected macropores in calcium phosphate cement (CPC) is an effective strategy to promote its degradation and osteogenesis. However, little attention has been given to the osteogenic effect of the CPC scaffolds with pre-forming and in-situ forming interconnected macropores. Herein, two types of CPC scaffolds were prepared by infiltrating CPC pastes into 3D-printed polycaprolactone (PCL) and poly(lactic-co-glycolic acid) (PLGA) networks. Meanwhile, the sacrificial PCL network within CPC was dissolved to obtain the CPC scaffold with approximately 300 μm macropores, whereas the PLGA network was retained within the CPC to obtain the PLGA/CPC scaffold. The results indicated that the PLGA/CPC scaffold showed higher degradation rate and compressive strength compared to the CPC scaffold with pre-forming interconnected macropores. However, the proliferation rate and alkaline phosphatase activity of mouse bone mesenchymal stem cells cultured with the CPC scaffold were superior to those cultured with the PLGA/CPC scaffold. In addition, greater formation of new bone and material degradation in the CPC scaffold compared to the PLGA/CPC scaffold after implanted in the rabbit femoral defects. [ABSTRACT FROM AUTHOR]

The design and construction of a new and excellent synthetic graft is of great significance in the field of bone defect repair and reconstruction. In this study, a dopamine modified chitosan hydrogel doped with Cu ions with a mild photothermal effect was designed to provide a better microenvironment to advance the bone repair via promote the angiogenesis and osteogenesis. Characterizations showed the successful synthesis of the material while it also presented excellent biocompatibility and mild photothermal effect under the irradiation of near-infrared light. Further, it could enhance the angiogenesis of HUVECs cells through promoting the ability of migration and tube formation and enhance the osteogenic differentiation of MC3T3-E1 cells via increasing the content of vital osteogenic factors including Runx2, Col-1, OPN, OCN, OSX, etc. The in vivo experiment also testified that it could promote the bone defect repair in rat models. These results indicate the multifunctional hydrogel is an ideal material for the treatment of bone defects and has good clinical application potential. [ABSTRACT FROM AUTHOR]

Abstract Simultaneously modulating the inflammatory microenvironment and promoting local bone regeneration is one of the main challenges in treating bone defects. In recent years, osteoimmunology has revealed that the immune system plays an essential regulatory role in bone regeneration and that macrophages are critical components. In this work, a mussel-inspired immunomodulatory and osteoinductive dual-functional hydroxyapatite nano platform (Gold/hydroxyapatite nanocomposites functionalized with polydopamine - PDA@Au-HA) is developed to accelerate bone tissues regeneration by regulating the immune microenvironment. PDA coating endows nanomaterials with the ability to scavenge reactive oxygen species (ROS) and anti-inflammatory properties, and it also exhibits an immunomodulatory ability to inhibit M1 macrophage polarization and activate M2 macrophage secretion of osteogenesis-related cytokines. Most importantly, this nano platform promotes the polarization of M2 macrophages and regulates the crosstalk between macrophages and pre-osteoblast cells to achieve bone regeneration. Au-HA can synergistically promote vascularized bone regeneration through sustained release of Ca and P particles and gold nanoparticles (NPs). This nano platform has a synergistic effect of good compatibility, scavenging of ROS, and anti-inflammatory and immunomodulatory capability to accelerate the bone repair process. Thus, our research offers a possible therapeutic approach by exploring PDA@Au-HA nanocomposites as a bifunctional platform for tissue regeneration.

Magnesium (Mg) is abundant in humans. Studies have shown that Mg2+ significantly affects physiological processes such as osteogenesis, osteoblast adhesion and motility, immunomodulation, and angiogenesis. Mg-based alloy porous scaffolds have attracted increasing attention because of their degradability and mechanical properties. Hence, wire-cut EDM was used to fabricate porous scaffolds. In addition, fluoride treatment afforded an MgF2 coating, and racemic polylactic acid PDLLA was used as the carrier of rhBMP-2, which was evenly coated on the surface of the passivated porous alloy scaffold to slowly release growth factors and slow down the degradation rate. The rat femoral condyle defect model experiment was performed to study the in vivo bone regeneration capacity of porous scaffolds and compare the differences in the healing effect with or without rhBMP-2. The enhanced corrosion resistance of the porous scaffold was confirmed through in vitro immersion experiments. Micro-CT implied that porous scaffold with rhBMP-2 induced new bone formation and the new bone formation along the pores, as well as the histological examination in vivo. In summary, the porous scaffold promotes bone formation and has great potential for clinical translation.

Objective To investigate the osteogenic properties of a methacrylated gelatin (GelMA) / bone marrow mesenchymal stem cells (BMSCs) composite hydrogel applied to the skull defect area of rats and to provide an experimental basis for the development of bone regeneration biomaterials. Methods This study was approved by the Animal Ethics Committee of Nanjing University. A novel photocurable composite biohydrogel was developed by constructing photoinitiators [lthium phenyl (2,4,6-trimethylbenzoyl) phosphinate, LAP], GelMA, and BMSCs. The surface morphology and elemental composition of the gel were examined using scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDX). The compressive strength of the gel was evaluated using an electronic universal testing machine. After in vitro culture for 1, 2, and 5 days, the proliferation of the BMSCs in the hydrogels was assessed using a CCK-8 assay, and their survival and morphology were examined through confocal microscopy. A 5 mm critical bone deficiency model was generated in a rat skull. The group receiving composite hydrogel treatment was referred to as the GelMA/BMSCs group, whereas the untreated group served as the control group. At the 4th and 8th weeks, micro-CT scans were taken to measure the bone defect area and new bone index, while at the 8th week, skull samples from the defect area were subjected to H&E staining, van Gieson staining, and Goldner staining to evaluate the quality of bone regeneration and new bone formation. Results SEM observed that the solidified GelMA showed a 3D spongy gel network with uniform morphology, the porosity of GelMA was 73.41% and the pore size of GelMA was (28.75 ± 7.13) μm. EDX results showed that C and O were evenly distributed in the network macroporous structure of hydrogel. The hydrogel compression strength was 152 kPa. On the 5th day of GelMA/BMSCs culture, the cellular morphology transitioned from oval to spindle shaped under microscopic observation, accompanied by a significant increase in cell proliferation (159.4%, as determined by the CCK-8 assay). At 4 weeks after surgery, a 3D reconstructed micro-CT image revealed a minimal reduction in bone defect size within the control group and abundant new bone formation in the GelMA/BMSCs group. At 8 weeks after surgery, no significant changes were observed in the control group's bone defect area, with only limited evidence of new bone growth; however, substantial healing of skull defects was evident in the GelMA/BMSCs group. Quantitative analysis at both the 4- and 8-week examinations indicated significant improvements in the new bone volume (BV), new bone volume/total bone volume (BV/TV), bone surface (BS), and bone surface/total bone volume (BS/TV) in the GelMA/BMSCs group compared to those in the control group (P

[Display omitted] Orderly hierarchical structure with balanced mechanical, chemical, and electrical properties is the basis of the natural bone microenvironment. Inspired by nature, we developed a piezocatalytically-induced controlled mineralization strategy using piezoelectric polymer poly-L-lactic acid (PLLA) fibers with ordered micro-nano structures to prepare biomimetic tissue engineering scaffolds with a bone-like microenvironment (pcm-PLLA), in which PLLA-mediated piezoelectric catalysis promoted the in-situ polymerization of dopamine and subsequently regulated the controllable growth of hydroxyapatite crystals on the fiber surface. PLLA fibers, as analogs of mineralized collagen fibers, were arranged in an oriented manner, and ultimately formed a bone-like interconnected pore structure; in addition, they also provided bone-like piezoelectric properties. The uniformly sized HA nanocrystals formed by controlled mineralization provided a bone-like mechanical strength and chemical environment. The pcm-PLLA scaffold could rapidly recruit endogenous stem cells, and promote their osteogenic differentiation by activating cell membrane calcium channels and PI3K signaling pathways through ultrasound-responsive piezoelectric signals. In addition, the scaffold also provided a suitable microenvironment to promote macrophage M2 polarization and angiogenesis, thereby enhancing bone regeneration in skull defects of rats. The proposed piezocatalytically-induced controllable mineralization strategy provides a new idea for the development of tissue engineering scaffolds that can be implemented for multimodal physical stimulation therapy. [ABSTRACT FROM AUTHOR]

Simultaneously modulating the inflammatory microenvironment and promoting local bone regeneration is one of the main challenges in treating bone defects. In recent years, osteoimmunology has revealed that the immune system plays an essential regulatory role in bone regeneration and that macrophages are critical components. In this work, a mussel-inspired immunomodulatory and osteoinductive dual-functional hydroxyapatite nano platform (Gold/hydroxyapatite nanocomposites functionalized with polydopamine - PDA@Au-HA) is developed to accelerate bone tissues regeneration by regulating the immune microenvironment. PDA coating endows nanomaterials with the ability to scavenge reactive oxygen species (ROS) and anti-inflammatory properties, and it also exhibits an immunomodulatory ability to inhibit M1 macrophage polarization and activate M2 macrophage secretion of osteogenesis-related cytokines. Most importantly, this nano platform promotes the polarization of M2 macrophages and regulates the crosstalk between macrophages and pre-osteoblast cells to achieve bone regeneration. Au-HA can synergistically promote vascularized bone regeneration through sustained release of Ca and P particles and gold nanoparticles (NPs). This nano platform has a synergistic effect of good compatibility, scavenging of ROS, and anti-inflammatory and immunomodulatory capability to accelerate the bone repair process. Thus, our research offers a possible therapeutic approach by exploring PDA@Au-HA nanocomposites as a bifunctional platform for tissue regeneration. [ABSTRACT FROM AUTHOR]

3D printing was widely used for the modification of bioceramic structures. Here, Bioactive titanium dioxide (TiO 2) ceramics with macropore structures were prepared by controlling the pore size through 3D printing, and further obtained secondary micropores by altering the sintering temperature. The structures and in vitro bioactivity of materials were characterized, and the properties of the ceramics for osteogenic differentiation of rabbits bone marrow mesenchymal stem cells (rBMSCs) were investigated. The results showed that titanium dioxide ceramics could induce apatite formation in SBF, which indicated it is bioactive. All materials exhibited porous structures, which could promote the proliferation and osteogenic differentiation of rBMSCs. Importantly, the structure with 200 μm pore size significantly promoted the proliferation and adhesion of cells. Furthermore, more secondary micropores formed on the surface of materials with the decreased sintering temperature, which promoted cell proliferation. The pore size of 400 μm significantly upregulated the expression of osteogenesis-related genes, including Col I, ALP, Runx2, and OPN. It had the strongest osteogenic ability when sintered at 1100 °C compared to other groups. This implies that the 3D-printed TiO 2 ceramics have good osteogenic properties, and the hierarchical structure consisting of macroscopic pores and secondary micropores can control it well. [Display omitted] [ABSTRACT FROM AUTHOR]

Continuous administration of low‐intensity whole‐body vibration (WBV) gradually diminishes bone mechanosensitivity over time, leading to a weakening of its osteogenic effect. We investigated whether discretizing WBV into bouts with short rest intervals was effective in enhancing osteoporotic bone repair. Ten‐week‐old female mice were ovariectomized and underwent drill‐hole defect surgery (Day 0) on the right tibial diaphysis at 11 weeks of age. The mice underwent one of three regimens starting from Day 1 for 5 days/week: continuous WBV at 45 Hz and 0.3 g for 7.5 min/day (cWBV); 3‐s bouts of WBV at 45 Hz, 0.3 g followed by 9‐s rest intervals, repeated for 30 min/day (repeated bouts of whole‐body vibration with short rest intervals [rWBV]); or a sham treatment. Both the cWBV and rWBV groups received a total of 20,250 vibration cycles per day. On either Day 7 or 14 posteuthanasia (n = 6/group/timepoint), the bone and angiogenic vasculature in the defect were computed tomography imaged using synchrotron light. By Day 14, the bone repair was most advanced in the rWBV group, showing a higher bone volume fraction and a more uniform mineral distribution compared with the sham group. The cWBV group exhibited an intermediate level of bone repair between the sham and rWBV groups. The rWBV group had a decrease in large‐sized angiogenic vessels, while the cWBV group showed an increase in such vessels. In conclusion, osteoporotic bone repair was enhanced by WBV bouts with short rest intervals, which may potentially be attributed to the improved mechanosensitivity of osteogenic cells and alterations in angiogenic vasculature. [ABSTRACT FROM AUTHOR]

Some studies have reported that tacrolimus (FK506), an immunosuppressant, may have positive effects on bone formation. However, the precise effects of FK506 on bone repair or osteoblasts remain inadequately elucidated, and limited research has explored the outcomes of its use in an in vivo mouse model. This study aims to examine the effects of FK506 on bone repair and osteoblast functions using bone defect and BMP-2-induced ectopic ossification mouse models, as well as cultured primary mouse osteoblasts treated with FK506. We established mouse models of femur bone defect and BMP-2-induced ectopic ossification to evaluate the effect of FK506 on new bone formation, respectively. Additionally, primary mouse osteoblasts were cultured with FK506 and examined for gene expressions related to osteoblast differentiation. While FK506 promoted the repair of bone defect areas in the femur of the bone defect mouse model, it also led to widespread abnormal bone formation outside the intended area. Additionally, following the implantation of a collagen sponge containing BMP-2 into mouse muscle tissue, FK506 was found to promote ectopic ossification and enhance BMP-2-induced osteoblast differentiation in vitro. Our findings also revealed that FK506 increased the number of immature osteoblasts in the absence of BMP-2 without affecting osteoblast differentiation. Furthermore , direct effects were observed, reducing the ability of osteoblasts to support osteoclastogenesis. These results indicate that FK506 increases new bone formation during bone repair and influences the proliferation of immature osteoblasts, as well as osteoblast-supported osteoclastogenesis. [Display omitted] • FK506 increases new bone formation during bone repair. • BMP-2-induced ectopic ossification is promoted by FK506. • FK506 enhances BMP-2-induced osteoblast differentiation. • FK506 increases osteoblasts in the absence of BMP-2. • FK506 has effects on osteoblast-supported osteoclastogenesis. [ABSTRACT FROM AUTHOR]

A composite bone cement based on α-TCP with self-reinforcing characteristics is prepared by compounding cellulose whiskers and polyvinyl alcohol in different proportions. In this system, we are inspired by the sea cucumber, which can alter the stiffness of their inner dermis reversibly. Through the formation of hydrogen bonds between the hydroxyl groups on the cellulose whiskers and PVA, the bone cement matrix can be strengthened during the curing process of cement. In the process of bone cement blending, there is more water, the hydrogen bond connection is destroyed, so the slurry has better fluidity at this time. As the hydration of the bone cement progresses, the reduction of the water phase leads to the formation of a permeable network structure of hydrogen bond connections between the whiskers. The dual-phase action of PVA and whiskers greatly increases the mechanical strength of the bone cement system (5.5 to 23.8 MPa), while the presence of polyvinyl alcohol improves the toughness of the bone cement system. This work was supposed to explore whether the chemoresponsive materials can be adapted to biomedical materials, for example, bone repair. [ABSTRACT FROM AUTHOR]

The repair of bone defects necessitates the establishment of sophisticated gradients. However, most strategies for gradient casting require specialized apparatus and have high equipment requirements. Therefore, there is a strong desire to develop a simple method for constructing gradient scaffolds that mimic the hierarchical structure of native bone. In this study, we prepared poly (vinyl alcohol)/bacterial cellulose (PVA/BC) scaffolds with gradient hydroxyapatite (HAp) content using the buoyancy-driven gradient (BG) method. Scanning electron microscopy characterization revealed that HAp gradient scaffold exhibited the gradient microstructure and HAp content. Furthermore, HAp gradient scaffold demonstrated enhanced adhesion, spreading, and proliferation of MC3T3-E1 cells and displayed excellent osteogenic ability. Additionally, when applied in subcutaneous implantation models in mice, HAp gradient scaffold showed superior biocompatibility compared to other scaffolds tested in vitro. These results present a straightforward approach for fabricating gradient HAp bone scaffolds that hold great potential as candidate materials for bone regeneration. [ABSTRACT FROM AUTHOR]

BACKGROUND: The sclerotic zone in the femoral head is an important imaging feature in the progression of steroid-induced femoral head necrosis, which is associated with disease prognosis. Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) has been shown to possess biological activities such as osteogenesis, angiogenesis and anti-mitochondrial apoptosis, which may be closely related to bone repair of steroid-induced femoral head necrosis. OBJECTIVE: To screen for the differential proteins in the sclerotic zone of steroid-induced osteonecrosis of the femoral head versus the normal zone, to screen for hub proteins in the sclerotic zone, and to verify the differential expression of hub proteins in the femoral head specimens following steroid-induced femoral head necrosis, and to to explore the repair pattern of the sclerotic zone following steroid-induced femoral head necrosis. METHODS: Femoral head samples were collected from patients with steroid-induced osteonecrosis of the femoral head receiving total hip arthroplasty. The differentially expressed genes in the sclerotic zone and the normal zone were screened by Tandem Mass Tags and analyzed by GO and KEGG signaling pathways to construct a protein-protein interaction network and screen hub genes. In addition, the expression of hub genes in the sclerotic zone was verified by immunohistochemistry and western blot. RESULTS AND CONCLUSION: Quantitative protein profiling by Tandem Mass Tags revealed that 609 proteins were significantly differentially expressed (Log2FC > 1.20, Log2FC < 0.84 and P < 0.05) in the sclerotic zone of the femoral head compared with the normal zone, of which 290 proteins were upregulated and 319 proteins were downregulated. The GO and KEGG pathway enrichment analyses revealed that among the top 10 enriched pathways, Wnt signaling pathway and life-cycle regulatory pathway were closely related to bone repair; in the life-cycle regulatory pathway, PGC-1α was one of the important proteins. In addition, western blot results verified the low expression of PGC-1α and NRF1 in the sclerotic zone and high expression of Cleaved Caspase-3 in the sclerotic zone compared with the normal zone of steroid-induced femoral head necrosis specimens. Light microscopic immunohistochemical results showed the distribution of PGC-1α, NRF1 and Cleaved Caspase-3 positive expression in the sclerotic and normal zones in the femoral head tissue specimens, indicating the presence of their expression in bone trabeculae, osteoblasts and bone marrow. In contrast, the brown area of the sclerotic zone of femoral head necrosis stained darker and showed more obvious expression of Cleaved Caspase-3. To conclude, in the sclerotic zone of steroid-induced femoral head necrosis, biological behaviors including activation of osteogenesis-related pathways such as Wnt and oxidative apoptosis characterized by low expression of PGC-1 are observed. Low expression of PGC-1α in the sclerotic zone of steroid-induced femoral head necrosis may be associated with the activation of oxidative apoptosis. [ABSTRACT FROM AUTHOR]

Deferoxamine, an iron chelator used to treat diseases caused by excess iron, has had a Food and Drug Administration-approved status for many years. A large number of studies have confirmed that deferoxamine can reduce inflammatory response and promote angiogenesis. Blood vessels play a crucial role in sustaining vital life by facilitating the delivery of immune cells, oxygen, and nutrients, as well as eliminating waste products generated during cellular metabolism. Dysfunction in blood vessels may contribute significantly to the development of life-threatening diseases. Anti-angiogenesis therapy and pro-angiogenesis/angiogenesis strategies have been frequently recommended for various diseases. Herein, we describe the mechanism by which deferoxamine promotes angiogenesis and summarize its application in chronic wounds, bone repair, and diseases of the respiratory system. Furthermore, we discuss the drug delivery system of deferoxamine for treating various diseases, providing constructive ideas and inspiration for the development of new treatment strategies. [ABSTRACT FROM AUTHOR]

Bone repair is faced with obstacles such as slow repair rates and limited bone regeneration capacity. Delayed healing even nonunion could occur in bone defects, influencing the life quality of patients severely. Photobiomodulation (PBM) utilizes different light sources to derive beneficial therapeutic effects with the advantage of being non-invasive and painless, providing a promising strategy for accelerating bone repair. In this review, we summarize the parameters, mechanisms, and effects of PBM regulating bone repair, and further conclude the current clinical application of PBM devices in bone repair. The wavelength of 635–980 nm, the output power of 40–100 mW, and the energy density of less than 100 J/cm2 are the most commonly used parameters. New technologies, including needle systems and biocompatible and implantable optical fibers, offer references to realize an efficient and safe strategy for bone repair. Further research is required to establish the reliability of outcomes from in vivo and in vitro studies and to standardize clinical trial protocols. [Display omitted] [ABSTRACT FROM AUTHOR]

Introduction: Glucocorticoids delay fracture healing and induce osteoporosis. Angiogenesis plays an important role in bone repair after bone injury. Plasminogen activator inhibitor-1 (PAI-1) is the principal inhibitor of plasminogen activators and an adipocytokine that regulates metabolism. However, the mechanisms by which glucocorticoids delay bone repair remain unclear. Materials and methods: Therefore, we herein investigated the roles of PAI-1 and angiogenesis in glucocorticoid-induced delays in bone repair after femoral bone injury using PAI-1-deficient female mice intraperitoneally administered dexamethasone (Dex). Results: PAI-1 deficiency significantly attenuated Dex-induced decreases in the number of CD31-positive vessels at damaged sites 4 days after femoral bone injury in mice. PAI-1 deficiency also significantly ameliorated Dex-induced decreases in the number of CD31- and endomucin-positive type H vessels and CD31-positive- and endomucin-negative vessels at damaged sites 4 days after femoral bone injury. Moreover, PAI-1 deficiency significantly mitigated Dex-induced decreases in the expression of vascular endothelial growth factor as well as hypoxia inducible factor-1α, transforming growth factor-β1, and bone morphogenetic protein-2 at damaged sites 4 days after femoral bone injury. Conclusion: The present results demonstrate that Dex-reduced angiogenesis at damaged sites during the early bone-repair phase after femoral bone injury partly through PAI-1 in mice. [ABSTRACT FROM AUTHOR]

Nano-hydroxyapatite (n-HA) is the main inorganic component of natural bone, which has been widely used as a reinforcing filler for polymers in bone materials, and it can promote cell adhesion, proliferation, and differentiation. It can also produce interactions between cells and material surfaces through selective protein adsorption and has therefore always been a research hotspot in orthopedic materials. However, n-HA nano-particles are inherently easy to agglomerate and difficult to disperse evenly in the polymer. In addition, there are differences in trace elements between n-HA nano-particles and biological apatite, so the biological activity needs to be improved, and the slow degradation in vivo, which has seriously hindered the application of n-HA in bone fields, is unacceptable. Therefore, the modification of n-HA has been extensively reported in the literature. This article reviewed the physical modification and various chemical modification methods of n-HA in recent years, as well as their modification effects. In particular, various chemical modification methods and their modification effects were reviewed in detail. Finally, a summary and suggestions for the modification of n-HA were proposed, which would provide significant reference for achieving high-performance n-HA in biomedical applications. [ABSTRACT FROM AUTHOR]

Implant therapy is a common treatment option in dentistry and orthopedics, but its application is often associated with an increased risk of microbial contamination of the implant surfaces that cause bone tissue impairment. This study aims to develop two silver-enriched platelet-rich plasma (PRP) multifunctional scaffolds active at the same time in preventing implant-associated infections and stimulating bone regeneration. Commercial silver lactate (L) and newly synthesized silver deoxycholate:β-Cyclodextrin (B), were studied in vitro. Initially, the antimicrobial activity of the two silver soluble forms and the PRP enriched with the two silver forms has been studied on microbial planktonic cells. At the same time, the biocompatibility of silver-enriched PRPs has been assessed by an MTT test on human primary osteoblasts (hOBs). Afterwards, an investigation was conducted to evaluate the activity of selected concentrations and forms of silver-enriched PRPs in inhibiting microbial biofilm formation and stimulating hOB differentiation. PRP-L (0.3 µg/mm2) and PRP-B (0.2 µg/mm2) counteract Staphylococcus aureus, Staphylococcus epidermidis and Candida albicans planktonic cell growth and biofilm formation, preserving hOB viability without interfering with their differentiation capability. Overall, the results obtained suggest that L- and B-enriched PRPs represent a promising preventive strategy against biofilm-related implant infections and demonstrate a new silver formulation that, together with increasing fibrin binding protecting silver in truncated cone-shaped cyclic oligosaccharides, achieved comparable inhibitory results on prokaryotic cells at a lower concentration. [ABSTRACT FROM AUTHOR]

We investigated the impact of mesenchymal stem cell (MSC) therapy on treating bilateral human hip osteonecrosis, analyzing 908 cases. This study assesses factors such as tissue source and cell count, comparing core decompression with various cell therapies. This research emphasizes bone repair according to pre-treatment conditions and the specificities of cell therapy in osteonecrosis repair, indicating a potential for improved bone repair strategies in hips without femoral head collapse. This study utilized a single-center retrospective analysis to investigate the efficacy of cellular approaches in the bone repair of osteonecrosis. It examined the impact on bone repair of tissue source (autologous bone marrow concentrate, allogeneic expanded, autologous expanded), cell quantity (from none in core decompression alone to millions in cell therapy), and osteonecrosis stage and volume. Excluding hips with femoral head collapse, it focused on patients who had bilateral hip osteonecrosis, both pre-operative and post-operative MRIs, and a follow-up of over five years. The analysis divided these patients into seven groups based on match control treatment variations in bilateral hip osteonecrosis, primarily investigating the outcomes between core decompression, washing effect, and different tissue sources of MSCs. Younger patients (<30 years) demonstrated significantly better repair volumes, particularly in stage II lesions, than older counterparts. Additionally, bone repair volume increased with the number of implanted MSCs up to 1,000,000, beyond which no additional benefits were observed. No significant difference was observed in repair outcomes between different sources of MSCs (BMAC, allogenic, or expanded cells). The study also highlighted that a 'washing effect' was beneficial, particularly for larger-volume osteonecrosis when combined with core decompression. Partial bone repair was the more frequent event observed, while total bone repair of osteonecrosis was rare. The volume and stage of osteonecrosis, alongside the number of injected cells, significantly affected treatment outcomes. In summary, this study provides comprehensive insights into the effectiveness and variables influencing the use of mesenchymal stem cells in treating human hip osteonecrosis. It emphasizes the potential of cell therapy while acknowledging the complexity and variability of results based on factors such as age, cell count, and disease stage. [ABSTRACT FROM AUTHOR]

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BACKGROUND: Hydroxyapatite is the main inorganic component of bone tissue. The polymer has the structure and function of a biomimetic extracellular matrix. The composites of hydroxyapatite and polymer have been widely studied. OBJECTIVE: To summarize the research status of hydroxyapatite composite polymer materials for bone tissue repair. METHODS: The articles collected in PubMed, Web of Science, CNKI and WanFang databases were searched from January 2010 to April 2023. The Chinese and English search terms were “hydroxyapatite, polymer, composites, degradability, bone defect, bone repair”. Finally, 75 articles were included for review. RESULTS AND CONCLUSION: Polymers often used in composite with hydroxyapatite for bone tissue repair include natural polymers (collagen, chitosan, alginate, serine protein, cellulose, hyaluronic acid,and polyhydroxybutyrate) and synthetic polymers [polylactic acid, polylactic acid-hydroxyacetic acid copolymer, poly(has-lactide), poly(amino acid) and poly(vinyl alcohol)]. The mechanical properties and osteoinductivity of hydroxyapatite/polymer composites were improved compared with pure hydroxyapatite. Hydroxyapatite composite with polymers can be made into porous scaffolds, hydrogels, and coatings for bone repair. Hydroxyapatite/polymer composites can accelerate bone reconstruction with a slow release of loaded drugs and cytokines due to their bionic extracellular matrix structure and function. Based on the diversity of causes of bone defects and the fact that bone repair is a complex continuous process involving multiple biological factors and proteins, repair materials with mechanical properties matching bone tissue, degradation processes synchronized with bone repair, and efficient osteogenesis and vascularization need to be further investigated. [ABSTRACT FROM AUTHOR]

Deer bone in traditional Chinese medicine is valued for its unique biomimetic bone matrix components. Icariin (Ica), which is claimed by Chinese medicine as a bone-repairing agent, is also widely accepted. In this report, a novel Icaencapsulated PLGA/nano deer bone meal (Ica@PLGA/nBM) biomimetic microsphere was fabricated. The Ica could be released from microspheres in a controlled manner. In vitro results showed that the microsphere had good biocompatibility due to the addition of nBM and the MC3T3-E1 cells could adhere to and grow well on the microspheres. Moreover, Ica and nBM in microspheres could synergically promote the ALP activity of MC3T3-E1 cells significantly (p < 0.05), which indicated the acceleration of osteogenic differentiation. The RT-PCR results showed that the expression levels of bone matrix proteins (Col1 & OPN) were enhanced by the composite (p < 0.05). In addition, Ica and nBM in microspheres also obviously promoted the expression of RUNX2 and BMP-2, respectively (p < 0.05). The in vivo results demonstrated the effective promotion of Ica@PLGA/nBM on complete bony connection to cover the defect site and the bone defect repair. And the Ica(M)@PLGA/nBM microspheres provided the best repair results. All the results confirmed that the Ica@PLGA/nBM composite biomimetic microsphere has the potential for clinical application. [ABSTRACT FROM AUTHOR]

Isotretinoin is an oral medication commonly utilized to treat severe acne. It belongs to the class of retinoids and is a synthetic form of vitamin A. Possible changes in bone tissue associated with the systemic administration of Isotretinoin for long periods and in high doses, such as hypercalcemia, osteopenia, diffuse hyperostosis, or even skeletal deformities, are reported in scientific studies. The objective of this literature review was to analyze the available scientific literature on the systemic administration of Isotretinoin and its effects on bone tissue. To this end, articles that demonstrate effects of Isotretinoin on bone metabolism, bone mineral density, bone formation, and resorption, in addition to possible changes generated in this tissue were considered valid for inclusion in this literature review. The search for articles that fit the premise of this work was carried out in the PubMed/MEDLINE database. In a preliminary search, 85 articles were obtained; after in-depth investigation and checking of the inclusion and exclusion criteria, 21 articles were selected, with 17 articles reporting the effect of systemic administration of Isotretinoin in humans and four articles analyzing the effect generated by this substance systemically administrated in animals, more specifically in rats. After analyzing the selected articles, it was possible to observe several reports on hyperostosis or even changes in the formation of bone structures in human patients. Concerning animals, the largest number of studies addressed the changes caused in the formation or development of bone structures by the systemic administration of Isotretinoin. From the current analyses, and given the wide use of Isotretinoin, it is necessary to know its viability and influence on tissues. Its clinical efficacy seems to overcome any of the skeletal side effects observed; however, more studies are necessary to properly evaluate and prove the effects generated on bone tissues as well as other structures. [ABSTRACT FROM AUTHOR]

Severe loss of bone mass may require grafting, and, among the alternatives available, there are natural biomaterials that can act as scaffolds for the cell growth necessary for tissue regeneration. Collagen and elastin polymers are a good alternative due to their biomimetic properties of bone tissue, and their characteristics can be improved with the addition of polysaccharides such as chitosan and bioactive compounds such as jatoba resin and pomegranate extract due to their antigenic actions. The aim of this experimental protocol was to evaluate bone neoformation in experimentally made defects in the mandible of rats using polymeric scaffolds with plant extracts added. Thirty rats were divided into group 1, with a mandibular defect filled with a clot from the lesion and no graft implant (G1-C, n = 10); group 2, filled with collagen/chitosan/jatoba resin scaffolds (G2-CCJ, n = 10); and group 3, with collagen/nanohydroxyapatite/elastin/pomegranate extract scaffolds (G3-CHER, n = 10). Six weeks after surgery, the animals were euthanized and samples from the surgical areas were submitted to macroscopic, radiological, histological, and morphometric analysis of the mandibular lesion repair process. The results showed no inflammatory infiltrates in the surgical area, indicating good acceptance of the scaffolds in the microenvironment of the host area. In the control group (G1), there was a predominance of reactive connective tissue, while in the grafted groups (G2 and G3), there was bone formation from the margins of the lesion, but it was still insufficient for total bone repair of the defect within the experimental period standardized in this study. The histomorphometric analysis showed that the mean percentage of bone volume formed in the surgical area of groups G1, G2, and G3 was 17.17 ± 2.68, 27.45 ± 1.65, and 34.07 ± 0.64 (mean ± standard deviation), respectively. It can be concluded that these scaffolds with plant extracts added can be a viable alternative for bone repair, as they are easily manipulated, have a low production cost, and stimulate the formation of new bone by osteoconduction. [ABSTRACT FROM AUTHOR]

Natural bone tissue has the certain function of self-regeneration and repair, but it is difficult to repair large bone damage. Recently, although autologous bone grafting is the “gold standard” for improving bone repair, it has high cost, few donor sources. Besides, allogeneic bone grafting causes greater immune reactions, which hardly meet clinical needs. The bone tissue engineering (BTE) has been developed to promote bone repair. Gelatin, due to its biocompatibility, receives a great deal of attention in the BTE research field. However, the disadvantages of natural gelatin are poor mechanical properties and single structural property. With the development of BTE, gelatin is often used in combination with a range of natural, synthetic polymers, and inorganic materials to achieve synergistic effects for the complex physiological process of bone repair. The review delves into the fundamental structure and unique properties of gelatin, as well as the excellent properties necessary for bone scaffold materials. Then this review explores the application of modified gelatin three-dimensional (3D) scaffolds with various structures in bone repair, including 3D fiber scaffolds, hydrogels, and nanoparticles. In addition, the review focuses on the excellent efficacy of composite bone tissue scaffolds consisting of modified gelatin, various natural or synthetic polymeric materials, as well as bioactive ceramics and inorganic metallic/non-metallic materials in the repair of bone defects. The combination of these gelatin-based composite scaffolds provides new ideas for the design of scaffold materials for bone repair with good biosafety.

Structural alteration of synthetic implants aims to achieve better bioactivity, higher cellular response, and regulated degradability, all of which are critical criteria for a biomaterial to serve as a graft in bone regeneration. The aim of this work was to synthesize silicon-substituted hydroxyapatite and test its bioactivity in simulated body fluid (SBF) by proving the use of sodium metasilicate (Na2SiO3.9H2O) as an affordable precursor of silica. Thus, the study evaluated the in vitro bone-bonding capacity of hydroxyapatite (Ca10(PO4)6(OH)2) (HA) substituted with silicate ion (Ca10(PO4)6-x(SiO4)x(OH)2-x; SixHA). The SixHA with x = 0.4 was synthesized by utilizing a wet precipitation method with sodium metasilicate as a low-cost silica alternative for alkoxysilane precursors. The SixHA was then examined for properties such as morphology, elemental composition, phase composition, and the nature of chemical bonds using scanning electron microscopy (SEM), energy dispersive X-ray analysis (EDX), X-ray diffractometry (XRD), and Fourier transformed infrared spectroscopy (FTIR), respectively. An in vitro bioactivity experiment was also carried out by incubating the SixHA in simulated body fluid (SBF) at 36.5 °C for 7 and 14 days. The obtained results revealed the substitution of SiO44- for some PO43- groups in the hydroxyapatite structure. The SixHA nucleated more apatite crystals on its surface and demonstrated some degradability during the periods of immersion in SBF. The characteristics of the SixHA imply that it could be used as a graft in bone restoration applications, thus signifying that sodium metasilicate could serve as an economic silica source for silicon-substituted hydroxyapatite production.

Bone repair is a complex physiological process. The nerves within the bone can regulate bone tissue regeneration through the secretion of bioactive factors and interactions with cells within the bone. Recent studies have sought to leverage the principles of neurovascular coupling in the creation of bioactive materials, yielding promising results. This article reviews nerves and vessels within the bone, the role of neural signals in bone repair, and potential mechanisms of neurovascular coupling in bone repair, expecting to provide a thorough understanding on the function of neurovascular coupling in bone repair as well as fresh perspectives on the scientific research and clinical treatment of bone repair strategies.

Biphasic calcium phosphate (BCP) ceramics are valued for their osteoconductive properties but have limited osteogenic and angiogenic activities, which restricts their clinical utility in bone defect repair. Silicon doping has emerged as an effective strategy to enhance these biological functions of BCP. However, the biological impact of BCP is influenced by the level of silicon doping, necessitating determination of the optimal concentration to maximize efficacy in bone repair. This study investigated the effects of silicon doping on both the physicochemical and biological properties of BCP, with a specific focus on osteogenic and angiogenic potentials. Results indicated that silicon doping exceeding 4 mol.% led to the formation of α-TCP, accelerating BCP degradation, enhancing silicon ion release, and promoting mineralization product formation. Simultaneously, silicon doping increased the porosity of BCP scaffolds, which typically reduces their compressive strength. Nevertheless, scaffolds doped with ≤4 mol.% silicon maintained compressive strengths exceeding 2 MPa. In vitro biological experiments indicated that higher levels of silicon doping (≥6 mol.%) partially inhibited the successful differentiation of stem cells and the vascularization of endothelial cells. Optimal conditions for promoting osteogenic differentiation and angiogenesis were identified between 2 and 4 mol.% silicon doping, with an optimal level of approximately 4 mol.%. Subsequent in vivo experiments confirmed that BCP scaffolds doped with 4 mol.% silicon effectively promoted vascularization and new bone formation, highlighting their potential for clinical bone defect repair.

Fabrication of mineralized materials through the nature‐mimicking dynamic biomineralization process has attracted great interest but remains a huge challenge till now. Here, a drug‐mineralized hydrogel (DMH) with spontaneous dynamic mineralization behaviors is reported, which highly mimics the dynamic mineralization process of natural tissues. The hydrogel is facilely fabricated via directly mixing sodium hyaluronate (HA) with alendronate sodium (ADA) and CaCl2 in deionized water. The resultant hydrogel possesses a white‐to‐semi‐transparent transition and a soft‐to‐hard transition during incubation at 37 °C. Mechanism studies reveal that the spontaneous dynamic change of the hydrogel is ascribed to the HA‐regulated dynamic mineralization of ADA/Ca2+ complexes, where amorphous ADA/Ca2+ complexes will gradually transform into mineral crystals with the prolongation of incubation time. Owing to the dynamic transformation process, the DMH shows excellent injectability and moldability at the initial stage. More importantly, the DMH exhibits a sustained release behavior of ADA in vitro, superior adhesiveness with bone, biodegradability, and good biocompatibility. As a result, the developed DMH demonstrates promising uses for accelerating bone repair in a rat cranial defect model. Overall, the research provides a general strategy to prepare drug‐mineralized hydrogels with spontaneous dynamic mineralization behaviors, which may find potential uses in various biomedical fields. [ABSTRACT FROM AUTHOR]

Promoting the efficiency of bone regeneration in bone loss diseases is a significant clinical challenge. Traditional therapies often fail to achieve better therapeutic outcomes and shorter treatment times. However, in recent years, extracellular vesicles (EVs) have gained significant attention due to their exceptional osteogenic function in bone regeneration and superior therapeutic effects compared to traditional cell therapy. EVs have emerged as a promising therapy for tissue defect regeneration due to their various physiological functions, such as regulating the immune response and promoting tissue repair and regeneration. Moreover, EVs have good biocompatibility, low immunogenicity, and long-term stability, and can be improved through pretreatment and other methods. Studies investigating the mechanisms by which extracellular vesicles promote bone regeneration and applying EVs from different sources using various methods to animal models of bone defects have increased. Therefore, this paper reviews the types of EVs used for bone regeneration, their sources, roles, delivery pathways, scaffold biomaterials, and applications. [ABSTRACT FROM AUTHOR]

Bone morphogenetic protein (BMP) and platelet-derived growth factor (PDGF) are known to regulate/stimulate osteogenesis, playing vital roles in bone homeostasis, rendering them strong candidates for osteoporosis treatment. We evaluated the effects of recombinant human BMP-7 (rhBMP7) and PDGF-BB (rhPDGF-BB) in an oophorectomy-induced osteoporosis rat model. Forty Sprague Dawley rats underwent oophorectomy surgery; treatments commenced on the 100th day post-surgery when all animals exhibited signs of osteoporosis. These peptide growth factors were administered intraocularly (iv) once or twice a week and the animals were monitored for a total of five weeks. Two weeks after the conclusion of the treatments, the animals were euthanized and tissues were collected for assessment of alkaline phosphatase, X-ray, micro-CT, and histology. The results indicate that the most promising treatments were 20 µg/kg rhPDGF-BB + 30 µg/kg rhBMP-7 twice a week and 30 µg/kg BMP-7 twice a week, showing significant increases of 15% (p < 0.05) and 13% (p < 0.05) in bone volume fraction and 21% (p < 0.05) and 23% (p < 0.05) in trabecular number, respectively. In conclusion, rhPDGF-BB and rhBMP-7 have demonstrated the ability to increase bone volume and density in this osteoporotic animal model, establishing them as potential candidates for osteoporosis treatment. [ABSTRACT FROM AUTHOR]

Most studies have highlighted the critical influence of bioactive metal ions and pore structure on the bone repair performance of calcium phosphate. In this study, porous calcium phosphate ceramic microspheres with different porosities (45 %, 60 %, and 75 %) and pore sizes (20, 40, and 100 μm) were constructed by combining the extrusion-rolling and pore-forming agent methods, and they were then characterized as well as their physicochemical and biological properties. On this basis, the screened porous calcium phosphate microspheres were further coated with magnesium phosphate to improve the performance of osteogenesis and angiogenesis. The results demonstrated that pore size and porosity promoted the degradation properties. However, excessive pore size and porosity also resulted in a significant decline in the mechanical performance and biological properties of the microspheres. Successful magnesium phosphate coating of ceramic microspheres did not adversely affect their physicochemical performance and allowed stable release of magnesium ions, which further enhanced the biological properties of porous ceramic microspheres, such as cell proliferation, osteogenic differentiation, and angiogenic properties. This study presents an efficient and practical processing method to further enhance the properties and expand the applications of calcium phosphate materials. [ABSTRACT FROM AUTHOR]