Engineered Hemostatic Biomaterials for Sealing Wounds.

Hemostatic biomaterials show great promise in wound control for the treatment of uncontrolled bleeding associated with damaged tissues, traumatic wounds, and surgical incisions. A surge of interest has been directed at boosting hemostatic properties of bioactive materials via mechanisms triggering the coagulation cascade. A wide variety of biocompatible and biodegradable materials has been applied to the design of hemostatic platforms for rapid blood coagulation. Recent trends in the design of hemostatic agents emphasize chemical conjugation of charged moieties to biomacromolecules, physical incorporation of blood-coagulating agents in biomaterials systems, and superabsorbing materials in either dry (foams) or wet (hydrogel) states. In addition, tough bioadhesives are emerging for efficient and physical sealing of incisions. In this Review, we highlight the biomacromolecular design approaches adopted to develop hemostatic bioactive materials. We discuss the mechanistic pathways of hemostasis along with the current standard experimental procedures for characterization of the hemostasis efficacy. Finally, we discuss the potential for clinical translation of hemostatic technologies, future trends, and research opportunities for the development of next-generation surgical materials with hemostatic properties for wound management.

A Microfluidic Contact Lens to Address Contact Lens-Induced Dry Eye.

The contact lens (CL) industry has made great strides in improving CL-wearing experiences. However, a large amount of CL wearers continue to experience ocular dryness, known as contact lens-induced dry eye (CLIDE), stemming from the reduction in tear volume, tear film instability, increased tear osmolarity followed by inflammation and resulting in ocular discomfort and visual disturbances. In this article, to address tear film thinning between the CL and the ocular surface, the concept of using a CL with microchannels to deliver the tears from the pre-lens tear film (PrLTF) to the post-lens ocular surface using in vitro eye-blink motion is investigated. This study reports an eye-blink mimicking system with microfluidic poly(2-hydroxyethyl methacrylate) (poly(HEMA)) hydrogel with integrated microchannels to demonstrate eye-blink assisted flow through microchannels. This in vitro experimental study provides a proof-of-concept result that tear transport from PrLTF to post-lens tear film can be enhanced by an artificial eyelid motion in a pressure range of 0.1-5 kPa (similar to human eyelid pressure) through poly(HEMA) microchannels. Simulation is conducted to support the hypothesis. This work demonstrates the feasibility of developing microfluidic CLs with the potential to help prevent or minimize CLIDE and discomfort by the enhanced transport of pre-lens tears to the post-lens ocular surface.

Bio-macromolecular design roadmap towards tough bioadhesives.

Emerging sutureless wound-closure techniques have led to paradigm shifts in wound management. State-of-the-art biomaterials offer biocompatible and biodegradable platforms enabling high cohesion (toughness) and adhesion for rapid bleeding control as well as robust attachment of implantable devices. Tough bioadhesion stems from the synergistic contributions of cohesive and adhesive interactions. This Review provides a biomacromolecular design roadmap for the development of tough adhesive surgical sealants. We discuss a library of materials and methods to introduce toughness and adhesion to biomaterials. Intrinsically tough and elastic polymers are leveraged primarily by introducing strong but dynamic inter- and intramolecular interactions either through polymer chain design or using crosslink regulating additives. In addition, many efforts have been made to promote underwater adhesion via covalent/noncovalent bonds, or through micro/macro-interlock mechanisms at the tissue interfaces. The materials settings and functional additives for this purpose and the related characterization methods are reviewed. Measurements and reporting needs for fair comparisons of different materials and their properties are discussed. Finally, future directions and further research opportunities for developing tough bioadhesive surgical sealants are highlighted.

Micro and Nanoscale Technologies for Diagnosis of Viral Infections.

Viral infection is one of the leading causes of mortality worldwide. The growth of globalization significantly increases the risk of virus spreading, making it a global threat to future public health. In particular, the ongoing coronavirus disease 2019 (COVID-19) pandemic outbreak emphasizes the importance of devices and methods for rapid, sensitive, and cost-effective diagnosis of viral infections in the early stages by which their quick and global spread can be controlled. Micro and nanoscale technologies have attracted tremendous attention in recent years for a variety of medical and biological applications, especially in developing diagnostic platforms for rapid and accurate detection of viral diseases. This review addresses advances of microneedles, microchip-based integrated platforms, and nano- and microparticles for sampling, sample processing, enrichment, amplification, and detection of viral particles and antigens related to the diagnosis of viral diseases. Additionally, methods for the fabrication of microchip-based devices and commercially used devices are described. Finally, challenges and prospects on the development of micro and nanotechnologies for the early diagnosis of viral diseases are highlighted.

Nano-porous anodic alumina: fundamentals and applications in tissue engineering.

Recently, nanomaterials have been widely utilized in tissue engineering applications due to their unique properties such as the high surface to volume ratio and diversity of morphology and structure. However, most methods used for the fabrication of nanomaterials are rather complicated and costly. Among different nanomaterials, anodic aluminum oxide (AAO) is a great example of nanoporous structures that can easily be engineered by changing the electrolyte type, anodizing potential, current density, temperature, acid concentration and anodizing time. Nanoporous anodic alumina has often been used for mammalian cell culture, biofunctionalization, drug delivery, and biosensing by coating its surface with biocompatible materials. Despite its wide application in tissue engineering, thorough in vivo and in vitro studies of AAO are still required to enhance its biocompatibility and thereby pave the way for its application in tissue replacements. Recognizing this gap, this review article aims to highlight the biomedical potentials of AAO for applications in tissue replacements along with the mechanism of porous structure formation and pore characteristics in terms of fabrication parameters.

Poly-Catecholic Functionalization of Biomolecules for Rapid Gelation, Robust Injectable Bioadhesion, and Near-Infrared Responsiveness.

Mussel-inspired catechol-functionalization of degradable natural biomaterials has garnered significant interest as an approach to achieve bioadhesion for sutureless wound closure. However, conjugation capacity in standard coupling reactions, such as carbodiimide chemistry, is limited by low yield and lack of abundant conjugation sites. Here, a simple oxidative polymerization step before conjugation of catechol-carrying molecules (i.e., 3,4-dihydroxy-l-phenylalanine, l-DOPA) as a potential approach to amplify catechol function in bioadhesion of natural gelatin biomaterials is proposed. Solutions of gelatin modified with poly(l-DOPA) moieties (GelDOPA) are characterized by faster physical gelation and increased viscosity, providing better wound control on double-curved tissue surfaces compared to those of l-DOPA-conjugated gelatin. Physical hydrogels treated topically with low concentrations of NaIO4 solutions are crosslinked on-demand via through-thickness diffusion. Poly(l-DOPA) conjugates enhance crosslinking density compared to l-DOPA conjugated gelatin, resulting in lower swelling and enhanced cohesion in physiological conditions. Together with cohesion, more robust bioadhesion at body temperature is achieved by poly(l-DOPA) conjugates, exceeding those of commercial sealants. Further, poly(l-DOPA) motifs introduced photothermal responsiveness via near-infrared (NIR) irradiation for controlled drug release and potential applications in photothermal therapy. The above functionalities, along with antibacterial activity, render the proposed approach an effective biomaterial design strategy for wound closure applications.

A wireless patch for the monitoring of C-reactive protein in sweat.

The quantification of protein biomarkers in blood at picomolar-level sensitivity requires labour-intensive incubation and washing steps. Sensing proteins in sweat, which would allow for point-of-care monitoring, is hindered by the typically large interpersonal and intrapersonal variations in its composition. Here we report the design and performance of a wearable and wireless patch for the real-time electrochemical detection of the inflammatory biomarker C-reactive (CRP) protein in sweat. The device integrates iontophoretic sweat extraction, microfluidic channels for sweat sampling and for reagent routing and replacement, and a graphene-based sensor array for quantifying CRP (via an electrode functionalized with anti-CRP capture antibodies-conjugated gold nanoparticles), ionic strength, pH and temperature for the real-time calibration of the CRP sensor. In patients with chronic obstructive pulmonary disease, with active or past infections or who had heart failure, the elevated concentrations of CRP measured via the patch correlated well with the protein's levels in serum. Wearable biosensors for the real-time sensitive analysis of inflammatory proteins in sweat may facilitate the management of chronic diseases.

Aerogel-Based Biomaterials for Biomedical Applications: From Fabrication Methods to Disease-Targeting Applications.

Aerogel-based biomaterials are increasingly being considered for biomedical applications due to their unique properties such as high porosity, hierarchical porous network, and large specific pore surface area. Depending on the pore size of the aerogel, biological effects such as cell adhesion, fluid absorption, oxygen permeability, and metabolite exchange can be altered. Based on the diverse potential of aerogels in biomedical applications, this paper provides a comprehensive review of fabrication processes including sol-gel, aging, drying, and self-assembly along with the materials that can be used to form aerogels. In addition to the technology utilizing aerogel itself, it also provides insight into the applicability of aerogel based on additive manufacturing technology. To this end, how microfluidic-based technologies and 3D printing can be combined with aerogel-based materials for biomedical applications is discussed. Furthermore, previously reported examples of aerogels for regenerative medicine and biomedical applications are thoroughly reviewed. A wide range of applications with aerogels including wound healing, drug delivery, tissue engineering, and diagnostics are demonstrated. Finally, the prospects for aerogel-based biomedical applications are presented. The understanding of the fabrication, modification, and applicability of aerogels through this study is expected to shed light on the biomedical utilization of aerogels.

Template-Enabled Biofabrication of Thick 3D Tissues with Patterned Perfusable Macrochannels.

Interconnected pathways in 3D bioartificial organs are essential to retaining cell activity in thick functional 3D tissues. 3D bioprinting methods have been widely explored in biofabrication of functionally patterned tissues; however, these methods are costly and confined to thin tissue layers due to poor control of low-viscosity bioinks. Here, cell-laden hydrogels that could be precisely patterned via water-soluble gelatin templates are constructed by economical extrusion 3D printed plastic templates. Tortuous co-continuous plastic networks, designed based on triply periodic minimal surfaces (TPMS), serve as a sacrificial pattern to shape the secondary sacrificial gelatin templates. These templates are eventually used to form cell-encapsulated gelatin methacryloyl (GelMA) hydrogel scaffolds patterned with the complex interconnected pathways. The proposed fabrication process is compatible with photo-crosslinkable hydrogels wherein prepolymer casting enables incorporation of high cell populations with high viability. The cell-laden hydrogel constructs are characterized by robust mechanical behavior. In vivo studies demonstrate a superior cell ingrowth into the highly permeable constructs compared to the bulk hydrogels. Perfusable complex interconnected networks within cell-encapsulated hydrogels may assist in engineering thick and functional tissue constructs through the permeable internal channels for efficient cellular activities in vivo.

Additively manufactured metallic biomaterials.

Metal additive manufacturing (AM) has led to an evolution in the design and fabrication of hard tissue substitutes, enabling personalized implants to address each patient's specific needs. In addition, internal pore architectures integrated within additively manufactured scaffolds, have provided an opportunity to further develop and engineer functional implants for better tissue integration, and long-term durability. In this review, the latest advances in different aspects of the design and manufacturing of additively manufactured metallic biomaterials are highlighted. After introducing metal AM processes, biocompatible metals adapted for integration with AM machines are presented. Then, we elaborate on the tools and approaches undertaken for the design of porous scaffold with engineered internal architecture including, topology optimization techniques, as well as unit cell patterns based on lattice networks, and triply periodic minimal surface. Here, the new possibilities brought by the functionally gradient porous structures to meet the conflicting scaffold design requirements are thoroughly discussed. Subsequently, the design constraints and physical characteristics of the additively manufactured constructs are reviewed in terms of input parameters such as design features and AM processing parameters. We assess the proposed applications of additively manufactured implants for regeneration of different tissue types and the efforts made towards their clinical translation. Finally, we conclude the review with the emerging directions and perspectives for further development of AM in the medical industry.

Droplet-based microfluidics in biomedical applications.

Droplet-based microfluidic systems have been employed to manipulate discrete fluid volumes with immiscible phases. Creating the fluid droplets at microscale has led to a paradigm shift in mixing, sorting, encapsulation, sensing, and designing high throughput devices for biomedical applications. Droplet microfluidics has opened many opportunities in microparticle synthesis, molecular detection, diagnostics, drug delivery, and cell biology. In the present review, we first introduce standard methods for droplet generation (i.e. passive and active methods) and discuss the latest examples of emulsification and particle synthesis approaches enabled by microfluidic platforms. Then, the applications of droplet-based microfluidics in different biomedical applications are detailed. Finally, a general overview of the latest trends along with the perspectives and future potentials in the field are provided.

Stretchable and Bioadhesive Gelatin Methacryloyl-Based Hydrogels Enabled by in Situ Dopamine Polymerization.

Hydrogel patches with high toughness, stretchability, and adhesive properties are critical to healthcare applications including wound dressings and wearable devices. Gelatin methacryloyl (GelMA) provides a highly biocompatible and accessible hydrogel platform. However, low tissue adhesion and poor mechanical properties of cross-linked GelMA patches (i.e., brittleness and low stretchability) have been major obstacles to their application for sealing and repair of wounds. Here, we show that adding dopamine (DA) moieties in larger quantities than those of conjugated counterparts to the GelMA prepolymer solution followed by alkaline DA oxidation could result in robust mechanical and adhesive properties in GelMA-based hydrogels. In this way, cross-linked patches with ∼140% stretchability and ∼19 000 J/m3 toughness, which correspond to ∼5.7 and ∼3.3× improvement, respectively, compared to that of GelMA controls, were obtained. The DA oxidization in the prepolymer solution was found to play an important role in activating adhesive properties of cross-linked GelMA patches (∼4.0 and ∼6.9× increase in adhesion force under tensile and shear modes, respectively) due to the presence of reactive oxidized quinone species. We further conducted a parametric study on the factors such as UV light parameters, the photoinitiator type (i.e., lithium phenyl-2,4,6-trimethylbenzoylphosphinate, LAP, versus 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone, Irgacure 2959), and alkaline DA oxidation to tune the cross-linking density and thereby hydrogel compliance for better adhesive properties. The superior adhesion performance of the resulting hydrogel along with in vitro cytocompatibility demonstrated its potential for use in skin-attachable substrates.

Reliability, Criterion and Concurrent Validity of the Farsi Translation of DIVA-5: A Semi-Structured Diagnostic Interview for Adults With ADHD.

Objectives: This study evaluated the psychometrics of the Farsi translation of diagnostic interview for attention-deficit hyperactivity disorder (ADHD) in adults (DIVA-5) based on DSM-5 criteria. Methods: Referrals to a psychiatric outpatient clinic (N = 120, 61.7% males, mean age 34.35 ± 9.84 years) presenting for an adult ADHD (AADHD) diagnosis, were evaluated using the structured clinical interviews for DSM-5 (SCID-5 & SCID-5-PD) and the DIVA-5. The participants completed Conner's Adult ADHD Rating Scale-Self Report-Screening Version (CAARS-S-SV). Results: According to the SCID-5 and DIVA-5 diagnoses, 55% and 38% of the participants had ADHD, respectively. Diagnostic agreement was 81.66% between DIVA-5/SCID-5 diagnoses, 80% between SCID-5/CAARS-S-SV, and 71.66% between DIVA-5/CAARS-S-SV. Test-retest and inter-rater reliability results for the DIVA-5 were good to excellent. Conclusion: Findings support the validity and reliability of the Farsi translation of DIVA-5 among the Farsi-speaking adult outpatient population.

Additively Manufactured Gradient Porous Ti-6Al-4V Hip Replacement Implants Embedded with Cell-Laden Gelatin Methacryloyl Hydrogels.

Laser additive manufacturing has led to a paradigm shift in the design of next-generation customized porous implants aiming to integrate better with the surrounding bone. However, conflicting design criteria have limited the development of fully functional porous implants; increasing porosity improves body fluid/cell-laden prepolymer permeability at the expense of compromising mechanical stability. Here, functionally gradient porosity implants and scaffolds designed based on interconnected triply periodic minimal surfaces (TPMS) are demonstrated. High local porosity is defined at the implant/tissue interface aiming to improve the biological response. Gradually decreasing porosity from the surface to the center of the porous constructs provides mechanical strength in selective laser melted Ti-6Al-4V implants. The effect of unit cell size is studied to discover the printability limit where the specific surface area is maximized. Furthermore, mechanical studies on the unit cell topology effects suggest that the bending-dominated architectures can provide significantly enhanced strength and deformability, compared to stretching-dominated architectures. A finite element (FE) model developed also showed great predictability (within ∼13%) of the mechanical responses of implants to physical activities. Finally, in vitro biocompatibility studies were conducted for two-dimensional (2D) and three-dimensional (3D) cases. The results of the 2D in conjunction with surface roughness show favored physical cell attachment on the implant surface. Also, the results of the 3D biocompatibility study for the scaffolds incorporated with a cell-laden gelatin methacryloyl (GelMA) hydrogel show excellent viability. The design procedure proposed here provides new insights into the development of porous hip implants with simultaneous high mechanical and biological responses.

Sacrificial 3D printing of shrinkable silicone elastomers for enhanced feature resolution in flexible tissue scaffolds.

Silicone implants and scaffolds are emerging as potential replacement of flexible tissues, cosmetic and biomedical device implants due to their bioinert and flexible characteristics. The state-of-the-art direct-write silicone three-dimensional (3D) printers however cannot easily 3D print structures with sub-millimeter dimensions because of high viscosity and long curing times of their prepolymers. In the present study, a template-assisted 3D printing of ordered porous silicone constructs is demonstrated. The sacrificial molds were fabricated by low-cost and well-accessible material extrusion 3D printers. The 3D printed molds represent interconnected tortuous high specific surface area porous architectures based on triply periodic minimal surfaces (TPMS) in which the silicone prepolymer is cast and cured. We engineered silicone prepolymer with additives allowing on-demand structural shrinkage upon solvent treatment. This enabled 3D printing at a larger scale compatible with extrusion 3D printer resolution followed by isotropic shrinkage. This procedure led to a volumetric shrinkage of up to ~70% in a highly controllable manner. In this way, pore sizes in the order of 500-600 µm were obtained. The porous constructs were characterized with full strain recovery under extreme compressive deformations of up to 85% of the initial scaffold length. We further demonstrated the ability to infill cell-laden hydrogels such as gelatin methacryloyl (GelMA) into the interconnected pores while maintaining the cell viability of ~90%.

The Reliability of the Social Responsiveness Scale-2 in an Iranian Typically Developing Group of Children.

Objective: The Social Responsiveness Scale-2 (SRS-2) is a well-known screening instrument to assess autistic spectrum symptoms quantitatively. This study assessed the different types of reliability of the Farsi translation of the scale. Method : This scale was translated into Farsi and back translated considering all aspects of methodology in translation. Then, based on stratified sampling, 533 7-11-year-old students were randomly selected from the mainstream schools located in the central parts of Tehran, the capital of Iran. For all the students, SRS-2 was completed by both the parents and teachers. To check retest reliability, the test was administered again for 15% of the total participants after a 2-4 week-period. Cronbach's alpha coefficient, split-half" and Gottman" methods, and intra-class correlation coefficient (ICC) were used. Results: The mean total raw score was 48.47 (±23.63) and 53.17 (±27.33) in the sequence of the parents and teachers' reports. The internal consistency (Cronbach's alpha; 0.86 and 0.89), test-retest reliability (ICC; 0.72 and 0.83 for parents and teacher' ratings, respectively), and interrater reliability (ICC; 0.72) showed well-accepted measurement performance. Conclusion: The findings indicated that the Farsi SRS-2 can be used as a reliable instrument to measure social responsiveness as autistic symptoms in Iranian child population.

Extrusion and Microfluidic-based Bioprinting to Fabricate Biomimetic Tissues and Organs.

Next generation engineered tissue constructs with complex and ordered architectures aim to better mimic the native tissue structures, largely due to advances in three-dimensional (3D) bioprinting techniques. Extrusion bioprinting has drawn tremendous attention due to its widespread availability, cost-effectiveness, simplicity, and its facile and rapid processing. However, poor printing resolution and low speed have limited its fidelity and clinical implementation. To circumvent the downsides associated with extrusion printing, microfluidic technologies are increasingly being implemented in 3D bioprinting for engineering living constructs. These technologies enable biofabrication of heterogeneous biomimetic structures made of different types of cells, biomaterials, and biomolecules. Microfluiding bioprinting technology enables highly controlled fabrication of 3D constructs in high resolutions and it has been shown to be useful for building tubular structures and vascularized constructs, which may promote the survival and integration of implanted engineered tissues. Although this field is currently in its early development and the number of bioprinted implants is limited, it is envisioned that it will have a major impact on the production of customized clinical-grade tissue constructs. Further studies are, however, needed to fully demonstrate the effectiveness of the technology in the lab and its translation to the clinic.

3D-Printed Ultra-Robust Surface-Doped Porous Silicone Sensors for Wearable Biomonitoring.

Three-dimensional flexible porous conductors have significantly advanced wearable sensors and stretchable devices because of their specific high surface area. Dip coating of porous polymers with graphene is a facile, low cost, and scalable approach to integrate conductive layers with the flexible polymer substrate platforms; however, the products often suffer from nanoparticle delamination and overtime decay. Here, a fabrication scheme based on accessible methods and safe materials is introduced to surface-dope porous silicone sensors with graphene nanoplatelets. The sensors are internally shaped with ordered, interconnected, and tortuous internal geometries (i.e., triply periodic minimal surfaces) using fused deposition modeling (FDM) 3D-printed sacrificial molds. The molds were dip coated to transfer-embed graphene onto the silicone rubber (SR) surface. The presented procedure exhibited a stable coating on the porous silicone samples with long-term electrical resistance durability over ∼12 months period and high resistance against harsh conditions (exposure to organic solvents). Besides, the sensors retained conductivity upon severe compressive deformations (over 75% compressive strain) with high strain-recoverability and behaved robustly in response to cyclic deformations (over 400 cycles), temperature, and humidity. The sensors exhibited a gauge factor as high as 10 within the compressive strain range of 2-10%. Given the tunable sensitivity, the engineered biocompatible and flexible devices captured movements as rigorous as walking and running to the small deformations resulted by human pulse.

Micro and nanoscale technologies in oral drug delivery.

Oral administration is a pillar of the pharmaceutical industry and yet it remains challenging to administer hydrophilic therapeutics by the oral route. Smart and controlled oral drug delivery could bypass the physiological barriers that limit the oral delivery of these therapeutics. Micro- and nanoscale technologies, with an unprecedented ability to create, control, and measure micro- or nanoenvironments, have found tremendous applications in biology and medicine. In particular, significant advances have been made in using these technologies for oral drug delivery. In this review, we briefly describe biological barriers to oral drug delivery and micro and nanoscale fabrication technologies. Micro and nanoscale drug carriers fabricated using these technologies, including bioadhesives, microparticles, micropatches, and nanoparticles, are described. Other applications of micro and nanoscale technologies are discussed, including fabrication of devices and tissue engineering models to precisely control or assess oral drug delivery in vivo and in vitro, respectively. Strategies to advance translation of micro and nanotechnologies into clinical trials for oral drug delivery are mentioned. Finally, challenges and future prospects on further integration of micro and nanoscale technologies with oral drug delivery systems are highlighted.

Early maladaptive schemas in depression and somatization disorder.

Cognitive theories of depression posit that early maladaptive schemas (EMSs) are key vulnerability factors for psychological disorders. In this study, we investigated specific EMSs as shared or distinct cognitive vulnerability factors for depression and somatization disorder. The sample consisted of patients with Major depressive disorder (N = 30) and Somatization disorder (N = 30) from a community hospital or a psychiatric clinic. Participants completed the Structured Clinical Interview for DSM-IV (SCID), the Beck Depression Inventory-II (BDI-II), and the short form of the Young Schema Questionnaire (YSQ-SF). Depressed patients exhibited significantly higher levels of all five schema domains and specific maladaptive schemas, including emotional deprivation, mistrust and abuse, social isolation and alienation, defectiveness and shame, failure, subjugation, emotional inhibition, and insufficient self-control or self-discipline. Moreover, depressed patients exhibited significantly higher levels of social isolation, emotional inhibition, as well as the overvigilance and inhibition domain when depressive symptom severity was controlled. Our results provide preliminary evidence that specific EMSs distinguish patients with depression and somatization. Suggestions for future research include the need to have a non-psychiatric control group, to evaluate the absolute role of EMSs in Somatization Disorder.