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• Prebiotic chemistry inspired polymer (AMNT30) was applied to develop antimicrobial media. • AMNT30 coating took place at room temperature via spontaneous polymerization. • AMNT30 coated zeolite enabled enhanced loading of silver and copper on the surface. • Excellent disinfection by silver coated materials lasted up to 100 pore volumes at high flow rates. • Metal leaching from the media was stabilized with AMNT30 at different water qualities. Greywater and stormwater have received significant attention due to increasing water scarcity. Passive filtration such as biofiltration has been a popular treatment method with its low energy input and environmental friendliness. However, pathogen removal capacity needs improvement to achieve safe water quality. In this study, a prebiotic chemistry inspired copolymer based on aminomalononitrile and 3,4,5-trihydroxybenzaldehyde (AMNT30) was introduced to develop antimicrobial media for passive filtration. The AMNT30 polymer provided an adhesive coating on zeolite substrates following a spontaneous polymerisation process at room temperature. AMNT30 coated media were investigated for metal loading capacity, surface morphology, E. coli removal and metal leaching after filtration of different water sources (i.e. stormwater, greywater, and deionised water) at low/high conductivity. The coating enhanced metal ion loading on the surface and demonstrated that >8 log reduction of E. coli can be achieved for silver loaded materials compared to a 1 log reduction for copper loaded materials. The coating also increased the stability of the metals on the media irrespective of inflow characteristics. This study provided the first example using AMNT30 to create antimicrobial water purification media. It is expected that this technology will find applications in the water treatment industry. [ABSTRACT FROM AUTHOR]

Implantable electrodes have been utilized for decades to stimulate, sense, or monitor a broad range of biological processes, with examples ranging from glucose monitoring devices to cochlear implants. While the underlying science related to the application of electrodes is a mature field, preclinical and clinical studies have demonstrated that there are still significant challenges in vivo associated with a lack of control over tissue-material interfacial interactions, especially over longer time frames. Herein we discuss the current challenges and opportunities for implantable electrodes and the associated bioelectronic interfaces across the clinical landscape with a focus on emerging technologies and the obstacles of biofouling, microbial colonization, and the foreign body response. Overcoming these challenges is predicted to open the door for a new generation of implantable medical devices and significant associated clinical impact. STATEMENT OF SIGNIFICANCE: Implantable electrodes have been utilised for decades to stimulate, sense, or monitor a broad range of biological processes, with examples ranging from glucose monitoring devices to cochlear implants. Next-generation bioelectronic implantable medical devices promise an explosion of new applications that have until this point in time been impossible to achieve. However, there are several persistent biological challenges hindering the realisation of these new applications. We present a clinical perspective on how these biological challenges have shaped the device market and clinical trial landscape. Specifically, we present statistical breakdowns of current device applications and discuss biofouling, the foreign body response, and microbial colonisation as the main factors that need to be addressed before a new generation of devices can be explored., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Scaffolds for bone defect treatment should ideally support vascularization and promote bone formation, to facilitate the translation into biomedical device applications. This study presents a novel approach utilizing 3D-printed water-dissolvable polyvinyl alcohol (PVA) sacrificial molds to engineer polymerized High Internal Phase Emulsion (polyHIPE) scaffolds with microchannels and distinct multiscale porosity. Two sacrificial mold variants (250 µm and 500 µm) were generated using fused deposition modeling, filled with HIPE, and subsequently dissolved to create polyHIPE scaffolds containing microchannels. In vitro assessments demonstrated significant enhancement in cell infiltration, proliferation, and osteogenic differentiation, underscoring the favorable impact of microchannels on cell behavior. High loading efficiency and controlled release of the osteogenic factor BMP-2 were achieved, with microchannels facilitating release of the growth factor. Evaluation in a mouse critical-size calvarial defect model revealed enhanced vascularization and bone formation in microchanneled scaffolds containing BMP-2. This study not only introduces an accessible method for creating multiscale porosity in polyHIPE scaffolds but also emphasizes its capability to enhance cellular infiltration, controlled growth factor release, and in vivo performance. The findings suggest promising applications in bone tissue engineering and regenerative medicine, and are expected to facilitate the translation of this type of biomaterial scaffold. STATEMENT OF SIGNIFICANCE: This study holds significance in the realm of biomaterial scaffold design for bone tissue engineering and regeneration. We demonstrate a novel method to introduce controlled multiscale porosity and microchannels into polyHIPE scaffolds, by utilizing 3D-printed water-dissolvable PVA molds. The strategy offers new possibilities for improving cellular infiltration, achieving controlled release of growth factors, and enhancing vascularization and bone formation outcomes. This microchannel approach not only marks a substantial stride in scaffold design but also demonstrates its tangible impact on enhancing osteogenic cell differentiation and fostering robust bone formation in vivo. The findings emphasize the potential of this methodology for bone regeneration applications, showcasing an interesting advancement in the quest for effective and innovative biomaterial scaffolds to regenerate bone defects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The role of frequently touched surfaces in the transmission of infectious diseases is well-documented, and the urgent need for effective surface technologies with antipathogen activity has been highlighted by the recent global pandemic and rise in antimicrobial resistance. Here, we have explored combinations of up to 3 different classes of compounds within a polymeric matrix to enable the fabrication of coatings with broad-spectrum activity. Compounds were either based on metals or metal oxides, namely, copper, silver, and copper oxide, essential oils, namely, cinnamaldehyde, tea tree oil, and carvacrol oil, or cationic polymers, namely, poly(ε-lysine) and poly(hexamethylene biguanide). These compounds were mixed into a polymer matrix, coated, and dried to yield durable coatings. Coatings containing up to 7.5% (w/w) of the compounds were assessed in the zone of inhibition and biofilm assays using Staphylococcus aureus and Pseudomonas aeruginosa , as well as infectivity assays using human coronavirus OC43. Our data demonstrate that a selected combination of additives was able to provide a 5-log reduction in the colony-forming units of both bacteria and a 4-log reduction in viral infectivity. This simple but highly effective technology is expected to find applications in environments such as hospitals, aged care facilities, or public transport., Competing Interests: The authors declare the following competing financial interest(s): The authors declare the following competing interest: Vishek Batra, Ghian Tjandaputra and Tony Tan have a financial interest in Coatd Pty Ltd, which is seeking to commercialize anti-pathogen surface technologies., (© 2024 The Authors. Published by American Chemical Society.)

Surface coating technology is broadly demanded across various fields, including marine and biomedical materials; therefore, a facile and versatile approach is desired. This study proposed an attractive surface coating strategy using photo-crosslinkable benzophenone (BP) moiety for biomaterials application. BP-containing "bioglue" polymer can effectively crosslink with all kinds of surfaces and biomolecules. Upon exposure to ultraviolet (UV) light, free radical reaction from the BP glue facilitates the immobilization of diverse molecules onto different substrates in a straightforward and user-friendly manner. Through either one-step, mixing the bioglue with targeted biomolecules, or two-step methods, pre-coating the bioglue and then adding targeted biomolecules, polyacrylic acid (PAA), cyclic RGD-containing peptides, and proteins (gelatin, collagen, and fibronectin) were successfully immobilized on substrates. After drying the bioglue, targeted biomolecules can still be immobilized on the surfaces preserving their bioactivity. Cell culture on biomolecule-immobilized surfaces using NIH 3T3 fibroblasts and human bone marrow stem cells (hBMSCs) showed significant improvement of cell adhesion and activity compared to the unmodified control in serum-free media after 24 hours. Furthermore, hBMSCs on the fibronectin-immobilized surface showed an increased calcium deposition after 21 days of osteogenic differentiation, suggesting that the immobilized fibronectin is highly bioactive. Given the straightforward protocol and substrate-independent bioglue, the proposed coating strategy is promising in broad-range fields., Competing Interests: The authors declare no competing interests., (This journal is © The Royal Society of Chemistry.)

Urinary catheters and other medical devices associated with the urinary tract such as stents are major contributors to nosocomial urinary tract infections (UTIs) as they provide an access path for pathogens to enter the bladder. Considering that catheter-associated urinary tract infections (CAUTIs) account for approximately 75% of UTIs and that UTIs represent the most common type of healthcare-associated infections, novel anti-infective device technologies are urgently required. The rapid rise of antimicrobial resistance in the context of CAUTIs further highlights the importance of such preventative strategies. In this review, the risk factors for pathogen colonization in the urinary tract are dissected, taking into account the nature and mechanistics of this unique environment. Moreover, the most promising next-generation preventative strategies are critically assessed, focusing in particular on anti-infective surface coatings. Finally, emerging approaches in this field and their likely clinical impact are examined., (© 2023 The Authors. Journal of Biomedical Materials Research Part A published by Wiley Periodicals LLC.)

The development of simple, cost-effective, rapid, and quantitative diagnostic tools remains critical to monitor infectious COVID-19 disease. Although numerous diagnostic platforms, including rapid antigen tests, are developed and used, they suffer from limited accuracy, especially when tested with asymptomatic patients. Here, a unique approach to fabricate a nanochannel-based electrochemical biosensor that can detect the entire virion instead of virus fragments, is demonstrated. The sensing platform has uniform nanoscale channels created by the convective assembly of polystyrene (PS) beads on gold electrodes. The PS beads are then functionalized with bioreceptors while the gold surface is endowed with anti-fouling properties. When added to the biosensor, SARS-CoV-2 virus particles block the nanochannels by specific binding to the bioreceptors. The nanochannel blockage hinders the diffusion of a redox probe; and thus, allows quantification of the viral load by measuring the changes in the oxidation current before and after virus incubation. The biosensor shows a low limit of detection of ≈1.0 viral particle mL -1 with a wide detection range up to 10 8 particles mL -1 in cell culture media. Moreover, the biosensor is able to differentiate saliva samples with SARS-CoV-2 from those without, demonstrating the potential of this technology for translation into a point-of-care biosensor product., (© 2022 The Authors. Small published by Wiley-VCH GmbH.)

Microgels are microscale particles of hydrogel that can be laden with cells and used to create macroporous tissue constructs. Their ability to support cell-ECM and cell-cell interactions, along with the high levels of nutrient and metabolite exchange facilitated by their high surface area-to-volume ratio, means that they are attracting increasing attention for a variety of tissue regeneration applications. Here, we present methods for fabricating and modifying the structure of microfluidic devices using commonly available laboratory consumables including pipet tips and PTFE and silicon tubing to produce microgels. Different microfluidic devices realized the controlled generation of a wide size range (130-800 μm) of microgels for cell encapsulation. Subsequently, we describe the process of encapsulating mesenchymal stromal cells in microgels formed by photo-cross-linking of gelatin-norbornene and PEG dithiol. The introduced pipet-based chip offers simplicity, tunability, and versatility, making it easily assembled in most laboratories to effectively produce cell-laden microgels for various applications in tissue engineering.

Purpose: The Lumi-Solve photo-angioplasty drug eluting balloon catheter (DEBc) may afford safety advantages over current DEBc. Lumi-Solve utilises the guidewire (GW) port and lumen to deliver fibre-optic UV365nm light to the angioplasty balloon which may be problematic. We explore and evaluate alternative Lumi-Solve design options to circumvent fibre-optic use of the GW port and lumen which may enhance efficacy and clinical utility., Methods: Effects of guidewire shadowing (GWS) on visible and UV365nm light transmission were evaluated and modelled in-silico. To evaluate the effect of a dedicated intra-balloon fibre-optic port, modified angioplasty balloons and sections of translucent polyethylene terephthalate (PET) GW port tubing were utilised. Investigation of the effect of GWS on chemical and biological photo-activation of balloon surface drug was performed utilising LCMS analysis and inhibition of histone deacetylase activity (HDACi) was measured in human umbilical vein endothelial cells (HUVEC)., Results: Parallel fibre-optic and GW port configurations generated a GWS of approximately 18.0% of the evaluable balloon surface area and attenuated both visible and UV light intensity by 20.0-25.0% and reduced chemical photo-activation of balloon surface drug and HDACi by at least 40-45%. Alternative fibre-optic port configurations including a spiral design significantly mitigated GWS effects on UV light transmission., Conclusions: To avoid use of the GW port and its associated complications a dedicated third port and lumen for the Lumi-Solve fibre-optic may be required. To maximize balloon surface chemical and biological photo-activation, non-parallel, intra-balloon, fibre-optic lumen trajectories, including a spiral design may be useful., (© 2023. The Author(s).)

Microfluidic technology is applied across various research areas including organ-on-chip (OOC) systems. The main material used for microfluidics is polydimethylsiloxane (PDMS), a silicone elastomer material that is biocompatible, transparent, and easy to use for OOC systems with well-defined microstructures. However, PDMS-based OOC systems can absorb hydrophobic and small molecules, making it difficult and erroneous to make quantitative analytical assessments for such compounds. In this paper, we explore the use of a synthetic fluoropolymer, poly(4,5-difluoro-2,2-bis(trifluoromethyl)-1,3-dioxole- co -tetrafluoroethylene) (Teflon™ AF 2400), with excellent "non-stick" properties to functionalize OOC systems. Cannabinoids, including cannabidiol (CBD), are classes of hydrophobic compounds with a great potential for the treatment of anxiety, depression, pain, and cancer. By using CBD as a testing compound, we examined and systematically quantified CBD absorption into PDMS by means of an LC-MS/MS analysis. In comparison to the unmodified PDMS microchannels, an increase of approximately 30× in the CBD signal was detected with the fluoropolymer surface modification after 3 h of static incubation. Under perfusion conditions, we observed an increase of nearly 15× in the CBD signals from the surface-modified microchannels than from the unmodified microchannels. Furthermore, we also demonstrated that fluoropolymer-modified microchannels are compatible for culturing hCMEC/D3 endothelial cells and for CBD perfusion experiments.

The advancement of nanofabrication technologies has transformed the landscape of engineered nano-bio interfaces, especially with vertically aligned nanoneedles (NNs). This enables scientists to venture into new territories, widening NN applications into increasingly more complex cellular manipulation and interrogation. Specifically, for intracellular delivery application, NNs have been shown to mediate the delivery of various bioactive cargos into a wide range of cells-a physical method termed "nanoinjection". Silicon (Si) nanostructures demonstrated great potential in nanoinjection, whereas the use of polymeric NNs for nanoinjection has rarely been explored. Furthermore, the underlying mechanism of interaction at the cell-NN interface is subtle and multifaceted, and not fully understood-underpinned by the design versatility of the NN biointerface. Recent studies have suggested that actin dynamic plays a pivotal role influencing the delivery efficacy. In this study, we fabricated a new class of NNs-a programmable polymeric nanotubes (NTs)-from polystyrene (PS) cell cultureware, designed to facilitate mRNA delivery into mouse embryonic fibroblast GPE86 cells. The PSNT delivery platform was able to mediate mRNA delivery with high delivery efficiency (∼83%). We also investigated the role of actin cytoskeleton in PSNTs mediated intracellular delivery by introducing two actin inhibitors-cytochalasin D (Cyto D) and jasplakinolide (Jas)-to cause dysfunctional cytoskeleton, via inhibiting actin polymerization and depolymerization, respectively (before and after the establishment of cell-PSNT interface). By inhibiting actin dynamics 12 h before cell-PSNT interfacing (pre-interface treatment), the mRNA delivery efficiencies were significantly reduced to ∼3% for Cyto D-treated samples and ∼1% for Jas-treated sample, as compared to their post-interface (2 h after cell-PSNT interfacing) counterpart (∼46% and ∼68%, respectively). The added flexibility of PSNTs have shown to help withstand mechanical breakage stemming from cytoskeletal forces in contrast to the SiNTs. Such findings will step-change our capacity to use programmable polymeric NTs in fundamental cellular processes related to intracellular delivery.

Objectives: Driveline infections are a major complication of ventricular assist device (VAD) therapy. A newly introduced Carbothane driveline has preliminarily demonstrated anti-infective potential against driveline infections. This study aimed to comprehensively assess the anti-biofilm capability of the Carbothane driveline and explore its physicochemical characteristics., Methods: We assessed the Carbothane driveline against biofilm formation of leading microorganisms causing VAD driveline infections, including Staphylococcus aureus , Staphylococcus epidermidis , Pseudomonas aeruginosa and Candida albicans , using novel in vitro biofilm assays mimicking different infection micro-environments. The importance of physicochemical properties of the Carbothane driveline in microorganism-device interactions were analyzed, particularly focusing on the surface chemistry. The role of micro-gaps in driveline tunnels on biofilm migration was also examined., Results: All organisms were able to attach to the smooth and velour sections of the Carbothane driveline. Early microbial adherence, at least for S. aureus and S. epidermidis , did not proceed to the formation of mature biofilms in a drip-flow biofilm reactor mimicking the driveline exit site environment. The presence of a driveline tunnel however, promoted staphylococcal biofilm formation on the Carbothane driveline. Physicochemical analysis of the Carbothane driveline revealed surface characteristics that may have contributed to its anti-biofilm activity, such as the aliphatic nature of its surface. The presence of micro-gaps in the tunnel facilitated biofilm migration of the studied bacterial species., Conclusion: This study provides experimental evidence to support the anti-biofilm activity of the Carbothane driveline and uncovered specific physicochemical features that may explain its ability to inhibit biofilm formation., Competing Interests: Dr. Yue Qu, Prof. David McGiffin, Dr. Helmut Thissen, and Prof. Anton Peleg received a Medtronic External Research Program that financially supported this study. Medtronic played no direct role in the design of the study, interpretation of the results, and writing-up the manuscript. Prof. David McGiffin is a proctor for Abbott-implantation of HeartMate III ventricular assist device., (© 2023 The Authors.)

A variant of the cold spray (CS) technique was applied for the functionalization of polymer-based materials such as polydimethylsiloxane (PDMS) to improve the extent of mammalian cell interactions with these substrates. This was demonstrated by the embedment of porous titanium (pTi) into PDMS substrates using a single-step CS technique. CS processing parameters such as gas pressure and temperature were optimized to achieve the mechanical interlocking of pTi in the compressed PDMS to fabricate a unique hierarchical morphology possessing micro-roughness. As evidenced by the preserved porous structure, the pTi particles did not undergo any significant plastic deformation upon impact with the polymer substrate. The thickness of the particle embedment layer was determined, by cross-sectional analysis, ranging from 120 μm to over 200 μm. The behavior of osteoblast-like cells MG63 coming into contact with the pTi-embedded PDMS was examined. The results showed that the pTi-embedded PDMS samples promoted 80-96% of cell adhesion and proliferation during the early stages of incubation. The low cytotoxicity of the pTi-embedded PDMS was confirmed, with cell viability of the MG63 cells being above 90%. Furthermore, the pTi-embedded PDMS facilitated the production of alkaline phosphatase and calcium deposition in the MG63 cells, as demonstrated by the higher amount of alkaline phosphatase (2.6 times) and calcium (10.6 times) on the pTi-embedded PDMS sample fabricated at 250 °C, 3 MPa. Overall, the work demonstrated that the CS process provided flexibility in the parameters used for the production of the modified PDMS substrates and is highly efficient for the fabrication of coated polymer products. The results obtained in this study suggest that a tailorable porous and rough architecture could be achieved that promoted osteoblast function, indicating that the method has promise in the design of titanium-polymer composite materials applied to biomaterials used in musculoskeletal applications.

An approach to differentially modify the internal surface of porous silicon nanoparticles (pSiNPs) with hydrophobic dodecene and the external surface with antifouling poly- N -(2-hydroxypropyl) acrylamide (polyHPAm) as well as a cell-targeting peptide was developed. Specifically, to generate these core-shell pSiNPs, the interior surface of a porous silicon (pSi) film was hydrosilylated with 1-dodecene, followed by ultrasonication to create pSiNPs. The new external surfaces were modified by silanization with a polymerization initiator, and surface-initiated atom transfer radical polymerization was performed to introduce polyHPAm brushes. Afterward, a fraction of the polymer side chain hydroxyl groups was activated to conjugate cRGDfK─a peptide with a high affinity and selectivity for the α ν β 3 integrin receptor that is overexpressed in prostate and melanoma cancers. Finally, camptothecin, a hydrophobic anti-cancer drug, was successfully loaded into the pores. This drug delivery system showed excellent colloidal stability in a cell culture medium, and the in vitro drug release kinetics could be fine-tuned by the combination of internal and external surface modifications. In vitro studies by confocal microscopy and flow cytometry revealed improved cellular association attributed to cRGDfK. Furthermore, the cell viability results showed that the drug-loaded and peptide-functionalized nanoparticles had enhanced cytotoxicity toward a C4-2B prostate carcinoma cell line in both 2D cell culture and a 3D spheroid model.

Loss of effective antibiotics through antimicrobial resistance (AMR) is one of the greatest threats to human health. By 2050, the annual death rate resulting from AMR infections is predicted to have climbed from 1.27 million per annum in 2019, up to 10 million per annum. It is therefore imperative to preserve the effectiveness of both existing and future antibiotics, such that they continue to save lives. One way to conserve the use of existing antibiotics and build further contingency against resistant strains is to develop alternatives. Non-biological complex drugs (NBCDs) are an emerging class of therapeutics that show multi-mechanistic antimicrobial activity and hold great promise as next generation antimicrobial agents. We critically outline the focal advancements for each key material class, including antimicrobial polymer materials, carbon nanomaterials, and inorganic nanomaterials, and highlight the potential for the development of antimicrobial resistance against each class. Finally, we outline remaining challenges for their clinical translation, including the need for specific regulatory pathways to be established in order to allow for more efficient clinical approval and adoption of these new technologies.

We report a next-generation, biocide-free, and durable marine antifouling coating technology. To achieve this, we combined two different polymers previously developed by us. First, we synthesized well-defined 2-hydroxypropyl acrylamide (HPA) based bottlebrush polymers with concentrated polymer brush (CPB) structures, which exhibit excellent bioinertness, and second, we synthesized photoreactive copolymers of 2-hydroxypropyl acrylamide (HPA) and N -benzophenone acrylamide (BPA), which can be cross-linked by exposure to sunlight for 30 min. Simply mixing the bottlebrush polymers with the photoreactive copolymers and applying these as a coating provided a scalable method for achieving effective antifouling properties in one step on a broad range of polymer substrate materials. The resistance of bottlebrushes against acid and base hydrolysis was demonstrated in accelerated degradation experiments at 80 °C, and the coating thickness was found to be stable after 3 months of incubation in sea water. Optimized coatings prevented cypris larva attachment for up to 9 days and prevented the settling of marine organisms in the sea for up to 73 days. Due to the ease of application, long-term durability, and effective antifouling performance, our bottlebrush coating technology is expected to be exploited in biocide-free marine paints.

Porous silicon nanoparticles (pSiNPs) are widely utilized as drug carriers due to their excellent biocompatibility, large surface area, and versatile surface chemistry. However, the dispersion in pore size and biodegradability of pSiNPs arguably have hindered the application of pSiNPs for controlled drug release. Here, a step-changing solution to this problem is described involving the design, synthesis, and application of three different linker-drug conjugates comprising anticancer drug doxorubicin (DOX) and different stimulus-cleavable linkers (SCLs) including the photocleavable linker (ortho-nitrobenzyl), pH-cleavable linker (hydrazone), and enzyme-cleavable linker (β-glucuronide). These SCL-DOX conjugates are covalently attached to the surface of pSiNP via copper (I)-catalyzed alkyne-azide cycloaddition (CuAAC, i.e., click reaction) to afford pSiNP-SCL-DOXs. The mass loading of the covalent conjugation approach for pSiNP-SCL-DOX reaches over 250 µg of DOX per mg of pSiNPs, which is notably twice the mass loading achieved by noncovalent loading. Moreover, the covalent conjugation between SCL-DOX and pSiNPs endows the pSiNPs with excellent stability and highly controlled release behavior. When tested in both in vitro and in vivo tumor models, the pSiNP-SCL-DOXs induces excellent tumor growth inhibition., (© 2022 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH.)

This paper presents the development of advanced Ti implants with enhanced antibacterial activity. The implants were engineered using additive manufacturing three-dimensional (3D) printing technology followed by surface modification with electrochemical anodization and hydrothermal etching, to create unique hierarchical micro/nanosurface topographies of microspheres covered with sharp nanopillars that can mechanically kill bacteria in contact with the surface. To achieve enhanced antibacterial performance, fabricated Ti implant models were loaded with gallium nitrate as an antibacterial agent. The antibacterial efficacy of the fabricated substrates with the combined action of sharp nanopillars and locally releasing gallium ions (Ga 3+ ) was evaluated toward Staphylococcus aureus and Pseudomonas aeruginosa . Results confirm the significant antibacterial performance of Ga 3+ -loaded substrates with a 100% eradication of bacteria. The nanopillars significantly reduced bacterial attachment and prevented biofilm formation while also killing any bacteria remaining on the surface. Furthermore, 3D-printed surfaces with microspheres of diameter 5-30 μm and interspaces of 12-35 μm favored the attachment of osteoblast-like MG-63 cells, as confirmed via the assessment of their attachment, proliferation, and viability. This study provides important progress toward engineering of next-generation 3D-printed implants, that combine surface chemistry and structure to achieve a highly efficacious antibacterial surface with dual cytocompatibility to overcome the limitations of conventional Ti implants.

Injectable hydrogels have been employed extensively as versatile materials for cartilage regeneration due to their excellent biocompatibility, tunable structure, and ability to accommodate bioactive factors, as well as their ability to be locally delivered via minimally invasive injection to fill irregular defects. More recently, in vitro and in vivo studies have revealed that processing these materials to produce cell-laden microgels can enhance cell-cell and cell-matrix interactions and boost nutrient and metabolite exchange. Moreover, these studies have demonstrated gene expression profiles and matrix regeneration that are superior compared to conventional injectable bulk hydrogels. As cell-laden microgels and their application in cartilage repair are moving closer to clinical translation, this review aims to present an overview of the recent developments in this field. Here we focus on the currently used biomaterials and crosslinking strategies, the innovative fabrication techniques being used for the production of microgels, the cell sources used, the signals used for induction of chondrogenic differentiation and the resultant biological responses, and the ability to create three-dimensional, functional cartilage tissues. In addition, this review also covers the current clinical approaches for repairing cartilage as well as specific challenges faced when attempting the regeneration of damaged cartilage tissue. New findings related to the macroporous nature of the structures formed by the assembled microgel building blocks and the novel use of microgels in 3D printing for cartilage tissue engineering are also highlighted. Finally, we outline the challenges and future opportunities for employing cell-laden microgels in clinical applications., (Crown Copyright © 2021. Published by Elsevier Ltd. All rights reserved.)

Antimicrobial resistance (AMR) is threatening modern medicine. While the primary cost of AMR is paid in the healthcare domain, the agricultural and environmental domains are also reservoirs of resistant microorganisms and hence perpetual sources of AMR infections in humans. Consequently, the World Health Organisation and other international agencies are calling for surveillance of AMR in all three domains to guide intervention and risk reduction strategies. Technologies for detecting AMR that have been developed for healthcare settings are not immediately transferable to environmental and agricultural settings, and limited dialogue between the domains has hampered opportunities for cross-fertilisation to develop modified or new technologies. In this feature, we discuss the limitations of currently available AMR sensing technologies used in the clinic for sensing in other environments, and what is required to overcome these limitations.

Despite the wide use of aliphatic polyesters, such as poly(L-lactic acid) (PLLA) and poly(ε-caprolactone) (PCL), for many biomedical applications, these materials are limited due to their hydrophobic properties and lack of functional groups to bond with ligands to enhance the cell reorganization. Recently, a composite consisting of bioglass and PCL was demonstrated to enhance the mechanical strength and to improve the degradation rate. Although numerous approaches have been developed to improve the wettability of aliphatic polyesters to create a favorable interface with cells, only few surface modification methods can be independently applied to surfaces with different material. In this work, mesoporous bioglass (MBG) nanoparticles embedded in PCL films were modified by the polymerization of aminomalonitrile (AMN) with 3,4,5-trihydroxybenzaldehyde (THBA). The copolymer layer was further utilized as a mediator to conjugate chitosan and evaluate the antibacterial efficacy. Our results show that the hydrophilicity of the composite membranes significantly improved after treatment. In addition, after immersion in simulated body fluid (SBF) for 14 days, hydroxyapatite formation was only observed on the treated membranes. This result demonstrates that the surface treatment did not alter the MBG bioactivity. Moreover, the cell culture results reveal that the extension level of cells and expression of alkaline phosphatase activity (ALP) of osteoblast-like (MG63) cells were higher on treated composite films compared to untreated ones. The results imply that the treatment procedure can be simultaneously and homogeneously applied to the organic/inorganic composites. In addition, Staphylococcus aureus adhesion on AMN-co-THBA and chitosan/ AMN-co-THBA was significantly lower than untreated PCL. Moreover, the percentage of dead bacteria was highest on the chitosan/ AMN-co-THBA membranes. These results indicate that the AMN-co-THBA modification can be used in composite materials and complex constructs, and it provides a potential method to create versatile surface properties for biomedical applications., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: Paclitaxel (PTX)-coated drug eluting balloon catheters (DEBc) used in the management of neointimal hyperplasia (NIH) have been associated with safety concerns. Alternative coating agents and targeted delivery systems may improve safety and DEBc efficacy. Utilizing a multi-platform approach we designed, developed and evaluated Lumi-Solve, a novel DEBc, coated with ultraviolet (UV) 365 nm-activated caged metacept-3 (c-MCT-3), an epigenetic agent from the histone deacetylase inhibitor (HDACi) class., Methods: In vitro catheter and contrast media transmission of UV365nm was evaluated spectroscopically. UV365nm conversion of c-MCT-3 to MCT-3 was evaluated chromatographically. Cellular toxicity and HDACi activity of c-MCT-3 ∓UV365nm was evaluated in vitro. In vivo UV365nm conversion of c-MCT-3 to MCT-3 was evaluated in an ovine carotid artery model., Results: Catheter material and dilute contrast media did not attenuate UV365nm transmission or c-MCT-3 activation. c-MCT-3 demonstrated less cellular toxicity than MCT-3 and PTX. UV365nm-activated c-MCT-3 demonstrated HDACi activity. In vivo activation of c-MCT-3 produced MCT-3., Conclusions: Lumi-Solve, a novel DEBc device developed utilizing a combination of chemical, fibre-optic and catheter based technology platforms, demonstrated potential for targeted delivery of bioactive HDACi to the blood vessel wall supporting direct application to the management of NIH and warranting additional in vivo studies., (© 2021. Biomedical Engineering Society.)

The generation of complex physicochemical signals on the surface of biomedical materials is still challenging despite the fact that a broad range of surface modification methods have been developed over the last few decades. Colloidal self-assembled patterns (cSAPs) are combinations of unique colloids differing in size and surface chemistry acting as building blocks that can be programmed to generate surface patterns with exquisite control of complexity. This study reports on producing a variety of pre-modified colloids for the fabrication of cSAPs as well as post-assembly modifications to yield complex surfaces. The surface of cSAPs presents hierarchical micro- and nanostructures, localized hydrophilic/hydrophobic characteristics, and tunable surface functionality imparted by the individual colloids. The selected cSAPs can control bacterial adhesion ( S. aureus , P. aeruginosa , and E. coli ) and affect the cell cycle of human bone marrow stem cells (hBMSCs). Moreover, in a mouse subcutaneous model, cSAPs with selective [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium (SBMA) modification can reduce the inflammatory response after being challenged with bacteria. This study reveals that functionalized cSAPs are versatile tools for controlling cellular responses at biointerfaces, which is instructive for biomaterials or biodevices.

Over the last thirty years, research in nanomedicine has widely been focused on applications in cancer therapeutics. However, despite the plethora of reported nanoscale drug delivery systems that can successfully eradicate solid tumor xenografts in vivo, many of these formulations have not yet achieved clinical translation. This issue particularly pertains to the delivery of small interfering RNA (siRNA), a highly attractive tool for selective gene targeting. One of the likely reasons behind the lack of translation is that current in vivo models fail to recapitulate critical elements of clinical solid tumors that may influence drug response, such as cellular heterogeneity in the tumor microenvironment. This study incorporates a more clinically relevant model for assessing siRNA delivery systems; ex vivo culture of prostate cancer harvested from patients who have undergone radical prostatectomy, denoted patient-derived explants (PDE). The model retains native human tissue architecture, microenvironment, and cell signaling pathways. Porous silicon nanoparticles (pSiNPs) behavior in this model is investigated and compared with commonly used 3D cancer cell spheroids for their efficacy in the delivery of siRNA directed against the androgen receptor (AR), a key driver of prostate cancer., (© 2020 Wiley-VCH GmbH.)

Cells are able to perceive complex mechanical cues from their microenvironment, which in turn influences their development. Although the understanding of these intricate mechanotransductive signals is evolving, the precise roles of substrate microtopography in directing cell fate is still poorly understood. Here, UV nanoimprint lithography is used to generate micropillar arrays ranging from 1 to 10 µm in height, width, and spacing to investigate the impact of microtopography on mechanotransduction. Using mesenchymal stem cells (MSCs) as a model, stark pattern-specific changes in nuclear architecture, lamin A/C accumulation, chromatin positioning, and DNA methyltransferase expression, are demonstrated. MSC osteogenesis is also enhanced specifically on micropillars with 5 µm width/spacing and 5 µm height. Intriguingly, the highest degree of osteogenesis correlates with patterns that stimulated maximal nuclear deformation which is shown to be dependent on myosin-II-generated tension. The outcomes determine new insights into nuclear mechanotransduction by demonstrating that force transmission across the nuclear envelope can be modulated by substrate topography, and that this can alter chromatin organisation and impact upon cell fate. These findings have potential to inform the development of microstructured cell culture substrates that can direct cell mechanotransduction and fate for therapeutic applications in both research and clinical sectors., Competing Interests: The authors declare no conflict of interest., (© 2021 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Antifouling treatment is critical to certain biomedical devices for their functions and patients' life. Facial, versatile, and universal coating methods to conjugate antifouling materials on a wide variety of biomaterials are beneficial for the fabrication of low-fouling biomedical devices. We developed a simple one-step coating method for surface conjugation of zwitterionic poly(sulfobetaine) via deposition of self-polymerized pyrogallol (PG). Poly(pyrogallol) could deposit copolymers of sulfobetaine methacrylate and aminoethyl methacrylate (pSBAE) on various biomaterials. pSBAE coatings inhibited as high as 99.8% of the adhesion of L929 cells and reduced protein adsorption significantly. The resistance against L929 cell adhesion was increased with increasing coating time and was positively correlated with the surface hydrophilicity and film thickness. Such a coating was robust to resist harsh sterilization conditions and stable for long-term storage in phosphate-buffered saline. We expect that the simple low-fouling pSBAE coating is applicable to the manufacture of medical devices., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

Targeted delivery of chemotherapeutics to cancer cells has the potential to yield high drug concentrations in cancer cells while minimizing any unwanted side effects. However, the development of multidrug resistance in cancer cells may impede the accumulation of chemotherapy drugs within these, decreasing its therapeutic efficacy. Downregulation of multidrug resistance-related proteins such as MRP1 with small interfering RNA (siRNA) is a promising approach in the reversal of drug resistance. The co-delivery of doxorubicin (Dox) and siRNA against MRP1 (siMRP1) by using nanoparticles comprised of biocompatible porous silicon (pSi) presents itself as a novel opportunity to utilize the biomaterial's high loading capacity and large accessible surface area. Additionally, to increase the selectivity and retention of the delivery vehicle at the tumor site, nanobodies were incorporated onto the nanoparticle surface via a polyethylene glycol (PEG) linker directed towards either the epidermal growth factor receptor (EGFR) or the prostate specific membrane antigen (PSMA). The nanobody-displaying pSi nanoparticles (pSiNPs) demonstrated effective gene silencing, inhibiting MRP1 expression by 74 ± 6% and 74 ± 4% when incubated with EGFR-pSiNPs and PSMA-pSiNPs, respectively, in prostate cancer cells. The downregulation of MRP1 led to a further increase in cytotoxicity when both siRNA and Dox were delivered in conjunction in both cancer cell monocultures and spheroids when compared to free Dox or Dox and a scrambled sequence of siRNA. Altogether, nanobody-displaying pSiNPs are an effective carrier for the dual delivery of both siRNA and Dox for cancer treatment.

The effective control of biointerfacial interactions is of outstanding interest in a broad range of biomedical applications, ranging from cell culture tools to biosensors and implantable medical devices. For many of these applications, highly specific interactions between cells and material surfaces are desired. Sophisticated control over these interactions requires reducing or preventing non-specific interactions on the one hand and displaying highly specific signals that can be recognized by extracellular receptors on the other. We have recently developed ultra-low fouling coatings that can be applied in a single step using photoreactive copolymers of 2-hydroxypropyl acrylamide and N-benzophenone acrylamide. Here, we have expanded this approach by incorporating polymerizable peptide monomers into these copolymers. The monomers QQGWFGAGK(acrylamide) and acrylamide-GAGQQGWF were synthesized after identifying the QQGWF sequence as a binding motif for CD44 by phage display for the first time. Our results demonstrate that UV-crosslinked coatings fabricated using the QQGWFGAGK(acrylamide) monomer are effective at selectively binding hMSC in the presence of HepG2 and HEK293 cells due to the difference in CD44 expression. Our results also demonstrate that the peptide modified coatings retain their low biofouling character using a BCA protein binding assay as well as an E. coli bacterial attachment assay over a 24 h period. Our approach provides an alternative to traditional integrin-mediated selective cell binding on surfaces and opens the door to new diagnostic applications, exploiting the fact that the transmembrane protein CD44 is highly expressed in multiple diseases., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Here, we have developed and evaluated a microfluidic-based human blood-brain-barrier (μBBB) platform that models and predicts brain tissue uptake of small molecule drugs and nanoparticles (NPs) targeting the central nervous system. By using a photocrosslinkable copolymer that was prepared from monomers containing benzophenone and N -hydroxysuccinimide ester functional groups, we were able to evenly coat and functionalize μBBB chip channels in situ , providing a covalently attached homogenous layer of extracellular matrix proteins. This novel approach allowed the coculture of human endothelial cells, pericytes, and astrocytes and resulted in the formation of a mimic of cerebral endothelium expressing tight junction markers and efflux proteins, resembling the native BBB. The permeability coefficients of a number of compounds, including caffeine, nitrofurantoin, dextran, sucrose, glucose, and alanine, were measured on our μBBB platform and were found to agree with reported values. In addition, we successfully visualized the receptor-mediated uptake and transcytosis of transferrin-functionalized NPs. The BBB-penetrating NPs were able to target glioma cells cultured in 3D in the brain compartment of our μBBB. In conclusion, our μBBB was able to accurately predict the BBB permeability of both small molecule pharmaceuticals and nanovectors and allowed time-resolved visualization of transcytosis. Our versatile chip design accommodates different brain disease models and is expected to be exploited in further BBB studies, aiming at replacing animal experiments.

A broad range of medical devices initiate an immune reaction known as the foreign body response (FBR) upon implantation. Here, collagen deposition at the surface of the implant occurs as a result of the FBR, ultimately leading to fibrous encapsulation and, in many cases, reduced function or failure of the device. Despite significant efforts, the prevention of fibrotic encapsulation has not been realized at this point in time. However, many next-generation medical technologies including cellular therapies, sensors and devices depend on the ability to modulate and control the FBR. For these technologies to become viable, significant advances must be made in understanding the underlying mechanism of this response as well as in the methods modulating this response. In this review, we highlight recent advances in the development of materials and coatings providing a reduced FBR and emphasize key characteristics of high-performing approaches. We also provide a detailed overview of the state-of-the-art in strategies relying on controlled drug release, the surface display of bioactive signals, materials-based approaches, and combinations of these approaches. Finally, we offer perspectives on future directions in this field., (Copyright © 2020. Published by Elsevier B.V.)

Background: Driveline infections remain a major complication of ventricular assist device (VAD) implantation. This study aimed to characterize in vivo microbial biofilms associated with driveline infections and host tissue integration of implanted drivelines., Methods: A total of 9 infected and 13 uninfected drivelines were obtained from patients with VAD undergoing heart transplantation in Australia between 2016 and 2018. Each driveline was sectioned into 11 pieces of 1.5 cm in length, and each section was examined by scanning electron microscopy (SEM) and viable counts for microbial biofilms. Microorganisms were cultured and identified. Host tissue integration of clinical drivelines was assessed with micro-computed tomography (CT) and SEM. An in vitro interstitial biofilm assay was used to simulate biofilm migration in the driveline tunnel, and time-lapse microscopy was performed., Results: Of the 9 explanted, infected drivelines, all had organisms isolated from varying depths along the velour section of the drivelines, and all were consistent with the swab culture results of the clinically infected exit site. SEM and micro-CT suggested insufficient tissue integration throughout the driveline velour, with microgaps observed. Clinical biofilms presented as microcolonies within the driveline tunnel, with human tissue as the sub-stratum, and were resistant to anti-microbial treatment. Biofilm migration mediated by a dispersal-seeding mechanism was observed., Conclusions: This study of explanted infected drivelines showed extensive anti-microbial-resistant biofilms along the velour, associated with microgaps between the driveline and the surrounding tissue. These data support the enhancement of tissue integration into the velour as a potential preventive strategy against driveline infections by preventing biofilm migration that may use microgaps as mediators., (Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Understanding the interactions of stem cells with surface topography can give us an invaluable tool in controlling stemness and fate of stem cells for further use in biomedical applications. In this study, we have fabricated topographical features using a class of cell culture substrates called binary colloidal crystals (BCCs), that are made by self-assembly of mixtures of spherical micron sized silica (Si) and nanometer sized polystyrene (PS) or poly (methyl methacrylate) (PMMA) particles. The substrates formed are arrays of ordered, hexagonally packed large Si particles inter-dispersed with the PS particles that are stabilized by gentle heating, which melts the PS or PMMA forming substrates suitable for cell culture. BCC substrates were used for culture of mouse embryonic stem cells (mESCs). Compared to tissue culture plates, COM1 (Si5-PMMA0.4), COM2 (Si5-PS0.4) and COM4 (Si2-PSC0.22) have shown to provide a better support for mESC proliferation in the presence of the cytokine leukemia inhibitory factor (LIF). The behavior of mESCs with the BCCs in presence and absence of LIF, was further explored and it was found that interaction of mESCs with the culture substrate can be controlled by tuning surface topography and roughness, which is determined by the size and type of particles used in making BCCs. Furthermore, it was shown that limiting cell-surface interactions and controlling colony shape can promote stemness maintenance on COM1 and COM2 substrates as indicated by better proliferation and higher expression of pluripotency genes including Nanog both in presence and in absence of LIF. Together with higher expression of GATA6 gene, it can be stated that these surfaces can be used for endodermic priming of mESCs. Therefore, we believe that these surfaces, especially COM1 and COM2 surfaces can be beneficial as stem cell culture systems for further use in biomedical research., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Medical device associated infections remain a significant problem for all classes of devices at this point in time. Here, we have developed a surface modification technique to fabricate multifunctional coatings that combine antifouling and antimicrobial properties. Zwitterionic polymers providing antifouling properties and quaternary ammonium containing polymers providing antimicrobial properties were combined in these coatings. Throughout this study, aminomalononitrile (AMN) was used to achieve one-step coatings incorporating different polymers. The characterization of coatings was carried out using static water contact angle (WCA) measurements, X-ray photoelectron spectroscopy (XPS), profilometry, and scanning electron microscopy (SEM), whereas the biological response in vitro was analyzed using Staphylococcus epidermidis and Escherichia coli as well as L929 fibroblast cells. Zwitterionic polymers synthesized from sulfobetaine methacrylate and 2-aminoethyl methacrylate were demonstrated to reduce bacterial attachment when incorporated in AMN assisted coatings. However, bacteria in suspension were not affected by this approach. On the other hand, alkylated polyethylenimine polymers, synthesized to provide quaternary ammonium groups, were demonstrated to have contact killing properties when incorporated in AMN assisted coatings. However, the high bacterial attachment observed on these surfaces may be detrimental in applications requiring longer-term bactericidal activity. Therefore, AMN-assisted coatings containing both quaternary and zwitterionic polymers were fabricated. These multifunctional coatings were demonstrated to significantly reduce the number of live bacteria not only on the modified surfaces, but also in suspension. This approach is expected to be of interest in a range of biomedical device applications.

Most gelatin hydrogels used in regenerative medicine applications today are fabricated by photocrosslinking due to the convenience and speed of this method. However, in most cases photoinitiators are used, which require UV light, which, in turn, can cause cell and tissue damage, or using functionalized gelatin. Recently, ruthenium (II) tris-bipyridyl chloride has been studied as an initiator that can induce dityrosine bond formation using visible light. In addition, continuous fibrils and small particles are often used to reinforce composite materials. Therefore, this study investigated the visible-light-induced photocrosslinking of native gelatin molecules via dityrosine bonds formation as well as gel reinforcement by collagen fibrils and mesoporous bioactive glass (MBG) particles. The results show that collagen and MBG exerted a synergistic effect on maintaining gel integrity with a dental LED curing light when the irradiation time was shortened to 30 s. Without the two reinforcing components, the gel could not form a geometric shape stable gel even when the exposure time was 120 s. The shear strength increased by 62% with the collagen and MBG compared with the blank control. Furthermore, our results demonstrate that the addition of collagen and MBG enhanced gel stability in an artificial saliva solution. These results demonstrate the considerable advantages of using tyrosine-containing biomolecules, and using a dental LED curing light for the crosslinking of hydrogels in terms of their suitability and feasibility for use as bioadhesives in confined clinical working space, such as the oral cavity, and in application as in situ-crosslinked injectable hydrogels.

Staphylococcus capitis is an opportunistic pathogen often implicated in bloodstream infections in the neonatal intensive care unit (NICU). This is assisted by its ability to form biofilms on indwelling central venous catheters (CVC), which are highly resistant to antibiotics and the immune system. We sought to understand the fundamentals of biofilm formation by S. capitis in the NICU, using seventeen clinical isolates including the endemic NRCS-A clone and assessing nine commercial and two modified polystyrene surfaces. S. capitis clinical isolates from the NICU initiated biofilm formation only in response to hyperosmotic conditions, followed by a developmental progression driven by icaADBC expression to establish mature biofilms, with polysaccharide being their major extracellular polymer substance (EPS) matrix component. Physicochemical features of the biomaterial surface, and in particular the level of the element oxygen present on the surface, significantly influenced biofilm development of S. capitis . A lack of highly oxidized carbon species on the surface prevented the immobilization of S. capitis EPS and the formation of mature biofilms. This information provides guidance in regard to the preparation of hyperosmolar total parenteral nutrition and the engineering of CVC surfaces that can minimize the risk of catheter-related bloodstream infections caused by S. capitis in the NICU., (Copyright © 2020 Qu, Li, Cameron, Easton, Zhu, Zhu, Salwiczek, Muir, Thissen, Daley, Forsythe, Peleg and Lithgow.)

Ventilator-associated pneumonia (VAP) is a highly common hospital-acquired infection affecting people that require mechanical ventilation. The endotracheal tube (ETT) used during the ventilation process provides a surface that can allow bacterial colonization and biofilm formation, which can lead to VAP. Although various approaches, including ETT design and material selection, as well as antimicrobial coatings have been employed to minimize adverse events, VAP remains a significant unresolved clinical issue. In this study, we have utilized a novel styrylbenzene-based antimicrobial (BCP3) in a simple and robust coating that allows its long-term release at an effective level. BCP3 was applied onto PVC ETT segments blended together with poly(lactic- co -glycolic acid) via a facile dip-coating process with controlled loadings. In vitro studies demonstrated concentration-dependent release of BCP3 from the coatings for at least 31 days. Bacterial assays using major VAP culprits, Staphylococcus aureus and Pseudomonas aeruginosa, demonstrated significant growth inhibition, with a stronger effect on S. aureus . Despite its ability to inhibit bacterial growth, BCP3 showed no cytotoxicity toward mammalian (L929) fibroblasts, which makes it attractive from a clinical perspective. The coating procedure was successfully translated to coat the entire ETTs, making it highly amenable for large-scale manufacturing., Competing Interests: The authors declare the following competing financial interest(s): The research described in the manuscript was supported by Boulos & Cooper Pharmaceuticals, which seeks to commercialize a range of novel antimicrobial compounds.The authors declare that Ramiz A. Boulos is a founder of Boulos & Cooper Pharmaceuticals., (Copyright © 2020 American Chemical Society.)