pH-Responsive Polymeric Micelle Dynamic Complexes for Selective Killing of Helicobacter pylori.

Helicobacter pylori, the world's most common chronic infection-causing pathogen, is responsible for causing gastric ulcers, the fourth-leading cause of cancer-related death globally in 2020. In recent years, the effectiveness of the current treatment regimen (two antibiotics and one proton pump inhibitor) has often been plagued with problems such as resistance and the undesired elimination of commensal bacteria. Herein, we report the synthesis of block and random copolycarbonates, functionalized with cationic guanidinium and anionic acetate functional groups, aimed at selectively killing H. pylori in the acidic environment of the stomach, while remaining nontoxic to the commensal bacteria in the gut. The compositions of the polymers were fine-tuned so that the polymers were readily dispersed in water without any difficulty at both pH 3.0 and 7.4. The self-assembly behavior of the polymers at different pH values by dynamic light scattering showed that the random and block copolymers formed stable micelles in a simulated gastric environment (pH 3.0) while aggregated at pH 7.4. Both polymers demonstrated stronger antibacterial activity against H. pylori than the guanidinium-functionalized homopolymer without any acetate functional group at pH 3.0. The block copolymer was significantly more bactericidal at pH 3.0 across the concentrations tested, as compared to the random copolymer, while it did not show significant toxicity toward rat red blood cells (rRBCs) and HK-2 cells or bactericidal effect toward E. coli (a common gut bacterium) and nor caused aggregation of rRBCs at its effective concentration and at physiological pH of 7.4. Additionally, both the block and random copolymers were much more stable against hydrolysis at pH 3.0 than at pH 7.4. This study provides insight into the influence of both polymer architecture and dynamic assembly on the bioactivities of antimicrobial polymers, where the disassembly of coacervates into narrowly dispersed micelles at pH 3 make them potent antimicrobials aided by the protonated carboxylic acid block.

Engineering Themes in Plant Forms and Functions.

Living structures constantly interact with the biotic and abiotic environment by sensing and responding via specialized functional parts. In other words, biological bodies embody highly functional machines and actuators. What are the signatures of engineering mechanisms in biology? In this review, we connect the dots in the literature to seek engineering principles in plant structures. We identify three thematic motifs-bilayer actuator, slender-bodied functional surface, and self-similarity-and provide an overview of their structure-function relationships. Unlike human-engineered machines and actuators, biological counterparts may appear suboptimal in design, loosely complying with physical theories or engineering principles. We postulate what factors may influence the evolution of functional morphology and anatomy to dissect and comprehend better the why behind the biological forms.

Interpenetrating Polymer Network Hydrogels Formed Using Antibiotics as a Dynamic Crosslinker for Treatment of Infected Wounds.

Antibacterial hydrogels, particularly antibiotic-loaded hydrogels, are promising wound dressing materials for treatment of bacteria-infected wound. However, it is challenging to achieve sustained release of antibiotics from hydrogels through physical encapsulation of the antibiotics. Herein, an interpenetrating polymer network P(AA-co-HEMA)Gen hydrogel is reported with double crosslinking formed by free radical polymerization of 2-hydroxyethyl methacrylate (HEMA) and acrylic acid (AA), while using the antibiotic gentamicin (Gen) as the dynamic physical crosslinker. Gentamicin is incorporated into the hydrogel networks via electrostatic interaction between the carboxyl groups of poly(acrylic acid) and the amino groups of gentamicin, which leads to pH-responsive drug release and a significant increase in mechanical strength (i.e., elastic modulus, viscous modulus, and compressive modulus). More importantly, the hydrogels with optimal compositions demonstrate long-lasting antibacterial activity against both Gram-positive bacteria (Staphylococcus aureus) and Gram-negative bacteria (Escherichia coli) over 28 d. The in vivo studies that are conducted in an S. aureus-infected full-thickness skin wound model demonstrate that the double crosslinking hydrogels loaded with gentamicin eliminate bacteria in the wounds more effectively and significantly accelerate wound healing as compared to 3M dressing and the control without any treatment. Taken together, this antibiotic-loaded interpenetrating polymer network hydrogel is potentially a promising wound dressing material for the treatment of bacteria-infected wound.

Drug-free neutrally charged polypeptide nanoparticles as anticancer agents.

Cationic synthetic anticancer polymers and peptides have attracted increasing attention for advancing cancer treatment without causing drug resistance development. To circumvent in vivo instability and toxicity caused by cationic charges of the anticancer polymers/peptides, we report, for the first time, a nanoparticulate delivery system self-assembled from a negatively charged pH-sensitive polypeptide poly(ethylene glycol)-b-poly(ʟ-lysine)-graft-cyclohexene-1,2-dicarboxylic anhydride and a cationic anticancer polypeptide guanidinium-functionalized poly(ʟ-lysine) (PLL-Gua) via electrostatic interaction. The formation of nanoparticles (Gua-NPs) neutralized the positive charges of PLL-Gua. Both PLL-Gua and Gua-NPs killed cancer cells in a dose- and time-dependent manner, and induced cell death via apoptosis. Confocal microscopic studies demonstrated that PLL-Gua and Gua-NPs readily entered cancer cells, and Gua-NPs were taken up by the cells via endocytosis. Notably, Gua-NPs and PLL-Gua exhibited similar in vitro anticancer efficacy against MCF-7 and resistant MCF-7/ADR. PLL-Gua and Gua-NPs also induced similar morphological changes in MCF-7/ADR cells compared to MCF-7 cells, further indicating their ability to bypass drug resistance mechanisms in the MCF-7/ADR cells. More importantly, Gua-NPs with higher LD50 and enhanced tumor accumulation significantly inhibited tumor growth with negligible side effects in vivo. Our findings shed light on the in vivo delivery of anticancer peptides and opened a new avenue for cancer treatment.

Topology Optimisation for Compliant Hip Implant Design and Reduced Strain Shielding.

Stiff total hip arthroplasty implants can lead to strain shielding, bone loss and complex revision surgery. The aim of this study was to develop topology optimisation techniques for more compliant hip implant design. The Solid Isotropic Material with Penalisation (SIMP) method was adapted, and two hip stems were designed and additive manufactured: (1) a stem based on a stochastic porous structure, and (2) a selectively hollowed approach. Finite element analyses and experimental measurements were conducted to measure stem stiffness and predict the reduction in stress shielding. The selectively hollowed implant increased peri-implanted femur surface strains by up to 25 percentage points compared to a solid implant without compromising predicted strength. Despite the stark differences in design, the experimentally measured stiffness results were near identical for the two optimised stems, with 39% and 40% reductions in the equivalent stiffness for the porous and selectively hollowed implants, respectively, compared to the solid implant. The selectively hollowed implant's internal structure had a striking resemblance to the trabecular bone structures found in the femur, hinting at intrinsic congruency between nature's design process and topology optimisation. The developed topology optimisation process enables compliant hip implant design for more natural load transfer, reduced strain shielding and improved implant survivorship.