Reduced complexity for sound zones with subband block adaptive filters and a loudspeaker line array.

Sound zones are used to reproduce individual audio content to multiple people in a room using a set of loudspeakers with controllable input signals. To allow the reproduction of individual audio to dynamically change, e.g., due to moving listeners, changes in the number of listeners, or changing room transfer functions, an adaptive formulation is proposed. This formulation is based on frequency domain block adaptive filters and given room transfer functions. To reduce computational complexity, the system is extended to subband processing without cross-adaptive filters. The computational savings come from recognizing that sound zones consist of part-solutions which are inherently band limited, hence, several subbands can be ignored. To validate the theoretical findings, a 27-channel loudspeaker array was constructed, and measurements were performed in anechoic and reflective environments. The results show that the subband solution performs identically to a full-rate solution but at a reduced computational complexity.

Photo-cross-linked and pH-Switchable Soft Polymer Nanocapsules from Polyglycidyl Ethers.

Soft polymer nanocapsules and microgels, which can adapt their shape and, at the same time, sequester and release molecular payloads in response to an external trigger, are a challenging complement to vesicular structures like polymersomes. In this work, we report the synthesis of such capsules by photo-cross-linking of coumarin-substituted polyglycidyl ethers, which we prepared by Williamson etherification of epichlorohydrin (ECH) repeating units with 7-hydroxycoumarin in copolymers with tert-butyl glycidyl ether (tBGE). To control capsule size, we employed the prepolymers in an o/w miniemulsion, where they formed a gel layer at the interface upon irradiation at 365 nm by [2π + 2π] photodimerization of the coumarin groups. Upon irradiation at 254 nm, the reaction could be reversed and the gel wall could be repeatedly disintegrated and rebuilt. We further demonstrated (i) reversible hydrophilization of the gels by hydrolysis of the lactone rings in coumarin dimers as a mechanism to manipulate the permeability of the capsules and (ii) binding functional molecules as amides. Thus, the presented nanogels are remarkably versatile and can be further used as a carrier system.

Performance of low-frequency sound zones with very fast room impulse response measurements.

Sound zone methods aim to control the sound field produced by an array of loudspeakers to render a given audio content in specific areas while making it almost inaudible in others. At low frequencies, control filters are based on information of the electro-acoustical path between loudspeakers and listening areas, contained in the room impulse responses (RIRs). This information can be acquired wirelessly through ubiquitous networks of microphones. In that case and for real-time applications in general, short acquisition and processing times are critical. In addition, limiting the amount of data that should be retrieved and processed can also reduce computational demands. Furthermore, such a framework would enable fast adaptation of control filters in changing acoustic environments. This work explores reducing the amount of time and information required to compute control filters when rendering and updating low-frequency sound zones. Using real RIR measurements, it is demonstrated that in some standard acoustic rooms, acquisition times on the order of a few hundred milliseconds are sufficient for accurately rendering sound zones. Moreover, an additional amount of information can be removed from the acquired RIRs without degrading the performance.

Vascularized 3D Human Skin Models in the Forefront of Dermatological Research.

In vitro engineered skin models are emerging as an alternative platform to reduce and replace animal testing in dermatological research. Despite the progress made in recent years, considerable challenges still exist for the inclusion of diverse cell types within skin models. Blood vessels, in particular, are essential in maintaining tissue homeostasis and are one of many primary contributors to skin disease inception and progression. Substantial efforts in the past have allowed the successful fabrication of vascularized skin models that are currently utilized for disease modeling and drugs/cosmetics testing. This review first discusses the need for vascularization within tissue-engineered skin models, highlighting their role in skin grafting and disease pathophysiology. Second, the review spotlights the milestones and recent progress in the fabrication and utilization of vascularized skin models. Additionally, advances including the use of bioreactors, organ-on-a-chip devices, and organoid systems are briefly explored. Finally, the challenges and future outlook for vascularized skin models are addressed.

Peptide-Functionalized Electrospun Meshes for the Physiological Cultivation of Pulmonary Alveolar Capillary Barrier Models in a 3D-Printed Micro-Bioreactor.

In vitro environments that realize biomimetic scaffolds, cellular composition, physiological shear, and strain are integral to developing tissue models of organ-specific functions. In this study, an in vitro pulmonary alveolar capillary barrier model is developed that closely mimics physiological functions by combining a synthetic biofunctionalized nanofibrous membrane system with a novel three-dimensional (3D)-printed bioreactor. The fiber meshes are fabricated from a mixture of polycaprolactone (PCL), 6-armed star-shaped isocyanate-terminated poly(ethylene glycol) (sPEG-NCO), and Arg-Gly-Asp (RGD) peptides by a one-step electrospinning process that offers full control over the fiber surface chemistry. The tunable meshes are mounted within the bioreactor where they support the co-cultivation of pulmonary epithelial (NCI-H441) and endothelial (HPMEC) cell monolayers at air-liquid interface under controlled stimulation by fluid shear stress and cyclic distention. This stimulation, which closely mimics blood circulation and breathing motion, is observed to impact alveolar endothelial cytoskeleton arrangement and improve epithelial tight junction formation as well as surfactant protein B production compared to static models. The results highlight the potential of PCL-sPEG-NCO:RGD nanofibrous scaffolds in combination with a 3D-printed bioreactor system as a platform to reconstruct and enhance in vitro models to bear a close resemblance to in vivo tissues.

Topographical influence of electrospun basement membrane mimics on formation of cellular monolayer.

Functional unit of many organs like lung, kidney, intestine, and eye have their endothelial and epithelial monolayers physically separated by a specialized extracellular matrix called the basement membrane. The intricate and complex topography of this matrix influences cell function, behavior and overall homeostasis. In vitro barrier function replication of such organs requires mimicking of these native features on an artificial scaffold system. Apart from chemical and mechanical features, the choice of nano-scale topography of the artificial scaffold is integral, however its influence on monolayer barrier formation is unclear. Though studies have reported improved single cell adhesion and proliferation in presence of pores or pitted topology, corresponding influence on confluent monolayer formation is not well reported. In this work, basement membrane mimic with secondary topographical cues is developed and its influence on single cells and their monolayers is investigated. We show that single cells cultured on fibers with secondary cues form stronger focal adhesions and undergo increased proliferation. Counterintuitively, absence of secondary cues promoted stronger cell-cell interaction in endothelial monolayers and promoted formation of integral tight barriers in alveolar epithelial monolayers. Overall, this work highlights the importance of choice of scaffold topology to develop basement barrier function in in vitro models.

Mimicking the Natural Basement Membrane for Advanced Tissue Engineering.

Advancements in the field of tissue engineering have led to the elucidation of physical and chemical characteristics of physiological basement membranes (BM) as specialized forms of the extracellular matrix. Efforts to recapitulate the intricate structure and biological composition of the BM have encountered various advancements due to its impact on cell fate, function, and regulation. More attention has been paid to synthesizing biocompatible and biofunctional fibrillar scaffolds that closely mimic the natural BM. Specific modifications in biomimetic BM have paved the way for the development of in vitro models like alveolar-capillary barrier, airway models, skin, blood-brain barrier, kidney barrier, and metastatic models, which can be used for personalized drug screening, understanding physiological and pathological pathways, and tissue implants. In this Review, we focus on the structure, composition, and functions of in vivo BM and the ongoing efforts to mimic it synthetically. Light has been shed on the advantages and limitations of various forms of biomimetic BM scaffolds including porous polymeric membranes, hydrogels, and electrospun membranes This Review further elaborates and justifies the significance of BM mimics in tissue engineering, in particular in the development of in vitro organ model systems.

A facile method for grafting functional hydrogel films on PTFE, PVDF, and TPX polymers.

The use of polymeric materials in biomedical applications requires a judicious control of surface properties as they are directly related to cellular interactions and biocompatibility. The most desired chemical surface properties include hydrophilicity and the presence of functional groups for surface modification. In this work, we describe a method to graft a highly stable, ultra-thin, amine-functional hydrogel layer onto highly inert surfaces of poly(tetrafluoroethylene) (PTFE), poly(vinylidene fluoride) (PVDF), and poly(4-methyl-1-pentene) (PMP or TPX). Covalent grafting is realized with hydrophilic poly(vinylamine-co-acetamide)s by C-H insertion crosslinking (CHic) chemistry initiated by UV light. These polyvinylamides carry tetrafluorophenyl azide groups as photo or thermo activated binding sites and contain further free amine groups, which can be used to bind peptides such as biological ligands, polysaccharides, or other hydrogel layers. The covalently bound surface layers resist intensive Soxhlet extraction confirming the stability of the coating. Fluorescent staining verified the accessibility of free primary amine groups, which can be used for the functionalization of the surface with bioactive molecules. The coating demonstrates hydrophobic wetting behavior when conditioned in air and hydrophilic wetting behavior when conditioned in water showing the presence of loosely crosslinked polymer chains that can re-orient. We believe that the reported application of CHic for the surface modification of fluorinated polymers like PTFE and PVDF as well as TPX can form the basis for advanced biocompatible and biofunctional surface engineering.

Radiolabeled Nanocarriers as Theranostics-Advancement from Peptides to Nanocarriers.

Endogenous targeted radiotherapy is emerging as an integral modality to treat a variety of cancer entities. Nevertheless, despite the positive clinical outcome of the treatment using radiolabeled peptides, small molecules, antibodies, and nanobodies, a high degree of hepatotoxicity and nephrotoxicity still persist. This limits the amount of dose that can be injected. In an attempt to mitigate these side effects, the use of nanocarriers such as nanoparticles (NPs), dendrimers, micelles, liposomes, and nanogels (NGs) is currently being explored. Nanocarriers can prolong circulation time and tumor retention, maximize radiation dosage, and offer multifunctionality for different targeting strategies. In this review, the authors first provide a summary of radiation therapy and imaging and discuss the new radiotracers that are used preclinically and clinically. They then highlight and identify the advantages of radio-nanomedicine and its potential in overcoming the limitations of endogenous radiotherapy. Finally, the review points to the ongoing efforts to maximize the use of radio-nanomedicine for efficient clinical translation.

Tuning the Elasticity of Nanogels Improves Their Circulation Time by Evading Immune Cells.

Peptide receptor radionuclide therapy is used to treat solid tumors by locally delivering radiation. However, due to nephro- and hepato-toxicity, it is limited by its dosage. To amplify radiation damage to tumor cells, radiolabeled nanogels can be used. We show that by tuning the mechanical properties of nanogels significant enhancement in circulation half-life of the gel could be achieved. We demonstrate why and how small changes in the mechanical properties of the nanogels influence its cellular fate. Nanogels with a storage modulus of 37 kPa were minimally phagocytosed by monocytes and macrophages compared to nanogels with 93 kPa modulus. Using PET/CT a significant difference in the blood circulation time of the nanogels was shown. Computer simulations affirmed the results and predicted the mechanism of cellular uptake of the nanogels. Altogether, this work emphasizes the important role of elasticity even for particles that are inherently soft such as nano- or microgels.

Thiolactone-Functional Pullulan for In Situ Forming Biogels.

Gelation in the presence of cells with minimum cytotoxicity is highly desirable for materials with applications in tissue engineering. Herein, the naturally occurring polysaccharide pullulan is functionalized with thiolactones that undergo ring-opening addition of amines. As a result, the modified pullulan can be cross-linked with diamines and/or amine-containing biological substrates enhancing the system's versatility (e.g., gelatin and cell-binding ligands GHK/GRGDS). Thiolactone degrees of substitution of 2.5 or 5.0 mol % are achieved, and respective hydrogels exhibit mesh sizes of 27.8 to 49.1 nm. Cell proliferation studies on chosen gels (G' ≅ 500 Pa, over 14 days) demonstrate that for normal human dermal fibroblasts (NHDFs), both gelatin and GRGDS equally support cell proliferation, while in the case of hepatocytes (HepG2), the presence of GRGDS and GHK improve cell proliferation 10-fold compared to gelatin. Cells remain viable and in one instance were successfully encapsulated by in situ gelation, altogether confirming the mild and biocompatible nature of this strategy to produce biogels using biologically active substrates as cross-linkers.

Protease Responsive Nanogels for Transcytosis across the Blood-Brain Barrier and Intracellular Delivery of Radiopharmaceuticals to Brain Tumor Cells.

Despite profound advances in treatment approaches, gliomas remain associated with very poor prognoses. The residual cells after incomplete resection often migrate and proliferate giving a seed for highly resistant gliomas. The efficacy of chemotherapeutic drugs is often strongly limited by their poor selectivity and the blood brain barrier (BBB). Therefore, the development of therapeutic carrier systems for efficient transport across the BBB and selective delivery to tumor cells remains one of the most complex problems facing molecular medicine and nano-biotechnology. To address this challenge, a stimuli sensitive nanogel is synthesized using pre-polymer approach for the effective delivery of nano-irradiation. The nanogels are cross-linked via matrix metalloproteinase (MMP-2,9) substrate and armed with Auger electron emitting drug 5-[125 I]Iodo-4"-thio-2"-deoxyuridine ([125 I]ITdU) which after release can be incorporated into the DNA of tumor cells. Functionalization with diphtheria toxin receptor ligand allows nanogel transcytosis across the BBB at tumor site. Functionalized nanogels efficiently and increasingly explore transcytosis via BBB co-cultured with glioblastoma cells. The subsequent nanogel degradation correlates with up-regulated MMP2/9. Released [125 I]ITdU follows the thymidine salvage pathway ending in its incorporation into the DNA of tumor cells. With this concept, a highly efficient strategy for intracellular delivery of radiopharmaceuticals across the challenging BBB is presented.

Bottom-up assembly of biomedical relevant fully synthetic extracellular vesicles.

Extracellular vesicles (EVs) are fundamental for intercellular communication and influence nearly every process in cell physiology. However, because of their intricate molecular complexity, quantitative knowledge on their signaling mechanisms is missing, particularly impeding their therapeutic application. We used a complementary and quantitative engineering approach based on sequential synthetic bottom-up assembly of fully functional EVs with precisely controlled lipid, protein, and RNA composition. We show that the functionalities of synthetic EVs are analogous to natural EVs and demonstrate their programmable therapeutic administration for wound healing and neovascularization therapy. We apply transcriptome profiling to systematically decode synergistic effects between individual EV constituents, enabling analytical dissection and a fundamental understanding of EV signaling.

Microgel that swims to the beat of light.

Complementary to the quickly advancing understanding of the swimming of microorganisms, we demonstrate rather simple design principles for systems that can mimic swimming by body shape deformation. For this purpose, we developed a microswimmer that could be actuated and controlled by fast temperature changes through pulsed infrared light irradiation. The construction of the microswimmer has the following features: (i) it is a bilayer ribbon with a length of 80 or 120 [Formula: see text]m, consisting of a thermo-responsive hydrogel of poly-N-isopropylamide coated with a 2-nm layer of gold and equipped with homogeneously dispersed gold nanorods; (ii) the width of the ribbon is linearly tapered with a wider end of 5 [Formula: see text]m and a tip of 0.5 [Formula: see text]m; (iii) a thickness of only 1 and 2 [Formula: see text]m that ensures a maximum variation of the cross section of the ribbon along its length from square to rectangular. These wedge-shaped ribbons form conical helices when the hydrogel is swollen in cold water and extend to a filament-like object when the temperature is raised above the volume phase transition of the hydrogel at [Formula: see text]. The two ends of these ribbons undergo different but coupled modes of motion upon fast temperature cycling through plasmonic heating of the gel-objects from inside. Proper choice of the IR-light pulse sequence caused the ribbons to move at a rate of 6 body length/s (500 [Formula: see text]m/s) with the wider end ahead. Within the confinement of rectangular container of 30 [Formula: see text]m height and 300 [Formula: see text]m width, the different modes can be actuated in a way that the movement is directed by the energy input between spinning on the spot and fast forward locomotion.

Reconstruction of Ultra-thin Alveolar-capillary Basement Membrane Mimics.

Alveolar-capillary basement membrane (BM) is ultra-thin (<2 µm) extracellular matrix that maintains integral epithelial-endothelial cell layers. In vitro reconstructions of alveolar-capillary barrier supported on synthetic scaffolds closely resembling the fibrous and ultra-thin natural BM are essential in mimicking the lung pathophysiology. Although BM topology and dimensions are well known to significantly influence cellular behavior, conventionally used BM mimics fail to recreate this natural niche. To overcome this, electrospun ultra-thin 2 µm poly(caprolactone) (PCL) nanofibrous mesh is used to establish an alveolar-capillary barrier model of lung endothelial/epithelial cells. Transepithelial electrical resistance (TEER) and permeability studies reveal integral tight junctions and improved mass transport through the highly porous PCL meshes compared to conventional dense membranes with etched pores. The chemotaxis of neutrophils is shown across the barrier in presence of inflammatory response that is naturally impeded in confined regions. Conventional requirement of 3 µm or larger pore size can lead to barrier disruption due to epithelial/endothelial cell invasion. Despite high porosity, the interconnected BM mimic prevents barrier disruption and allows neutrophil transmigration, thereby demonstrating the physiological relevance of the thin nanofibrous meshes. It is envisioned that these bipolar cultured barriers would contribute to an organ-level in vitro model for pathological disease, environmental pollutants, and nanotoxicology.

A New Approach to Harness Probiotics Against Common Bacterial Skin Pathogens: Towards Living Antimicrobials.

In this study, the potential of certain lactic acid bacteria-classified as probiotics and known to be antimicrobially active against pathogens or food-poisoning microorganisms-was evaluated with respect to their activity against bacterial skin pathogens. The aim of the study was to develop a plaster/bandage for the application of inhibitory substances produced by these probiotics when applied to diseased skin. For this purpose, two Streptococcus salivarius strains and one Lactobacillus plantarum were tested for production of antimicrobials (bacteriocin-like substances) active against Gram-positive and Gram-negative pathogens using established methods. A newly designed membrane test ensured that the probiotics produce antimicrobials diffusible through membranes. Target organisms used were Cutibacterium acnes, Staphylococcus aureus, and Pseudomonas aeruginosa. Moreover, the L. plantarum 8P-A3 strain was tested against additional bacteria involved in skin disorders. The Lactobacillales used were active against all potential skin pathogens tested. These probiotics could be enclosed between polymer membranes-one tight, the other permeable for their products, preserved by vacuum drying, and reactivated after at least three months storage. Importantly, the reactivated pads containing the probiotics demonstrated antibacterial activity on agar plates against all pathogens tested. This suggests that the probiotic containing pads may be topically applied for the treatment of skin disorders without the need for a regular antibiotic treatment or as an adjunctive therapy.

Trypsin-Free Cultivation of 3D Mini-Tissues in an Adaptive Membrane Bioreactor.

The production of large scaffold-free tissues is a key challenge in regenerative medicine. Nowadays, temperature-responsive polymers allow intact tissue harvesting without needing proteolytic enzymes. This method is limited to tissue culture plastic with limited upscaling capacity and plain process control. Here, a thermoresponsive hollow fiber membrane bioreactor is presented to produce large scaffold-free tissues. Intact tissues, rich in cell-to-cell connections and ECM, are harvested from a poly(N-vinylcaprolactam) microgel functionalized poly(ether sulfone)/poly(vinylpyrrolidone) hollow fiber membrane by a temperature shift. The harvested 3D tissues adhere in successive cultivation and exhibit high vitality for several days. The facile adsorptive coating waives the need for extensive surface treatment. The research is anticipated to be a starting point for upscaling the production of interconnected tissues enabling new opportunities in regenerative medicine, large-scale drug screening on physiological relevant tissues, and potentially opening new chances in cell-based therapies.

Sound field reconstruction in rooms: Inpainting meets super-resolution.

In this paper, a deep-learning-based method for sound field reconstruction is proposed. The possibility to reconstruct the magnitude of the sound pressure in the frequency band 30-300 Hz for an entire room by using a very low number of irregularly distributed microphones arbitrarily arranged is shown. Moreover, the approach is agnostic to the location of the measurements in the Euclidean space. In particular, the presented approach uses a limited number of arbitrary discrete measurements of the magnitude of the sound field pressure in order to extrapolate this field to a higher-resolution grid of discrete points in space with a low computational complexity. The method is based on a U-net-like neural network with partial convolutions trained solely on simulated data, which itself is constructed from numerical simulations of Green's function across thousands of common rectangular rooms. Although extensible to three dimensions and different room shapes, the method focuses on reconstructing the two-dimensional plane of a rectangular room from measurements of the three-dimensional sound field. Experiments using simulated data together with an experimental validation in a real listening room are shown. The results suggest a performance which may exceed conventional reconstruction techniques for a low number of microphones and computational requirements.

Poly(vinylamine-co-N-isopropylacrylamide) linear polymer and hydrogels with tuned thermoresponsivity.

The fabrication of functional hydrogels with tuned thermoresponsivity is a major challenge. To meet this challenge we copolymerize N-isopropylacrylamide (NIPAm) with N-vinylformamide (NVF) in different ratios with the formamide group being subsequently selectively hydrolyzed to the corresponding amine (VAm). The copolymers are crosslinked with phenylcarbonate telechelic glycol. The influence of the NIPAm : VAm ratio on the thermoresponsitiviy is investigated in terms of absorbance, rheology, NMR spectroscopy, relaxometry, and diffusometry. Phase transition temperatures, change in the entropy of the polymer-water system, and width of the transition in the process of coil-to-globule and swollen-to-collapsed network transitions were evaluated by a two state model and Boltzmann sigmoidal function.

Nanovesicles displaying functional linear and branched oligomannose self-assembled from sequence-defined Janus glycodendrimers.

Cell surfaces are often decorated with glycoconjugates that contain linear and more complex symmetrically and asymmetrically branched carbohydrates essential for cellular recognition and communication processes. Mannose is one of the fundamental building blocks of glycans in many biological membranes. Moreover, oligomannoses are commonly found on the surface of pathogens such as bacteria and viruses as both glycolipids and glycoproteins. However, their mechanism of action is not well understood, even though this is of great potential interest for translational medicine. Sequence-defined amphiphilic Janus glycodendrimers containing simple mono- and disaccharides that mimic glycolipids are known to self-assemble into glycodendrimersomes, which in turn resemble the surface of a cell by encoding carbohydrate activity via supramolecular multivalency. The synthetic challenge of preparing Janus glycodendrimers containing more complex linear and branched glycans has so far prevented access to more realistic cell mimics. However, the present work reports the use of an isothiocyanate-amine "click"-like reaction between isothiocyanate-containing sequence-defined amphiphilic Janus dendrimers and either linear or branched oligosaccharides containing up to six monosaccharide units attached to a hydrophobic amino-pentyl linker, a construct not expected to assemble into glycodendrimersomes. Unexpectedly, these oligoMan-containing dendrimers, which have their hydrophobic linker connected via a thiourea group to the amphiphilic part of Janus glycodendrimers, self-organize into nanoscale glycodendrimersomes. Specifically, the mannose-binding lectins that best agglutinate glycodendrimersomes are those displaying hexamannose. Lamellar "raft-like" nanomorphologies on the surface of glycodendrimersomes, self-organized from these sequence-defined glycans, endow these membrane mimics with high biological activity.