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Silicate-based biomaterials—clinically applied fillers and promising candidates—can act as a highly biocompatible substrate for osteostimulative osteogenic cell growth in vitro and in vivo.

Correction for ‘Core–shell bioceramic fiber-derived biphasic granules with adjustable core compositions for tuning bone regeneration efficacy’ by Zhaonan Bao et al., J. Mater. Chem. B, 2023, 11, 2417–2430, https://doi.org/10.1039/D3TB90052E.

Spatial dimension of pores and interconnection in macroporous scaffolds is of particular importance in facilitating endogenous cell migration and bone tissue ingrowth. However, it is still a challenge to widely tune structure parameters of scaffolds by conventional methods because of inevitable pore geometrical deformation and poor pore interconnectivity. Here, the long-term in vivo biological performances of nonstoichiometric bioceramic scaffolds with different pore dimensions were assessed in critical-size femoral bone defect model. The 6% Mg-substituted wollastonite (CSi-Mg6) powders were prepared via wet-chemical precipitation and the scaffolds elaborately printed by ceramic stereolithography, displaying designed constant pore strut and tailorable pore height (200, 320, 450, 600 μm), were investigated thoroughly in the bone regeneration process. Together with detailed structural stability and mechanical properties were collaboratively outlined. Both μCT and histological analyses indicated that bone tissue ingrowth was retarded in 200 μm scaffolds in the whole stage (2–16 weeks) but the 320 μm scaffolds showed appreciable bone tissue in the center of porous constructs at 6–10 weeks and matured bone tissue were uniformly invaded in the whole pore networks at 16 weeks. Interestingly, the neo-tissue ingrowth was facilitated in the 450 μm and 600 μm scaffolds after 2 weeks and higher extent of bone regeneration and remodeling at the later stage. These new findings provide critical information on how engineered porous architecture impact bone regeneration in vivo. Simultaneously, this study shows important implications for optimizing the porous scaffolds design by advanced additive manufacture technique to match the clinical translation with high performance., Graphical abstract Image 1, Highlights • 6% Mg-substituted wollastonite (CSi-Mg6) bioceramic show appreciable bioactivity and mechanical strength. • Porous CSi-Mg6 scaffolds with precisely controlled pore dimensions are fabricated by ceramic stereolithography. • The favorable pore geometries facilitating neo-bone ingrowth into the center pores of scaffolds are decoded. • CAD-assisted stereolithography opens up opportunities for developing scaffolds with tailored pore architecture.

The pore geometry and structural stability of porous bioceramic are two critical variables in determining bone ingrowth. However, a significant limitation of current studies is that these two factors are often coupled due to the porous bioceramic fabrication technique, to which extent does each factor contribute to mechanical evolution. Herein we explored the effect of pore geometry on structural strength of Ca-silicate bioceramic scaffolds fabricated by stereolithography. The 3D virtual pore networks with constant porosity and average pore size were derived from the computer-assisted designing models containing strut- or curve surface-based unit cell. The cylindrical pore structure showed superior compressive and flexural resistance among the scaffolds with different pore geometries; the hexagonal cellular structure contributed on high specific compressive strength (≥50 kN∙m/Kg) and curve surface-based (skeletal-IWP, sheet-gyroid) scaffolds showed appreciable specific flexural strength (≥20 kN∙m/Kg). Furthermore, the pore structure-mechanical evolution relationships could be evaluated by immersing the scaffolds in Tris buffer for 8 weeks, and the scaffold bio-dissolution could be tuned by pore geometry design to tailor the ion release and strength decay. Basically, both Avizo software and finite element analysis demonstrate that the constant pore size models can be designed with similar total porosity but quite different stress distribution, and thus it is helpful for optimizing porous bioceramic designs with respect to their required structural and mechanical stability.

The development of injectable cement-like biomaterials via a minimally invasive approach has always attracted considerable clinical interest for modern bone regeneration and repair. Although α-tricalcium phosphate (α-TCP) powders may readily react with water to form hydraulic calcium-deficient hydroxyapatite (CDHA) cement, its long setting time, poor anti-collapse properties, and low biodegradability are suboptimal for a variety of clinical applications. This study aimed to develop new injectable α-TCP-based bone cements via strontium doping, α-calcium sulfate hemihydrate (CSH) addition and liquid phase optimization. A combination of citric acid and chitosan was identified to facilitate the injectable and anti-washout properties, enabling higher resistance to structure collapse. Furthermore, CSH addition (5 %-15 %) was favorable for shortening the setting time (5-20 min) and maintaining the compressive strength (10-14 MPa) during incubation in an aqueous buffer medium. These α-TCP-based composites could also accelerate the biodegradation rate and new bone regeneration in rabbit lateral femoral bone defect models in vivo. Our studies demonstrate that foreign ion doping, secondary phase addition and liquid medium optimization could synergistically improve the physicochemical properties and biological performance of α-TCP-based bone cements, which will be promising biomaterials for repairing bone defects in situations of trauma and diseased bone.

This study aimed to describe the 25‐hydroxyvitamin D (25(OH)D) and parathyroid hormone (PTH) status of Southeast Chinese individuals influenced by season. The secondary aim was to determine the cutoff for sufficient 25(OH)D in a four‐season region. From January 2011 to June 2014, a total of 17 646 individuals were evaluated in our study. The serum levels of PTH were detected simultaneously in 5579 cases. A total of 25(OH)D and intact PTH were measured by the electrochemiluminescent immunoassay. The distribution of the concentration, prevalence and seasonal variability of 25(OH)D and PTH were studied. The mean 25(OH)D concentration in our study was 43.00(30.40) nmol/L. The prevalence of insufficiency (25(OH)D

Surface chemistry and mechanical stability determine the osteogenic capability of bone implants. The development of high-strength bioactive scaffolds for in-situ repair of large bone defects is challenging because of the lack of satisfying biomaterials. In this study, highly bioactive Ca-silicate (CSi) bioceramic scaffolds were fabricated by additive manufacturing and then modified for pore-wall reinforcement. Pure CSi scaffolds were fabricated using a direct ink writing technique, and the pore-wall was modified with 0%, 6%, or 10% Mg-doped CSi slurry (CSi, CSi-Mg6, or CSi-Mg10) through electrostatic interaction. Modified CSi@CSi-Mg6 and CSi@CSi-Mg10 scaffolds with over 60% porosity demonstrated an appreciable compressive strength beyond 20 MPa, which was ~2-fold higher than that of pure CSi scaffolds. CSi-Mg6 and CSi-Mg10 coating layers were specifically favorable for retarding bio-dissolution and mechanical decay of scaffolds in vitro. In-vivo investigation of critical-size femoral bone defects repair revealed that CSi@CSi-Mg6 and CSi@CSi-Mg10 scaffolds displayed limited biodegradation, accelerated new bone ingrowth (4-12 weeks), and elicited a suitable mechanical response. In contrast, CSi scaffolds exhibited fast biodegradation and retarded new bone regeneration after 8 weeks. Thus, tailoring of the chemical composition of pore-wall struts of CSi scaffolds is beneficial for enhancing the biomechanical properties and bone repair efficacy.

Additive manufacture has recently been proposed as a versatile process for fabricating porous bioceramic scaffolds for bone repair and tissue engineering; however, to control or tailor the biodegradation of the porous biomaterials is still a challenge. Here, the core-shell-structured biphasic bioceramic porous scaffolds with tailorable ion release and biodegradation were prepared by direct ink writing technique with coaxially aligned bi-nozzle system. Our method employed rapidly gelling filaments of wollastonite (CSi) and diopside without and with Zn or Sr doping (Dio, ZnDio, SrDio) derived from bi-flow of sodium alginate-loaded bioceramic slurries, and varying the powder slurry design made it easy to create core-shell struts (e.g. CSi@Dio, CSi@ZnDio, CSi@SrDio) with adjustable bioceramic-phase distribution. It was found that the Zn- or Sr-doping could readily adjust the mechanical strength and biodegradation rate in the early stage. Furthermore, when 30% organic microspheres were pre-mixed into the powder slurry, the controllable high-density micropores could be introduced into the shell layer after sintering (e.g. CSi@Dio-p, CSi@ZnDio-p, CSi@SrDio-p), and thus permeability is maximally tuned and favorable for ion release through the porous shell layer. This new core-shell direct ink writing strategy can be used to fabricate a variety of biphasic bioceramic scaffolds with adjustable physicochemical properties which could be potentially beneficial for improving biological performance and bone repair in situ.

Pore architecture in bioceramic scaffolds plays an important role in facilitating vascularization efficiency during bone repair or orbital reconstruction. Many investigations have explored this relationship but lack integrating pore architectural features in a scaffold, hindering optimization of architectural parameters (geometry, size and curvature) to improve vascularization and consequently clinical outcomes. To address this challenge, we have developed an integrating design strategy to fabricate different pore architectures (cube, gyroid and hexagon) with different pore dimensions (∼350, 500 and 650 μm) in the silicate-based bioceramic scaffolds via digital light processing technique. The sintered scaffolds maintained high-fidelity pore architectures similar to the printing model. The hexagon- and gyroid-pore scaffolds exhibited the highest and lowest compressive strength (from 15 to 55 MPa), respectively, but the cube-pore scaffolds showed appreciable elastic modulus. Moreover, the gyroid-pore architecture contributed on a faster ion dissolution and mass decay in vitro. It is interesting that both μCT and histological analyses indicate vascularization efficiency was challenged even in the 650-μm pore region of hexagon-pore scaffolds within 2 weeks in rabbit models, but the gyroid-pore constructs indicated appreciable blood vessel networks even in the 350-μm pore region at 2 weeks and high-density blood vessels were uniformly invaded in the 500- and 650-μm pore at 4 weeks. Angiogenesis was facilitated in the cube-pore scaffolds in comparison with the hexagon-pore ones within 4 weeks. These studies demonstrate that the continuous pore wall curvature feature in gyroid-pore architecture is an important implication for biodegradation, vascular cell migration and vessel ingrowth in porous bioceramic scaffolds.

The inorganic powder slurry extrusion printing technique known as robocasting is an interesting method to fabricate complex porous architectures whereby feedstocks containing organic binders and powders are printed and the resulting scaffolds are subjected to sintering. A major limiting factor of this technique is the simultaneous tailoring of vascularization efficacy and osteogenic activity, usually done by adding the secondary phase in the organic slurry before the writing step. Mechanical mixing of biphasic powders is required to avoid compromising the biological performance and physical defects caused by significantly different physicochemical properties. This study addresses this issue by developing a selective ion doping and microstructure tuning for the production of bioceramic scaffolds with a binozzle robocasting process. Different metal ions (Sr

We have developed the new core-shell bioceramic CSi-Sr4@CaP-px microspheres with tuning porous shell layer so that the biodegradation of both CSi-Sr4 core and CaP shell is readily adjusted synergistically. This is for the first time, to the best of our knowledge, that the bioceramic scaffolds concerning gradient distribution and microstructure-tailoring design is available for tailoring biodegradation and ion release (bioactivity) to optimizing osteogenesis. Furthermore, it is possibly helpful to develop new bioactive scaffold system for time-dependent tailoring bioactivity and microporous structure to significantly enhance bone regeneration and repair applications, especially in some non-load-bearing arbitrary 3D anatomical bone and teeth defects.

Osteochondral defect refers to the damage of cartilage as well as subchondral bone. Cartilage tissue engineering focusing on the regeneration of cartilage and disregarding the subchondral bone always leads to partial regeneration of the damage, resulting in poor mechanical and physiological properties. A scaffold suitable for in situ inductive regeneration of both types of tissues is urgently needed. In this study, a biphasic scaffold integrated by macro-porous fibrin and 3D-printed wollastonite (containing 8% MgSiO3 (CS-Mg8)) scaffolds, either preloaded with rabbit bone marrow mesenchymal stem cells (BMSCs) or not, were fabricated and used to repair osteochondral defects in vivo (full thickness osteochondral defects in rabbits, 4 mm in diameter and 4 mm in depth with bone marrow blood effusion). The fibrin scaffold had a pore size of 100–200 μm, and was degraded gradually and reached weight loss over 80% at 28 days. The presence of BMSCs could accelerate the degradation rate. BMSCs could well proliferate...

Tissue integration of orbital implants, following orbital enucleation treatment, represents a challenge for rapid fibrovascularization, long-time stability, anti-infection, and even induction of vascule regeneration. The objective of this study was to develop porous calcium-magnesium silicate materials, with good stability, bioactivity, and antibacterial potential as new orbital fillers. Three-dimensional (3D) diopside scaffolds (low dissolvability) were fabricated by direct ceramic ink writing assembly and then followed by one-step sintering at 1150 °C for 3 h. The pore wall of the scaffold was modified by another calcium-magnesium silicate, such as bredigite or akermanite, which dissolves quickly but shows greater angiogenic potential. These two Ca-Mg-silicates can be coated onto the pore strut, and the coating layers were observed to slowly dissolve in Tris buffer. The vascularization-favorable Cu ions, which had been doped into the bredigite or akermanite coating, could also be measured in the immersion medium. A primary angiogenic test in a panniculus carnosus muscle model in rabbit indicated that the Cu-doped bredigite and akermanite coatings were significantly beneficial for the neovascularization in the early stages. These results suggest that the diopside-based porous materials modified with functional coatings hold great potential for application in orbital reconstruction.

Bioactive ceramics are promising candidates as 3D porous substrates for bone repair in bone regenerative medicine. However, they are often inefficient in clinical applications due to mismatching mechanical properties and compromised biological performances. Herein, the additional Sr dopant is hypothesized to readily adjust the mechanical and biodegradable properties of the dilute Mg-doped wollastonite bioceramic scaffolds with different pore geometries (cylindrical-, cubic-, gyroid-) by ceramic stereolithography. The results indicate that the compressive strength of Mg/Sr co-doped bioceramic scaffolds could be tuned simultaneously by the Sr dopant and pore geometry. The cylindrical-pore scaffolds exhibit strength decay with increasing Sr content, whereas the gyroid-pore scaffolds show increasing strength and Young’s modulus as the Sr concentration is increased from 0 to 5%. The ion release could also be adjusted by pore geometry in Tris buffer, and the high Sr content may trigger a faster scaffold bio-dissolution. These results demonstrate that the mechanical strengths of the bioceramic scaffolds can be controlled from the point at which their porous structures are designed. Moreover, scaffold bio-dissolution can be tuned by pore geometry and doping foreign ions. It is reasonable to consider the nonstoichiometric bioceramic scaffolds are promising for bone regeneration, especially when dealing with pathological bone defects.

Study Design: Technique note.Objectives: To describe our modified oblique lumbar interbody fusion (OLIF) technique in the reconstruction of the L5-S1 segment.Summary of Background Data: Recently, OLIF has been generally recognized as an effective procedure in the treatment of various spinal pathologies at L2-L5 segments. However, the usage of OLIF at the L5-S1 segment doesn’t have gained widespread acceptance in spine community. Some authors still concern about the feasibility of OLIF used in lumbosacral fusion Methods: Ten consecutive patients underwent L5-S1 interbody fusion using the OLIF technique in our institution. The L5–S1 disc space is approached via one retroperitoneal oblique corridor between the psoas muscle and the great vessels. The discectomy and endplate preparation are performed through a surgical window developed on the anterolateral side of L5-S1 disc. A secondary cage insertion technique is used for safe placement of interbody fusion cages.Results: Of the 10 patients, 6 were males and 4 were females, with an average age of 55.4±6.8 years. There were 8 single-level and 2 two-level procedures, including 2 at L4–L5 and 10 at L5–S1. Preoperative axial MR images confirmed 1 patient with type I LCIV (left common iliac vein), 6 with type II LCIV and 3 with type III LCIV. The average blood loss was 133.4±88.5 ml, and the average operative times were 153.6±38.3 minutes. Postoperative radiographs examination confirmed all patients obtained a better reconstruction at the lumbosacral junction. Two patients with type III LCIV sustained iliolumbar vein laceration during the exposure, and no other perioperative complications were encountered.Conclusion: Our novel OLIF L5-S1 technique is a more feasible procedure of lumbosacral fusion, which shared the common surgical plane with OLIF L2-5, allowing for L2 to S1 reproducible multi-levels interbody fusions via a retroperitoneal oblique corridor between the psoas muscle and the great vessels. Detailed preoperative plan and meticulous intraoperative manipulation are prerequisite for the success of OLIF L5-S1 procedure.

Using artificial biomaterials in bone regenerative medicine for highly efficient osteoconduction into the bone defect to decrease the bone healing time is still a challenge. In this research, magnesium (Mg)-doped wollastonite (∼10% Mg was substituted for calcium (Ca) in β-CaSiO3) (CSi-Mg10) bioceramic scaffolds with ultrahigh mechanical strength were fabricated using ceramic ink writing three dimensional (3D) printing. To evaluate the potential of other additives on the new bone regeneration efficiency, β-tricalcium phosphate (β-TCP) was introduced to the CSi-Mg10 ceramic ink at a concentration of 15% and the biphasic bioceramic scaffolds (CSi-Mg10/TCP15) were also fabricated using 3D printing. The mechanical characterization indicated that introduction of β-TCP led to nearly 50% mechanical decay, although the effect of the two heating schedules (one- and two-step sintering) on the compressive and flexural strengths of the scaffolds was significantly different. The bone regeneration results in critical sized calvarial defect of rabbits showed that the CSi-Mg10/TCP15 scaffolds displayed a markedly higher osteogenic capability than those on the CSi-Mg10 and β-TCP scaffolds after eight weeks, and reached ∼35% new bone tissue regeneration at 12 weeks postoperatively. These findings demonstrate that the CSi-Mg10/TCP15 bioceramic scaffolds can be well suited for stimulating in situ bone regeneration and for use in tissue engineering applications.

The regeneration and repair of damaged load-bearing segmental bones require considerable mechanical strength for the artificial implants. The ideal biomaterials should also facilitate the production of porous implants with high bioactivity desirable for stimulating new bone growth. Here we developed a new mechanically strong, highly bioactive dilute magnesium-doped wollastonite (CaSiO3–Mg; CSi–Mg) porous scaffold by the robocasting technique. The sintered scaffolds had interconnected pores 350 µm in size and over 50% porosity with appreciable compressive strength (>110 MPa), 5–10 times higher than those of pure CSi and β-TCP porous ceramics. Extensive in vitro and in vivo investigations revealed that such Ca–silicate bioceramic scaffolds were particularly beneficial for osteogenic cell activity and osteogenic capacity in critical size femoral bone defects. The CSi–Mg porous constructs were accompanied by an accelerated new bone growth (6–18 weeks) and a mechanically outstanding elastoplastic response to finally match the strength (10–15 MPa) of the rabbit femur host bone after 18 weeks, and the material itself experienced mild resorption and apatite-like phase transformation. In contrast, the new bone regeneration in the β-TCP scaffolds was substantially retarded after 6–12 weeks of implantation, and exhibited a low level of mechanical strength (

The integration of physicochemical and biological performances in root canal treatment represents a challenge for long-time antileakage, antibacterial, and even inducing periradicular cementum/bone tissue regeneration. The objective of this work is to develop a β-Ca2SiO3 (β-C2Si)-based cement as a new root canal filler with good antibacterial ability, sealability and bioactivity. β-C2Si powders with controllable free CaO content were prepared by regulating the calcium/silicate molar ratio in reaction medium. It was demonstrated that a composite paste with 10-30 wt% α-gypsum at a liquid-to-powder ratio of 0.6 ml g-1 remained injectable for 12 min and provided a significant pH rise during setting. Notably, the hydraulic cements with high free CaO contents exhibited bactericidal or bacteriostatic properties against three bacterial strains, Streptococci mutans, Actinomyces naeslundii, and Actinomyces viscosus, which were demonstrated by the agar diffusion method. Also, the injected paste in root canal ex vivo showed extremely low microleakage of Rhodamine B but a good apatite-mineralization response. Therefore, these intrinsic antibacterial activity, bioactivity, injectability and tight adaption to root canal sealability make β-C2Si/α-gypsum composites preferential candidates for application in endodontics, such as root-end filling, pulp capping therapy, microleakage prevention, as well as for inducing hard tissue regeneration.

Osteoporosis is a severe skeletal disorder. Patients have a low bone mineral density and bone structural deterioration. Mounting lines of evidence suggest that inappropriate apoptosis of osteoblasts/osteocytes leads to maladaptive bone remodelling in osteoporosis. It has been suggested that transplantation of stem cells, including mesenchymal stem cells, may alter the trajectory of bone remoulding and mitigate osteoporosis in animal models. However, stem cells needed to be carefully stored and characterized before usage. In addition, there is great batch‐to‐batch variation in stem cell production. Here, we fabricated therapeutic polymer microparticles from the secretome and membranes of mesenchymal stem cells (MSCs). These synthetic MSCs contain growth factors secreted by MSCs. In addition, these particles display MSC surface molecules. In vitro, co‐culture with synthetic MSCs increases the viability of osteoblast cells. In a rat model of ovariectomy‐induced osteoporosis, injection of synthetic MSCs mitigated osteoporosis by reducing cell apoptosis and systemic inflammation, but increasing osteoblast numbers. Synthetic MSC offers a promising therapy to manage osteoporosis.

Osteoarthritis is a type of joint disease that results from the breakdown of joint cartilage and underlying bone and is believed to be caused by mechanical stress on the joint and low-grade inflammatory processes. Acamprosate significantly ameliorates the pathological features of experimental autoimmune encephalomyelitis due to its anti-inflammatory effect. The aims of the present study were to investigate the anti-arthritis activities of acamprosate and elucidate the underlying mechanisms. Adjuvant-induced arthritis (AIA) was induced by intradermal injection of complete Freund's adjuvant. Male Wistar rats were randomly divided into five groups: (1) sham control group, (2) AIA group, (3) acamprosate 10 mg/kg (AIA + ACA10), (4) acamprosate 30 mg/kg (AIA + ACA30), and (5) acamprosate 100 mg/kg (AIA + ACA100). Paw swelling and the arthritis index were measured, and the production of IL-1β, IL-6, and TNF-α was detected by ELISA in serum. The expression of inflammation-related molecules, including c-Raf, ERK1/2, and NF-κB, was determined by Western blotting. We found that acamprosate significantly suppressed paw swelling and the arthritis index in AIA rats. Moreover, acamprosate also significantly suppressed the production of TNF-α, IL-1β, and IL-6 in serum, which is elevated by AIA induction. Finally, acamprosate inhibited p-c-Raf and p-ERK1/2 and NF-κB activation after AIA treatment. These results indicate that acamprosate has an anti-inflammatory effect on adjuvant-induced arthritic rats via inhibiting the ERK/MAPK and NF-κB signaling pathways, and acamprosate may serve as a promising novel therapeutic agent for osteoarthritis.

BackgroundChronic Achilles tendinopathy is common in the general population, and platelet-rich plasma (PRP) is seeing increased use to treat this problem. However, studies disagree as to whether PRP confers a beneficial effect for chronic Achilles tendinopathy, and no one to our knowledge ha

Although great strides have been made in medical technology, low back/neck pain and intervertebral disc degeneration initiated from disc degenerative disease remains a clinical challenge. Within the field of regenerative medicine therapy, we have sought to improve the biomechanical transformation of spinal fusion procedures conducted using biodegradable porous implants. Specifically, we have focused on developing mechanically strong bioceramic cages for spinal fusion and functional recovery. Herein, we fabricated the akermanite (AKE) ceramic-based porous cages using low-melting bioactive glass (BG) and 3D printing technology. The osteogenic cell adhesion on the cages was evaluated in vitro, and the spinal fusion was tested in the intervertebral disc trauma model. The results indicated that incorporation of 15% or 30% BG into AKE (i.e., AKE/BG15 and AKE/BG30) could enhance the compressive strength of bioceramic cages by 2- or 5-fold higher than the pure AKE cages (AKE/BG0). In comparison with porous β-tricalcium phosphate cages, the surface of AKE/BG15 and AKE/BG30 cages greatly promoted the growth and alkaline phosphatase expression of osteogenic cells. Histological and biomechanical analysis showed that the AKE/BG15 and AKE/BG30 readily stimulated the new bone tissue growth and improved the spinal biomechanics recovery. In the AKE/BG15 and AKE/BG30 cage groups, 4-6 of the rabbits demonstrated a successful fusion. In contrast, only 0-1 of the initial seeded AKE/BG0 and tricalcium phosphate cages resulted in fusion at 12 weeks post-operatively. In summary, the akermanite-based cages showed an increased bone regenerative effect within an intervertebral disc trauma model, and thus, provided a promising candidate for improving spinal fusion surgery.

Background Spinal cord ischemia is a serious injury that threatens human health and life. Furthermore, it was widely accepted that miR-136 was mediated in the spinal injury, while whether it regulated neurocytes apoptosis in I/R-induced spinal cord injury remains unclear. Methods Spinal cord ischemia injury (SCII) rats were induced by clamping the nontraumatic vascular clip on the abdominal aorta. Real-time PCR was conducted to determine the mRNA expression, and western blot was carried out to measure protein expression. TUNEL assay was used to measure cell apoptosis. Results MiR-136 was up-regulated, while Tissue Inhibitor of Metalloproteinases-3 (TIMP3) was down-regulated in both SCII rats and hypoxic neurocytes. MiR-136 overexpression protected neurocytes against injury that induced by hypoxia. TIMP3 was the target gene of miR-136. Hypoxia supplementation decreased the expression of miR-136, promoted TIMP3 expression, and urged cell apoptosis, cells transfected with miR-136 mimic reversed the effect that induced by hypoxia, while cells co-transfected with pcDNA-TIMP3 abolished the results that induced by overexpressed miR-136. Conclusion MiR-136 regulated neurocytes apoptosis of SCII by mediating TIMP3.

This study describes the fabrication and biological evaluation of core-shell bilayered bioceramic microspheres with adjustable compositional distribution via a coaxial bilayer capillary system. Beyond the homogeneous hybrid composites, varying the diameter of capillary nozzles and the composition of the bioceramic slurries makes it easy to create bilayered β-tricalcium phosphate (CaP)/β-calcium silicate (CaSi) microspheres with controllable compositional distribution in the core or shell layer. Primary investigations in vitro revealed that biodegradation could be adjusted by compositional distribution or shell thickness and that poorly soluble CaP located on the shell layer of CaP or CaSi@CaP microspheres was particularly beneficial for mesenchymal stem cell adhesion and growth in the early stage, but the ion release from the CaP@CaSi exhibited a potent stimulating effect on alkaline phosphatase expression of the cells at longer times. When the bilayered microspheres (CaSi@CaP, CaP@CaSi) and the monolayered microspheres (CaP, CaSi) were implanted into the critical-sized femoral bone defect in rabbit models, significant differences in osteogenic capacity over time were measured at 6-18 weeks post implantation. The CaP microspheres showed the lowest biodegradation rate and slow new bone regeneration, whereas the CaSi@CaP showed a fast degradation of the CaSi core through the porous CaP shell so that a significant osteogenic response was observed at 12-18 weeks. The CaP@CaSi microspheres possessed excellent surface bioactivity and osteogenic activity, whereas the CaSi microspheres group exhibited a poor bone augmentation in the later stage due to extreme biodegradation. These findings demonstrated that the bioactive response in such core-shell-structured bioceramic systems could be adjusted by compositional distribution, and this strategy can be used to fabricate a variety of bioceramic microspheres with adjustable biodegradation rates and enhanced biological response for bone regeneration applications in medicine.

// Xiao-Yi Chen 1, * , San-Zhong Xu 2, * , Xuan-Wei Wang 2, * , Xian-Yan Yang 3 , Liang Ma 3 , Lei Zhang 4 , Guo-Jing Yang 4 , Fan Yang 1 , Lin-Hong Wang 1 , Xin-Li Zhang 5 , Kang Ting 5 , Chang-You Gao 3 , Xiao-Zhou Mou 1 , Zhong-Ru Gou 3 and Hai Zou 6 1 Clinical Research Institute, Zhejiang Provincial People’s Hospital, Hangzhou 310014, China 2 The First Affiliated Hospital, School of Medicine of Zhejiang University, Hangzhou 310009, China 3 Zhejiang-California International Nanosystems Institute, Zhejiang University, Hangzhou 310058, China 4 Rui’an People’s Hospital & The 3rd Affiliated Hospital to Wenzhou Medical University, Rui’an 325005, China 5 Dental and Craniofacial Research Institute, School of Dentistry, University of California, Los Angeles, CA 90095, USA 6 Department of Cardiology, Zhejiang Provincial People’s Hospital, Hangzhou 310014, China * These authors have contributed equally to this work Correspondence to: Xiao-Zhou Mou, email: mouxz@zjheart.com Zhong-Ru Gou, email: zhrgou@zjheart.com Hai Zou, email: haire1993@163.com Keywords: mineral micronutrients, microparticles, osteogenic differentiation, rOMSCs, rMSCs Received: January 02, 2017 Accepted: March 06, 2017 Published: March 28, 2017 ABSTRACT Osteoporosis is a disease characterized by structural deterioration of bone tissue, leading to skeletal fragility with increased fracture risk. Calcium phosphates (CaPs) are widely used in bone tissue engineering strategies as they have similarities to bone apatite except for the absence of trace elements (TEs) in the CaPs. Bioactive glasses (BGs) have also been used successfully in clinic for craniomaxillofacial and dental applications during the last two decades due to their excellent potential for bonding with bone and inducing osteoblastic differentiation. In this study, we evaluated the osteogenic effects of the ionic dissolution products of the quaternary Si-Sr-Zn-Mg-codoped CaP (TEs-CaP) or 45S5 Bioglass® (45S5 BG), both as mixtures and separately, on rat bone marrow-derived mesenchymal stem cells (rOMSCs & rMSCs) from osteoporotic and normal animals, using an MTT test and Alizarin Red S staining. The materials enhanced cell proliferation and osteogenic differentiation, especially the combination of the BG and TEs-CaP. Analysis by quantitative PCR and ELISA indicated that the expression of osteogenic-specific genes and proteins were elevated. These investigations suggest that the TEs-CaP and 45S5 BG operate synergistically to create an extracellular environment that promotes proliferation and terminal osteogenic differentiation of both osteoporotic and normal rMSCs.

Osteoporotic femur fractures are the most common fragility fracture and account for approximately one million injuries per year. Local intervention by intra-marrow injection is potentially a good choice for preventing osteoporotic bone loss when the osteoporotic femoral fracture was treated. Previously, it was shown that trace element co-doped calcium phosphate (teCaP) implants could stimulate osteoporotic bone marrow mesenchymal stem cell activity in vitro and bone regeneration in femoral bone defects in osteoporotic animal models. They hypothesized that local intra-marrow injection of teCaP particles could improve bone function because the teCaP can sustain release of biologically essential inorganic minerals and improve bone remodeling in osteoporosis. The teCaP and CaP particles were synthesized in simulated body fluid with and without adding silicon, zinc and strontium ions. Female rats (8 months) were ovariectomized (OVX) or sham-operated, and then intervened in the femoral marrow space at 12 months old. Groups include: (1) saline water; (2) CaP particles; and (3) teCaP particles. After 2-3 months of intervention, the sham groups showed higher bone mineral density (MBD) in the femur, and teCaP group increased the BMD in the OVX groups. The compressive strength of the OVX-teCaP group was significantly higher than that in the OVX-CaP group. Significant differences between OVX-teCaP and OVX-CaP groups were found for bone mineral microarchitecture, bone mineral density, and trace mineral content, but not for feces composition. These results confirm the teCaP particles could suppress osteoporotic bone loss by local intramarrow injection. Therefore, this biomaterial could be used as a next-generation combination treatment for osteoporotic trauma and osteoporosis itself. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1422-1432, 2017.

A rational design of fully interconnected porous constructs of biomaterials with controlled pore-wall bioactivity and biodegradation is of importance in the advancement of bone regenerative medicine. We hypothesize that the layered structure of hybrid bioceramics produces time-dependent biological performances to tune osteogenic responses. We thereby developed core-shell-structured nonstoichiometric Ca silicate (nCSi) spheres and evaluated the effect of spatiotemporal distribution of bi-component nCSi on osteogenic capability. The alginate-based 4% Sr-, 6% Mg-, or 10% Mg-doped nCaSi (i.e. CSi-Sr4, CSi-Mg6, CSi-Mg10) slurries were extruded into a Ca2+-rich solution through the core or shell layer of a coaxial bilayer nozzle, and after drying and sintering treatments, the core-shell nCSi ceramic spheres were prepared. The improved sintering property and denser structure of CSi-Mg6 and CSi-Mg10 shells readily retarded bioactive ion release and biodegradation of CSi-Sr4@CSi-Mg6 and CSi-Sr4@CSi-Mg10 spheres compared with those of CSi-Sr4@CSi-Sr4. When the spheres were implanted into the femoral bone defect in rabbits, the differences in biodegradation and bone regeneration rate in relation to microsphere scaffolds were measured at 6-18 weeks post-implantation. CSi-Sr4@CSi-Mg10 showed slow biodegradation and new bone regeneration, whereas CaSi-Sr4@CSi-Sr4 showed a much faster degradation such that a low osteogenic capacity was observed with prolongation of time. However, CSi-Sr4@CSi-Mg6 spheres displayed expected biodegradation and osteogenic activity with time. These results confirmed the slight tailoring in both doping ions and that component distribution of nCSi is beneficial for adjusting osteogenesis of core-shell spheres. By rationally choosing foreign ion doping, this concept may represent a versatile strategy for the production of a variety of core-shell bioactive ceramics for bone regeneration and repair applications.

Background Spinal cord injury (SCI) is a severe central nervous system trauma. The present study aimed to evaluate the effect of HIF-1α on inflammation in spinal cord injury (SCI) to uncover the molecular mechanisms of anti-inflammation. Results HIF-1α was reduced in SCI model rats and HIF-1α activation reduced TNF-α, IL-1β, IL-6 and IL-18 levels in SCI model rats. Meanwhile, Circ 0001723 expression was down-regulated and miR-380-3p expression was up-regulated in SCI model rats. In vitro model, down-regulation of Circ 0001723 promoted TNF-α, IL-1β, IL-6 and IL-18 levels, compared with control negative group. However, over-expression of Circ 0001723 reduced TNF-α, IL-1β, IL-6 and IL-18 levels in vitro model. Down-regulation of Circ 0001723 suppressed HIF-1α protein expressions and induced NLRP3 and Caspase-1 protein expressions in vitro model by up-regulation of miR-380-3p. Next, inactivation of HIF-1α reduced the pro-inflammation effects of Circ 0001723 in vitro model. Then, si-NLRP3 also inhibited the pro-inflammation effects of Circ 0001723 in vitro model via promotion of autophagy. Conclusions We concluded that HIF-1α reduced inflammation in spinal cord injury via miR-380-3p/ NLRP3 by Circ 0001723.

Mechanical strength and its long-term stability of bioceramic scaffolds is still a problem to treat the osteonecrosis of the femoral head. Considering the long-term stability of diopside (DIO) ceramic but poor mechanical strength, we developed the DIO-based porous bioceramic composites via dilute magnesium substituted wollastonite reinforcing and three-dimensional (3D) printing. The experimental results showed that the secondary phase (i.e. 10% magnesium substituting calcium silicate; CSM10) could readily improve the sintering property of the bioceramic composites (DIO/CSM10-x, x = 0–30) with increasing the CSM10 content from 0% to 30%, and the presence of the CSM10 also improved the biomimetic apatite mineralization ability in the pore struts of the scaffolds. Furthermore, the flexible strength (12.5–30 MPa) and compressive strength (14–37 MPa) of the 3D printed porous bioceramics remarkably increased with increasing CSM10 content, and the compressive strength of DIO/CSM10-30 showed a limited decay (from 37 MPa to 29 MPa) in the Tris buffer solution for a long time stage (8 weeks). These findings suggest that the new CSM10-reinforced diopside porous constructs possess excellent mechanical properties and can potentially be used to the clinic, especially for the treatment of osteonecrosis of the femoral head work as a bioceramic rod., Graphical abstract Image 1, Highlights • 10% Mg-substituted wollastonite (CSM10) may be used to reinforce the diopside (DIO) bioceramic. • DIO/CSM10 porous bioceramics may be fabricated via 3D printing and pressureless sintering. • DIO/CSM10 porous bioceramics indicate excellent mechanical strength and bioactivity. • DIO/CSM10 porous rod is potentially a good candidate to treat the osteonecrosis of femoral head.

The chitosan/alginate-trace element-codoped octacalcium phosphate/nano-sized bioactive glass (CS/ALG-teOCP/nBG) composite membranes were prepared by a layer-by-layer coating method for the functional requirement of guided bone regeneration (GBR). The morphology, mechanical properties and moisture content of the membranes was studied by scanning electron microscopy (SEM) observation, mechanical and swelling test. The results showed that the teOCP/nBG distributed uniformly in the composite membranes, and such as-prepared composite membrane exhibited an excellent tensile strength, accompanying with mechanical decay with immersion in aqueous medium. Cell culture and MTT assays showed that the surface microstructure and the ion dissolution products from teOCP/nBG components could enhance the cell proliferation, and especially the composite membranes was suitable for supporting the adhesion and growth behavior of human bone marrow mesenchymal stem cells (hBMSCs) in comparison with the CS/ALG pure polymer membranes. These results suggest that the new CS/ALG-teOCP/nBG composite membrane is highly bioactive and biodegradable, and favorable for guiding bone regeneration.

Mechanical strength of bioceramic scaffolds is a problem to treat the load bearing bone defects. We developed the Mg-doping wollastonite (CSi-Mg)-based scaffolds with high strength via 3D printing technology. The effect of pore size, β-tricalcium phosphate (β-TCP) content (x%), and heating schedule on the strength of scaffolds were investigated systematically. Incorporation of β-TCP could readily adjust the sintering properties of the CSi-Mg scaffolds and the scaffolds with high (20–30%) and low (10–20%) β-TCP possess much high strength (80–100 MPa or 120–140 MPa) after undergoing one- or two-step sintering. Meanwhile, the CSi-Mg/TCPx (x = 10, 20) with medium-pore (∼320 μm) had over 100 MPa in compression and ∼52% in porosity. In particular, the composite scaffolds maintained appreciable strength (over 50 MPa) after immersion in Tris buffer for a long time stage (6 weeks). These findings demonstrate that the CSi-Mg/TCPx scaffolds are promising for treating some challengeable bone defects, especially for load-bearing bone repair.

Methylprednisolone exhibits anti-inflammatory antioxidant properties, and rosiglitazone acts as an anti-inflammatory and antioxidant by activating peroxisome proliferator-activated receptor-γ in the spinal cord. Methylprednisolone and rosiglitazone have been clinically used during the early stages of secondary spinal cord injury. Because of the complexity and diversity of the inflammatory process after spinal cord injury, a single drug cannot completely inhibit inflammation. Therefore, we assumed that a combination of methylprednisolone and rosiglitazone might promote recovery of neurological function after secondary spinal cord injury. In this study, rats were intraperitoneally injected with methylprednisolone (30 mg/kg) and rosiglitazone (2 mg/kg) at 1 hour after injury, and methylprednisolone (15 mg/kg) at 24 and 48 hours after injury. Rosiglitazone was then administered once every 12 hours for 7 consecutive days. Our results demonstrated that a combined treatment with methylprednisolone and rosiglitazone had a more pronounced effect on attenuation of inflammation and cell apoptosis, as well as increased functional recovery, compared with either single treatment alone, indicating that a combination better promoted recovery of neurological function after injury.

A root canal sealer plays some important roles in accomplishing various functions including antibacteria and anti-microleakage. Meanwhile, such a sealer is also expected to readily induce apatite mineralization in damaged periapical tissues and reconstruct the surrounding alveolar bone. Taking the potent antibacterial ability of some biologically essential trace elements into account, we explore the effects of Zn or Cu doping in β-dicalcium silicate (β-C2Si) on the physicochemical modification and biological functions of its self-curing cement and compare with the β-C2Si cement free of foreign ion doping. An interesting aspect of the Zn or Cu doping in β-C2Si was the prolongation of setting time and the decrease of mechanical strength, but retardation in the degradation and improvement of anti-microleakage. Furthermore, the β-C2Si doped with 10% Cu exhibited more excellent antibacterial properties against P. gingivalis and E. faecalis. Additionally, there was similar apatite formation ability and cell growth on the β-C2Si cements with and without Zn-/Cu-doping within the initial 1–5 d. Totally, it is demonstrated that the physicochemical and biological performances are favorably altered with Zn or Cu doping in β-C2Si with a consequent effect on setting time, chemical stability (ion release, degradation), anti-microleakage, and antibacterial activity. Therefore, it is indicated that the Zn or Cu-doped β-C2Si is promising as a multifunctional root canal sealer.

To investigate the role of miR-372/Beclin-1 on nerve cell apoptosis induced by spinal cord ischemia/reperfusion injury (SCII). We established in vivo and in vitro SCII model. MiR-372 and Beclin-1 expressions in spinal cord tissues of SCII rats and SCII nerve cells were measured. The cell apoptosis was detected by flow cytometry. MiR-372 inhibitor was used to reduce miR-372 expression. Dual luciferase reporter assay was used to confirm the interaction between miR-372 and Beclin-1. MiR-372 expression in spinal cord tissues of SCII rats and SCII nerve cells was increased, while Beclin-1 expression was decreased. Knockdown of miR-372 could inhibit SCII nerve cell apoptosis. In addition, MiR-372 could negatively regulate Beclin-1 expression. Autophagy inhibitor could inhibit autophagy to promote the apoptosis of SCII nerve cells through decreasing Beclin-1, while interference of miR-372 changed the effect of autophagy inhibitor. Interference of miR-372 could reduce nerve cell apoptosis in SCII via increasing autophagy by up-regulating Beclin-1.

Controllable mechanical strength and biodegradation of bioceramic scaffolds is a great challenge to treat the load-bearing bone defects. Herein a new strategy has been developed to fabricate porous bioceramic scaffolds with adjustable component distributions based on varying the core-shell-structured nozzles in three-dimensional (3D) direct ink writing platform. The porous bioceramic scaffolds composed of different nonstoichiometic calcium silicate (nCSi) with 0%, 4% or 10% of magnesium-substituting-calcium ratio (CSi, CSi-Mg4, CSi-Mg10) was fabricated. Beyond the mechanically mixed composite scaffolds, varying the different nCSi slurries through the coaxially aligned bilayer nozzle makes it easy to create core-shell bilayer bioceramic filaments and better control of the different nCSi distribution in pore strut after sintering. It was evident that the magnesium substitution in CSi contributed to the increase of compressive strength for the single-phasic scaffolds from 11.2 MPa (CSi), to 39.4 MPa (CSi-Mg4) and 80 MPa (CSi-Mg10). The nCSi distribution in pore struts in the series of core-shell-strut scaffolds could significantly adjust the strength [e.g. CSi@CSi-Mg10 (58.9 MPa) vs CSi-Mg10@CSi (30.4 MPa)] and biodegradation ratio in Tris buffer for a long time stage (6 weeks). These findings demonstrate that the nCSi components with different distributions in core or shell layer of pore struts lead to tunable strength and biodegradation inside their interconnected macropore architectures of the scaffolds. It is possibly helpful to develop new bioactive scaffolds for time-dependent tailoring mechanical and biological performances to significantly enhance bone regeneration and repair applications, especially in some load-bearing bone defects.