Smart Delivery Systems Based on Poly(glycidyl methacrylate)s-Coated Organic/Inorganic Core-Shell Nanohybrids.

Smart delivery systems have gained momentum over the last few decades due to their potential to realize enhanced therapeutic efficacy. Poly(glycidyl methacrylate)s (PGMAs), which spring up like mushrooms, have drawn great attention in the theranostics field, especially in multifunctional theranostic systems. The marriage of PGMAs with functional inorganic cores is expected to integrate diagnosis (e.g., fluorescence, X-ray computed tomography, magnetic resonance, photoacoustic and upconversion luminescence imaging), treatment, or multimodal synergistic therapies (e.g., chemotherapy, gene therapy, photothermal therapy) in one pot for personalized medicine. In this review, recent progress in various PGMA-coated nanohybrids based on the type of integrated inorganic nanoparticle, including silica nanoparticles, magnetic nanoparticles, quantum dots, gold nanoparticles, gold nanorods, metal-organic frameworks, cellulose nanocrystals, and their core-shell nanostructures is systematically reviewed. Future work in this field is anticipated to be devoted to developing efficient real-time-imaging-guided multimodal synergistic therapies.

Zn(2+)-Triggered Drug Release from Biocompatible Zirconium MOFs Equipped with Supramolecular Gates.

A new theranostic nanoplatform, comprising of monodisperse zirconium metal-organic frameworks (MOFs) as drug carriers and carboxylatopillar[5]arene-based supramolecular switches as gating entities, is constructed, and controlled drug release triggered by bio-friendly Zn(2+) ions (abundant in synaptic vesicles) and auxiliary thermal stimulus is realized. This on-command drug delivery system exhibits large pore sizes for drug encapsulation, excellent biodegradability and biocompatibility, extremely low cytotoxicity and premature drug release, and superior dual-stimuli responsiveness, opening a new avenue in targeted drug delivery and controlled release of therapeutic agents, especially in the treatment of central nervous system diseases.

Acetylcholine-triggered cargo release from supramolecular nanovalves based on different macrocyclic receptors.

Acetylcholine (ACh), a neurotransmitter located in cholinergic synapses, can trigger cargo release from mesoporous silica nanoparticles equipped with calixarene- or pillarene-based nanovalves by removing macrocycles from the stalk components. The amount and speed of cargo release can be controlled by varying the concentration of ACh in solution or changing the type of gating macrocycle. Although this proof-of-concept study is far from a real-life application, it provides a possible route to treat diseases related to the central nervous system.

Enhanced Degradability of the Apatite-Based Calcium Phosphate Cement Incorporated with Amorphous MgZnCa Alloy.

Degradability is vital for bone filling and plays an important role in bone regeneration. Evidence indicates that apatite-based calcium phosphate cement (ACPC) is a prospective biomaterial for bone repair with enhanced osteogenesis. However, poor degradability restricts their clinical application. In this study, MgZnCa-doped ACPC (MgZnCa/ACPC) composites were fabricated by adding 3 (wt) % amorphous MgZnCa powder in the solid phase of ACPC to enhance the biodegradation and bioactivity of the apatite ACPC. The chemical and the physical properties of the MgZnCa/ACPC composite were investigated and compared with the ACPC composite. The results showed that the incorporation of MgZnCa improved both the degradability and the compressive strength of the ACPC composite. X-ray diffraction and Fourier transform infrared spectrometry analysis suggested significant changes in the microstructures of the composites due to the incorporation and the anodic dissolution of MgZnCa alloy. These findings indicate that the MgZnCa/ACPC composite is capable of facilitating bone repair and regeneration by endowing favorable degradation property.

Enhanced efficacy of sirolimus-eluting bioabsorbable magnesium alloy stents in the prevention of restenosis.

PURPOSE: To determine the efficacy of sirolimus-eluting bioabsorbable magnesium alloy stents (SEBMAS) in restenosis prevention. METHODS: A balloon-expandable bioabsorbable magnesium alloy stent (BMAS) was created and coated with biodegradable poly(lactic acid-co-trimethylene carbonate) that contained the antiproliferative drug sirolimus (140 ± 40 µg/cm²). Both the uncoated BMAS and the coated SEBMAS were deployed 2 cm apart in balloon-injured infrarenal abdominal aortas of 20 New Zealand white rabbits. The stented aortic segments were removed at 30, 60, 90, and 120 days (5 rabbits per interval) after implantation. The average stent strut sectional area of each group was measured to evaluate the degree of magnesium corrosion and to forecast the biodegradation time profile of the magnesium stent. Histology and histopathology of the sectioned stented aortic segments were performed to evaluate neointima formation, endothelialization, and inflammation. RESULTS: The SEBMAS degraded gradually after being implanted into the rabbit aorta, and total biocorrosion occurred after ~120 days. In all groups, the lumen area was significantly greater, but the neointimal area was significantly smaller in SEBMAS segments compared with the uncoated BMAS segments (p < 0.05) at all time points. There was no significant difference in the injury or inflammation scores between the groups. Endothelialization was delayed at 30 days in the SEBMAS segments vs. the uncoated BMAS segments. CONCLUSION: SEBMAS further reduces intimal hyperplasia and improves the lumen area when compared to uncoated BMAS; however, it delays vascular healing and endothelialization.

Antibacterial effect of 317L stainless steel contained copper in prevention of implant-related infection in vitro and in vivo.

Bone and intramedullary bacterial infections are one of the most serious complications of the surgical repair of fractures. To reduce the incidence of implant-related infections, several biomaterial surface treatments with integrated antibiotics, antiseptics, or metal ions have been developed for implants. In this study, we evaluated the antibacterial activity and biocompatibility of 317L stainless steel containing 4.5% copper alloy (317L-Cu) in vitro and in vivo using an animal model. Common pathogens of implant-related infections are Staphylococcus aureus and Escherichia coli, which were injected into implant materials to study their antimicrobial potential. We compared antimicrobial potential of 317L-Cu with 317L stainless steel (317L) and titanium (Ti-6Al-4V) alloys as controls. Compared with controls, 317L-Cu materials inhibited colonization by both bacteria in vitro and in vivo. Compared with 317L and Ti-6Al-4V controls, 317L-Cu showed no significant difference in colony formation of osteoblast-like cells on metal surfaces after 72 h of incubation in vitro. Metal screws containing these materials were also made for our vivo study in a rabbit model. Tissue-implants were analyzed for infection and inflammatory changes by hematoxylin-eosin staining of implants in bone. The screw tract inflammation and infection of 317L-Cu was minimal, although some inflammatory cells gathered at acutely infected sites. In addition, after materials had been implanted for 14 days in vivo, the expression of insulin-like growth factor-1 (IGF-1) in osteoblasts around 317L-Cu screws tracts had increased compared with 317L and Ti-6Al-4V controls. Overall, 317L-Cu demonstrated strong antimicrobial activity and biocompatibility in vitro and in vivo and may be used as a biomaterial to reduce implant-related infections.

Study on a biodegradable antibacterial Fe-Mn-C-Cu alloy as urinary implant material.

Biodegradable Fe based alloys have been investigated for fracture fixation and cardiovascular support to overcome complications of permanent implants. This study was focused on the development of a new Fe-Mn-C-Cu alloy with antibacterial and anti-encrustation properties as a urinary implant material. The microstructure and mechanical properties of the alloy were studied. The degradation behavior, antibacterial and anti-encrustation properties were evaluated by immersion test, antibacterial test and encrustation test, respectively. The results showed that Fe-Mn-C-Cu alloy was a non-magnetic, biodegradable, anti-bacterial and anti-encrustation alloy that could inhibit the biofilm and stone formations on its surface through the dual effects of degradation and Cu ions release. The study revealed the preliminary mechanisms of anti-infection and anti-encrustation for Fe-Mn-C-Cu alloy due to the continuous release of Cu2+ ions, which provides a new idea for application of biodegradable Fe-based material and the treatment of urinary tract infections and stones in the urinary system.

In vitro degradation and antibacterial property of a copper-containing micro-arc oxidation coating on Mg-2Zn-1Gd-0.5Zr alloy.

Copper (Cu) has a good antibacterial effect and micro-arc oxidation (MAO) coating has good corrosion resistance for magnesium (Mg) alloys. If they are combined together, the coated Mg alloy is expected to have both good corrosion resistance and antibacterial effect. In this work, the degradation, antibacterial property and cytotoxicity of a Cu-containing MAO coating on an extruded Mg-2Zn-1Gd-0.5Zr alloy were systematically studied. The results revealed that the addition of Cu could further improve the degradation resistance of MAO coated alloy. After two weeks immersion, the corrosion rate of Cu + MAO coated alloy was 0.16 mm/y, lower than those of both MAO coated and uncoated alloy. The release of Cu2+ from Cu + MAO coated alloy inhibited the bacterial proliferation. After 12 h co-culture, the antibacterial rate reached 96%. Cytotoxicity test (MG63 cell) showed that Cu + MAO coated alloy had good biocompatibility. The Cu + MAO coating has great potential for application on Mg alloys due to its good corrosion resistance, antibacterial property and good biocompatibility.

Effects of magnesium coating on bone-implant interfaces with and without polyether-ether-ketone particle interference: A rabbit model based on porous Ti6Al4V implants.

We investigated the effects of magnesium (Mg) on osteogenesis and bone resorption at a porous structure interface. A three-dimensional (3D)-printed porous Ti6Al4V implant coated with Mg was introduced, and polyether-ether-ketone wear particles were added to generate an animal model of implant loosening. We also examined the effects of Mg leach liquor on osteoblast/osteoclast gene expression, alkaline phosphatase activity, collagen secretion, tartrate-resistant acid phosphatase activity, and bone resorption in vitro. Mg inhibited the early stage of osteoclast differentiation and inhibited bone resorption in vitro and in vivo. However, Mg did not enhance osteogenesis in vitro or in vivo in the porous structures or in peripheral areas around the implants. For implants with porous structures, the Mg coating did not improve the osteogenic ability by itself, but could restrain peri-implant osteolysis, which may make it favorable for use in patients with osteoporosis. Further studies are needed to examine the precise mechanism of Mg-induced anti-osteolysis and the long-term effects of Mg-coated implants in humans. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 2388-2396, 2019.

Study of engineered low-modulus Mg/PLLA composites as potential orthopaedic implants: An in vitro and in vivo study.

Low molecular weight poly-lactic acid (PLLA) is a polymer matrix of orthopaedic implants. The PLLA matrix incorporating bioactive magnesium ion (Mg2+) enhances bone regeneration. But the optimal ratio of Mg2+ to PLLA matrix has not been well reported and is worthy of study. We synthesized silane-coated Mg/PLLA composites containing 1%, 2%, 3%, 4% and 5% Mg micro-particles. The mechanical properties, in vitro cytocompatibility, cell viability and osteogenesis differentiation and in vivo performance of silane-coated Mg/PLLA composites were evaluated. These results showed that the bending and tensile strength of PLLA matrix was reduced by incorporation of Mg micro-particles. Mg/PLLA composites with higher Mg micro-particles ratio showed higher Mg2+ leaching rate and pH value in immersion solutions. MC3T3-E1 pre-osteoblasts incubated with Mg/PLLA composites containing higher ratio of Mg micro-particles showed higher cytocompatibility, cell viability, osteogenesis differentiation and migration. In vitro cellular responses showed that MC3T3-E1 pre-osteoblasts had the highest cell viability at 50 ppm Mg2+. In vivo animal studies showed there was no change in serum Mg2+ concentration after implanting Mg/PLLA composites comparing with control and the implants of silane-coated Mg/PLLA composites accelerated bone formation. In summary, our study revealed the feasibility of silane-coated Mg/PLLA composites as orthopaedic implants. Silane-coated Mg/PLLA composites with Mg micro-particles ratio of 3% ∼ 5% were optimal substitutes for bone regeneration.

Corrosion and biological performance of biodegradable magnesium alloys mediated by low copper addition and processing.

Mg-Cu alloys were designed by introducing the well-known antibacterial property of copper into magnesium alloy to solve the infection problem especially under the neutralised environment in vitro. In this paper, the Mg-Cu alloys with further processing by solution and extrusion were studied to optimise the corrosion-related performance for their future application. It was shown that the differences in the property profile of Mg-Cu alloys are dependent on different compositions as well as on different microstructures that are obtained by the different processing routes. Galvanic corrosion can be significantly relieved by solution treatment and extrusion due to decrease and well distribution of cathodic Mg2Cu phases. Negligible cytotoxicity were observed with rBMSCs incubation. Antibacterial assays proved that the alloys reduced the viability of Staphylococcus aureus by high alkalinity and copper ions releasing, especially in comparison with pure magnesium. Finally, the as-solutionized Mg-0.1Cu alloy showed the optimal corrosion properties and promising antibacterial activity, which warranted its potentials as antibacterial biodegradable implant materials.

Mechanical properties of magnesium alloys for medical application: A review.

Magnesium alloys as a class of biodegradable metals have great potential to be used as implant materials, which attract much attention. In this review, the mechanical properties of magnesium alloys for medical applications are summarized. The methods to improve the mechanical properties of biodegradable magnesium alloys and the mechanical behaviors of Mg alloys in biomedical application are illustrated. Finally the challenges and future development of biodegradable magnesium alloys are presented.

Biocompatibility and neurotoxicity of magnesium alloys potentially used for neural repairs.

Nerve injury, especially the large-size nerve damage, is a serious problem affecting millions of people. Entubulation of two ends of the injured nerve by using an implantable device, e.g., nerve guidance conduit (NGC), to guide the regeneration of nerve tissue is a promising approach for treating the large-size nerve defect. Magnesium (Mg) and its alloys are biodegradable, conductive, and own good mechanical properties. Mg2+ ion, one of the main degradation products of Mg and its alloys, was reported to promote the proliferation of neural stem cells and their neurite production. Thus, Mg and its alloys are potential materials for fabricating the nerve repair implants, such as NGC or scaffold. However, the compatibility of Mg alloys to cells, especially neurons is not clear. In this work, NZ20 (Mg-2Nd-Zn), ZN20 (Mg-2Zn-Nd) and Mg-10Li magnesium alloys were selected for study, due to the improved mechanical properties of NZ20 and ZN20 alloys and bio-function of Li+ ions from Mg-10Li to nervous system, respectively. The degradation behavior and biocompatibility were studied by in vitro degradation test and cell adhesion assay, respectively. Specifically, the cytocompatibility to dorsal root ganglion (DRG) neurons, RF/6A choroid-retina endothelial cells, and osteoblasts in the cell culture media containing Mg alloy extracts were investigated. The results showed that Mg alloys degraded at different rates in cell culture media and artificial cerebrospinal fluid. The three alloy extracts showed negligible toxic effects on the endothelial cells and osteoblasts at short term (1 day), while NZ20 extract inhibited the proliferation of these two types of cells. The effect of Mg alloy extracts on cell proliferation was also concentration-dependent. For DRG neurons, ZN20 and Mg-10Li alloy extracts showed no neural toxicity compared with control group. The results of the present work show a potential and feasibility of Mg-10Li and ZN20 for nerve repair applications.

Investigation of the inner corrosion layer formed in pulse electrodeposition coating on Mg-Sr alloy and corresponding degradation behavior.

Magnesium-based metals are considered as promising biodegradable orthopedic implant materials due to their potentials of enhancing bone healing and reconstruction, and in vivo absorbable characteristic without second operation for removal. However, the rapid corrosion has limited their clinical applications. Ca-P coating by electrodeposition has been supposed to be effective to control the degradation rate and enhance the bioactivity. In this work, a brushite coating was fabricated on the Mg-Sr alloy by pulse electrodeposition (PED) to evaluate its efficacy for orthopedic application. Interestingly, an inner corrosion layer was observed between the PED coating and the alloy substrate. Meanwhile the results of in vitro immersion and electrochemical tests showed that the corrosion resistance of the coated alloy was undermined in comparison with the uncoated alloy. It was deduced that the existence of this corrosion layer was attributed to the worse corrosion performance of the alloy. The mechanism on formation of the inner corrosion layer and its influence on consequent degradation were analyzed. It can be concluded that the electrodeposition coating should be not suitable for those magnesium alloys with poor corrosion resistance such as the Mg-Sr alloy. More importantly, it should be noted that the process of coating formation combined with the nature of substrate alloy is important to evaluate the efficacy of coating for biodegradable Mg-based implants application.

The fluoride coated AZ31B magnesium alloy improves corrosion resistance and stimulates bone formation in rabbit model.

This study aimed to evaluate the effect of fluorine coated Mg alloy and clarify its mechanism in bone formation. We implanted the fluorine coated AZ31B Mg alloy screw (group F) in rabbit mandibular and femur in vivo. Untreated AZ31B Mg alloy screw (group A) and titanium screw (group T) were used as control. Then, scanning electron microscopy, the spectral energy distribution analysis, hard and decalcified bone tissues staining were performed. Immunohistochemistry was employed to examine the protein expressions of bone morphogenetic protein 2 (BMP-2) and collagen type I in the vicinity of the implant. Compared with the group A, the degradation of the alloy was reduced, the rates of Mg corrosion and Mg ion release were slowed down, and the depositions of calcium and phosphate increased in the group F in the early stage of implantation. Histological results showed that fluorine coated Mg alloy had well osteogenic activity and biocompatibility. Moreover, fluoride coating obviously up-regulated the expressions of collagen type I and BMP-2. This study confirmed that the fluorine coating might improve the corrosion resistance of AZ31B Mg alloy and promote bone formation by up-regulated the expressions of collagen type I and BMP-2.

Tailoring the degradation and biological response of a magnesium-strontium alloy for potential bone substitute application.

Bone defects are very challenging in orthopedic practice. There are many practical and clinical shortcomings in the repair of the defect by using autografts, allografts or xenografts, which continue to motivate the search for better alternatives. The ideal bone grafts should provide mechanical support, fill osseous voids and enhance the bone healing. Biodegradable magnesium-strontium (Mg-Sr) alloys demonstrate good biocompatibility and osteoconductive properties, which are promising biomaterials for bone substitutes. The aim of this study was to evaluate and pair the degradation of Mg-Sr alloys for grafting with their clinical demands. The microstructure and performance of Mg-Sr alloys, in vitro degradation and biological properties including in vitro cytocompatibility and in vivo implantation were investigated. The results showed that the as-cast Mg-Sr alloy exhibited a rapid degradation rate compared with the as-extruded alloy due to the intergranular distribution of the second phase and micro-galvanic corrosion. However, the initial degradation could be tailored by the coating protection, which was proved to be cytocompatible and also suitable for bone repair observed by in vivo implantation. The integrated fracture calluses were formed and bridged the fracture gap without gas bubble accumulation, meanwhile the substitutes simultaneously degraded. In conclusion, the as-cast Mg-Sr alloy with coating is potential to be used for bone substitute alternative.

Comparison study of different coatings on degradation performance and cell response of Mg-Sr alloy.

To solve the problem of rapid degradation for magnesium-based implants, surface modification especially coating method is widely studied and showed the great potential for clinical application. However, as concerned to the further application and medical translation for biodegradable magnesium alloys, there are still lack of data and comparisons among different coatings on their degradation and biological properties. This work studied three commonly used coatings on Mg-Sr alloy, including micro-arc oxidation coating, electrodeposition coating and chemical conversion coating, and compared these coatings for requirements of favorable degradation and biological performances, how each of these coating systems has performed. Finally the mechanism for the discrepancy between these coatings is proposed. The results indicate that the micro-arc oxidation coating on Mg-Sr alloy exhibited the best corrosion resistance and cell response among these coatings, and is proved to be more suitable for the orthopedic application.

Biodegradable Mg-Cu alloys with enhanced osteogenesis, angiogenesis, and long-lasting antibacterial effects.

A series of biodegradable Mg-Cu alloys is designed to induce osteogenesis, stimulate angiogenesis, and provide long-lasting antibacterial performance at the same time. The Mg-Cu alloys with precipitated Mg2Cu intermetallic phases exhibit accelerated degradation in the physiological environment due to galvanic corrosion and the alkaline environment combined with Cu release endows the Mg-Cu alloys with prolonged antibacterial effects. In addition to no cytotoxicity towards HUVECs and MC3T3-E1 cells, the Mg-Cu alloys, particularly Mg-0.03Cu, enhance the cell viability, alkaline phosphatase activity, matrix mineralization, collagen secretion, osteogenesis-related gene and protein expressions of MC3T3-E1 cells, cell proliferation, migration, endothelial tubule forming, angiogenesis-related gene, and protein expressions of HUVECs compared to pure Mg. The favorable osteogenesis and angiogenesis are believed to arise from the release of bioactive Mg and Cu ions into the biological environment and the biodegradable Mg-Cu alloys with osteogenesis, angiogenesis, and long-term antibacterial ability are very promising in orthopedic applications.

Biodegradable Mg-Cu alloy implants with antibacterial activity for the treatment of osteomyelitis: In vitro and in vivo evaluations.

Treatment of chronic osteomyelitis (bone infection) remains a clinical challenge; in particular, it requires an implantable material with improved antibacterial activity. Here, we prepared biodegradable magnesium (Mg)-copper (Cu) alloys with different Cu contents (0.05, 0.1, and 0.25 wt%) and assessed their potential for treating methicillin-resistant Staphylococcus aureus-induced osteomyelitis. We evaluated the microstructures, mechanical properties, corrosion behavior, and ion release of the alloys in vitro, and their biocompatibility and antibacterial activity in vitro and in vivo. The antibacterial activity of the Mg-Cu alloys in vitro was demonstrated by microbiological counting assays, bacterial viability assays, biofilm formation observations, and the expression of biofilm, virulence, and antibiotic-resistance associated genes. The antibacterial activity of Mg-Cu alloys in vivo was confirmed by imaging examination, microbiological cultures, and histopathology. The biocompatibility of Mg-Cu alloys was confirmed by cell proliferation, vitality, and morphology assays in vitro and Cu(2+) or Mg(2+) ion assays, blood biochemical tests, and histological evaluation in vivo. The alloy containing 0.25 wt% Cu exhibited the highest antibacterial activity among the tested alloys, with favorable biocompatibility. Collectively, our results indicate the potential utility of Mg-Cu alloy implants with 0.25 wt% Cu in treating orthopedic infections.

Study on microstructure and properties of extruded Mg-2Nd-0.2Zn alloy as potential biodegradable implant material.

Mg-2Nd-0.2Zn (NZ20) alloy was prepared for the application as biodegradable implant material in this study. The effects of the extrusion process on microstructure, mechanical and corrosion properties of the alloy were investigated. The as-cast alloy was composed of α-Mg matrix and Mg12Nd eutectic compound. The solution treatment could lead to the Mg12Nd phase dissolution and the grain coarsening. The alloy (E1) preheated at 380°C for 1h and extruded at 390°C presents fine grains with amounts of tiny Mg12Nd particles uniformly dispersed throughout the boundaries and the interior of the grains. The alloy (E2) preheated at 480°C for 1h and extruded at 500°C exhibits relatively larger grains with few nano-scale Mg12Nd phase particles dispersed. The alloy of E1, compared with E2, showed relatively lower corrosion rate, higher yield strength and slightly lower elongation.