Mixed Matrix Membrane with Penetrating Subnanochannels: A Versatile Nanofluidic Platform for Selective Metal Ion Conduction.

Biological ion channels penetrated through cell membrane form unique transport pathways for selective ionic conductance. Replicating the success of ion selectivity with mixed matrix membranes (MMMs) will enable new separation technologies but remains challenging. Herein, we report a soft substrate-assisted solution casting method to develop MMMs with penetrating subnanochannels for selective metal ion conduction. The MMMs are composed of penetrating Prussian white (PW) microcubes with subnanochannels in dense polyimide (PI) matrices, achieving selective monovalent metal ion conduction. The ion selectivity of K+ /Mg2+ is up to 14.0, and the ion conductance of K+ can reach 45.5 µS with the testing diameter of 5 mm, which can be further improved by increasing the testing area. Given the diversity of nanoporous materials and polymer matrices, we expect that the MMMs with penetrating subnanochannels could be developed into a versatile nanofluidic platform for various emerging applications.

Harnessing 4D Printing Bioscaffolds for Advanced Orthopedics.

The development of programmable functional biomaterials makes 4D printing add a new dimension, time (t), based on 3D structures (x, y, z), therefore, 4D printed constructs could transform their morphology or function over time in response to environmental stimuli. Nowadays, highly efficient bone defect repair remains challenging in clinics. Combining programmable biomaterials, living cells, and bioactive factors, 4D bioprinting provides greater potential for constructing dynamic, personalized, and precise bone tissue engineering scaffolds by complex structure formation and functional maturation. Therefore, 4D bioprinting has been regarded as the next generation of bone repair technology. This review focuses on 4D printing and its advantages in orthopedics. The applications of different smart biomaterials and 4D printing strategies are briefly introduced. Furthermore, one summarizes the recent advancements of 4D printing in bone tissue engineering, uncovering the addressed and unaddressed medical requirements. In addition, current challenges and future perspectives are further discussed, which will offer more inspiration about the clinical transformation of this emerging 4D bioprinting technology in bone regeneration.

Selenite reduced uptake/translocation of cadmium via regulation of assembles and interactions of pectins, hemicelluloses, lignins, callose and Casparian strips in rice roots.

Selenium (Se) can reduce cadmium (Cd) uptake/translocation via regulating pectins, hemicelluloses and lignins of plant root cell walls, but the detailed molecular mechanisms are not clear. In this study, six hydroponic experiments were set up to explore the relationships of uptake/translocation inhibition of Cd by selenite (Se(IV)) with cell wall component (CWC) synthesis and/or interactions. Cd and Se was supplied (alone or combinedly) at 1.0 mg L-1 and 0.5 mg L-1, respectively, with the treatment without Cd and Se as the control. When compared to the Cd1 treatment, the Se0.5Cd1 treatment 1) significantly increased total sugar concentrations in pectins, hemicelluloses and callose, suggesting an enhanced capacity of binding Cd or blocking Cd translocation; 2) stimulated the deposition of Casparian strips (CS) in root endodermis and exodermis to block Cd translocation; 3) stimulated the release of C-O-C (-OH- or -O-) and CO (carboxyl, carbonyl, or amide) to combine Cd; 4) regulated differential expression genes (DEGs) and metabolites (DMs) correlated with synthesis and/or interactions of CWSs to affect cell wall net structure to affect root cell division, subsequent root morphology and finally elemental uptake; and 5) stimulated de-methylesterification of pectins via reducing expression abundances of many DMs and DEGs in the Yang Cycle to reduce supply of methyls to homogalacturonan, and regulated gene expressions of pectin methylesterase to release carboxyls to combine Cd; and 6) down-regulated gene expressions associated with Cd uptake/translocation.

Core/Shell PEGS/HA Hybrid Nanoparticle Via Micelle-Coordinated Mineralization for Tumor-Specific Therapy.

Nanomicelles, by virtue of their prominent biocompatibility, degradability, and ability to solubilize hydrophobic drugs, have been widely used as the most effective delivery platform for anticancer drugs. However, undesirable drug-loading capacity, unfeasible modification, poor in vivo stability, and intratumoral penetration remain to be addressed. Herein, we introduce a novel core/shell PEGylated poly(glycerol sebacate) (PEGS)/hydroxyapatite (HA) hybrid nanomicelle based on a unique triblock PEGS substrate with functional carboxyls in terminals and free hydroxyls as pendant groups. The hydrophobic doxorubicin (DOX) can be controllably encapsulated in the core of nanomicelles via hydrogen bonding, and ensuing in situ mineralization of HA occurs as a shell layer with the electrostatic effect between the carboxylate radical (COO-) and calcium ion (Ca2+). Through optimizing the coordination of PEGS nanomicelles and HA mineralization, 20-30 nm spherical nanoparticles can be formed with considerable drug loading (0.38 mg DOX/1 mg nanoparticles) and a sensitive pH-responsive release (about 50% release amount at pH 5.6 while <5% release amount at pH 7.4 in 24 h). In further in vitro studies, this PEGS/HA hybrid nanoparticle system exhibits excellent selective tumor inhibitory efficacy, while in in vivo studies, high efficacy of tumor suppression and low incidence of toxicity can be evidenced in a DOX-loaded PEGS/HA group (71.7% decrease in average tumor volume compared to a control group after 15 day hypodermic treatment). The core/shell PEGS/HA nanoparticle coordinated with PEGS nanomicelles and in situ HA mineralization represents high drug-loading capacity, multifunctional possibility, and tumor-selective and responsive release profiles and could offer a highly promising platform for tumor therapy in clinical application.

Localization and promotion of recombinant human bone morphogenetic protein-2 bioactivity on extracellular matrix mimetic chondroitin sulfate-functionalized calcium phosphate cement scaffolds.

Localization of recombinant human bone morphogenetic protein-2 (rhBMP-2) with continuous and effective osteogenic stimulation is still a great challenge in the field of bone regeneration. To achieve this aim, rhBMP-2 was tethered on chondroitin sulfate (CS)-functionalized calcium phosphate cement (CPC) scaffolds through specific noncovalent interactions. CS, one of the core glycosaminoglycans, was covalently conjugated onto CPC scaffolds with the assistance of polydopamine (PDA) and further immobilized rhBMP-2 in a biomimetic form. The CPC-PDA-CS scaffolds not only controlled the release kinetics and presentation state of rhBMP-2 but also effectively increased the expression levels of bone morphogenetic protein receptors (BMPRs) and enhanced the recognitions of the remaining rhBMP-2 to BMPRs. Strikingly, the rhBMP-2-loaded CPC-PDA-CS significantly promoted the cellular surface translocation of BMPRs (especially BMPR-IA). In vivo studies demonstrated that, compared with the rhBMP-2 upon CPC and CPC-PDA, the rhBMP-2 upon CPC-PDA-CS exhibited sustained release and induced high quality and more ectopic bone formation. Collectively, these results suggest that rhBMP-2 can be localized within CS-functionalized CPC scaffolds and exert continuous, long-term, and effective osteogenic stimulation. Thus, this work could provide new avenues in mimicking bone extracellular matrix microenvironment and localizing growth factor activity for enhanced bone regeneration. STATEMENT OF SIGNIFICANCE: A bioinspired chondroitin sulfate (CS)-functionalized calcium phosphate cement (CPC) platform was developed to tether recombinant human bone morphogenetic protein-2 (rhBMP-2), which could exhibit continuous, long-term, and effective osteogenic stimulation in bone tissue engineering. Compared with rhBMP-2-loaded CPC, the rhBMP-2-loaded CPC-polydopamine-CS scaffolds induced higher expression of bone morphogenetic protein receptors (BMPRs), greater cellular surface translocation of bone morphogenetic protein receptor-IA, higher binding affinity of BMPRs/rhBMP-2, and thus higher activation of the drosophila gene mothers against decapentaplegic protein-1/5/8 (Smad1/5/8) and extracellular-regulated protein kinases-1/2 (ERK1/2) signaling. This work can provide new guidelines for the design of BMP-2-based bioactive materials for bone regeneration.

Urethane-based low-temperature curing, highly-customized and multifunctional poly(glycerol sebacate)-co-poly(ethylene glycol) copolymers.

Poly (glycerol sebacate) (PGS), a tough elastomer, has been widely explored in tissue engineering due to the desirable mechanical properties and biocompatibility. However, the complex curing procedure (high temperature and vacuum) and limited hydrophilicity (∼90° of wetting angle) greatly impede its functionalities. To address these challenges, a urethane-based low-temperature setting, PEGylated PGS bioelastomer was developed with and without solvent. By simultaneously tailoring PEG and hexamethylene diisocyanate (HDI) contents, the elastomers X-P-mUs (X referred to the PEG content and m referred to HDI content) with a broad ranging mechanical properties and customized hydrophilicity were constructed. The X-P-mUs synthesized exhibited adjustable tensile Young's modulus, ultimate tensile strength and elongation at break in the range of 1.0 MPa-14.2 MPa, 0.3 MPa-7.6 MPa and 53.6%-272.8%, with the water contact angle varying from 28.6° to 71.5°, respectively. Accordingly, these elastomers showed favorable biocompatibility in vitro and mild host response in vivo. Furthermore, the potential applications of X-P-mU elastomers prepared with solvent-base and solvent-free techniques in biomedical fields were investigated. The results showed that these X-P-mU elastomers with high molding capacity at mild temperature could be easily fabricated into various shapes, used as reinforcement for fragile materials, and controllable delivery of drugs and proteins with excellent bioactivity, demonstrating that the X-P-mU elastomers could be tailored as potential building blocks for diverse applications in biomedical research. STATEMENT OF SIGNIFICANCE: Poly(glycerol sebacate) (PGS), a tough biodegradable elastomer, has received great attentions in biomedical field. But the complex curing procedure and limited hydrophilicity greatly hamper its functionality. Herein, a urethane-based low-temperature setting, PEGylated PGS (PEGS-U) bioelastomer with highly-customized mechanical properties, hydrophilicity and biodegradability was first explored. The synthesized PEGS-U showed favorable biocompatibility both in vitro and in vivo. Furthermore, the PEGS-U elastomer could be easily fabricated into various shapes, used as reinforcement for fragile materials, and controllable delivery of drugs and proteins with excellent bioactivity. This versatile, user-tunable bioelastomers should be a promising biomaterials for biomedical applications.