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Bacterial biofilms are a major healthcare concern resulting in refractory conditions such as chronic wounds, implant infections and failure, and multidrug-resistant infections. Aggressive and invasive strategies are employed to cure biofilm infections but are prone to long and expensive treatments, adverse side-effects, and low patient compliance. Recent strategies such as ultrasound-based therapies and antimicrobial nanomaterials have shown some promise in the effective eradication of biofilms. However, maximizing therapeutic effect while minimizing healthy tissue damage is a key challenge that needs to be addressed. Here a combination treatment involving ultrasound and antimicrobial polymeric nanoparticles (PNPs) that synergistically eradicate bacterial biofilms is reported. Ultrasound treatment rapidly disrupts biofilms and increases penetration of antimicrobial PNPs thereby enhancing their antimicrobial activity. This results in superior biofilm toxicity, while allowing for a two- to sixfold reduction in both the concentration of PNPs as well as the duration of ultrasound. Furthermore, that this reduction minimizes cytotoxicity toward fibroblast cells, while resulting in a 100- to 1000-fold reduction in bacterial concentration, is demonstrated., (© 2022 Wiley-VCH GmbH.)

Diabetic foot ulcers (DFUs) are chronic wounds, with 20% of cases resulting in amputation, despite intervention. A recently approved tissue engineering product-a cell-free collagen-glycosaminoglycan (GAG) scaffold-demonstrates 50% success, motivating its functionalization with extracellular matrix (ECM). Induced pluripotent stem cell (iPSC) technology reprograms somatic cells into an embryonic-like state. Recent findings describe how iPSCs-derived fibroblasts ("post-iPSF") are proangiogenic, produce more ECM than their somatic precursors ("pre-iPSF"), and their ECM has characteristics of foetal ECM (a wound regeneration advantage, as fetuses heal scar-free). ECM production is 45% higher from post-iPSF and has favorable components (e.g., Collagen I and III, and fibronectin). Herein, a freeze-dried scaffold using ECM grown by post-iPSF cells (Post-iPSF Coll) is developed and tested vs precursors ECM-activated scaffolds (Pre-iPSF Coll). When seeded with healthy or DFU fibroblasts, both ECM-derived scaffolds have more diverse ECM and more robust immune responses to cues. Post-iPSF-Coll had higher GAG, higher cell content, higher Vascular Endothelial Growth Factor (VEGF) in DFUs, and higher Interleukin-1-receptor antagonist (IL-1ra) vs. pre-iPSF Coll. This work constitutes the first step in exploiting ECM from iPSF for tissue engineering scaffolds., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Extracellular vesicles (EVs) are emerging as a promising alternative approach to cell-therapies. However, to realize the potential of these nanoparticles as new regenerative tools, healthcare materials that address the current limitations of systemic administration need to be developed. Here, two technologies for controlling the structure of alginate based microgel suspensions are used to develop sustained local release of EVs, in vitro. Microparticles formed using a shearing technique are compared to those manufactured using vibrational technology, resulting in either anisotropic sheet-like or spheroid particles, respectively. EVs harvested from preosteoblasts are isolated using differential ultracentrifugation and successfully loaded into the two systems, while maintaining their structures. Promisingly, in addition to exhibiting even EV distribution and high stability, controlled release of vesicles from both structures is exhibited, in vitro, over the 12 days studied. Interestingly, a significantly greater number of EVs are released from the suspensions formed by shearing (69.9 ± 10.5%), compared to the spheroids (35.1 ± 7.6%). Ultimately, alterations to the hydrogel physical structures have shown to tailor nanoparticle release while simultaneously providing ideal material characteristics for clinical injection. Thus, the sustained release mechanisms achieved through manipulating the formation of such biomaterials provide a key to unlocking the therapeutic potential held within EVs., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Mutation of Dedicator of cytokinesis 8 (DOCK8) has previously been reported to provide resistance to the Th17 cell dependent EAE in mice. Contrary to expectation, we observed an elevation of Th17 cells in two different DOCK8 mutant mouse strains in the steady state. This was specific for Th17 cells with no change in Th1 or Th2 cell populations. In vitro Th cell differentiation assays revealed that the elevated Th17 cell population was not due to a T cell intrinsic differentiation bias. Challenging these mutant mice in the EAE model, we confirmed a resistance to this autoimmune disease with Th17 cells remaining elevated systemically while cellular infiltration in the CNS was reduced. Infiltrating T cells lost the bias toward Th17 cells indicating a relative reduction of Th17 cells in the CNS and a Th17 cell specific migration disadvantage. Adoptive transfers of Th1 and Th17 cells in EAE-affected mice further supported the Th17 cell-specific migration defect, however, DOCK8-deficient Th17 cells expressed normal Th17 cell-specific CCR6 levels and migrated toward chemokine gradients in transwell assays. This study shows that resistance to EAE in DOCK8 mutant mice is achieved despite a systemic Th17 bias., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Electroconductive substrates are emerging as promising functional materials for biomedical applications. Here, the development of biohybrids of collagen and pristine graphene that effectively harness both the biofunctionality of the protein component and the increased stiffness and enhanced electrical conductivity (matching native cardiac tissue) obtainable with pristine graphene is reported. As well as improving substrate physical properties, the addition of pristine graphene also enhances human cardiac fibroblast growth while simultaneously inhibiting bacterial attachment (Staphylococcus aureus). When embryonic-stem-cell-derived cardiomyocytes (ESC-CMs) are cultured on the substrates, biohybrids containing 32 wt% graphene significantly increase metabolic activity and cross-striated sarcomeric structures, indicative of the improved substrate suitability. By then applying electrical stimulation to these conductive biohybrid substrates, an enhancement of the alignment and maturation of the ESC-CMs is achieved. While this in vitro work has clearly shown the potential of these materials to be translated for cardiac applications, it is proposed that these graphene-based biohybrid platforms have potential for a myriad of other applications-particularly in electrically sensitive tissues, such as neural and neural and musculoskeletal tissues., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

DNA origami is a DNA-based nanotechnology that utilizes programmed combinations of short complementary oligonucleotides to fold a large single strand of DNA into precise 2D and 3D shapes. The exquisite nanoscale shape control of this inherently biocompatible material is combined with the potential to spatially address the origami structures with diverse cargoes including drugs, antibodies, nucleic acid sequences, small molecules, and inorganic particles. This programmable flexibility enables the fabrication of precise nanoscale devices that have already shown great potential for biomedical applications such as: drug delivery, biosensing, and synthetic nanopore formation. Here, the advances in the DNA-origami field since its inception several years ago are reviewed with a focus on how these DNA-nanodevices can be designed to interact with cells to direct or probe their behavior., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Natural biological processes are intricately controlled by the timing and spatial distribution of various cues. To mimic this precise level of control, the physical sizes of gold nanoparticles are utilized to sterically entrap them in hydrogel materials, where they are subsequently released only in response to ultrasound. These nanoparticles can transport bioactive factors to cells and direct cell behavior on-demand., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)