Early osteoimmunomodulation by mucin hydrogels augments the healing and revascularization of rat critical-size calvarial bone defects

The design principle of osteogenic bone grafts has shifted from immunological inertness to limiting foreign body response to combined osteoimmunomodulatory activity to promote high-quality endogenous bone regeneration.Recently developed immunomodulatory mucin hydrogels have been shown to elicit very low complement activation and suppress macrophage release and activation after implantation in vivo.However,their immunoregulatory activity has not yet been studied in the context of tissue repair.Herein,we synthesized mucin-monetite composite materials and investigated their early osteoimmunomodulation using a critical-size rat bone defect model.We demonstrated that the composites can polarize macrophages towards the M2 phenotype at weeks 1 and 2.The early osteoimmunomodulation enhanced early osteogenesis and angiogenesis and ultimately promoted fracture healing and engraftment(revascularization of the host vasculature)at weeks 6 and 12.Overall,we demonstrated the applicability of mucin-based immunomodulatory biomaterials to enhance tissue repair in tissue engineering and regenerative medicine.

A programmed surface on polyetheretherketone for sequentially dictating osteoimmunomodulation and bone regeneration to achieve ameliorative osseointegration under osteoporotic conditions

Polyetheretherketone(PEEK)is a desirable alternative to conventional biomedical metals for orthopedic implants due to the excellent mechanical properties.However,the inherent bioinertness of PEEK contributes to inferior osseointegration of PEEK implants,especially under pathological conditions of osteoporosis.Herein,a programmed surface is designed and fabricated on PEEK to dictate osteoimmunomodulation and bone regeneration sequentially.A degradable hybrid coating consisting of poly(lactide-co-glycolide)and alendronate(ALN)loaded nano-hydroxyapatite is deposited on PEEK and then interleukin-4(IL-4)is grafted onto the outer surface of the hybrid coating with the aid of N_(2) plasma immersion ion implantation and subsequent immersion in IL-4 solution.Dominant release of IL-4 together with ALN and Ca^(2+) during the first few days synergistically mitigates the early acute inflammatory reactions and creates an osteoimmunomodulatory microenvironment that facilitates bone regeneration.Afterwards,slow and sustained delivery of ALN and Ca^(2+) in the following weeks boosts osteogenesis and suppresses osteoclastogenesis simultaneously,consequently ameliorating bone-implant osseointegration even under osteoporotic conditions.By taking into account the different phases in bone repair,this strategy of constructing advanced bone implants with sequential functions provides customizable and clinically viable therapy to osteoporotic patients.

Puerarin@Chitosan composite for infected bone repair through mimicking the bio-functions of antimicrobial peptides

It is important to eliminate lipopolysaccharide(LPS)along with killing bacteria in periprosthetic joint infection(PJI)therapy for promoting bone repair due to its effect to regulate macrophages response.Although natural antimicrobial peptides(AMPs)offer a good solution,the unknown toxicity,high cost and exogenetic immune response hamper their applications in clinic.In this work,we fabricated a nanowire-like composite material,named P@C,by combining chitosan and puerarin via solid-phase reaction,which can finely mimic the bio-functions of AMPs.Chitosan,serving as the bacteria membrane puncture agent,and puerarin,serving as the LPS target agent,synergistically destroy the bacterial membrane structure and inhibit its recovery,thus endowing P@C with good antibacterial property.In addition,P@C possesses good osteoimmunomodulation due to its ability of LPS elimination and macrophage differentiation modulation.The in vivo results show that P@C can inhibit the LPS induced bone destruction in the Escherichia coli infected rat.P@C exhibits superior bone regeneration in Escherichia coli infected rat due to the comprehensive functions of its superior antibacterial property,and its ability of LPS elimination and immunomodulation.P@C can well mimic the functions of AMPs,which provides a novel and effective method for treating the PJI in clinic.

Improvement of antibacterial, anti-inflammatory, and osteogenic properties of OGP loaded Co-MOF coating on titanium implants for advanced osseointegration

The bacterial infection,especially for methicillin-resistant Staphylococcus aureus(MRSA),and the associated severe inflammatory response could extremely limit the crosstalk of RAW264.7 cells and mesenchymal stem cells(MSCs)and lead to the undesirable osseointegration of peri–implants.It is highly demanded to modify the surface of titanium(Ti)implant to improve its anti-bacterial and anti-inflammatory properties and facilitate its disabled osseointegration.Herein,in our study,a multifunctional coating of zeolitic imidazolate frameworks-67 encapsulated osteogenic growth peptide(OGP)(ZO)was fabricated on titanium dioxide nanotubes(TNT)substrates(TNT-ZO)via the electrophoresis deposition(EPD)approach.The TNT-ZO substrates exhibited excellent antibacterial activity indicated by the reactive oxygen species(ROS)generation,outer membrane(OM)and inner membrane(IM)permeabilization change,adenosine triphosphate(ATP)decrease,and intracellular compounds(DNA/RNA)leakage.Importantly,the regulation effects of TNT-ZO coating modified titanium substrates on the RAW264.7-MSCs crosstalk could induce the anti-inflammatory and osteogenic microenvironment via multiple paracrine signaling of Runx2,BMP2,VEGF,and TGF-β1.The promoted effects of coating structure were investigated in vivo,including antibacterial effect,osteogenic differentiation of mesenchymal stem cells,and anti-inflammation of RAW264.7 cells,as well as infected bone regeneration and repair in bone defect transplantation model.The results demonstrated that MRSA was effectively eliminated by the hydrolysis of ZIF-67 nanoparticles on TNT-ZO substrates.Furthermore,the excellent osseointegration of peri–implants was realized simultaneously by modulating the crosstalk of RAW264.7-MSCs.This study could provide a novel approach to designing a multifunctional coating on the Ti implants for infected bone regeneration in orthopedic applications.

Improvement of bone formation by bionic hydroxyapatite nanorod via the regulation of macrophage polarization

Bone defects are common clinical problems in the world,and there are many biomaterials used for treat-ing them.However,there is still a paucity of bioactive materials capable of modulating the immune mi-croenvironment.Therefore,it is necessary to identify new therapeutic strategies to regulate the immune microenvironment of the bone defect to further promote osteogenesis.Hydroxyapatite(HAP)is an impor-tant mineral for the framework of the human body.Recently,HAP has become a key research object for bone tissue engineering applications due to its unique tailored properties and similarity to bone tissue.Here,we prepared rod-shaped HAP(rHAP)with different concentrations(0,100,200,and 300μg/mL).The slowly released Ca^(2+)of 200μg/mL rHAP can induce macrophage phenotype 2(M2)polarization to decrease inflammatory cytokine secretion via the PI3K-Akt and Wnt/β-catenin pathways.In addition,rHAP can induce osteogenesis through the osteogenic differentiation of rat bone marrow mesenchymal stem cells.In conclusion,the 200μg/mL rHAP shows the potential for osteoimmunomodulation in a bone defect in vitro and in vivo,which is beneficial to the treatment of bone defects.

Osteoimmunomodulatory effects of biomaterial modification strategies on macrophage polarization and bone regeneration

Biomaterials as bone substitutes are always considered as foreign bodies that can trigger host immune responses.Traditional designing principles have been always aimed at minimizing the immune reactions by fabricating inert biomaterials.However,clinical evidence revealed that those methods still have limitations and many of which were only feasible in the laboratory.Currently,osteoimmunology,the very pioneering concept is drawing more and more attention-it does not simply regard the immune response as an obstacle during bone healing but emphasizes the intimate relationship of the immune and skeletal system,which includes diverse cells,cytokines,and signaling pathways.Properties of biomaterials like topography,wettability,surface charge,the release of cytokines,mediators,ions and other bioactive molecules can impose effects on immune responses to interfere with the skeletal system.Based on the bone formation mechanisms,the designing methods of the biomaterials change from immune evasive to immune reprogramming.Here,we discuss the osteoimmunomodulatory effects of the new modification strategies—adjusting properties of bone biomaterials to induce a favorable osteoimmune environment.Such strategies showed potential to benefit the development of bone materials and lay a solid foundation for the future clinical application.

Mesoporous silica rods with cone shaped pores modulate inflammation and deliver BMP-2 for bone regeneration

Biomaterials with suitable osteoimmunomodulation properties and ability to deliver osteoinductive biomolecules,such as bone morphogenetic proteins,are desired for bone regeneration.Herein,we report the development of mesoporous silica rods with large cone-shaped pores(MSR-CP)to load and deliver large protein drugs.It is noted that those cone-shaped pores on the surface modulated the immune response and reduced the pro-inflammatory reaction of stimulated macrophage.Furthermore,bone morphogenetic proteins 2(BMP-2)loaded MSR-CP facilitated osteogenic differentiation and promoted osteogenesis of bone marrow stromal cells.In vivo tests confirmed BMP-2 loaded MSR-CP improved the bone regeneration performance.This study provides a potential strategy for the design of drug delivery systems for bone regeneration.

Zn/Sr dual ions-collagen co-assembly hydroxyapatite enhances bone regeneration through procedural osteo-immunomodulation and osteogenesis

The immune microenvironment induced by biomaterials played vital roles in bone regeneration.Hydroxyapatite(HA)and its ion-substituted derivates represent a large class of core inorganic materials for bone tissue engineering.Although ion substitution was proved to be a potent way to grant HA more biological functions,few studies focused on the immunomodulatory properties of ion-doped HA.Herein,to explore the potential osteoimmunomodulatory effects of ion-doped HA,zinc and strontium co-assembled into HA through a collagen template biomimetic way(ZnSr-Col-HA)was successfully achieved.It was found that ZnSr-Col-HA could induce a favorable osteo-immune microenvironment by stimulating macrophages.Furthermore,ZnSr-Col-HA demonstrated a procedural promoting effect on osteogenic differentiation of bone marrow mesenchymal stem cells(BMSCs)in vitro.Specifically,the osteo-immune microenvironment acted as a dominant factor in promoting osteogenic gene expressions at the early stage through OSM signal pathway.Whereas the direct stimulating effects on BMSCs by Zn^(2+)/Sr^(2+) were more effectively at the later stage with Nfatc1/Maf and Wnt signals activated.In vivo study confirmed strong promoting effects of ZnSr-Col-HA on critical-sized cranial defect repair.The current study indicated that such a combined biomaterial design philosophy of dual ion-doping and biomimetic molecular co-assembly to endow HA applicable osteoimmunomodulatory characteristics might bring up a new cutting-edge concept for bone regeneration study.

High proportion strontium-doped micro-arc oxidation coatings enhance early osseointegration of titanium in osteoporosis by anti-oxidative stress pathway

The excessive accumulation of reactive oxygen species(ROS)under osteoporosis precipitates a microenvironment with high levels of oxidative stress(OS).This could significantly interfere with the bioactivity of conventional titanium implants,impeding their early osseointegration with bone.We have prepared a series of strontium(Sr)-doped titanium implants via micro-arc oxidation(MAO)to verify their efficacy and differences in osteoinduction capabilities under normal and osteoporotic(high OS levels)conditions.Apart from the chemical composition,all groups exhibited similar physicochemical properties(morphology,roughness,crystal structure,and wettability).Among the groups,the low Sr group(Sr25%)was more conducive to osteogenesis under normal conditions.In contrast,by increasing the catalase(CAT)/superoxide dismutase(SOD)activity and decreasing ROS levels,the high Sr-doped samples(Sr75% and Sr100%)were superior to Sr25% in inducing osteogenic differentiation of MC3T3-E1 cells and the M2 phenotype polarization of RAW264.7 cells,thus enhancing early osseointegration.Furthermore,the results of both in vitro cell co-culture and in vivo studies also showed that the high Sr-doped samples(especially Sr100%)had positive effects on osteoimmunomodulation under the OS microenvironment.Ultimately,the collated findings indicated that the high proportion Sr-doped MAO coatings were more favorable for osteoporosis patients in implant restorations.