Hydrogel loaded with bone marrow stromal cell-derived exosomes promotes bone regeneration by inhibiting inflammatory responses and angiogenesis

BACKGROUND Bone healing is a complex process involving early inflammatory immune regu-lation,angiogenesis,osteogenic differentiation,and biomineralization.Fracture repair poses challenges for orthopedic surgeons,necessitating the search for efficient healing methods.AIM To investigate the underlying mechanism by which hydrogel-loaded exosomes derived from bone marrow mesenchymal stem cells(BMSCs)facilitate the process of fracture healing.METHODS Hydrogels and loaded BMSC-derived exosome(BMSC-exo)gels were charac-terized to validate their properties.In vitro evaluations were conducted to assess the impact of hydrogels on various stages of the healing process.Hydrogels could recruit macrophages and inhibit inflammatory responses,enhance of human umbilical vein endothelial cell angiogenesis,and promote the osteogenic differen-tiation of primary cranial osteoblasts.Furthermore,the effect of hydrogel on fracture healing was confirmed using a mouse fracture model.RESULTS The hydrogel effectively attenuated the inflammatory response during the initial repair stage and subsequently facilitated vascular migration,promoted the formation of large vessels,and enabled functional vascularization during bone repair.These effects were further validated in fracture models.CONCLUSION We successfully fabricated a hydrogel loaded with BMSC-exo that modulates macrophage polarization and angiogenesis to influence bone regeneration.

Icariin accelerates bone regeneration by inducing osteogenesisangiogenesis coupling in rats with type 1 diabetes mellitus

BACKGROUND Icariin(ICA),a natural flavonoid compound monomer,has multiple pharmacological activities.However,its effect on bone defect in the context of type 1 diabetes mellitus(T1DM)has not yet been examined.AIM To explore the role and potential mechanism of ICA on bone defect in the context of T1DM.METHODS The effects of ICA on osteogenesis and angiogenesis were evaluated by alkaline phosphatase staining,alizarin red S staining,quantitative real-time polymerase chain reaction,Western blot,and immunofluorescence.Angiogenesis-related assays were conducted to investigate the relationship between osteogenesis and angiogenesis.A bone defect model was established in T1DM rats.The model rats were then treated with ICA or placebo and micron-scale computed tomography,histomorphometry,histology,and sequential fluorescent labeling were used to evaluate the effect of ICA on bone formation in the defect area.RESULTS ICA promoted bone marrow mesenchymal stem cell(BMSC)proliferation and osteogenic differentiation.The ICA treated-BMSCs showed higher expression levels of osteogenesis-related markers(alkaline phosphatase and osteocalcin)and angiogenesis-related markers(vascular endothelial growth factor A and platelet endothelial cell adhesion molecule 1)compared to the untreated group.ICA was also found to induce osteogenesis-angiogenesis coupling of BMSCs.In the bone defect model T1DM rats,ICA facilitated bone formation and CD31hiEMCNhi type H-positive capillary formation.Lastly,ICA effectively accelerated the rate of bone formation in the defect area.CONCLUSION ICA was able to accelerate bone regeneration in a T1DM rat model by inducing osteogenesis-angiogenesis coupling of BMSCs.

Novel frontiers for bone regeneration:application progress of mesenchymal stem cell-derived exosomes in bone tissue engineering

Identifying an effective way to promote bone regeneration for patients who suffer from bone defects is urgently demanded.In recent years,mesenchymal stem cells(MSCs)have drawed wide attention in bone regeneration.Besides,several studies have indicated the secretions of MSCs,especially exosomes,play a vital role in bone regeneration process.Exosomes can transfer“cargos”of proteins,RNA,DNA,lipids,to regulate fate of recipient cells by affecting their proliferation,differentiation,migration and gene expression.In this paper,the application of MSCs-derived exosomes in bone tissue engineering is reviewed,and the potential therapeutic role of exosome microRNA in bone regeneration is emphasized.

Comparative study of chitosan/fibroin–hydroxyapatite and collagen membranes for guided bone regeneration in rat calvarial defects: micro-computed tomography analysis

This study aimed to utilize micro-computed tomography （micro-CT） analysis to compare new bone formation in rat calvarial defects using chitosan/fibroin-hydroxyapatite （CFB-HAP） or collagen （Bio-Gide） membranes. Fifty-four （54） rats were studied. A circular bony defect （8 mm diameter） was formed in the centre of the calvaria using a trephine bur. The CFB-HAP membrane was prepared by thermally induced phase separation. In the experimental group （n= 18）, the CFB-HAP membrane was used to cover the bony defect, and in the control group （n= 18）, a resorbable collagen membrane （Bio-Gide） was used. In the negative control group （n= 18）, no membrane was used. In each group, six animals were euthanized at 2, 4 and 8 weeks after surgery. The specimens were then analysed using micro-CT. There were significant differences in bone volume （BV） and bone mineral density （BMD） （P〈O.05） between the negative control group and the membrane groups. However, there were no significant differences between the CFB-HAP group and the collagen group. We concluded that the CFB-HAP membrane has significant potential as a guided bone regeneration （GBR） membrane.

Current and future uses of skeletal stem cells for bone regeneration

The postnatal skeleton undergoes growth,modeling,and remodeling.The human skeleton is a composite of diverse tissue types,including bone,cartilage,fat,fibroblasts,nerves,blood vessels,and hematopoietic cells.Fracture nonunion and bone defects are among the most challenging clinical problems in orthopedic trauma.The incidence of nonunion or bone defects following fractures is increasing.Stem and progenitor cells mediate homeostasis and regeneration in postnatal tissue,including bone tissue.As multipotent stem cells,skeletal stem cells(SSCs)have a strong effect on the growth,differentiation,and repair of bone regeneration.In recent years,a number of important studies have characterized the hierarchy,differential potential,and bone formation of SSCs.Here,we describe studies on and applications of SSCs and/or mesenchymal stem cells for bone regeneration.

In vitro and in vivo evaluations of Mg-Zn-Gd alloy membrane on guided bone regeneration for rabbit calvarial defect

To develop a biodegradable membrane with guided bone regeneration(GBR),a Mg-2.0Zn-1.0Gd alloy(wt.%,MZG)membrane with Ca-P coating was designed and fabricated in this study.The microstructure,hydrophilicity,in vitro degradation,cytotoxicity,antibacterial effect and in vivo regenerative performance for the membrane with and without Ca-P coating were evaluated.After coating,the membrane exhibited an enhance hydrophilicity and corrosion resistance,showed good in vitro cytocompatibility upon MC3T3E-1 cells,and exhibited excellent antibacterial effect against E.coli,Staphylococcus epidermis and Staphylococcus aureus,simultaneously.In vivo experiment using the rabbit calvarial defect model confirmed that Ca-P coated MZG membrane underwent progressive degradation without inflammatory reaction and significantly improved the new bone formation at both 1.5 and 3 months after the surgery.All the results strongly indicate that MZG with Ca-P coating have great potential for clinical application as GBR membranes.

Preparation and Characterization of Chitosan/β-GP Membranes for Guided Bone Regeneration

Bioabsorbable chitosan/β-glycerol phosphate （CS/β-GP） composite membranes were fabricated through a relatively PH neutral and mild sol-gel process for guided bone regeneration （GBR）.Their structural properties,morphology,and tensile strength were investigated.FTIR and XRD analyses indicated that there were chemical bonds between the CS andβ-GP.SEM analysis revealed that the CS/β-GP composite membranes had a porous structure both at the surface and in sublayers.Even though the incorporation ofβ-GP in the CS matrix decreased the initial tensile strength of the membrane,the CS/β-GP membranes were still fit for GBR application with their tensile strength of roughly 1MPa.The concentration ofβ-GP was proportional to the pore size and thickness but was inversely proportional to the tensile strength of the CS/β-GP membrane.The present findings indicate that,based on its characteristics,the CS/β-GP composite membrane is a potential bioresorbable membrane for use in guided bone regeneration.

Current evidence on potential of adipose derived stem cells to enhance bone regeneration and future projection

Injuries to the postnatal skeleton are naturally repaired through successive stepsinvolving specific cell types in a process collectively termed “bone regeneration”.Although complex, bone regeneration occurs through a series of well-orchestratedstages wherein endogenous bone stem cells play a central role. In most situations,bone regeneration is successful;however, there are instances when it fails andcreates non-healing injuries or fracture nonunion requiring surgical or therapeuticinterventions. Transplantation of adult or mesenchymal stem cells (MSCs) definedby the International Society for Cell and Gene Therapy (ISCT) as CD105+-CD90+CD73+CD45-CD34-CD14orCD11b-CD79αorCD19-HLA-DR- is beinginvestigated as an attractive therapy for bone regeneration throughout the world.MSCs isolated from adipose tissue, adipose-derived stem cells (ADSCs), aregaining increasing attention since this is the most abundant source of adult stemcells and the isolation process for ADSCs is straightforward. Currently, there isnot a single Food and Drug Administration (FDA) approved ADSCs product forbone regeneration. Although the safety of ADSCs is established from their usagein numerous clinical trials, the bone-forming potential of ADSCs and MSCs, ingeneral, is highly controversial. Growing evidence suggests that the ISCT definedphenotype may not represent bona fide osteoprogenitors. Transplantation of bothADSCs and the CD105- sub-population of ADSCs has been reported to induce bone regeneration. Most notably, cells expressing other markers such as CD146,AlphaV, CD200, PDPN, CD164, CXCR4, and PDGFRα have been shown torepresent osteogenic sub-population within ADSCs. Amongst other strategies toimprove the bone-forming ability of ADSCs, modulation of VEGF, TGF-β1 andBMP signaling pathways of ADSCs has shown promising results. The U.S. FDAreveals that 73% of Investigational New Drug applications for stem cell-basedproducts rely on CD105 expression as the “positive” marker for adult stem cells.A concerted effort involving the scientific community, clinicians, industries, andregulatory bodies to redefine ADSCs using powerful selection markers andstrategies to modulate signaling pathways of ADSCs will speed up thetherapeutic use of ADSCs for bone regeneration.

Real-time-guided bone regeneration around standardized critical size calvarial defects using bone marrow-derived mesenchymal stem cells and collagen membrane with and without using tricalcium phosphate: an in vivo microcomputed tomographic and histologic e

The aim of the present real time in vivo micro-computed tomography （pCT） and histologic experiment was to assess the efficacy of guided bone regeneration （GBR） around standardized calvarial critical size defects （CSD） using bone marrow-derived mesenchymal stem cells （BMSCs）, and collagen membrane （CM） with and without tricalcium phosphate （TCP） graft material. In the calvaria of nine female Sprague-Dawley rats, full-thickness CSD （diameter 4.6 mm） were created under general anesthesia. Treatment-wise, rats were divided into three groups. In group 1, CSD was covered with a resorbable CM; in group 2, BMSCs were filled in CSD and covered with CM; and in group 3, TCP soaked in BMSCs was placed in CSD and covered with CM. All defects were closed using resorbable sutures. Bone volume and bone mineral density of newly formed bone （NFB） and remaining TCP particles and rate of new bone formation was determined at baseline, 2, 4, 6, and 10 weeks using in vivo pCT. At the lOth week, the rats were killed and calvarial segments were assessed histologically. The results showed that the hardness of NFB was similar to that of the native bone in groups I and 2 as compared to the NFB in group 3. Likewise, values for the modulus of elasticity were also significantly higher in group 3 compared to groups 1 and 2. This suggests that TCP when used in combination with BMSCs and without CM was unable to form bone of significant strength that could possibly provide mechanical ＂lock＂ between the natural bone and NFB. The use of BMSCs as adjuncts to conventional GBR initiated new bone formation as early as 2 weeks of treatment compared to when GBR is attempted without adiunct BMSC therapy.

3D-printed,bi-layer,biomimetic artificial periosteum for boosting bone regeneration

Periosteum,a membrane covering the surface of the bone,plays an essential role in maintaining the function of bone tissue—and especially in providing nourishment and vascularization during the bone regeneration process.Currently,most artificial periostea have relatively weak mechanical strength and a rapid degradation rate,and they lack integrated angiogenesis and osteogenesis functions.In this study,a bi-layer,biomimetic,artificial periosteum composed of a methacrylated gelatin–nano-hydroxyapatite(GelMA-nHA)cambium layer and a poly(N-acryloyl 2-lycine)(PACG)-GelMA-Mg^(2+)fibrous layer was fabricated via 3D printing.The GelMA-nHA layer is shown to undertake the function of improving osteogenic differentiation of rat bone marrow mesenchymal stem cells with the sustainable release of Ca^(2+) from nHA nanoparticles.The hydrogen-bonding-strengthened P(ACG-GelMA-L)-Mg^(2+)hydrogel layer serves to protect the inner defect site and prolong degradation time(60 days)to match new bone regeneration.Furthermore,the released magnesium ion exhibits a prominent effect in regulating the polarization phenotype of macrophage cells into theM2 phenotype and thus promotes the angiogenesis of the human umbilical vein endothelial cells in vitro.This bi-layer artificial periosteum was implanted into a critical-sized cranial bone defect in rats,and the 12-week post-operative outcomes demonstrate optimal new bone regeneration.

Synthesis and Characterization of UPPE-PLGA-rhBMP2 Scaffolds for Bone Regeneration

A novel unsaturated polyphosphoester(UPPE) was devised in our previous research,which is a kind of promising scaffold for improving bone regeneration.However,the polymerization process of UPPE scaffolds was unfavorable,which may adversely affect the bioactivity of osteoinductive molecules added if necessary,such as recombinant human bone morphogenetic protein-2(rhBMP2).The purpose of this study was to build a kind of optimal scaffold named UPPE-PLGA-rhBMP2(UPB) and to investigate the bioactivity of rhBMP2 in this scaffold.Furthermore,the cytotoxicity and biocompatibility of UPB scaffold was assessed in vitro.A W1/O/W2 method was used to fabricate PLGA-rhBMP2 microspheres,and then the microspheres were added to UPPE for synthesizing UPB scaffold.The morphological characters of PLGA-rhBMP2 microspheres and UPB scaffolds were observed under the scanning electron microscopy and laser scanning confocal microscopy.The cumulative release of UPB scaffolds was detected by using ELISA.The cytotoxicity and biocompatibility of UPB scaffolds were evaluated through examining the adsorption and apoptosis of bone marrow stromal cells(bMSCs) seeded on the surface of UPB scaffolds.The bioactivity of rhBMP2 in UPB scaffolds was assessed through measuring the alkaline phosphates(ALP) activity in bMSCs seeded.The results showed that UPB scaffolds sequentially exhibited burst and sustained release of rhBMP2.The cytotoxicity was greatly reduced when the scaffolds were immersed in buffer solution for 2 h.bMSCs attached and grew on the surface of soaked UPB scaffolds,exerting well biocompatibility.The ALP activity of bMSCs seeded was significantly enhanced,indicating that the bioactivity of rhBMP2 remained and still took effect after the unfavorable polymerization process of scaffolds.It was concluded that UPB scaffolds have low cytotoxicity,good biocompatibility and preserve bioactivity of rhBMP2.UPB scaffolds are promising in improving bone regeneration.

Enucleation combined with guided bone regeneration in small and medium-sized odontogenic jaw cysts

BACKGROUND The odontogenic jaw cyst is a cavity containing liquid,semifluid or gaseous components,with the development of the disease.In recent years,with the rapid development of oral materials and the transformation of treatment of jaw cysts,more options are available for treatment of postoperative bone defect of jaw cysts.Guided bone regeneration(GBR)places biomaterials in the bone defect,and then uses biofilm to separate the proliferative soft tissue and the slow-growing bone tissue to maintain the space for bone regeneration,which is widely used in the field of implantology.AIM To observe the clinical effect of GBR in repairing bone defect after enucleation of small and medium-sized odontogenic jaw cysts.METHODS From June 2018 to September 2020,13 patients(7 male,6 female)with odontogenic jaw cysts were treated in the Department of Oral Surgery,Ninth People’s Hospital,Shanghai Jiao Tong University School of Medicine.Adults without hypertension,heart disease,diabetes or other systemic diseases were selected.The diagnosis was based on the final pathological results:11 cases were diagnosed as apical cysts,one as primordial cyst,and one as dentigerous cyst.The lesions were located in the maxilla in seven cases,and in the mandible in six cases.All cases were treated with the same method of enucleation combined with GBR.RESULTS Three to four months after the operation,the boundary between the implant site and the surrounding normal stroma was not obvious in patients with small-sized odontogenic jaw cysts.The patients with tooth defects were treated with implant after 6 mo.For the patients with medium-sized odontogenic jaw cysts,the density of the center of the implant area was close to the normal mass at 6 mo after surgery,and there was a clear boundary between the periphery of the implant area and the normal mass.The boundary between the periphery of the implant area and the normal mass was blurred at 8-9 mo after surgery.Patients with tooth defects were treated with implants at>6 mo after the operation.CONCLUSION Enucleation combined with guided bone regeneration in small and medium-sized odontogenic jaw cysts can shorten the time of osteogenesis,increase the amount of new bone formation,reduce complications,and improve quality of life.

Genipin Cross-Linked Polyvinyl Alcohol-Gelatin Hydrogel for Bone Regeneration

Polyvinyl alcohol gelatin hydrogels were fabricated using genipin as a crosslinking agent for bone regeneration application. Optimized formulation of PVA-GE hydrogel was fabricated using genipin as crosslinking agent. Characterizations such as FTIR, morphology, porosity, pore size, degradation and swelling rate were investigated. Bone regeneration potential of optimized genipin cross-linked polyvinyl alcohol-gelatin (PVA20) hydrogels was assessed by implanting in rabbit’s femur defect for 1, 5 and 15 weeks period. Results showed interconnected porosity as observed in scanning electron microscopy and successful crosslinking as confirmed by FTIR analysis. Increased porosity (92% ± 2.46%) and pore size distribution (100 - 200 μm) were also observed as well as decrease in swelling rate (426% ± 10.50%). Bone formation was evident in micro-CT after 5 and 15 days of in vivo implantation period. Micro-CT analysis showed 32.67% increased bone formation of PVA-GE hydrogel defect compared with negative control after 15 weeks of in-vivo implantation. Histological analyses showed no inflammatory reaction post implantation and increase in cell matrix formation after 5 and 15 weeks. The combined physical and chemical method of crosslinking promises improved mechanical properties of PVA-GE hydrogel making it a potential scaffold for bone tissue engineering applications.

A Novel Guided Bone Regeneration Membrane Composed of Nano-hydroxyapatite and Aliphatic Polyester-amide

Hydrothermally synthesized nano-hydroxyapatite（n-HA ） varmg m wetght Jrom 10% to 30% was used us filler to make guided bone regeneration （ GBR ） composite membranes with navel aliphatic polyesteramide （ PEA ）. The structare and properties of PEA and its n- HA composites were investigated through TEM, IR, XRD, SEM and EDX. The shape and size of the n- HA crystals are similar to the apatite crystals in nataral bone. Molecule interactions are present between the n- HA and PEA in the compasite, which allows the uniform dispersion of n- HA in PEA matrix. This contributes enhanced mechanical property and bioactivhy to the compasite. The cytacompatibilhy of the composites has been investigated by culturing osteoblasts on the membranes. Good cell attachment and proliferation manner were observed on the membranes after 1 week. These results suggest that the PEA/ n-HA compasite membrane prepared in this study may serve us barrier membranes for guided bone regeneration and potential candidate scaffold for tissue engineering.

Evaluation for Bone Regeneration Mierospheres

The apatite-coated chitosan microspheres were fabricated by incubating chitosan in five times simulated body fluid. The apatite deposited on the microspheres was similar to natural bone mineral, as demonstrated by scanning electron microscopy, X-ray diffraction spectra and Fourier transformed-infrared spectroscopy analyses. Rat bone marrow-derived mesenchymal stem cells （BMSCs） were seeded on apatite- coated microspheres to investigate the effect of this scaffold on cell proliferation and differentiation. BMSCs seeded on uncoated microspheres were served as a control. In vivo experiment was evaluated by transplanting the microspheres loaded with or without BMSCs in 5-mm cranial defects of Wistar rats. Bone regeneration was investigated via micro-CT and histological analysis. It was found that apatite-coated chitosan microspheres could significantly promote the proliferation and alkaline phosphatase activity of BMSCs compared with uncoated microspheres. Histological slices and Micro-CT images at 8 weeks revealed much better regeneration of bone in the apatite-coated microspheres loaded with BMSCs than the control. In addition, the defect filled with pure microspheres induced little new bone formation. Our findings suggest that the apatite-coated chitosan microspheres scaffold is a promising carrier of stem cells for cranial bone tissue engineering.

A Case Report of Immediate Implant Placement Combined with Flap Surgery,Guided Bone Regeneration and Non-submerged Healing with a Labial Bone Wall Defect in the Esthetic Zone

[Basckground]This case report presented a methodology for immediate implantation in the esthetic zone with a facial bone defect along with flap surgery,guided bone regeneration,and non-submerged healing.[Case presentation]A 27-year-old female patient was complaining of the aesthetic complication that was caused via metallic staining of the neck of ceramic crowns in the maxillary right anterior region for one year.She has experienced immediate implantation along with flap surgery,guided bone regeneration(GBR),and non-submerged healing.The torque of the implant reached to the 35 N·cm to confirm primary stability.Six months after surgery,the healing abutment and the implant were fixed,the gingiva was healthy in the surgical area,and the nearby teeth and the opposite teeth were normal.[Results]The results of cone-beam computer tomography(CBCT)revealed that bone defects were filled with the newly formed bone.At the same time,the final impressions accomplished,and an all-ceramic crown was fit-placed.As a whole,the patient satisfaction rate was high.[Conclusions]Immediate implant placement with flap surgery,GBR,and non-submerged healing with a facial bone wall defect in the esthetic zone is an achievable process.

Bioceramic scaffolds with two-step internal/external modification of copper-containing polydopamine enhance antibacterial and alveolar bone regeneration capability

Magnesium-doped calcium silicate(CS)bioceramic scaffolds have unique advantages in mandibular defect repair;however,they lack antibacterial properties to cope with the complex oral microbiome.Herein,for the first time,the CS scaffold was functionally modified with a novel copper-containing polydopamine(PDA(Cu^(2+)))rapid deposition method,to construct internally modified(*P),externally modified(@PDA),and dually modified(*P@PDA)scaffolds.The morphology,degradation behavior,and mechanical properties of the obtained scaffolds were evaluated in vitro.The results showed that the CS*P@PDA had a unique micro-/nano-structural surface and appreciable mechanical resistance.During the prolonged immersion stage,the release of copper ions from the CS*P@PDA scaffolds was rapid in the early stage and exhibited long-term sustained release.The in vitro evaluation revealed that the release behavior of copper ions ascribed an excellent antibacterial effect to the CS*P@PDA,while the scaffolds retained good cytocompatibility with improved osteogenesis and angiogenesis effects.Finally,the PDA(Cu^(2+))-modified scaffolds showed effective early bone regeneration in a critical-size rabbit mandibular defect model.Overall,it was indicated that considerable antibacterial property along with the enhancement of alveolar bone regeneration can be imparted to the scaffold by the two-step PDA(Cu^(2+))modification,and the convenience and wide applicability of this technique make it a promising strategy to avoid bacterial infections on implants.

Bioactive materials from berberine-treated human bone marrow mesenchymal stem cells promote alveolar bone regeneration by regulating macrophage polarization

Alveolar bone regeneration has been strongly linked to macrophage polarization.M1 macrophages aggravate alveolar bone loss,whereas M2 macrophages reverse this process.Berberine(BBR),a natural alkaloid isolated and refined from Chinese medicinal plants,has shown therapeutic effects in treating metabolic disorders.In this study,we first discovered that culture supernatant(CS)collected from BBR-treated human bone marrow mesenchymal stem cells(HBMSCs)ameliorated periodontal alveolar bone loss.CS from the BBR-treated HBMSCs contained bioactive materials that suppressed the M1 polarization and induced the M2 polarization of macrophages in vivo and in vitro.To clarify the underlying mechanism,the bioactive materials were applied to different animal models.We discovered macrophage colony-stimulating factor(M-CSF),which regulates macrophage polarization and promotes bone formation,a key macromolecule in the CS.Injection of pure M-CSF attenuated experimental periodontal alveolar bone loss in rats.Colony-stimulating factor 1 receptor(CSF1R)inhibitor or anti-human M-CSF(M-CSF neutralizing antibody,Nab)abolished the therapeutic effects of the CS of BBR-treated HBMSCs.Moreover,AKT phosphorylation in macrophages was activated by the CS,and the AKT activator reversed the negative effect of the CSF1R inhibitor or Nab.These results suggest that the CS of BBR-treated HBMSCs modulates macrophage polarization via the M-CSF/AKT axis.Further studies also showed that CS of BBR-treated HBMSCs accelerated bone formation and M2 polarization in rat teeth extraction sockets.Overall,our findings established an essential role of BBR-treated HBMSCs CS and this might be the first report to show that the products of BBR-treated HBMSCs have active effects on alveolar bone regeneration.

Influence of Statins and Fibrates Drugs on Bone Health and Regeneration

In the medical and dental field, the importance and need for the study of materials and drugs for use as bone grafts or regeneration in injured areas due to the presence of fractures, infections or tumors that cause extensive loss of bone tissue is observed. Bone is a specialized, vascularized and dynamic connective tissue that changes throughout the life of the organism. When injured, it has a unique ability to regenerate and repair without the presence of scars, but in some situations, due to the size of the defect, the bone tissue does not regenerate completely. Thus, due to its importance, there is a great development in therapeutic approaches for the treatment of bone defects through studies that include autografts, allografts and artificial materials used alone or in association with bone grafts. Pharmaceuticals composed of biomaterials and osteogenic active substances have been extensively studied because they provide potential for tissue regeneration and new strategies for the treatment of bone defects. Statins work as specific inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMG-CoAreductase). They represent efficient drugs in lowering cholesterol, as they reduce platelet aggregation and thrombus deposition;in addition, they promote angiogenesis, reduce the β-amyloid peptide related to Alzheimer’s disease and suppress the activation of T lymphocytes. Furthermore, these substances have been used in the treatment of hypercholesterolemia and coronary artery disease. By inhibiting HMG-CoAreductase, statins not only inhibit cholesterol synthesis, but also exhibit several other beneficial pleiotropic effects. Therefore, there has been increasing interest in researching the effects of statins, including Simvastatin, on bone and osteometabolic diseases. However, statins in high doses cause inflammation in bone defects and inhibit osteoblastic differentiation, negatively contributing to bone repair. Thus, different types of studies with different concentrations of statins have been studied to positively or negatively correlate this drug with bone regeneration. In this review we will address the positive, negative or neutral effects of statins in relation to bone defects providing a comprehensive understanding of their application. Finally, we will discuss a variety of statin-based drugs and the ideal dose through a theoretical basis with preclinical, clinical and laboratory work in order to promote the repair of bone defects.

Drug-loading ZIF-8 for modification of microporous bone scaffold to promote vascularized bone regeneration

Surface modification of microporous bone scaffolds using nanoparticles has been broadly studied in bone tissue engineering.Aiming at improving vascularized bone regeneration(VBR),zeolitic imidazolate framework-8(ZIF-8)was encapsulated with dimethyloxallyl glycine(DMOG)and the drug-carrying nanoparticles(D@Z)could be uniformly coated onto the surface of the bone scaffold.The osteogenic and angiogenic actions of D@Z are closely correlated with the amount of slowly released DMOG,and in general,exhibited a favorable association.Then,the D7.5@Z group,which showed the greatest capacity to induce in vitro osteogenesis-angiogenesis coupling,was utilized for surface modification of the bone scaffold.Biological processes including phosphate-containing compound metabolic process,cell differentiation,cell proliferation and cell motility might contribute to enhanced ability to induce VBR by the coated scaffold and signaling pathways such as Rap1,Ras,phosphatidylinositol 3-kinase/protein kinase B(PI3K-AKT)and vascular endothelial growth factor(VEGF)signaling pathways participated in these processes.Finally,as depicted by in vitro real time-polymerase chain reaction(RT-PCR),Western blot(WB)and in vivo cranial bone defect model,the microporous scaffold coated with nano-D7.5@Z greatly promoted VBR.To conclude,nano-D@Z has significant promise for practical application in modification of microporous bone scaffolds to enhance VBR,and DMOG loading quantity has a beneficial influence on D@Z to improve osteogenesis-angiogenesis coupling.