Additive and Lithographic Manufacturing of Biomedical Scaffold Structures Using a Versatile Thiol-Ene Photocurable Resin.

Additive and lithographic manufacturing technologies using photopolymerisation provide a powerful tool for fabricating multiscale structures, which is especially interesting for biomimetic scaffolds and biointerfaces. However, most resins are tailored to one particular fabrication technology, showing drawbacks for versatile use. Hence, we used a resin based on thiol-ene chemistry, leveraging its numerous advantages such as low oxygen inhibition, minimal shrinkage and high monomer conversion. The resin is tailored to applications in additive and lithographic technologies for future biofabrication where fast curing kinetics in the presence of oxygen are required, namely 3D inkjet printing, digital light processing and nanoimprint lithography. These technologies enable us to fabricate scaffolds over a span of six orders of magnitude with a maximum of 10 mm and a minimum of 150 nm in height, including bioinspired porous structures with controlled architecture, hole-patterned plates and micro/submicro patterned surfaces. Such versatile properties, combined with noncytotoxicity, degradability and the commercial availability of all the components render the resin as a prototyping material for tissue engineers.

Biomedical engineering in low- and middle-income settings: analysis of current state, challenges and best practices.

Supporting the expansion of best practices in Biomedical Engineering (BME) can facilitate pathway toward the providing universal health coverage and more equitable and accessible healthcare technologies, especially in low- and middle-income (LMI) settings. These best practices can act as drivers of change and may involve scientific-technological issues, human intervention during technology development, educational aspects, social performance management for improved interactions along the medical technology life cycle, methods for managing resources and approaches for the establishment of regulatory frameworks. The aim of our study was to identify weaknesses and strengths of the scientific, technological, socio-political, regulatory and educational landscape in BME in LMI resource settings. We thus analysed the current state-of-the-art through six dimensions considered fundamental for advancing quality and equity in healthcare: 1) relevant and 2) emergent technologies, 3) new paradigms in medical technology development, 4) innovative BME education, 5) regulation and standardization for novel approaches, and 6) policy making. In order to evaluate and compare their relevance, maturity and implementation challenges, they were assessed through a questionnaire to which 100 professionals from 35 countries with recognized experience in the field of BME and its application to LMI settings responded. The results are presented and discussed, highlighting the main challenges and pinpointing relevant areas where intervention, including local lobbying and international promotion of best practices is necessary. We were also able to identify areas where minimal effort is required to make big changes in global health. Supplementary information: The online version contains supplementary material available at 10.1007/s12553-022-00657-8.

Auxetic Metamaterials for Biomedical Devices: Current Situation, Main Challenges, and Research Trends.

Auxetic metamaterials are characterized by a negative Poisson ratio (NPR) and display an unexpected property of lateral expansion when stretched and densification when compressed. Auxetic properties can be achieved by designing special microstructures, hence their classification as metamaterials, and can be manufactured with varied raw materials and methods. Since work in this field began, auxetics have been considered for different biomedical applications, as some biological tissues have auxetic-like behaviour due to their lightweight structure and morphing properties, which makes auxetics ideal for interacting with the human body. This research study is developed with the aim of presenting an updated overview of auxetic metamaterials for biomedical devices. It stands out for providing a comprehensive view of medical applications for auxetics, including a focus on prosthetics, orthotics, ergonomic appliances, performance enhancement devices, in vitro medical devices for interacting with cells, and advanced medicinal clinical products, especially tissue engineering scaffolds with living cells. Innovative design and simulation approaches for the engineering of auxetic-based products are covered, and the relevant manufacturing technologies for prototyping and producing auxetics are analysed, taking into consideration those capable of processing biomaterials and enabling multi-scale and multi-material auxetics. An engineering design rational for auxetics-based medical devices is presented with integrative purposes. Finally, key research, development and expected technological breakthroughs are discussed.

Modelling, additive layer manufacturing and testing of interlocking structures for joined components.

In this study, authors explore the application of modelling and additive layer manufacturing (ALM) for creating and testing materials with interlocking structures aimed to reduce the stress concentration along the edges of a typical lap joint. The effectiveness of this approach is discussed by means of modelling and experimental validation of joints with interlocking structures obtained by ALM. Considering the achieved results, ALM of interlocking structures constitutes an interesting alternative or complement to traditional joining processes, as it may help to minimize stress mismatches in the joining region. It may also prevent the use of adhesive or joining post processes, because the joint is created together with the joined components.

Innovative Design Methodology for Patient-Specific Short Femoral Stems.

The biomechanical performance of hip prostheses is often suboptimal, which leads to problems such as strain shielding, bone resorption and implant loosening, affecting the long-term viability of these implants for articular repair. Different studies have highlighted the interest of short stems for preserving bone stock and minimizing shielding, hence providing an alternative to conventional hip prostheses with long stems. Such short stems are especially valuable for younger patients, as they may require additional surgical interventions and replacements in the future, for which the preservation of bone stock is fundamental. Arguably, enhanced results may be achieved by combining the benefits of short stems with the possibilities of personalization, which are now empowered by a wise combination of medical images, computer-aided design and engineering resources and automated manufacturing tools. In this study, an innovative design methodology for custom-made short femoral stems is presented. The design process is enhanced through a novel app employing elliptical adjustment for the quasi-automated CAD modeling of personalized short femoral stems. The proposed methodology is validated by completely developing two personalized short femoral stems, which are evaluated by combining in silico studies (finite element method (FEM) simulations), for quantifying their biomechanical performance, and rapid prototyping, for evaluating implantability.

Materials degradation in non-thermal plasma generators by corona discharge.

Atmospheric corona discharge devices are being studied as innovative systems for cooling, sterilization, and propulsion, in several industrial fields, from robotics to medical devices, from drones to space applications. However, their industrial scale implementation still requires additional understanding of several complex phenomena, such as corrosion, degradation, and fatigue behaviour, which may affect final system performance. This study focuses on the corrosive behaviour of wires that perform as a high-voltage electrode subject to DC positive corona discharge in atmospheric air. The experiments demonstrate that the non-thermal plasma process promotes the growth of the oxidative films and modifies the physicochemical properties of the materials chosen as corona electrodes, hence affecting device operation. Surfaces exposed to this non-thermal plasma are electrically characterized by negative exponential decay of time-depend power and analysed with SEM. Implications on performance are analysed and discussed.

Artificial Intelligence Aided Design of Tissue Engineering Scaffolds Employing Virtual Tomography and 3D Convolutional Neural Networks.

Design requirements for different mechanical metamaterials, porous constructions and lattice structures, employed as tissue engineering scaffolds, lead to multi-objective optimizations, due to the complex mechanical features of the biological tissues and structures they should mimic. In some cases, the use of conventional design and simulation methods for designing such tissue engineering scaffolds cannot be applied because of geometrical complexity, manufacturing defects or large aspect ratios leading to numerical mismatches. Artificial intelligence (AI) in general, and machine learning (ML) methods in particular, are already finding applications in tissue engineering and they can prove transformative resources for supporting designers in the field of regenerative medicine. In this study, the use of 3D convolutional neural networks (3D CNNs), trained using digital tomographies obtained from the CAD models, is validated as a powerful resource for predicting the mechanical properties of innovative scaffolds. The presented AI-aided or ML-aided design strategy is believed as an innovative approach in area of tissue engineering scaffolds, and of mechanical metamaterials in general. This strategy may lead to several applications beyond the tissue engineering field, as we analyze in the discussion and future proposals sections of the research study.

Physical and Chemical Properties Characterization of 3D-Printed Substrates Loaded with Copper-Nickel Nanowires.

This study deals with the laser stereolithography manufacturing feasibility of copper-nickel nanowire-loaded photosensitive resins. The addition of nanowires resulted in a novel resin suitable for additive manufacturing technologies based on layer-by-layer photopolymerization. The pure and nanowire-loaded resin samples were 3D printed in a similar way. Their morphological, mechanical, thermal, and chemical properties were characterized. X-ray computed tomography revealed that 0.06 vol % of the composite resin was filled with nanowires forming randomly distributed aggregates. The increase of 57% in the storage modulus and 50% in the hardness when loading the resin with nanowire was attributed to the load transfer. Moreover, the decrease in the glass transition temperature from 57.9 °C to 52.8 °C in the polymeric matrix with nanowires evidenced a decrease in the cross-linking density, leading to a higher mobility of the polymer chains during glass transition. Consequently, this research demonstrates the successful dispersion and use of copper-nickel nanowires as a reinforcement material in a commercial resin for laser stereolithography.

Artificial Intelligence Aided Design of Microtextured Surfaces: Application to Controlling Wettability.

Artificial intelligence (AI) has emerged as a powerful set of tools for engineering innovative materials. However, the AI-aided design of materials textures has not yet been researched in depth. In order to explore the potentials of AI for discovering innovative biointerfaces and engineering materials surfaces, especially for biomedical applications, this study focuses on the control of wettability through design-controlled hierarchical surfaces, whose design is supported and its performance predicted thanks to adequately structured and trained artificial neural networks (ANN). The authors explain the creation of a comprehensive library of microtextured surfaces with well-known wettability properties. Such a library is processed and employed for the generation and training of artificial neural networks, which can predict the actual wetting performance of new design biointerfaces. The present research demonstrates that AI can importantly support the engineering of innovative hierarchical or multiscale surfaces when complex-to-model properties and phenomena, such as wettability and wetting, are involved.

Validación de un dispositivo point-of-care para la detección rápida de infección urinaria y susceptibilidad antimicrobiana / Validation of point-of-care device for rapid detection of urinary tract infection and antibiotic susceptibility

Resumen Introducción: Las infecciones del tracto urinario (ITU) presentan una elevada prevalencia en el ámbito comunitario. Un rápido diagnóstico microbiológico es esencial para asegurar una terapia adecuada y efectiva. Objetivo: Evaluar un kit de antibiograma rápido (KAR®) en formato point-of-care para la detección rápida de ITU y sensibilidad antimicrobiana. Material y Métodos: El dispositivo KAR® se diseñó y desarrolló en colaboración con ingenieros técnicos y microbiólogos clínicos. Su evaluación se realizó a través de un estudio multicéntrico en el que participaron tres hospitales españoles. Para ello, se realizaron distintos ensayos in vivo con el fin de determinar la correlación del dispositivo con las técnicas microbiológicas de referencia. Resultados: Se ensayó un total de 400 muestras de orinas procedentes de pacientes con sospecha de ITU. El dispositivo KAR® proporcionó rápidos resultados (tiempo medio de positividad de 7,8 ± 1,5 h) con 97% de sensibilidad, 89% de especificidad y 87% de concordancia para la detección de bacteriuria significativa. Los porcentajes de especificidad para los antimicrobianos testados fueron: ciprofloxacina (97%), fosfomicina (94%), cotrimoxazol (84%), ampicilina (80%) y amoxicilina/ácido clavulánico (55%). Conclusión: El dispositivo KAR® puede ser una herramienta útil para el diagnóstico de ITU en pacientes ambulatorios, especialmente en áreas de bajo nivel socio-económico.

Abstract Background: Urinary tract infections (UTI) presents a high prevalence in the community setting. Rapid and accurate microbiological diagnosis is essential to ensure adequate and effective therapy. Aim: To evaluate a rapid antibiogram kit (KAR®) in point-of-care format for rapid detection of UTI and antibiotic susceptibility. Methods: The KAR® device has been designed and developed in collaboration with technical engineers and clinical microbiologists. Its evaluation has been carried out through a multicenter study in which three Spanish hospitals have participated. Thus, different in vivo tests have been implemented in order to determine device correlation with the reference microbiological techniques. Results: During the study period, a total of 400 urine samples from patients with suspected ITU were tested. The KAR® device provided fast results (mean positivity time of 7,8 ± 1,5 hours) with 97% sensitivity, 89% specificity and 87% agreement for the detection of significant bacteriuria. The percentages of specificity for the antibiotics tested were: ciprofloxacin (97%), fosfomycin (94%),cotrimoxazole (84%), ampicillin (80%) and amoxicillin/clavulanic acid (55%). Conclusion: The KAR® device could be a useful tool for diagnosing UTI in outpatients, especially in areas of low socio-economic level.

Soft-Lithography of Polyacrylamide Hydrogels Using Microstructured Templates: Towards Controlled Cell Populations on Biointerfaces.

Polyacrylamide hydrogels are interesting materials for studying cells and cell-material interactions, thanks to the possibility of precisely adjusting their stiffness, shear modulus and porosity during synthesis, and to the feasibility of processing and manufacturing them towards structures and devices with controlled morphology and topography. In this study a novel approach, related to the processing of polyacrylamide hydrogels using soft-lithography and employing microstructured templates, is presented. The main novelty relies on the design and manufacturing processes used for achieving the microstructured templates, which are transferred by soft-lithography, with remarkable level of detail, to the polyacrylamide hydrogels. The conceived process is demonstrated by patterning polyacrylamide substrates with a set of vascular-like and parenchymal-like textures, for controlling cell populations. Final culture of amoeboid cells, whose dynamics is affected by the polyacrylamide patterns, provides a preliminary validation of the described strategy and helps to discuss its potentials.

Synergies between Surface Microstructuring and Molecular Nanopatterning for Controlling Cell Populations on Polymeric Biointerfaces.

Polymeric biointerfaces are already being used extensively in a wide set of biomedical devices and systems. The possibility of controlling cell populations on biointerfaces may be essential for connecting biological systems to synthetic materials and for researching relevant interactions between life and matter. In this study, we present and analyze synergies between an innovative approach for surface microstructuring and a molecular nanopatterning procedure of recent development. The combined set of techniques used may be instrumental for the development of a new generation of functional polymeric biointerfaces. Eukaryotic cell cultures placed upon the biointerfaces developed, both before and after molecular patterning, help to validate the proposal and to discuss the synergies between the surface microstructuring and molecular nanopatterning techniques described in the study. Their potential role in the production of versatile polymeric biointerfaces for lab- and organ-on-a-chip biodevices and towards more complex and biomimetic co-culture systems and cell cultivation set-ups are also examined.

Surgical Planning of Sacral Nerve Stimulation Procedure in Presence of Sacral Anomalies by Using Personalized Polymeric Prototypes Obtained with Additive Manufacturing Techniques.

Sacral nerve stimulation or sacral neuromodulation involves the implantation of a stimulating electrode lead through the sacral foramina. In patients with anatomical sacral anomalies, it can constitute a challenging procedure due to a lack of common reference points present in the normal anatomy. In this study, we present an innovative application of additive manufacturing for the planning of sacral nerve stimulation techniques and related surgical procedures in complex cases, and we verify that the use of personalized patient models may help to manage the presence of sacral anomalies. The use of two alternative additive manufacturing technologies working with thermoplastic and thermoset polymers, including fused deposition modeling as low-cost alternative and laser stereolithography as industrial gold standard, is compared in terms of viability, precision and overall production costs. They pay special attention to fidelity in terms of the bone microstructure reconstruction, which is necessary for adequately planning electrode insertion. Advantages and limitations of the alternative approaches are discussed and ideas for future developments and for solving current challenges are presented.

Rapid Prototyping of Personalized Articular Orthoses by Lamination of Composite Fibers upon 3D-Printed Molds.

Advances in additive manufacturing technologies and composite materials are starting to be combined into synergic procedures that may impact the biomedical field by helping to achieve personalized and high-performance solutions for low-resource settings. In this article, we illustrate the benefits of 3D-printed rapid molds, upon which composite fibers can be laminated in a direct and resource-efficient way, for the personalized development of articular splints. The rapid mold concept presented in this work allows for a flexible lamination and curing process, even compatible with autoclaves. We demonstrate the procedure by completely developing an autoclave-cured carbon fiber-epoxy composite ankle immobilizing, supporting, or protecting splint. These medical devices may support patients in their recovery of articular injuries and for promoting a more personalized medical care employing high-performance materials, whose mechanical response is analyzed and compared to that of commercial devices. In fact, this personalization is fundamental for enhanced ergonomics, comfort during rehabilitation, and overall aesthetics. The proposed design and manufacturing strategies may support the low-cost and user-centered development of a wide set of biomedical devices and help to delocalize the supply chain for involving local populations in the development of medical technology.

[Validation of point-of-care device for rapid detection of urinary tract infection and antibiotic susceptibility]. / Validación de un dispositivo point-of-care para la detección rápida de infección urinaria y susceptibilidad antimicrobiana.

BACKGROUND: Urinary tract infections (UTI) presents a high prevalence in the community setting. Rapid and accurate microbiological diagnosis is essential to ensure adequate and effective therapy. AIM: To evaluate a rapid antibiogram kit (KAR®) in point-of-care format for rapid detection of UTI and antibiotic susceptibility. METHODS: The KAR® device has been designed and developed in collaboration with technical engineers and clinical microbiologists. Its evaluation has been carried out through a multicenter study in which three Spanish hospitals have participated. Thus, different in vivo tests have been implemented in order to determine device correlation with the reference microbiological techniques. RESULTS: During the study period, a total of 400 urine samples from patients with suspected ITU were tested. The KAR® device provided fast results (mean positivity time of 7,8 ± 1,5 hours) with 97% sensitivity, 89% specificity and 87% agreement for the detection of significant bacteriuria. The percentages of specificity for the antibiotics tested were: ciprofloxacin (97%), fosfomycin (94%),cotrimoxazole (84%), ampicillin (80%) and amoxicillin/clavulanic acid (55%). CONCLUSION: The KAR® device could be a useful tool for diagnosing UTI in outpatients, especially in areas of low socio-economic level.

Modeling Living Cells Within Microfluidic Systems Using Cellular Automata Models.

Several computational models, both continuum and discrete, allow for the simulation of collective cell behaviors in connection with challenges linked to disease modeling and understanding. Normally, discrete cell modelling employs quasi-infinite or boundary-less 2D lattices, hence modeling collective cell behaviors in Petri dish-like environments. The advent of lab- and organ-on-a-chip devices proves that the information obtained from 2D cell cultures, upon Petri dishes, differs importantly from the results obtained in more biomimetic micro-fluidic environments, made of interconnected chambers and channels. However, discrete cell modelling within lab- and organ-on-a-chip devices, to our knowledge, is not yet found in the literature, although it may prove useful for designing and optimizing these types of systems. Consequently, in this study we focus on the establishment of a direct connection between the computer-aided designs (CAD) of microfluidic systems, especially labs- and organs-on-chips (and their multi-chamber and multi-channel structures), and the lattices for discrete cell modeling approaches aimed at the simulation of collective cell interactions, whose boundaries are defined directly from the CAD models. We illustrate the proposal using a quite straightforward cellular automata model, apply it to simulating cells with different growth rates, within a selected set of microsystem designs, and validate it by tuning the growth rates with the support of cell culture experiments and by checking the results with a real microfluidic system.

Biofabrication strategies for creating microvascular complexity.

Design and fabrication of effective biomimetic vasculatures constitutes a relevant and yet unsolved challenge, lying at the heart of tissue repair and regeneration strategies. Even if cell growth is achieved in 3D tissue scaffolds or advanced implants, tissue viability inevitably requires vascularization, as diffusion can only transport nutrients and eliminate debris within a few hundred microns. This engineered vasculature may need to mimic the intricate branching geometry of native microvasculature, referred to herein as vascular complexity, to efficiently deliver blood and recreate critical interactions between the vascular and perivascular cells as well as parenchymal tissues. This review first describes the importance of vascular complexity in labs- and organs-on-chips, the biomechanical and biochemical signals needed to create and maintain a complex vasculature, and the limitations of current 2D, 2.5D, and 3D culture systems in recreating vascular complexity. We then critically review available strategies for design and biofabrication of complex vasculatures in cell culture platforms, labs- and organs-on-chips, and tissue engineering scaffolds, highlighting their advantages and disadvantages. Finally, challenges and future directions are outlined with the hope of inspiring researchers to create the reliable, efficient and sustainable tools needed for design and biofabrication of complex vasculatures.

Engineering Human-Scale Artificial Bone Grafts for Treating Critical-Size Bone Defects.

The manufacturing of artificial bone grafts can potentially circumvent the issues associated with current bone grafting treatments for critical-size bone defects caused by pathological disorders, trauma, or massive tumor ablation. In this study, we report on a potentially patient-specific fabrication process in which replicas of bone defects, in particular zygomatic and mandibular bones and phalanxes of a hand finger, were manufactured by laser stereolithography and used as templates for the creation of PDMS molds. Gas-in-water foams were cast in the molds, rapidly frozen, freeze-dried, and cross-linked. Since bone matrix consists essentially of collagen and hydroxyapatite, biomimetic scaffolds were fabricated using gelatin and hydroxyapatite in a ratio very similar to that found in bone. The obtained composite scaffolds were excellent replicas of the original bone defects models and presented both a superficial and internal porous texture adequate for cellular and blood vessels infiltration. In particular, scaffolds exhibited a porous texture consisting of pores and interconnects with average size of about 300 and 100 µm, respectively, and a porosity of 90%. In vitro culture tests using hMSCs demonstrated scaffold biocompatibility and capacity in inducing differentiation toward osteoblasts progenitors. In vivo cellularized implants showed bone matrix deposition and recruitment of blood vessels. Overall, the technique/materials combination used in this work led to the fabrication of promising mechanically stable, bioactive, and biocompatible composite scaffolds with well-defined architectures potentially valuable in the regeneration of patient-specific bone defects.

Research on the Methods for the Mass Production of Multi-Scale Organs-On-Chips.

The success of labs- and organs-on-chips as transformative technologies in the biomedical arena relies on our capacity of solving some current challenges related to their design, modeling, manufacturability, and usability. Among present needs for the industrial scalability and impact promotion of these bio-devices, their sustainable mass production constitutes a breakthrough for reaching the desired level of repeatability in systematic testing procedures based on labs- and organs-on-chips. The use of adequate biomaterials for cell-culture processes and the achievement of the multi-scale features required, for in vitro modeling the physiological interactions among cells, tissues, and organoids, which prove to be demanding requirements in terms of production. This study presents an innovative synergistic combination of technologies, including: laser stereolithography, laser material processing on micro-scale, electroforming, and micro-injection molding, which enables the rapid creation of multi-scale mold cavities for the industrial production of labs- and organs-on-chips using thermoplastics apt for in vitro testing. The procedure is validated by the design, rapid prototyping, mass production, and preliminary testing with human mesenchymal stem cells of a conceptual multi-organ-on-chip platform, which is conceived for future studies linked to modeling cell-to-cell communication, understanding cell-material interactions, and studying metastatic processes.

Manufacturing of Polymeric Substrates with Copper Nanofillers through Laser Stereolithography Technique.

This study presents the additive manufacture of objects using mass-functionalized photo-resins, which are additively photopolymerized using the laser stereolithography technique. The mass functionalization is based on the incorporation of copper nanowires used as fillers at different concentrations. Cylindrical and tensile test probes are designed and manufactured in a layer-by-layer approach using a low-cost laser stereolithography system working with a layer thickness of 100   µ m . The morphological, mechanical, thermal and chemical results help to show the viability and potential that this combination of mass-functionalized resins and technological processes may have in the near future, once key challenges are solved. Finally, some potential applications are also discussed.