Xiurong Ke

Bone regeneration in 3D printing bioactive ceramic scaffolds with improved tissue/material interface pore architecture in thin-wall bone defect

Three-dimensional (3D) printing bioactive ceramics have demonstrated alternative approaches to bone tissue repair, but an optimized materials system for improving the recruitment of host osteogenic cells into the bone defect and enhancing targeted repair of the thin-wall craniomaxillofacial defects remains elusive. Herein we systematically evaluated the role of side-wall pore architecture in the direct-ink-writing bioceramic scaffolds on mechanical properties and osteogenic capacity in rabbit calvarial defects. The pure calcium silicate (CSi) and dilute Mg-doped CSi (CSi-Mg6) scaffolds with different layer thickness and macropore sizes were prepared by varying the layer deposition mode from single-layer printing (SLP) to double-layer printing (DLP) and then by undergoing one-, or two-step sintering. It was found that the dilute Mg doping and/or two-step sintering schedule was especially beneficial for improving the compressive strength (∼25-104 MPa) and flexural strength (∼6-18 MPa) of the Ca-silicate scaffolds. The histological analysis for the calvarial bone specimens in vivo revealed that the SLP scaffolds had a high osteoconduction at the early stage (4 weeks) but the DLP scaffolds displayed a higher osteogenic capacity for a long time stage (8-12 weeks). Although the DLP CSi scaffolds displayed somewhat higher osteogenic capacity at 8 and 12 weeks, the DLP CSi-Mg6 scaffolds with excellent fracture resistance also showed appreciable new bone tissue ingrowth. These findings demonstrate that the side-wall pore architecture in 3D printed bioceramic scaffolds is required to optimize for bone repair in calvarial bone defects, and especially the Mg doping wollastontie is promising for 3D printing thin-wall porous scaffolds for craniomaxillofacial bone defect treatment.

3D printing of Mg-substituted wollastonite reinforcing diopside porous bioceramics with enhanced mechanical and biological performances

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.

45S5 Bioglass analogue reinforced akermanite ceramic favorable for additive manufacturing mechanically strong scaffolds

Calcium–magnesium silicate bioceramics have attracted increased interest in the development of porous scaffolds for bone tissue engineering applications, mainly due to their excellent bioactivity and ability to bond to hard tissue. However, the shaping of these bioceramics into complex porous constructs is challenging, and, especially, conventional high temperature pressureless sintering is not always an effective method to improve their mechanical properties without further compromising their biologically relevant performances. Here we developed a low melting-point bioactive glass (BG)-assisted sintering approach to improve the mechanical properties of akermanite ceramics with and without intentionally manufacturing macroporous structures. The experimental results indicated that the 4 wt% B2O3-containing 45S5 BG analogue could readily reinforce akermanite ceramics at a 20–40 wt% content, and material extrusion 3D-printing followed by a pressureless sintering process could be employed to fabricate high-strength porous scaffolds with compressive strength (∼36 MPa) ten times higher than those of pure akermanite porous ceramics. Moreover, the composite porous ceramics showed slower biodegradation in Tris buffer in vitro and this did not heavily affect the strength of their porous formulation over a long time period (6 weeks). It is proposed that 3D printing followed by an NCS-B-assisted sintering process represents an effective alternative for developing high strength bioceramic scaffolds potentially for the repair of load-bearing segmental bone defects.

Prevalence and risk factors for postoperative delirium in total joint arthroplasty patients: A prospective study

BACKGROUND The aim of this prospective study was to investigate the incidence and clinical features of delirium after total joint arthroplasty, and to establish the potential risk factors for postoperative delirium. METHODS A total of 212 consecutive patients undergoing hip or knee arthroplasty, who met the inclusion and exclusive criteria were enrolled. The general characteristics, preoperative and postoperative hematological variables were documented respectively. According to the presence of delirium, all patients were divided into the delirium group and non-delirium group. Univariate and multivariate logistic regression were performed to identify the possible predictors for postoperative delirium. RESULTS At a minimum of 6months of follow-up, 35 patients were observed with postoperative delirium at an estimated total incidence of 16.5%. The incidence of delirium was statistically higher in hip arthroplasty (22.8%) than that in knee arthroplasty (7.1%). The multivariate regression analysis identified older age (OR=1.590, P=0.023), a history of stroke (OR=190.23, P=0.036), preoperative PaO2 (OR=1.277, P=0.018) and equivalent fentanyl dose (OR=1.010, P=0.012) as the predictive factors for postoperative delirium after total joint arthroplasty. CONCLUSIONS The incidence of postoperative delirium after total joint arthroplasty is higher than expected. Based on our findings, we suggest that the surgeons should focus on those patients who have these risk factors and ensure the appropriate management to avoid postoperative delirium.

3D robocasting magnesium-doped wollastonite/TCP bioceramic scaffolds with improved bone regeneration capacity in critical sized calvarial defects

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.

Core–shell-structured nonstoichiometric bioceramic spheres for improving osteogenic capability

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.

Enhancing the Osteogenic Capability of Core–Shell Bilayered Bioceramic Microspheres with Adjustable Biodegradation

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.

Intra-bone marrow injection of trace elements co-doped calcium phosphate microparticles for the treatment of osteoporotic rat

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.

Systematic evaluation of the osteogenic capacity of low-melting bioactive glass-reinforced 45S5 Bioglass porous scaffolds in rabbit femoral defects

Due to the low strength and high brittleness of 45S5 Bioglass®, it is still a great challenge for the three-dimensional porous 45S5 Bioglass® to treat mechanically required loaded bone defects. Therefore, 45S5 Bioglass®-derived bioactive glass-ceramic (BGC) porous scaffolds were fabricated at a low temperature sintering condition with and without the addition of 4% low-melting ZnO/B2O3 (ZB) bioactive glass as a reinforcing agent and using 350- or 500 μm paraffin microspheres as a porogen. The pore structure characterization for the scaffolds indicated that the scaffolds containing 4% ZB had very good macroporous structures of ∼313 and ∼448 μm in pore size and over 70% porosity with appreciable strength (>15 MPa), which was about four times higher than that those manufactured without ZB and with 350 μm porogen scaffolds. The open porosity was decreased with the addition of 4% ZB but the interconnected pore percentage (>50 μm) was increased with increasing the porogen size from 350 to 500 μm. In vivo investigations revealed that the stronger scaffolds containing 4% ZB and 500 μm porogen were particularly beneficial for osteogenic capacity in critical size femoral bone defects, accompanied with an accelerated bone ingrowth (6-18 weeks) and the material itself experiencing mild resorption. In contrast, both the scaffolds with smaller pore sizes exhibited a low level of new bone ingrowth (<32%) after 6-12 weeks implantation. These results suggest a promising application of such 45S5 Bioglass®-derived BGC scaffolds in a clinical setting, especially for mechanically loaded bone defects.

Core-shell Microspheres with Tunable Density of Shell Micropores Providing Tailorable Bone Repair

IMPACT STATEMENT 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.