Elucidating osseointegration in vivo in 3D printed scaffolds eliciting different foreign body responses.

Osseointegration between biomaterial and bone is critical for the clinical success of many orthopaedic and dental implants. However, the mechanisms of in vivo interfacial bonding formation and the role of immune cells in this process remain unclear. In this study, we investigated the bone-scaffold material interfaces in two different 3D printed porous scaffolds (polymer/hydroxyapatite and sintered hydroxyapatite) that elicited different levels of foreign body response (FBR). The polymer/hydroxyapatite composite scaffolds elicited more intensive FBR, which was evidenced by more FBR components, such as macrophages/foreign body giant cells and fibrous tissue, surrounding the material surface. Sintered hydroxyapatite scaffolds showed less intensive FBR compared to the composite scaffolds. The interfacial bonding appeared to form via new bone first forming within the pores of the scaffolds followed by growing towards strut surfaces. In contrast, it was previously thought that bone regeneration starts at biomaterial surfaces via osteogenic stem/progenitor cells first attaching to them. The material-bone interface of the less immunogenic hydroxyapatite scaffolds was heterogenous across all samples, evidenced by the coexistence of osseointegration and FBR components. The presence of FBR components appeared to inhibit osseointegration. Where FBR components were present there was no osseointegration. Our results offer new insight on the in vivo formation of bone-material interface, which highlights the importance of minimizing FBR to facilitate osseointegration for the development of better orthopaedic and dental biomaterials.

Evaluation of 'surgery-friendly' bone scaffold characteristics: 3D printed ductile BG/PCL scaffold with high inorganic content to repair critical bone defects.

The repair of irregular and complex critical bone defects remains a challenge in clinical practice. The application of 3D-printed bioceramics particle/polymer composite scaffolds in bone tissue engineering has been widely studied. At present, the inorganic particle content of the composite scaffolds is generally low, resulting in poor osteogenic activity. However, scaffold with high inorganic content are highly brittle, difficult to operate during surgery, and cannot be in close contact with surrounding bones. Therefore, it is of great significance to design a 'surgery-friendly' scaffold with high bioceramic content and good ductility. In this study, we used the solvent method to add high concentration (wt% 70%) bioglass (BG) into polycaprolactone (PCL), and polyethylene glycol was used as plasticizer to prepare 70% BG/PCL composite scaffolds with high ductility using 3D printing technology.In vitroexperiments showed that the scaffold had good mechanical properties: easy extension, easy folding and strong compressive resistance. It also showed good performance in biocompatibility and osteogenic activity. It was further observed that compared with pure BG or PCL implantation, the scaffold with higher BG content could have more new bone tissue appeared after 12 weeks. All these results indicate that 3D-printed 70% BG/PCL scaffolds have great potential for personalized repair of bone defects.

Pore Size of 3D-Printed Polycaprolactone/Polyethylene Glycol/Hydroxyapatite Scaffolds Affects Bone Regeneration by Modulating Macrophage Polarization and the Foreign Body Response.

3D-printed porous bioactive ceramic scaffolds have been widely used in bone defect repair. However, material implantation is often accompanied by a foreign body response (FBR), which may affect host tissue regeneration. The physical properties of biomaterials, including shape, pore size, and porosity, control the relevant immune responses during tissue regeneration. To the best of our knowledge, the effect of the pore size of 3D-printed scaffolds on the immune response and bone-biomaterial integration has not been studied in vivo. Polycaprolactone/polyethylene glycol/hydroxyapatite (PCL/PEG/HA) bioactive scaffolds with different pore sizes, including 209.9 ± 77.1 µm (P200), 385.5 ± 28.6 µm (P400), and 582.1 ± 27.2 µm (P600), were prepared with a pneumatic extrusion 3D printer. Compared with other pore sizes, P600 significantly reduced the FBR and induced more M2 macrophage infiltration, vascular ingrowth, and new bone formation. Immunohistochemical staining revealed that the MyD88 protein might be involved in macrophage polarization-related signal transduction in response to the pore size. Based on these results, bone regeneration requires the active participation of the immune response, and the P600 PCL/PEG/HA scaffold is a preferable candidate for the repair of bone defects.

Preparation and characterization of temperature-responsive magnetic composite particles for multi-modal cancer therapy.

The temperature-responsive magnetic composite particles were synthesized by emulsion-free polymerization of N-isopropylacrylamide (NIPAAm) and acrylamide (Am) in the presence of oleic acid-modified Fe(3)O(4) nanoparticles. The magnetic properties and heat generation ability of the composite particles were characterized. Furthermore, temperature and alternating magnetic field (AMF) triggered drug release behaviors of vitamin B(12)-loaded composite particles were also examined. It was found that composite particles enabled drug release to be controlled through temperature changes in the neighborhood of lower critical solution temperature. Continuous application of AMF resulted in an accelerated release of the loaded drug. On the other hand, intermittent AMF application to the composite particles resulted in an "on-off", stepwise release pattern. Longer release duration and larger overall release could be achieved by intermittent application of AMF as compared to continuous magnetic field. Such composite particles may be used for magnetic drug targeting followed by simultaneous hyperthermia and drug release.

Characterisation of bone regeneration in 3D printed ductile PCL/PEG/hydroxyapatite scaffolds with high ceramic microparticle concentrations.

3D printed bioactive glass or bioceramic particle reinforced composite scaffolds for bone tissue engineering currently suffer from low particle concentration (<50 wt%) hence low osteoconductivity. Meanwhile, composites with very high inorganic particle concentrations are very brittle. Scaffolds combining high particle content and ductility are urgently required for bone tissue engineering. Herein, 3D printed PCL/hydroxyapatite (HA) scaffolds with high ceramic concentration (up to 90 wt%) are made ductile (>100% breaking strain) by adding poly(ethylene glycol) which is biocompatible and FDA approved. The scaffolds require no post-printing washing to remove hazardous components. More exposure of HA microparticles on strut surfaces is enabled by incorporating higher HA concentrations. Compared to scaffolds with 72 wt% HA, scaffolds with higher HA content (90 wt%) enhance matrix formation but not new bone volume after 12 weeks implantation in rat calvarial defects. Histological analyses demonstrate that bone regeneration within the 3D printed scaffolds is via intramembranous ossification and starts in the central region of pores. Fibrous tissue that resembles non-union tissue within bone fractures is formed within pores that do not have new bone. The amount of blood vessels is similar between scaffolds with mainly fibrous tissue and those with more bone tissue, suggesting vascularization is not a deciding factor for determining the type of tissues regenerated within the pores of 3D printed scaffolds. Multinucleated immune cells are commonly present in all scaffolds surrounding the struts, suggesting a role of managing inflammation in bone regeneration within 3D printed scaffolds.

Magnesium-alloy rods reinforced bioglass bone cement composite scaffolds with cortical bone-matching mechanical properties and excellent osteoconductivity for load-bearing bone in vivo regeneration.

Various therapeutic platforms have been developed for repairing bone defects. However, scaffolds possess both cortical bone-matching mechanical properties and excellent osteoconductivity for load-bearing bone defects repair is still challenging in the clinic. In this study, inspired by the structure of the ferroconcrete, a high-strength bifunctional scaffold has been developed by combining surface-modified magnesium alloy as the internal load-bearing skeleton and bioglass-magnesium phosphate bone cement as the osteoconductive matrix. The scaffold combines the high mechanical strength and controllable biodegradability of surface-modified magnesium alloy with the excellent biocompatibility and osteoconductivity of bioglass-magnesium phosphate bone cement, thus providing support for load-bearing bone defects and subsequently bone regeneration. The scaffolds generate hydroxyapatite (HA) during the degrading in simulated body fluid (SBF), with the strength of the scaffold decreasing from 180 to 100 MPa in 6 weeks, which is still sufficient for load-bearing bone. Moreover, the scaffolds showed excellent osteoconductivity in vitro and in vivo. In a New Zealand White Rabbit radius defect model, the scaffolds degrade gradually and are replaced by highly matured new bone tissues, as assessed by image-based analyses (X-ray and Micro-CT) and histological analyses. The bone formation-related proteins such as BMP2, COL1a1 and OCN, all showed increased expression.

Customized Borosilicate Bioglass Scaffolds With Excellent Biodegradation and Osteogenesis for Mandible Reconstruction.

Graft reconstruction of the mandible is an important approach that aims at improving the appearance and functionality of defected mandibles. The traditional implant materials are generally bioinert, non-degradable, and that they lack favorable pore structures for cell proliferation, which limit their clinical application. In this study, we used boron-containing bioactive glass which was combined with a three-dimensional (3D) printing technology to construct an osteoinductive implant scaffold, according to the imaging instructions of CT scan on bone defects. Here, the boron-containing bioglass scaffold (B-BGs) was prepared through sol-gel processing and a 3D print technique. Different boron content of borosilicate bioglass was prepared by incorporating B2O3 (molar: 19.4 and 38.8%) into 58S bioglass to replace parts of SiO2. For fabricated mandible implants through three-dimensional 3D printing of B-BGs (size: 8 × 2 mm; pore size: 250 µm) modified with borosilicate bioglass powder and sodium alginate. Notably, the compressive strength of the B-BGs was about 3.8 Mpa, which supported mandibular activity. Subsequently, the excellent biocompatibility of B-BGs was confirmed using cytotoxicity in vitro studies. Finally, data from in vivo experiments demonstrated that the B-BGs could promote bone regeneration and they could almost get completely degraded within 4 weeks. Our results showed that the boron-containing bioglass could repair mandibular defects.

Injectable and bioactive bone cement with moderate setting time and temperature using borosilicate bio-glass-incorporated magnesium phosphate.

In this study, borosilicate bio-glass (BG) was incorporated into magnesium phosphate cement (MPC) for the purpose of developing an injectable and bioactive composite cement with suitable physicochemical and biocompatible performance. Results show that the BG-incorporated MPC possesses an excellent injectability, and can be used to fill in different 3D printed defect models using a syringe with a moderate setting time. Meanwhile, BG can retard the setting time and adjust the exothermic temperature of MPC. When the MPC/BG ratio was 3:1 (MPC3-BG), its corresponding setting time, peak temperature, anti-washout ratio and compressive strength were 9.9 ± 0.7 min, 45.8 ± 1.6 °C, 87%-90% and 13.5 MPa, respectively, which were suitable for injection and bone reparation. Characterizations of MPC3-BG showed that it had a faster degradation rate than MPC and the functional ions of boron and silicon could be released from the dissolution of the composite cement. In vitro and in vivo experiments also demonstrated that MPC3-BG had a stimulatory effect on the cell proliferation and new bone regeneration.

Mechano-Responsive, Tough, and Antibacterial Zwitterionic Hydrogels with Controllable Drug Release for Wound Healing Applications.

Acute wounds subject to frequent deformations are difficult to be treated because the healing process was easily interfered by external mechanical forces. Traditional wound dressings have limited efficacy because of their poor mechanical properties and skin adhesiveness and difficulty in the delivery of therapeutic drugs effectively. As such, tough and skin-adhesive wound dressings with sustainable and stimuli-responsive drug release properties for treatment of those wounds are highly desirable. For this purpose, we have developed a mechano-responsive poly(sulfobetaine methacrylate) hydrogel which aims to control the delivery of antibiotic drug upon application of mechanical forces. Diacrylated Pluronic F127 micelles were used as a macro-cross-linker of the hydrogel and loaded with hydrophobic antimicrobial drugs. The micelle-cross-linked hydrogel has excellent mechanical properties, with the ultimate tensile strength and tensile strain of up to 112 kPa and 1420%, respectively, and compressive stress of up to 1.41 MPa. Adhesiveness of the hydrogel to the skin tissue was ∼6 kPa, and it did not decrease significantly after repetitive adhesion cycles. Protein adsorption on the hydrogel was significantly inhibited compared to that on commercial wound dressings. Because of the mechano-responsive deformation of micelles, the release of drug from the hydrogel could be precisely controlled by the extent and cycles of mechanical loading and unloading, endowing the hydrogel with superior antibacterial property against both Gram-positive and Gram-negative bacteria. In addition, drug penetration into the skin tissue was enhanced by mechanical stress applied to the hydrogel. The micelle-cross-linked zwitterionic hydrogel also showed good cell biocompatibility, negligible skin irritation, and healing capacity to acute skin wounds in mice. Such a tough mechano-responsive hydrogel holds great promise as wound dressings for acute wounds subjected to frequent movements.

"The return of ceramic implants": Rose stem inspired dual layered modification of ceramic scaffolds with improved mechanical and anti-infective properties.

Nowadays, traditional ceramics for bone implants have considerably replaced by metal based biomedical materials, attributing to the friability of ceramics. However, ceramic implants possess excellent biocompatibility and longtime abrasion resistance. They should be more desirable for long-term uses of implants in case their fragility had been overcome. In the present work, inspired from natural rose, a dual-layer-modified ceramic scaffold was constructed by coating a superplastic layer of isocyanate (ISO) resin and a nano Zinc Oxide (nano-ZnO) layer on the ceramic scaffold. The ISO resin modification layer with 1 mm thickness, improved the mechanical properties of ceramic implants 2-3 times, and protect the ceramic implants from broken even drop from 1 m high. Moreover, such dual layered modification exhibited broad spectrum antibacterial behavior. In vivo biocompatible studies demonstrated that there was no obvious noticeable tissue damage in all major organs of mice after the implant surgeries.