Multi-omics analysis of human tendon adhesion reveals that ACKR1-regulated macrophage migration is involved in regeneration

Tendon adhesion is a common complication after tendon injury with the development of accumulated fibrotic tissues without effective anti-fibrotic therapies,resulting in severe disability.Macrophages are widely recognized as a fibrotic trigger during peritendinous adhesion formation.However,different clusters of macrophages have various functions and receive multiple regulation,which are both still unknown.In our current study,multi-omics analysis including single-cell RNA sequencing and proteomics was performed on both human and mouse tendon adhesion tissue at different stages after tendon injury.The transcriptomes of over 74000 human single cells were profiled.As results,we found that SPP1^(+)macrophages,RGCC^(+)endothelial cells,ACKR1^(+)endothelial cells and ADAM12^(+)fibroblasts participated in tendon adhesion formation.Interestingly,despite specific fibrotic clusters in tendon adhesion,FOLR2^(+)macrophages were identified as an antifibrotic cluster by in vitro experiments using human cells.Furthermore,ACKR1 was verified to regulate FOLR2^(+)macrophages migration at the injured peritendinous site by transplantation of bone marrow from Lysm-Cre;R26R^(tdTomato) mice to lethally irradiated Ackr1^(-/-)mice(Ackr1^(-/-)chimeras;deficient in ACKR1)and control mice(WT chimeras).Compared with WT chimeras,the decline of FOLR2^(+)macrophages was also observed,indicating that ACKR1 was specifically involved in FOLR2^(+)macrophages migration.Taken together,our study not only characterized the fibrosis microenvironment landscape of tendon adhesion by multi-omics analysis,but also uncovered a novel antifibrotic cluster of macrophages and their origin.These results provide potential therapeutic targets against human tendon adhesion.

Microglial depletion impairs glial scar formation and aggravates inflammation partly by inhibiting STAT3 phosphorylation in astrocytes after spinal cord injury

Astrocytes and microglia play an orchestrated role following spinal cord injury;however,the molecular mechanisms through which microglia regulate astrocytes after spinal cord injury are not yet fully understood.Herein,microglia were pharmacologically depleted and the effects on the astrocytic response were examined.We further explored the potential mechanisms involving the signal transducers and activators of transcription 3(STAT3)pathway.For in vivo experiments,we constructed a contusion spinal cord injury model in C57BL/6 mice.To deplete microglia,all mice were treated with colony-stimulating factor 1 receptor inhibitor PLX3397,starting 2 weeks prior to surgery until they were sacrificed.Cell proliferation was examined by 5-ethynyl-2-deoxyuridine(EdU)and three pivotal inflammatory cytokines were detected by a specific Bio-Plex Pro^(TM) Reagent Kit.Locomotor function,neuroinflammation,astrocyte activation and phosphorylated STAT3(pSTAT3,a maker of activation of STAT3 signaling)levels were determined.For in vitro experiments,a microglia and astrocyte coculture system was established,and the small molecule STA21,which blocks STAT3 activation,was applied to investigate whether STAT3 signaling is involved in mediating astrocyte proliferation induced by microglia.PLX3397 administration disrupted glial scar formation,increased inflammatory spillover,induced diffuse tissue damage and impaired functional recovery after spinal cord injury.Microglial depletion markedly reduced EdU+proliferating cells,especially proliferating astrocytes at 7 days after spinal cord injury.RNA sequencing analysis showed that the JAK/STAT3 pathway was downregulated in mice treated with PLX3397.Double immunofluorescence staining confirmed that PLX3397 significantly decreased STAT3 expression in astrocytes.Importantly,in vitro coculture of astrocytes and microglia showed that microglia-induced astrocyte proliferation was abolished by STA21 administration.These findings suggest that microglial depletion impaired astrocyte proliferation and astrocytic scar formation,and induced inflammatory diffusion partly by inhibiting STAT3 phosphorylation in astrocytes following spinal cord injury.

Biomechanical Study of Vertebral Compression Fracture Using Finite Element Analysis

This research aimed to mechanically analyze vertebral stress concentration in one healthy subject and one subject with osteoporotic first lumbar (L1) vertebral compression fracture by using finite element analysis (FEA). We constructed three-dimensional image-based finite element (FE) models (Th12L2) by using computed tomographic (CT) digital imaging and communications in medicine (DICOM) for each patient and then conducted exercise stress simulations on the spine models. The loadings on the 12th thoracic vertebra (Th12) due to compression, flexion, extension, lateral bending, and axial rotation were examined within the virtual space for both spine models. The healthy and vertebral compression fracture models were then compared based on the application of equivalent vertebral stress. The comparison showed that vertebral stress concentration increased with all stresses in the vertebral compression fracture models. In particular, compression and axial rotation caused remarkable increases in stress concentration in the vertebral compression fracture models. These results suggest that secondary vertebral compression fractures are caused not only by bone fragility but possibly also by the increase in vertebral stress concentration around the site of the initial

Biomechanical Study of the Effects of Balloon Kyphoplasty on the Adjacent Vertebrae

We used the finite element method (FEM) to investigate the stress profiles of vertebrae in patients who underwent balloon kyphoplasty (BKP) for vertebral fracture. BKP is often performed for persistent pain after vertebral fractures. However, fractures are frequently reported in the adjacent vertebrae after BKP. The purpose was to clarify the mechanism of fractures that occur in the adjacent vertebrae after BKP. The subjects were two patients (first case: 74-year-old woman;second case: 88-year-old woman) who had BKP for osteoporotic vertebral fractures (L1). A bone analysis software program, Mechanical Finder, was used to construct three-dimensional finite element models (T11-L3) from computed tomographic (CT) digital imaging and communications in medicine (DICOM) data. Moment loadings were examined to evaluate stress concentrations on the vertebrae. Young’s moduli were lower in the second case than in the first case at all vertebral levels. Maximum Drucker-Prager stresses after BKP were larger in the second case than in the first case for compression, flexion, extension, and axial rotation. Strain energy density decreased in L1 and increased in the adjacent ver-tebrae. Our results suggest that post-BKP fractures of the adjacent vertebrae not only are due to bone fragility, but also can be caused by increased rigidity in the vertebrae filled with bone cement, which increases stress concentration on the adjacent verte-brae and raises the likelihood of fracture.

Is Premenstrual Syndrome a Uterine Inflammatory Disease? Retrospective Evaluation of an Etiologic Approach

Objective: To retrospectively evaluate the efficacy of local uterine antibiotic and anti-inflammatory injections combined with cryotherapy for the treatment of severe Premenstrual Syndrome (PMS) and Premenstrual Dysphoric Disorder (PMDD). To validate the hypothesis of a uterine infectious/inflammatory etiology of PMS/PMDD. Methods: Clinical files of 161 women sequentially treated from September 1995 to April 2005, were collected for study. A subset of 148 patients (mean: 36.7 ± 7.8 years, range: 20.1 - 53.8 years) were eligible for statistical analysis. The ten most relevant PMS symptoms, namely depression, irritability, anxiety, fatigue, headache, edema, breast tenderness, abdominal bloating, pelvic pain and dysmenorrhea, were self-rated before and three menstrual cycles after treatment, using a 0 to 5 scale. The treatment consisted of cervical stromal antibiotic/anti-inflammatory injections combined with intracervical cryotherapy. Scores were compared using non-parametric tests for matched samples. Results: Before treatment, mean severity scores for the 10 symptoms were 3.97 ± 1.17, 4.26 ± 0.88, 3.41 ± 1.23, 3.91 ± 0.94, 3.35 ± 1.71, 2.28 ± 1.69, 2.13 ± 1.63, 4.51 ± 0.63, 2.28 ± 1.30, and 2.28 ± 1.88, respectively. Mean values after treatment were 0.54 ± 0.91, 0.51 ± 0.91, 0.32 ± 0.70, 0.42 ± 0.74, 0.43 ± 0.96, 0.22 ± 0.53, 0.39 ± 0.73, 1.01 ± 0.94, 0.28 ± 0.69, and 0.44 ± 0.92. All tests were statistically significant (p < 0.01). Conclusion: Both PMS physical and psycho-affective symptoms respond to local anti-inflammatory and antibiotic treatment of the uterus, showing a stable improvement after the treatment has ended. The results of this study suggest that the clinical pattern of PMS can be explained as an inflammatory mediated response to uterine infectious or traumatic insults. Further evidence is urgently needed in order to validate this innovative approach for widespread use in severe PMS/ PMDD cases.

GH treatment, BMI and different genotypes in patients with Prader-Willi syndrome and scoliosis: Is there any relationship?

The purpose of this study is to try to find a protocol defining a clinical diagnostic procedure for the patients to be admitted to the authors’ Institute to receive treatment for either suspected or confirmed diagnosis of spine deformity in Prader-Willi syndrome (PWS). The aim is to evaluate every subject from the diagnostic point of view, assessing variability of clinical expression and evolution of spinal deformity in the light of the related genetic aspects, thus providing a univocal protocol. The present series only includes patients (18 cases) with PWS, 7 hospitalized for surgical treatment of scoliosis, 11 followed-up at the authors’ institute only for conservative treatment of scoliosis. Both BMI tracks (weight/height2) and BMI Z-score (only for children older than 2 years) were assessed. Moreover, the GH treatment was evaluated for each group of patients as follows: being administered, suspended or no treatment. Finally, the gene was compared with BMI. No relationship was observed either between GH treatment and mean BMI or between genetics and mean BMI. More patients should be seen by the authors to confirm or refute the current findings.

Ultrasound-triggered piezocatalytic composite hydrogels for promoting bacterial-infected wound healing

Wound healing has become one of the basic issues faced by the medical community because of the susceptibility of skin wounds to bacterial infection.As such,it is highly desired to design a nanocomposite hydrogel with excellent antibacterial activity to achieve high wound closure effectiveness.Here,based on ultrasound-triggered piezocatalytic therapy,a multifunctional hydrogel is designed to promote bacteria-infected wound healing.Under ultrasonic vibration,the surface of barium titanate(BaTiO_(3),BT)nanoparticles embedded in the hydrogel rapidly generate reactive oxygen species(ROS)owing to the established strong built-in electric field,endowing the hydrogel with superior antibacterial efficacy.This modality shows intriguing advantages over conventional photodynamic therapy,such as prominent soft tissue penetration ability and the avoidance of serious skin phototoxicity after systemic administration of photosensitizers.Moreover,the hydrogel based on N-[tris(hydroxymethyl)methyl]acrylamide(THM),N-(3-aminopropyl)methacrylamide hydrochloride(APMH)and oxidized hyaluronic acid(OHA)exhibits outstanding self-healing and bioadhesive properties able to accelerate full-thickness skin wound healing.Notably,compared with the widely reported mussel-inspired adhesive hydrogels,OHA/THM-APMH hydrogel due to the multiple hydrogen bonds from unique tri-hydroxyl structure overcomes the shortage that catechol groups are easily oxidized,giving it long-term and repeatable adhesion performance.Importantly,this hybrid hydrogel confines BT nanoparticles to wound area and locally induced piezoelectric catalysis under ultrasound to eradicate bacteria,markedly improving the therapeutic biosafety and exhibits great potential for harmless treatment of bacteria-infected tissues.

Spinal cord conduits for spinal cord injury regeneration

Spinal cord injury(SCI),which causes irreversible damage in both sensory and motor function,is considered an insurmountable challenge in the field of medicine.The previous researchers have developed many kinds of biomaterials for SCI,and spinal cord conduits(SCCs)are an important classification for bridging spinal cord tissues while performing their corresponding functions.In this review,we first describe the original sources of the different polymers that determine the properties of the different SCCs.Afterwards,we focus on the different types of crosslinking methods used for preparing SCCs.Then,various practical applications and therapeutic effects of SCCs are summarized and discussed.Finally,we conclude the existing limitations of current SCCs.We hope that this paper will serve as a further inspiration for the development of SCCs in future.

Enhancement of critical-sized bone defect regeneration by magnesium oxide-reinforced 3D scaffold with improved osteogenic and angiogenic properties

The healing of critical-sized bone defects(CSD)remains a challenge in orthopedic medicine.In recent years,scaffolds with sophisticated microstructures fabricated by the emerging three-dimensional(3D)printing technology have lighted up the treatment of the CSD due to the elaborate microenvironments and support they may build.Here,we established a magnesium oxide-reinforced 3D-printed biocompos-ite scaffold to investigate the effect of magnesium-enriched 3D microenvironment on CSD repairing.The composite was prepared using a biodegradable polymer matrix,polycaprolactone(PCL),and the disper-sion phase,magnesium oxide(MgO).With the appropriate surface treatment by saline coupling agent,the MgO dispersed homogeneously in the polymer matrix,leading to enhanced mechanical performance and steady release of magnesium ion(Mg^(2+))for superior cytocompatibility,higher cell viability,advanced osteogenic differentiation,and cell mineralization capabilities in comparison with the pure PCL.The in-vivo femoral implantation and critical-sized cranial bone defect studies demonstrated the importance of the 3D magnesium microenvironment,as a scaffold that released appropriate Mg^(2+) exhibited remarkably increased bone volume,enhanced angiogenesis,and almost recovered CSD after 8-week implantation.Overall,this study suggests that the magnesium-enriched 3D scaffold is a potential candidate for the treatment of CSD in a cell-free therapeutic approach.

Rapid Ferroelectric‑Photoexcited Bacteria‑Killing of Bi_(4)Ti_(3)O_(12)/Ti_(3)C_(2)T_(x) Nanofiber Membranes

In this study,an antibacterial nanofiber membrane[polyvinylidene fluoride/Bi_(4)Ti_(3)O_(12)/Ti_(3)C_(2)T_(x)(PVDF/BTO/Ti_(3)C_(2)T_(x))]is fabricated using an electrostatic spinning process,in which the self-assembled BTO/Ti_(3)C_(2)T_(x) heterojunction is incorporated into the PVDF matrix.Benefiting from the internal electric field induced by the spontaneously ferroelectric polarization of BTO,the photoexcited electrons and holes are driven to move in the opposite direction inside BTO,and the electrons are transferred to Ti_(3)C_(2)T_(x) across the Schottky interface.Thus,directed charge separation and transfer are realized through the cooperation of the two components.The recombination of electron–hole pairs is maximumly inhibited,which notably improves the yield of reactive oxygen species by enhancing photocatalytic activity.Furthermore,the nanofiber membrane with an optimal doping ratio exhibits outstanding visible light absorption and photothermal conversion performance.Ulti-mately,photothermal effect and ferroelectric polarization enhanced photocatalysis endow the nanofiber membrane with the ability to kill 99.61%±0.28%Staphylococcus aureus and 99.71%±0.16%Escherichia coli under 20 min of light irradiation.This study brings new insights into the design of intelligent antibacterial textiles through a ferroelectric polarization strategy.

Corrigendum to“Magnesium cationic cue enriched interfacial tissue microenvironment nurtures the osseointegration of gamma-irradiated allograft bone”[Bioact.Mater.10C(April 2022)32-47]

The authors regret a mistake of funding numbers in the Acknowledgment Section failed to be corrected during proof reading.Below is the corrected funding statement in Acknowledgment SECTION This work was supported by the National Natural Science Foundation of China(NSFC)(Nos.81902189,81772354,82002303,31570980),Clinical Innovation Research Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory(2018GZR0201002),National Key Research and Development Plan(2018YFC1105103).

In vitro osteoclast-suppressing effect of sodium ibandronate

Background Bisphosphonates （BPs） have been reported to reduce local recurrence in giant cell tumor （GCT） of bone because of their osteoclast-suppressing effect; however, the optimal mode of delivery and the dose and duration of treatment of BPs remain to be established. To address these issues, it is first necessary to clarify the manner of action of BPs on osteoclasts. We herein evaluated the osteoclast-suppressing effect of sodium ibandronate in vitro. Methods Mouse osteoclasts （OCLs） were generated in vitro using mouse bone marrow mononuclear cells. First, various concentrations of sodium ibandronate and equal amounts of phosphate-buffered saline were added to cell culture media. The number of multinucleated cells （over three nuclei） was recorded in each group, OCL formation was compared and the most effective concentration of sodium ibandronate was determined. Then, high concentrations of sodium ibandronate were added to the experimental cell culture media; no ibandronate was given in the control group. Comparisons were made between the two groups in terms of OCL adhesion, migration, and bone resorption. Results OCL formation was suppressed by sodium ibandronate in vitro; the most pronounced effect was observed at the concentration of 10-5 mol/L. OCL migration and bone resorption were significantly suppressed at this concentration, though there was no effect on OCL adhesion. Conclusions Sodium ibandronate was effective in suppressing OCLs and decreasing resorption in GCT. The strong anti-OCL effectiveness at a high concentration in vitro indicates a topical mode of application.

Controlled release and biocompatibility of polymer/titania nanotube array system on titanium implants

Bacterial infection and tissue inflammation are the major causes of early failure of titanium-based orthopedic implants;thus,surgical implants with tunable drug releasing properties represent an appealing way to address some of these problems of bacterial infection and tissue inflammation in early age of orthopedic implants.In this work,a hybrid surface system composed of biodegradable poly(lactic-coglycolic acid)(PLGA)and titania nanotubes(TNTs)has been successfully constructed on Ti implants with the aim of preventing bacterial infection via long-term drug release.By varying the size of the TNTs and the thickness of the polymer film,the drug release profile can be tuned to achieve the optimal therapeutic action throughout the treatment time.The size of TNTs plays a dominant role in the drug loading dose of TNTs/PLGA hybrid coatings.In this work,TNTs with an average size of 80 nm can achieve the largest loading dose.Depending on the polymer thickness,significant improvement in the drug release characteristics is attained,for instance,reduced burst release(from 84%to 27%)and overall release time extended from 5 to over 40 days.In addition,the PLGA layers may favor the proliferation and osteogenesis of MC3T3-E1 mouse cells at an earlier stage.Therefore,this TNT/PLGA hybrid surface system can be employed as an effective bioplatform for improving both self-antibacterial performance and biocompatibility of Ti-based biomaterials.

ALD-induced TiO_(2)/Ag nanofilm for rapid surface photodynamic ion sterilization

The daily life of people in the intelligent age is inseparable from electronic device,and a number of bacteria on touch screens are increasingly threatening the health of users.Herein,a photocatalytic TiO_(2)/Ag thin film was synthesized on a glass by atomic layer deposition and subsequent in situ reduction.Ultraviolet-visible(UV-Vis)spectra showed that this film can harvest the simulated solar light more efficiently than that of pristine TiO_(2).The antibacterial tests in vitro showed that the antibacterial efficiency of the TiO_(2)/Ag film against S.aureus and E.coli was 98.2%and 98.6%,under visible light irradiation for 5 min.The underlying mechanism was that the in-situ reduction of Ag on the surface of TiO_(2)reduced the bandgap of TiO_(2)from 3.44 to 2.61 eV due to the formation of Schottky heterojunction at the interface between TiO_(2)and Ag.Thus,TiO_(2)/Ag can generate more reactive oxygen species for bacterial inactivation on the surface of electronic screens.More importantly,the TiO_(2)/Ag film had great biocompatibility with/without light irradiation.The platform not only provides a more convenient choice for the traditional antibacterial mode but also has limitless possibilities for application in the field of billions of touch screens.

Unbiased transcriptomic analyses reveal distinet effects of immune deficiency in CNS function with and without injury

The mammalian central nervous system (CNS) is considered an immune privileged system as it is separated from the periphery by the blood brain barrier (BBB). Yet, immune functions have been postulated to heavily influence the functional state of the CNS, especially after injury or during neurodegeneration. There is controversy regarding whether adaptive immune responses are beneficial or detrimental to CNS injury repair. In this study, we utilized immunocompromised SCID mice and subjected them to spinal cord injury (SCI). We analyzed motor function, electrophysiology, histochemistry, and performed unbiased RNA-sequencing. SCID mice displayed improved CNS functional recovery compared to WT mice after SCI. Weighted gene-coexpression network analysis (WGCNA) of spinal cord transcriptomes revealed that SCID mice had reduced expression of immune function-related genes and heightened expression of neural transmission-related genes after SCI, which was confirmed by immunohistochemical analysis and was consistent with better functional recovery. Transcriptomic analyses also indicated heightened expression of neurotransmission-related genes before injury in SCID mice, suggesting that a steady state of immune-deficiency potentially led to CNS hyper-connectivity. Consequently, SCID mice without injury demonstrated worse performance in Morris water maze test. Taken together, not only reduced inflammation after injury but also dampened steady-state immune function without injury heightened the neurotransmission program, resulting in better or worse behavioral outcomes respectively. This study revealed the intricate relationship between immune and nervous systems, raising the possibility for therapeutic manipulation of neural function via immune modulation.

Comments on ‘FNIP1 regulates adipocyte browning and systemic glucose homeostasis in mice by shaping intracellular calcium dynamics'

Owing to its remarkable benefits on metabolic health and its demonstrated presence in adult humans,beige or‘brite'adipocytes holdgreatpromiseto combat obesity and metabolic diseases.Delineation of the mechanisms involved inadipocyte‘beiging'or‘browning'is thus of particular interest.

Human acellular amniotic membrane implantation for lower third nasal reconstruction:a promising therapy to promote wound healing

Background:The lower third of the nose is one of the most important cosmetic units of the face, and its reconstructive techniques remain a big challenge. As an alternative approach to repair or regenerate the nasal tissue, the biomaterial-based strategy has been extensively investigated. The aim of this study is to determine the safety and efficacy of human acellular amniotic membrane (HAAM) to repair the full-thickness defects in the lower third of the nose in humans. Methods:In this study, 180 patients who underwent excision of skin lesions of the lower third of the nose from 2012 to 2016 were included;of the patients, 92 received HAAM and Vaseline gauze treatments, and the other 88 patients received Vaseline gauze treatment only. The haemostasis time and the duration of operation were recorded during surgery;after surgery, the time to pain disappearance, scab formation and wound healing, and the wound healing rate were measured. Results:Immediately after the HAAM implantation, a reduction of the haemostasis time and an accelerated disappearance of pain were observed. Compared with the control group, the formation and detachment of scab in patients who received the HAAM implantation were notably accelerated, postoperatively. When the diameter of the lesion exceeded 5 mm, the HAAM implantation was found to enhance the wound healing, although this enhancement was not seen when the diameter was less than 5 mm. Additionally, the HAAM implantation significantly reduced bleeding, wound infection and scar formation, postoperatively. Conclusions:HAAM-assisted healing is a promising therapy for lower third nasal reconstruction leading to rapid wound healing and fewer complications and thus has considerable potential for extensive clinical application in repairing skin wounds. Trial registration:ChiCTR1800017618, retrospectively registered on July 08, 2018.

Magnesium cationic cue enriched interfacial tissue microenvironment nurtures the osseointegration of gamma-irradiated allograft bone

Regardless of the advancement of synthetic bone substitutes,allograft-derived bone substitutes still dominate in the orthopaedic circle in the treatments of bone diseases.Nevertheless,the stringent devitalization process jeopardizes their osseointegration with host bone and therefore prone to long-term failure.Hence,improving osseointegration and transplantation efficiency remains important.The alteration of bone tissue microenvironment(TME)to facilitate osseointegration has been generally recognized.However,the concept of exerting metal ionic cue in bone TME without compromising the mechanical properties of bone allograft is challenging.To address this concern,an interfacial tissue microenvironment with magnesium cationc cue was tailored onto the gamma-irradiated allograft bone using a customized magnesium-plasma surface treatment.The formation of the Mg cationic cue enriched interfacial tissue microenvironment on allograft bone was verified by the scanning ion-selective electrode technique.The cellular activities of human TERT-immortalized mesenchymal stem cells on the Mg-enriched grafts were notably upregulated.In the animal test,superior osseointegration between Mg-enriched graft and host bone was found,whereas poor integration was observed in the gamma-irradiated controls at 28 days post-operation.Furthermore,the bony in-growth appeared on magnesium-enriched allograft bone was significant higher.The mechanism possibly correlates to the up-regulation of integrin receptors in mesenchymal stem cells under modified bone TME that directly orchestrate the initial cell attachment and osteogenic differentiation of mesenchymal stem cells.Lastly,our findings demonstrate the significance of magnesium cation modified bone allograft that can potentially translate to various orthopaedic procedures requiring bone augmentation.

Corrigendum to“Ultrasound-triggered piezocatalytic composite hydrogels for promoting bacterial-infected wound healing”[Bioact.Mater.24(2023)96-111]

The authors regret<that the SEM image of G12 hydrogel in Fig.2f was wrongly used during the assembly of Fig.2.The authors had checked the original data and replaced Fig.2f with the correction image.This error does not affect the scientific conclusions of the article in any way.>.The authors would like to apologise for any inconvenience caused.

Cross-talk between biometal ions and immune cells for bone repair

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 osteoim-munological 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,vana-dium,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.