Discovering design principles of collagen molecular stability using a genetic algorithm, deep learning, and experimental validation.

Collagen is the most abundant structural protein in humans, providing crucial mechanical properties, including high strength and toughness, in tissues. Collagen-based biomaterials are, therefore, used for tissue repair and regeneration. Utilizing collagen effectively during materials processing ex vivo and subsequent function in vivo requires stability over wide temperature ranges to avoid denaturation and loss of structure, measured as melting temperature (Tm). Although significant research has been conducted on understanding how collagen primary amino acid sequences correspond to Tm values, a robust framework to facilitate the design of collagen sequences with specific Tm remains a challenge. Here, we develop a general model using a genetic algorithm within a deep learning framework to design collagen sequences with specific Tm values. We report 1,000 de novo collagen sequences, and we show that we can efficiently use this model to generate collagen sequences and verify their Tm values using both experimental and computational methods. We find that the model accurately predicts Tm values within a few degrees centigrade. Further, using this model, we conduct a high-throughput study to identify the most frequently occurring collagen triplets that can be directly incorporated into collagen. We further discovered that the number of hydrogen bonds within collagen calculated with molecular dynamics (MD) is directly correlated to the experimental measurement of triple-helical quality. Ultimately, we see this work as a critical step to helping researchers develop collagen sequences with specific Tm values for intended materials manufacturing methods and biomedical applications, realizing a mechanistic materials by design paradigm.

Emerging Multiscale Biofabrication Approaches for Bacteriotherapy.

Bacteriotherapy is emerging as a strategic and effective approach to treat infections by providing putatively harmless bacteria (i.e., probiotics) as antagonists to pathogens. Proper delivery of probiotics or their metabolites (i.e., post-biotics) can facilitate their availing of biomaterial encapsulation via innovative manufacturing technologies. This review paper aims to provide the most recent biomaterial-assisted strategies proposed to treat infections or dysbiosis using bacteriotherapy. We revised the encapsulation processes across multiscale biomaterial approaches, which could be ideal for targeting different tissues and suit diverse therapeutic opportunities. Hydrogels, and specifically polysaccharides, are the focus of this review, as they have been reported to better sustain the vitality of the live cells incorporated. Specifically, the approaches used for fabricating hydrogel-based devices with increasing dimensionality (D)-namely, 0D (i.e., particles), 1D (i.e., fibers), 2D (i.e., fiber meshes), and 3D (i.e., scaffolds)-endowed with probiotics, were detailed by describing their advantages and challenges, along with a future overlook in the field. Electrospinning, electrospray, and 3D bioprinting were investigated as new biofabrication methods for probiotic encapsulation within multidimensional matrices. Finally, examples of biomaterial-based systems for cell and possibly post-biotic release were reported.

Soft, strong, tough, and durable bio-hydrogels via maximizing elastic entropy.

Load-bearing soft tissues are soft but strong, strong yet tough. These properties can only be replicated in synthetic hydrogels, which do not have the biocomplexity required by many biomedical applications. By contrast, natural hydrogels, although retaining the native complexity, are weak and fragile. Here we present a thermomechanical casting method to achieve the mechanical capabilities of synthetic materials in biopolymer hydrogels. The thermomechanical cast and chemically crosslinked biopolymer chains form a short-range disordered but long-range ordered structure in water. Upon stretch, the disordered structure transforms to a hierarchically ordered structure. This disorder-order transformation resembles the synergy of the disordered elastin and ordered collagen in load-bearing soft tissues. As entropy drives a reverse order-disorder transformation, the hydrogels can resist repeated cycles of loads without deterioration in mechanical properties. Gelatin hydrogels produced by this method combine tissue-like tunable mechanical properties that outperform the gelatin prepared by synthetic approaches, and in vivo biocomplexity beyond current natural systems. Unlike polymer engineering approaches, which rely on specific crosslinks provided by special polymers, this strategy utilizes the entropy of swollen chains and is generalizable to many other biopolymers. It could thus significantly accelerate translational success of biomaterials.

Assessment of Electrospun Poly(ε-caprolactone) and Poly(lactic acid) Fiber Scaffolds to Generate 3D In Vitro Models of Colorectal Adenocarcinoma: A Preliminary Study.

Three-dimensional scaffold-based culture has been increasingly gaining influence in oncology as a therapeutic strategy for tumors with a high relapse percentage. This study aims to evaluate electrospun poly(ε-caprolactone) (PCL) and poly(lactic acid) (PLA) scaffolds to create a 3D model of colorectal adenocarcinoma. Specifically, the physico-mechanical and morphological properties of PCL and PLA electrospun fiber meshes collected at different drum velocities, i.e., 500 rpm, 1000 rpm and 2500 rpm, were assessed. Fiber size, mesh porosity, pore size distribution, water contact angle and tensile mechanical properties were investigated. Caco-2 cells were cultured on the produced PCL and PLA scaffolds for 7 days, demonstrating good cell viability and metabolic activity in all the scaffolds. A cross-analysis of the cell-scaffold interactions with morphological, mechanical and surface characterizations of the different electrospun fiber meshes was carried out, showing an opposite trend of cell metabolic activity in PLA and PCL scaffolds regardless of the fiber alignment, which increased in PLA and decreased in PCL. The best samples for Caco-2 cell culture were PCL500 (randomly oriented fibers) and PLA2500 (aligned fibers). Caco-2 cells had the highest metabolic activity in these scaffolds, with Young's moduli in the range of 8.6-21.9 MPa. PCL500 showed Young's modulus and strain at break close to those of the large intestine. Advancements in 3D in vitro models of colorectal adenocarcinoma could move forward the development of therapies for this cancer.

Experimental Assessment of Cuff Pressures on the Walls of a Trachea-Like Model Using Force Sensing Resistors: Insights for Patient Management in Intensive Care Unit Settings.

The COVID-19 outbreak has increased the incidence of tracheal lesions in patients who underwent invasive mechanical ventilation. We measured the pressure exerted by the cuff on the walls of a test bench mimicking the laryngotracheal tract. The test bench was designed to acquire the pressure exerted by endotracheal tube cuffs inflated inside an artificial model of a human trachea. The experimental protocol consisted of measuring pressure values before and after applying a maneuver on two types of endotracheal tubes placed in two mock-ups resembling two different sized tracheal tracts. Increasing pressure values were used to inflate the cuff and the pressures were recorded in two different body positions. The recorded pressure increased proportionally to the input pressure. Moreover, the pressure values measured when using the non-armored (NA) tube were usually higher than those recorded when using the armored (A) tube. A periodic check of the cuff pressure upon changing the body position and/or when performing maneuvers on the tube appears to be necessary to prevent a pressure increase on the tracheal wall. In addition, in our model, the cuff of the A tube gave a more stable output pressure on the tracheal wall than that of the NA tube.

Visual-Based Defect Detection and Classification Approaches for Industrial Applications-A SURVEY.

This paper reviews automated visual-based defect detection approaches applicable to various materials, such as metals, ceramics and textiles. In the first part of the paper, we present a general taxonomy of the different defects that fall in two classes: visible (e.g., scratches, shape error, etc.) and palpable (e.g., crack, bump, etc.) defects. Then, we describe artificial visual processing techniques that are aimed at understanding of the captured scenery in a mathematical/logical way. We continue with a survey of textural defect detection based on statistical, structural and other approaches. Finally, we report the state of the art for approaching the detection and classification of defects through supervised and non-supervised classifiers and deep learning.

Sounds interesting: can sonification help us design new proteins?

Introduction: The practice of turning scientific data into music, a practice known as sonification, is a growing field. Driven by analogies between the hierarchical structures of proteins and many forms of music, multiple attempts of mapping proteins to music have been made. Previous works have either worked at a low level, mapping amino acid to notes, or at a higher level, using the overall structure as a basis for composition.Areas covered: We report a comprehensive mapping strategy that encompasses the encoding of the geometry of proteins, in addition to the amino acid sequence and secondary structure information. This leads to a piece of music that is both more complete and closely linked to the original protein. By using this mapping, we can invert the process and map music to proteins, retrieving not only the amino acid sequence but also the secondary structure and folding from musical data.Expert opinion: We can train a machine learning model on 'protein music' to generate new music that can be translated to new proteins. By selecting proper datasets and conditioning parameters on the generative model, we could tune de novo proteins with high level parameters to achieve certain protein design features.

Tongue Rehabilitation Device for Dysphagic Patients.

Dysphagia refers to difficulty in swallowing often associated with syndromic disorders. In dysphagic patients' rehabilitation, tongue motility is usually treated and monitored via simple exercises, in which the tongue is pushed against a depressor held by the speech therapist in different directions. In this study, we developed and tested a simple pressure/force sensor device, named "Tonic Tongue (ToTo)", intended to support training and monitoring tasks for the rehabilitation of tongue musculature. It consists of a metallic frame holding a ball bearing support equipped with a sterile disposable depressor, whose angular displacements are counterbalanced by extensional springs. The conversion from angular displacement to force is managed using a simple mechanical model of ToTo operation. Since the force exerted by the tongue in various directions can be estimated, quantitative assessment of the outcome of a given training program is possible. A first prototype of ToTo was tested on 26 healthy adults, who were trained for one month. After the treatment, we observed a statistically significant improvement with a force up to 2.2 N (median value) in all tested directions of pushing, except in the downward direction, in which the improvement was slightly higher than 5 N (median value). ToTo promises to be an innovative and reliable device that can be used for the rehabilitation of dysphagic patients. Moreover, since it is a self-standing device, it could be used as a point-of-care solution for in-home rehabilitation management of dysphasia.

3D fiber deposited polymeric scaffolds for external auditory canal wall.

The external auditory canal (EAC) is an osseocartilaginous structure extending from the auricle to the eardrum, which can be affected by congenital, inflammatory, and neoplastic diseases, thus reconstructive materials are needed. Current biomaterial-based approaches for the surgical reconstruction of EAC posterior wall still suffer from resorption (biological) and extrusion (synthetic). In this study, 3D fiber deposited scaffolds based on poly(ethylene oxide terephthalate)/poly(butylene terephthalate) were designed and fabricated to replace the EAC wall. Fiber diameter and scaffold porosity were optimized, leading to 200 ± 33 µm and 55% ± 5%, respectively. The mechanical properties were evaluated, resulting in a Young's modulus of 25.1 ± 7.0 MPa. Finally, the EAC scaffolds were tested in vitro with osteo-differentiated human mesenchymal stromal cells (hMSCs) with different seeding methods to produce homogeneously colonized replacements of interest for otologic surgery. This study demonstrated the fabrication feasibility of EAC wall scaffolds aimed to match several important requirements for biomaterial application to the ear under the Tissue Engineering paradigm, including shape, porosity, surface area, mechanical properties and favorable in vitro interaction with osteoinduced hMSCs. This study demonstrated the fabrication feasibility of outer ear canal wall scaffolds via additive manufacturing. Aimed to match several important requirements for biomaterial application to ear replacements under the Tissue Engineering paradigm, including shape, porosity and pore size, surface area, mechanical properties and favorable in vitro interaction with osteo-differentiated mesenchymal stromal cells.

Piezoelectric energy harvesting solutions.

This paper reviews the state of the art in piezoelectric energy harvesting. It presents the basics of piezoelectricity and discusses materials choice. The work places emphasis on material operating modes and device configurations, from resonant to non-resonant devices and also to rotational solutions. The reviewed literature is compared based on power density and bandwidth. Lastly, the question of power conversion is addressed by reviewing various circuit solutions.

3D Printed Piezoelectric BaTiO3/Polyhydroxybutyrate Nanocomposite Scaffolds for Bone Tissue Engineering.

Bone defects are a significant health problem worldwide. Novel treatment approaches in the tissue engineering field rely on the use of biomaterial scaffolds to stimulate and guide the regeneration of damaged tissue that cannot repair or regrow spontaneously. This work aimed at developing and characterizing new piezoelectric scaffolds to provide electric bio-signals naturally present in bone and vascular tissues. Mixing and extrusion were used to obtain nanocomposites made of polyhydroxybutyrate (PHB) as a matrix and barium titanate (BaTiO3) nanoparticles as a filler, at BaTiO3/PHB compositions of 5/95, 10/90, 15/85 and 20/80 (w/w%). The morphological, thermal, mechanical and piezoelectric properties of the nanocomposites were studied. Scanning electron microscopy analysis showed good nanoparticle dispersion within the polymer matrix. Considerable increases in the Young's modulus, compressive strength and the piezoelectric coefficient d31 were observed with increasing BaTiO3 content, with d31 = 37 pm/V in 20/80 (w/w%) BaTiO3/PHB. 3D printing was used to produce porous cubic-shaped scaffolds using a 90° lay-down pattern, with pore size ranging in 0.60-0.77 mm and good mechanical stability. Biodegradation tests conducted for 8 weeks in saline solution at 37 °C showed low mass loss (∼4%) for 3D printed scaffolds. The results obtained in terms of piezoelectric, mechanical and chemical properties of the nanocomposite provide a new promising strategy for vascularized bone tissue engineering.

Characterization of Cyclic Olefin Copolymers for Insulin Reservoir in an Artificial Pancreas.

Type-1 diabetes is one of the most prevalent metabolic disorders worldwide. It results in a significant lack of insulin production by the pancreas and the ensuing hyperglycemia, which needs to be regulated through a tailored administration of insulin throughout the day. Recent studies have shown great advancements in developing an implantable artificial pancreas. However, some improvements are still required, including the optimal biomaterials and technologies to produce the implantable insulin reservoir. Here, we discuss the employment of two types of cyclic olefin copolymers (Topas 5013L-10 and Topas 8007S-04) for an insulin reservoir fabrication. After a preliminary thermomechanical analysis, Topas 8007S-04 was selected as the best material to fabricate a 3D-printed insulin reservoir due to its higher strength and lower glass transition temperature (Tg). Fiber deposition modeling was used to manufacture a reservoir-like structure, which was employed to assess the ability of the material to prevent insulin aggregation. Although the surface texture presents a localized roughness, the ultraviolet analysis did not detect any significant insulin aggregation over a timeframe of 14 days. These interesting results make Topas 8007S-04 cyclic olefin copolymer a potential candidate biomaterial for fabricating structural components in an implantable artificial pancreas.

3D Printability of Silk/Hydroxyapatite Composites for Microprosthetic Applications.

Micro-prosthetics requires the fabrication of mechanically robust and personalized components with sub-millimetric feature accuracy. Three-dimensional (3D) printing technologies have had a major impact on manufacturing such miniaturized devices for biomedical applications; however, biocompatibility requirements greatly constrain the choice of usable materials. Hydroxyapatite (HA) and its composites have been widely employed to fabricate bone-like structures, especially at the macroscale. In this work, we investigate the rheology, printability, and prosthetic mechanical properties of HA and HA-silk protein composites, focusing on the roles of composition and water content. We correlate key linear and nonlinear shear rheological parameters to geometric outcomes of printing and explain how silk compensates for the inherent brittleness of printed HA components. By increasing ink ductility, the inclusion of silk improves the quality of printed items through two mechanisms: (1) reducing underextrusion by lowering the required elastic modulus and, (2) reducing slumping by increasing the ink yield stress proportional to the modulus. We demonstrate that the elastic modulus and compressive strength of parts fabricated from silk-HA inks are higher than those for rheologically comparable pure-HA inks. We construct a printing map to guide the manufacturing of HA-based inks with excellent final properties, especially for use in biomedical applications for which sub-millimetric features are required.

Evaluation of Anal Sphincter with High Resolution Anorectal Manometry and 3D Reconstruction in Patients with Anorectal Malformation.

BACKGROUND: Patients with anorectal malformation (ARM) need long-term follow-up, in order to evaluate fecal continence; the main predictors of longer-term success are the type of ARM, associated anomalies and sacral integrity. Three-Dimensional High Resolution Anorectal Manometry (3D-HRAM) gives detailed information on pressure on the anal complex profile. Our objective was to analyze anal sphincter activity in ARM patients with 3D-HRAM establishing the correlation between manometric and clinical data. METHODS: Forty ARM patients were submitted to 3D-HRAM: manometric, anatomical and clinical scores were correlated with each other and with the bowel management response (BM). RESULTS: A positive correlation between all scores and types of ARM was found: in high ARM and in patients with spinal anomalies (regardless to ARM type) lower scores were reported and even after BM they did not achieve good continence. CONCLUSIONS: 3D-HRAM gives detailed data on the functional activity of the anal sphincter complex. Our study revealed a correlation between manometric parameters and clinical outcomes, confirming spinal malformations and ARM type as the most important prognostic risk factors for a bad outcome. Specific sphincteric defects can also be explored with manometry, allowing for tailored bowel management strategies.

Sensing Devices for Detecting and Processing Acoustic Signals in Healthcare.

Acoustic signals are important markers to monitor physiological and pathological conditions, e.g., heart and respiratory sounds. The employment of traditional devices, such as stethoscopes, has been progressively superseded by new miniaturized devices, usually identified as microelectromechanical systems (MEMS). These tools are able to better detect the vibrational content of acoustic signals in order to provide a more reliable description of their features (e.g., amplitude, frequency bandwidth). Starting from the description of the structure and working principles of MEMS, we provide a review of their emerging applications in the healthcare field, discussing the advantages and limitations of each framework. Finally, we deliver a discussion on the lessons learned from the literature, and the open questions and challenges in the field that the scientific community must address in the near future.

Shanghai Fever: Not Only an Asian Disease.

Objectives: To describe a case of Shanghai fever disease and to analyze other published reports in non-Asiatic countries, defining clinical characteristics and highlighting that this is not only an Asian disease. Study design: A computerized search without language restriction was conducted using PubMed and Scopus; all references listed were hand-searched to identify any other relevant literature. An article was considered eligible for inclusion in the systematic review if it reported cases with Shanghai fever described in non-Asiatic countries. Our case was also included in the analysis. Results: Ten articles reporting 10 cases of Shanghai fever disease were considered. Fever, diarrhea and ecthyma gangrenosum were the most frequent symptoms observed. Blood was the most common site of isolation for Pseudomonas aeruginosa. Three patients underwent surgery due to necrotizing enteritis and intestinal perforation. Meningitis was documented in one case. None of the patients received antipseudomonal antibiotics within 24 h of admission. The outcome was good in nine cases; only one patient died due to multiple organ failure from Pseudomonas sepsis. No common primary immune deficiency was identified in these patients. Extremely young age (<1 year) was the only host factor predisposing to Shanghai fever. Conclusions: It is important to shed light on this disease in non-Asiatic countries and take into account that it can also affect healthy children. Pediatricians, therefore, should consider Shanghai fever among diagnoses in children with community-onset diarrhea, fever and skin lesions suggestive of ecthyma gangrenosum to start an appropriate treatment sooner and to reduce the mortality in these children.

Evaluation of Dysphagia and Inhalation Risk in Neurologically Impaired Children Using Esophageal High-Resolution Manometry with Swallowing Analysis.

BACKGROUND: Dysphagia in neurologically impaired children is associated with feeding difficulties, malnutrition and aspiration pneumonia. Esophageal high-resolution manometry (HRM) has been used in the diagnosis of motility disorders affecting the swallowing process. The aim of this study was to analyze swallowing functions in NI children by using HRM in order to establish swallow parameters identifying inhalation risk. METHODS: Twenty-five NI children with cerebral palsy were submitted to esophageal HRM with UES analysis, comparing the results with non-NI children. The following parameters were evaluated: maximum pressure and duration of contraction of the velopharynx (VP) and tongue base (TB), and maximal, minimal, resting pressure and relaxation duration of the upper esophageal sphincter (UES). RESULTS: pVP max, pTB max, pUES max and resting pressure were lower, while p UES minimal was higher and relaxation duration was shorter in NI children vs. the control group. Predictive values of inhalation risk were evaluated. CONCLUSIONS: This study evaluates inhalation risk in NI children using HRM to study UES function. Our results confirm the alterations described in NI children: insufficient contraction and clearing force for bolus transmission through the pharynx and incomplete UES relaxation can predispose to pharyngeal residues and inhalation independently of swallowing because of lower values of UES resting.

Designing and fabricating materials from fire using sonification and deep learning.

Fire has fascinated humankind since the prehistoric era. Rooted in the interactions between sound and flames, here we report a method to use fire for a variety of purposes, including sonification, art, and the design and manufacturing nature-inspired materials. We present a method to sonify fire, thereby offering a translation from the silent nature of flames, to represent audible information and to generate de novo flame images. To realize material specimen derived from fire, we use the autoencoder to generate image stacks to yield continuous 3D geometries that are manufactured using 3D printing. This represents the first generation of nature-inspired materials from fire and can be a platform to be used for other natural phenomena in the quest for de novo architectures, geometries, and design ideas, thus creating additional directions in artistic and scientific research through the creative manipulation of data with structural similarities across fields.

Cellulose-Based Fibrous Materials From Bacteria to Repair Tympanic Membrane Perforations.

Perforation is the most common illness of the tympanic membrane (TM), which is commonly treated with surgical procedures. The success rate of the treatment could be improved by novel bioengineering approaches. In fact, a successful restoration of a damaged TM needs a supporting biomaterial or scaffold able to meet mechano-acoustic properties similar to those of the native TM, along with optimal biocompatibility. Traditionally, a large number of biological-based materials, including paper, silk, Gelfoam®, hyaluronic acid, collagen, and chitosan, have been used for TM repair. A novel biopolymer with promising features for tissue engineering applications is cellulose. It is a highly biocompatible, mechanically and chemically strong polysaccharide, abundant in the environment, with the ability to promote cellular growth and differentiation. Bacterial cellulose (BC), in particular, is produced by microorganisms as a nanofibrous three-dimensional structure of highly pure cellulose, which has thus become a popular graft material for wound healing due to a number of remarkable properties, such as water retention, elasticity, mechanical strength, thermal stability, and transparency. This review paper provides a comprehensive overview of the current experimental studies of BC, focusing on the application of BC patches in the treatment of TM perforations. In addition, computational approaches to model cellulose and TM are summarized, with the aim to synergize the available tools toward the best design and exploitation of BC patches and scaffolds for TM repair and regeneration.

Bioinspired translation of classical music intode novoprotein structures using deep learning and molecular modeling.

Architected biomaterials, as well as sound and music, are constructed from small building blocks that are assembled across time- and length-scales. Here we present a novel deep learning-enabled integrated algorithmic workflow to merge the two concepts for radical discovery ofde novoprotein materials, exploiting musical creativity as the foundation, and extrapolating through a recursive method to increase protein complexity by successively injecting protein chemistry into the process. Indeed, music is one of the few universal expressions that can create bridges between cultures, find associations between seemingly unrelated concepts, and can be used as a novel way to generate bio-inspired designs that derive functions from the imaginations of the creative mind. Earlier work has offered a pathway to convert proteins into sound, and sound into proteins. Here we build on this paradigm and translate a piece of classical music into matter. Based on Bach's Goldberg variations, we offer a series of case studies to convert the musical data imagined by the composer into protein design, and folded into a 3D structure using deep learning. The quest we seek to address is to identify semblances, or memories, or information content in such musical creation, that offers new insights into pattern relationships between distinct manifestations of information. Using basic local alignment search tool analysis, we find that several fragments of the new proteins display similarities to existing protein sequences found in proteobacteria among other organisms, especially in regions of low complexity and repetitive motifs. The resulting protein forms the basis for iterative musical composition, and an evolutionary paradigm that defines a variational pathway for melodic development, complementing conventional creative or mathematical methods. This paper broadens the concept of what is understood as bio-inspiration to include a broad array of systems created by humans, animals, or other natural mechanisms.