Recent advances in smart stimuli-responsive biomaterials for bone therapeutics and regeneration

Bone defects combined with tumors, infections, or other bone diseases are challenging in clinical practice. Autologous and allogeneic grafts are two main traditional remedies, but they can cause a series of complications. To address this problem,researchers have constructed various implantable biomaterials. However, the original pathological microenvironment of bone defects, such as residual tumors, severe infection, or other bone diseases, could further affect bone regeneration. Thus, the rational design of versatile biomaterials with integrated bone therapy and regeneration functions is in great demand. Many strategies have been applied to fabricate smart stimuli-responsive materials for bone therapy and regeneration, with stimuli related to external physical triggers or endogenous disease microenvironments or involving multiple integrated strategies. Typical external physical triggers include light irradiation, electric and magnetic fields, ultrasound, and mechanical stimuli. These stimuli can transform the internal atomic packing arrangements of materials and affect cell fate, thus enhancing bone tissue therapy and regeneration. In addition to the external stimuli-responsive strategy, some specific pathological microenvironments, such as excess reactive oxygen species and mild acidity in tumors, specific p H reduction and enzymes secreted by bacteria in severe infection, and electronegative potential in bone defect sites, could be used as biochemical triggers to activate bone disease therapy and bone regeneration.Herein, we summarize and discuss the rational construction of versatile biomaterials with bone therapeutic and regenerative functions. The specific mechanisms, clinical applications, and existing limitations of the newly designed biomaterials are also clarified.

Magnesium-containing bioceramics stimulate exosomal miR-196a-5p secretion to promote senescent osteogenesis through targeting Hoxa7/MAPK signaling axis

Stem cell senescence is characterized by progressive functional dysfunction and secretory phenotypic changes including decreased proliferation,dysfunction of osteogenic and angiogenic differentiation,increased secretion of the senescence-associated secretory phenotype(SASP),which bring difficulties for bone repair.Rescuing or delaying senescence of aged bone marrow mesenchymal stem cells(O-BMSCs)was considered as effective strategy for bone regeneration in aging microenvironment.Magnesium(Mg)ion released from bioceramics was reported to facilitate bone regeneration via enhancing osteogenesis and alleviating senescence.In this study,Akermanite biocreamics(Akt)containing Mg ion as a model was demonstrated to promote osteogenesis and angiogenesis effects of O-BMSCs by activating the MAPK signaling pathway in vitro.Moreover,the enhanced osteogenesis effects might be attributed to enhanced Mg-containing Akt-mediated exosomal miR-196a-5p cargo targeting Hoxa7 and activation of MAPK signaling pathway.Furthermore,the in vivo study confirmed that 3D-printed porous Mg-containing Akt scaffolds effectively increased bone regeneration in cranial defects of aged rats.The current results indicated that the exosomal-miR-196a-5p/Hoxa7/MAPK signaling axis might be the potential mechanism underlying Akt-mediated osteogenesis.The exosome-meditaed therapy stimulated by the released Mg ion contained in Akt biocreamics or other biomaterials might serve as a candidate strategy for bone repair in aged individuals.

Engineering mesoporous bioactive glasses for emerging stimuli-responsive drug delivery and theranostic applications

Mesoporous bioactive glasses(MBGs),which belong to the category of modern porous nanomaterials,have garnered significant attention due to their impressive biological activities,appealing physicochemical properties,and desirable morphological features.They hold immense potential for utilization in diverse fields,including adsorption,separation,catalysis,bioengineering,and medicine.Despite possessing interior porous structures,excellent morphological characteristics,and superior biocompatibility,primitive MBGs face challenges related to weak encapsulation efficiency,drug loading,and mechanical strength when applied in biomedical fields.It is important to note that the advantageous attributes of MBGs can be effectively preserved by incorporating supramolecular assemblies,miscellaneous metal species,and their conjugates into the material surfaces or intrinsic mesoporous networks.The innovative advancements in these modified colloidal inorganic nanocarriers inspire researchers to explore novel applications,such as stimuli-responsive drug delivery,with exceptional in-vivo performances.In view of the above,we outline the fabrication process of calcium-silicon-phosphorus based MBGs,followed by discussions on their significant progress in various engineered strategies involving surface functionalization,nanostructures,and network modification.Furthermore,we emphasize the recent advancements in the textural and physicochemical properties of MBGs,along with their theranostic potentials in multiple cancerous and non-cancerous diseases.Lastly,we recapitulate compelling viewpoints,with specific considerations given from bench to bedside.

Advances in magnesium-containing bioceramics for bone repair

Reconstruction of bone defects or fractures caused by ageing,trauma and tumour resection is still a great challenge in clinical treatment.Although autologous bone graft is considered as gold standard,the source of natural bone is limited.In recent years,regenerative therapy based on bioactive materials has been proposed for bone reconstruction.Specially,numerous studies have indicated that bioactive ceramics including silicate and phosphate bioceramics exhibit excellent osteoinductivity and osteoconductivity,further promote bone regeneration.In addition,magnesium(Mg)element,as an indispensable mineral element,plays a vital role in promoting bone mineralisation and formation.In this review,different types of Mg-containing bioceramics including Mg-containing calcium phosphate-based bioceramics(such as Mg-hydroxyapatite,Mg-biphasic calcium phosphate),Mg-containing calcium silicate-based bioceramics(such as Mg_(2)SiO_(4),Ca_(2)MgSi_(2)O_(7) and Mg-doped bioglass),Mg-based biocements,Mg-containing metal/polymer-bioceramic composites were systematacially summarised.Additionally,the fabrication technologies and their materiobiological effects were deeply discussed.Clinical applications and perspectives of magnesium-containing bioceramics for bone repair are highlighted.Overall,Mg-containing bioceramics are regarded as regenerative therapy with their optimised performance.Furthermore,more in-depth two-way researches on their performance and structure are essential to satisfy their clinical needs.

Li-Mg-Si bioceramics provide a dynamic immuno-modulatory and repair-supportive microenvironment for peripheral nerve regeneration

Biomaterials can modulate the local immune and repair-supportive microenvironments to promote peripheral nerve regeneration. Inorganic bioceramics have been widely used for regulating tissue regeneration and local immune response. However, little is known on whether inorganic bioceramics can have potential for enhancing peripheral nerve regeneration and what are the mechanisms underlying their actions. Here, the inorganic lithium-magnesium-silicon (Li-Mg-Si, LMS) bioceramics containing scaffolds are fabricated and characterized. The LMS-containing scaffolds had no cytotoxicity against rat Schwann cells (SCs), but promoted their migration and differentiation towards a remyelination state by up-regulating the expression of neurotrophic factors in a β-catenin-dependent manner. Furthermore, using single cell-sequencing, we showed that LMS-containing scaffolds promoted macrophage polarization towards the pro-regenerative M2-like cells, which subsequently facilitated the migration and differentiation of SCs. Moreover, implantation with the LMS-containing nerve guidance conduits (NGCs) increased the frequency of M2-like macrophage infiltration and enhanced nerve regeneration and motor functional recovery in a rat model of sciatic nerve injury. Collectively, these findings indicated that the inorganic LMS bioceramics offered a potential strategy for enhancing peripheral nerve regeneration by modulating the immune microenvironment and promoting SCs remyelination.

Nanoparticles modified by polydopamine: Working as “drug” carriers

Inspired by the mechanism of mussel adhesion,polydopamine(PDA),a versatile polymer for surface modification has been discovered.Owing to its unique properties like extraordinary adhesiveness,excellent biocompatibility,mild synthesis requirements,as well as distinctive drug loading approach,strong photothermal conversion capacity and reactive oxygen species(ROS)scavenging facility,various PDA-modified nanoparticles have been desired as drug carriers.These nanoparticles with diverse nanostructures are exploited in multifunctions,consisting of targeting,imaging,chemical treatment(CT),photodynamic therapy(PDT),photothermal therapy(PTT),tissue regeneration ability,therefore have attracted great attentions in plenty biomedical applications.Herein,recent progress of PDA-modified nanoparticle drug carriers in cancer therapy,antibiosis,prevention of inflammation,theranostics,vaccine delivery and adjuvant,tissue repair and implant materials are reviewed,including preparation of PDA-modified nanoparticle drug carriers with various nanostructures and their drug loading strategies,basic roles of PDA surface modification,etc.The advantages of PDA modification in overcoming the existing limitations of cancer therapy,antibiosis,tissue repair and the developing trends in the future of PDA-modified nanoparticle drug carriers are also discussed.

A comparative study of the osteogenic performance between the hierarchical micro/submicro-textured 3D-printed Ti6Al4V surface and the SLA surface

Three-dimensional(3D)printed titanium and its alloys have broad application prospect in the field of biomedical implant materials,although the biological performance of the original surface should be improved.Learning from the development experience of conventional titanium implants,to construct a hierarchical hybrid topological surface is the future direction of efforts.Since the original 3D-printed(3D hereafter)Ti6Al4V surface inherently has micron-scale features,in the present study,we introduced submicron-scale pits on the original surface by acid etching to obtain a hierarchical micro/submicro-textured surface.The characteristic and biological performance of the 3D-printed and acid-etched(3DA hereafter)surface were evaluated in vitro and in vivo,compared with the conventional sandblasted,large-grit,acid-etched(SLA hereafter)surface.Our results suggested the adhesion,proliferation and osteogenic differentiation of bone marrow derived mesenchymal stromal cells(BMSCs),as well as the in vivo osseointegration on 3DA surfaces were significantly improved.However,the overall osteogenic performance of the 3DA surface was not as good as the conventional SLA surface.

Calcium silicate bioactive ceramics induce osteogenesis through oncostatin M

Immune reactions are a key factor in determining the destiny of bone substitute materials after implantation.Macrophages,the most vital factor in the immune response affecting implants,are critical in bone formation,as well as bone biomaterial-mediated bone repair.Therefore,it is critical to design materials with osteoimmunomodulatory properties to reduce host-to-material inflammatory responses by inducing macrophage polarization.Our previous study showed that calcium silicate(CS)bioceramics could significantly promote osteogenesis.Herein,we further investigated the effects of CS on the behavior of macrophages and how macrophages regulated osteogenesis.Under CS extract stimulation,the macrophage phenotype was converted to the M2 extreme.Stimulation by a macrophage-conditioned medium that was pretreated by CS extracts resulted in a significant enhancement of osteogenic differentiation of bone marrow mesenchymal stem cells(BMSCs),indicating the important role of macrophage polarization in biomaterial-induced osteogenesis.Mechanistically,oncostatin M(OSM)in the macrophage-conditioned medium promoted osteogenic differentiation of BMSCs through the ERK1/2 and JAK3 pathways.This in vivo study further demonstrated that CS bioceramics could stimulate osteogenesis better thanβ-TCP implants by accelerating new bone formation at defective sites in the femur.These findings improve our understanding of immune modulation of CS bioactive ceramics and facilitate strategies to improve the in vitro osteogenesis capability of bone substitute materials.

Gaseous sulfur trioxide induced controllable sulfonation promoting biomineralization and osseointegration of polyetheretherketone implants

Fabricating a desired porous structure on the surface of biomedical polyetheretherketone(PEEK)implants for enhancing biological functions is crucial and difficult due to its inherent chemical inertness.In this study,a porous surface of PEEK implants was fabricated by controllable sulfonation using gaseous sulfur trioxide(SO3)for different time(5,15,30,60 and 90 min).Micro-topological structure was generated on the surface of sulfonated PEEK implants preserving original mechanical properties.The protein absorption capacity and apatite forming ability was thus improved by the morphological and elemental change with higher degree of sulfonation.In combination of the appropriate micromorphology and bioactive sulfonate components,the cell adhesion,migration,proliferation and extracellular matrix secretion were obviously enhanced by the SPEEK-15 samples which were sulfonated for 15 min.Finding from this study revealed that controllable sulfonation by gaseous SO3 would be an extraordinarily strategy for improving osseointegration of PEEK implants by adjusting the microstructure and chemical composition while maintaining excellent mechanical properties.

Effect of quercetin on chondrocyte phenotype and extracellular matrix expression

Due to the poor repair ability of cartilage tissue,regenerative medicine still faces great challenges in the repair of large articular cartilage defects.Quercetin is widely applied as a traditional Chinese medicine in tissue regeneration including liver,bone and skin tissues.However,the evidence for its effects and internal mechanisms for cartilage regeneration are limited.In the present study,the effects of quercetin on chondrocyte function were systematically evaluated by CCK8 assay,PCR assay,cartilaginous matrix staining assays,immunofluorescence assay,and western blotting.The results showed that quercetin significantly up-regulated the expression of chondrogenesis genes and stimulated the secretion of GAG(glycosaminoglycan)through activating the ERK,P38 and AKT signalling pathways in a dose-dependent manner.Furthermore,in vivo experiments revealed that quercetin-loaded silk protein scaffolds dramatically stimulated the formation of new cartilage-like tissue with higher histological scores in rat femoral cartilage defects.These data suggest that quercetin can effectively stimulate chondrogenesis in vitro and in vivo,demonstrating the potential application of quercetin in the regeneration of cartilage defects.

Reducing relapse and accelerating osteogenesis in rapid maxillary expansion using an injectable mesoporous bioactive glass/fibrin glue composite hydrogel

Rapid maxillary expansion(RME),as a common treatment for craniomaxillofacial deformity,faces the challenge of high relapse rates and unsatisfactory therapeutic effects.In this study,a standardized Sprague-Dawley(SD)rat RME model was first established with a modified expander as well as retainer design and optimized anterior maxillary expanding force of 100 g which exerted the most synchronized mobility of mid-palatal suture and incisors.Via the standardized model,the high relapse rate was proven to be attributed to insufficient osteogenesis in expanded suture,requiring long-term retainer wearing in clinical situations.To reduce the relapse rate,mesoporous bioactive glass/fibrin glue(MBG/FG)composite hydrogels were developed for an in situ minimal invasive injection that enhance osteogenesis in the expanded palate.The component of 1 wt%MBG was adopted for enhanced mechanical strength,matched degradation rate and ion dissolution,excellent in vitro biocompatibility and osteoinductivity.Effects of 1%MBG/FG composite hydrogel on osteogenesis in expanded mid-palatal sutures with/without retention were evaluated in the standardized model.The results demonstrated that injection of 1%MBG/FG composite hydrogel significantly promoted bone formation within the expanded mid-palatal suture,inhibited osteoclastogenesis and benefited the balance of bone remodeling towards osteogenesis.Combination of retainer and injectable biomaterial was demonstrated as a promising treatment to reduce relapse rate and enhance osteogenesis after RME.The model establishment and the composite hydrogel development in this article might provide new insight to other craniomaxillofacial deformity treatment and design of bone-repairing biomaterials with higher regenerative efficiency.

Breaking the vicious cycle between tumor cell proliferation and bone resorption by chloroquine-loaded and bone-targeted polydopamine nanoparticles

The vicious cycle between tumor cell proliferation and bone resorption remarkably elevates the progression and metastasis of bone tumors.Here,we fabricated polyethylene glycol-conjugated alendronate-functionalized and chloroquine(CQ)-loaded polydopamine nanoparticles(PPA/CQ)for efficient treatment of bone tumors via breaking the vicious cycle.The nanoparticles were efficiently accumulated to the bone tissues,especially the osteolytic lesions around tumors.CQ released from PPA/CQ inhibited osteoclastogenesis via preventing the degradation of tumor necrosis factor(TNF)receptor-associated receptor 3 to attenuate the osteolysis in bone tumors.On the other hand,CQ blocked the autophagy in cancer cells,resulting in improved photothermal killing of cancer cells.Finally,the in vivo experiment revealed that PPA/CQ-associated treatment efficiently inhibited both tumor growth and osteolysis.This work suggests that autophagy inhibition-associated photothermal therapy could be a promising strategy for treating malignant bone tumors.