Emerging regenerative cell therapies for alveolar bone loss have begun to explore the use of cell laden hydrogels for minimally invasive surgery to treat small and spatially complex maxilla-oral defects.However,the oral cavity presents a unique and challenging environment for in vivo bone tissue engineering,exhibiting both hard and soft periodontal tissue as well as acting as key biocenosis for many distinct microbial communities that interact with both the external environment and internal body systems,which will impact on cell fate and subsequent treatment efficacy.Herein,we design and bioprint a facile 3D in vitro model of a human dentine interface to probe the effect of the dentine surface on human mesenchymal stem cells(hMSCs)encapsulated in a microporous hydrogel bioink.We demonstrate that the dentine substrate induces osteogenic differentiation of encapsulated hMSCs,and that both dentine andβ-tricalcium phosphate substrates stimulate extracellular matrix production and maturation at the gel-media interface,which is distal to the gel-substrate interface.Our findings demonstrate the potential for long-range effects on stem cells by mineralized surfaces during bone tissue engineering and provide a framework for the rapid development of 3D dentine-bone interface models.
William MacalesterAsme BoussahelRafael O.Moreno-TortoleroMark R.ShannonNicola WestDarryl HillAdam Perriman
For patients with osteoporosis,the therapeutic outcomes of osteoimplants are substantially affected by the impaired proliferation,migration,and osteogenic differentiation abilities of bone marrow mesenchymal stem cells(BMSCs).
Bone substitute material implantation has become an important treatment strategy for the repair of oral and maxillofacial bone defects.Recent studies have shown that appropriate inflammatory and immune cells are essential factors in the process of osteoinduction of bone substitute materials.Previous studies have mainly focused on innate immune cells such as macrophages.In our previous work,we found that T lymphocytes,as adaptive immune cells,are also essential in the osteoinduction procedure.As the most important antigen-presenting cell,whether dendritic cells(DCs)can recognize non-antigen biomaterials and participate in osteoinduction was still unclear.In this study,we found that surgical trauma associated with materials implantation induces necrocytosis,and this causes the release of high mobility group protein-1(HMGB1),which is adsorbed on the surface of bone substitute materials.Subsequently,HMGB1-adsorbed materials were recognized by the TLR4-MYD88-NFκB signal axis of dendritic cells,and the inflammatory response was activated.Finally,activated DCs release regeneration-related chemokines,recruit mesenchymal stem cells,and initiate the osteoinduction process.This study sheds light on the immune-regeneration process after bone substitute materials implantation,points out a potential direction for the development of bone substitute materials,and provides guidance for the development of clinical surgical methods.
Zifan ZhaoQin ZhaoHu ChenFanfan ChenFeifei WangHua TangHaibin XiaYongsheng ZhouYuchun Sun
Porous hydroxyapatite(HA)scaffolds are often used as bone repair materials,owing to their good biocompatibility,osteoconductivity and low cost.Vascularization and osteoinductivity of porous HA scaffolds were limited in clinical application,and these disadvantages were need to be improved urgently.We used water-in-oil gelation and pore former methods to prepare HA spheres and a porous cylindrical HA container,respectively.The prepared HA spheres were filled in container to assemble into composite scaffold.By adjusting the solid content of the slurry(solid mixture of chitin sol and HA powder)and the sintering temperature,the porosity and crystallinity of the HA spheres could be significantly improved;and mineralization of the HA spheres significantly improved the biological activity of the composite scaffold.The multigradient(porosity,crystallinity and mineralization)scaffold(HA-700)filled with the mineralized HA spheres exhibited a lower compressive strength;however,in vivo results showed that their vascularization ability were higher than those of other groups,and their osteogenic Gini index(Go:an index of bone mass,and inversely proportional to bone mass)showed a continuous decrease with the implantation time.This study provides a new method to improve porous HA scaffolds and meet the demands of bone tissue engineering applications.
Injectable hydrogels have been considered as promising materials for bone regeneration,but their osteoinduction and mechanical performance are yet to be improved.In this study,a novel biocompatible injectable and self-healing nano hybrid hydrogel was on-demand prepared via a fast(within 30 s)and easy gelation approach by reversible Schiff base formed between-CH=O of oxidized sodium alginate(OSA)and-NH2 of glycol chitosan(GCS)mixed with calcium phosphate nanoparticles(CaP NPs).Its raw materials can be ready in large quantities by a simple synthesis process.The mechanical strength,degradation and swelling behavior of the hydrogel can be readily controlled by simply controlling the molar ratio of-CH=O and-NH2.This hydrogel exhibits pH responsiveness,good degradability and biocompatibility.The hydrogel used as the matrix for mesenchymal stem cells can significantly induce the proliferation,differentiation and osteoinduction in vitro.These results showed this novel hydrogel is an ideal candidate for applications in bone tissue regeneration and drug delivery.
Panpan PanXiao ChenHuaran XingYonghui DengJingdi ChenFahad AAlharthiAbdulaziz AAlghamdiJiacan Su
The rapid in situ inhibition of bacterial contamination and subsequent infection without inducing drug resistance is highly vital for the successful implantation and long-term service of titanium(Ti)-based orthopedic implants.However,the instability and potential cytotoxicity of current coatings have deterred their clinical practice.In this study,anodic oxidized titania nanotubes(TNT)were modified with antibacterial polyhexamethylene guanidine(PG)with the assistance of 3,4-dihydroxyphenylacetic acid.Interestingly,the prepared TNT-PG coating exhibited superior in vitro antibacterial activity than flat Ti-PG coating and effectively killed typical pathogens such as Escherichia coli and superbug methicillinresistant Staphylococcus aureus with above 4-log reduction(>99.99%killed)in only 5 min.TNT-PG coating also exerted excellent hemocompatibility with red blood cells and nontoxicity toward mouse pre-osteoblasts(MC3 T3-E1)in 1 week of coculture.In addition,the efficient in vivo anti-infective property of this coating was observed in a rat subcutaneous infection model.More importantly,TNT-PG coating improved the expression of alkaline phosphatase and enhanced the extracellular matrix mineralization of pre-osteoblasts,denoting its osteoinductive capacity.This versatile TNT-PG coating with excellent antibacterial activity and biocompatibility could be a promising candidate for advanced orthopedic implant applications.
Ds-block elements have been gaining increasing attention in the field of biomaterials modification,owing to their excellent biological properties,such as antibiosis,osteogenesis,etc.However,their function mechanisms are not well understood and conflicting conclusions were drawn by previous studies on this issue,which are mainly resulted from the inconsistent experimental conditions.In this work,three most widely used ds-block elements,copper,zinc,and silver were introduced on titanium substrate by plasma immersion ion implantation method to investigate the rule of ds-block elements in the immune responses.Results showed that the implanted samples could decrease the inflammatory responses compared with Ti sample.The trend of anti-inflammatory effects of macrophages on samples was in correlation with cellular ROS levels,which was induced by the implanted biomaterials and positively correlated with the number of valence electrons of ds-block elements.The co-culture experiments of macrophages and bone marrow mesenchymal stem cells showed that these two kinds of cells could enhance the anti-inflammation and osteogenesis of samples by the paracrine manner of PGE2.In general,in their steady states on titanium substrate(Cu2+,Zn2+,Ag),the ds-block elements with more valence electrons exhibit better anti-inflammatory and osteogenic effects.Moreover,molecular biology experiments indicate that the PGE2-related signaling pathway may contribute to the desired immunoregulation and osteoinduction capability of ds-block elements.These findings suggest a correlation between the number of valence electrons of ds-block elements and the relevant biological responses,which provides new insight into the selection of implanted ions and surface design of biomaterials.
Lan ChenDonghui WangJiajun QiuXianming ZhangXingdan LiuYuqin QiaoXuanyong Liu
Hydrophilic bone morphogenetic protein 2(BMP2)is easily degraded and difficult to load onto hydrophobic carrier materials,which limits the application of polyester materials in bone tissue engineering.Based on soybean-lecithin as an adjuvant biosurfactant,we designed a novel cell-free-scaffold of polymer of poly(ε-caprolactone)and poly(lactide-co-glycolide)-co-polyetherimide with abundant entrapped and continuously released BMP2 for in vivo stem cell-capture and in situ osteogenic induction,avoiding the use of exogenous cells.The optimized bioactive osteo-polyester scaffold(BOPSC),i.e.SBMP-10SC,had a high BMP2 entrapment efficiency of 95.35%.Due to its higher porosity of 83.42%,higher water uptake ratio of 850%,and sustained BMP2 release with polymer degradation,BOPSCs were demonstrated to support excellent in vitro capture,proliferation,migration and osteogenic differentiation of mouse adipose derived mesenchymal stem cells(mADSCs),and performed much better than traditional BMP-10SCs with unmodified BMP2 and single polyester scaffolds(10SCs).Furthermore,in vivo capture and migration of stem cells and differentiation into osteoblasts was observed in mice implanted with BOPSCs without exogenous cells,which enabled allogeneic bone formation with a high bone mineral density and ratios of new bone volume to existing tissue volume after 6 months.The BOPSC is an advanced 3D cell-free platform with sustained BMP2 supply for in situ stem cell capture and osteoinduction in bone tissue engineering with potential for clinical translation.
