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Myocardial infarction (MI) is one of the fatal diseases in humans. Its incidence is constantly increasing annually all over the world. The problem is accompanied by the limited regenerative capacity of cardiomyocytes, yielding fibrous scar tissue formation. The propagation of electrical impulses in such tissue is severely hampered, negatively influencing the normal heart pumping function. Thus, reconstruction of the internal cardiac electrical connection is currently a major concern of myocardial repair. Conductive biomaterials with or without cell loading were extensively investigated to address this problem. This article introduces a detailed overview of the recent progress in conductive biomaterials and fabrication methods of conductive scaffolds for cardiac repair. After that, the advances in myocardial tissue construction in vitro by the restoration of intercellular communication and simulation of the dynamic electrophysiological environment are systematically reviewed. Furthermore, the latest trend in the study of cardiac repair in vivo using various conductive patches is summarized. Finally, we discuss the achievements and shortcomings of the existing conductive biomaterials and the properties of an ideal conductive patch for myocardial repair. We hope this review will help readers understand the importance and usefulness of conductive biomaterials in cardiac repair and inspire researchers to design and develop new conductive patches to meet the clinical requirements. Statement of significance After myocardial infarction, the infarcted myocardial area is gradually replaced by heterogeneous fibrous tissue with inferior conduction properties, resulting in arrhythmia and heart remodeling. Conductive biomaterials have been extensively adopted to solve the problem. Summarizing the relevant literature, this review presents an overview of the types and fabrication methods of conductive biomaterials, and focally discusses the recent advances in myocardial tissue construction in vitro and myocardial repair in vivo, which is rarely covered in previous reviews. As well, the deficiencies of the existing conductive patches and their construction strategies for myocardial repair are discussed as well as the improving directions. Confidently, the readers of this review would appreciate advantages and current limitations of conductive biomaterials/patches in cardiac repair.

This study aimed to evaluate the pulpal responses of monkey's pulp after direct pulp capping (DPC) with the novel mineral trioxide aggregate containing phosphorylated pullulan-based material (MTAPPL). Seventy-two teeth were randomly divided into four groups: MTAPPL; Nex-Cem MTA (NX); TheraCal LC (TH); and Dycal (DY). Histopathological changes in the pulps were observed at days 3, 7 and 70. On day 3, mild inflammatory responses were observed in the MTAPPL, no to moderate inflammatory responses in the TH, whereas moderate inflammatory responses in the NX and DY. No mineralized tissue formation (MTF) was observed in all groups. On day 7, no or mild inflammatory responses were observed in all groups. Initial MTF was observed except for DY. No inflammation with complete MTF including presence of odontoblast-like cells was observed in the MTAPPL, NX and TH groups at day 70. These findings indicate that MTAPPL could be an efficient DPC material.

Relevance. The study examines the possibility of using a mathematic model of an artificial neural network (ANN) for comparative quantitative morphological assessment of revascularized autograft remodeling after reconstructive surgery in patients with jaw defects.Materials and methods. Jawbone biopsies of 30 patients were histologically examined during the implant placement stage, 6, 9, 12 months after the reconstructive surgery with a revascularized fibular graft. Histology images were analyzed using a mathematic model created on the basis of GoogLeNet and trained on morphological images of bone maturation. Histology slides were digitized by a scanning microscope Leica SC2 and streamed through the neural network model. Results. During the follow-up period, jaw defect areas demonstrated relatively mature bone tissue formation with various intensity rates of remodeling and maturation of the newly-formed bone. At that, the results of the descriptive histology were consistent with the quantitative results of the ANN mathematic model, created on the basis of the softwarehardware system developed by the authors. The confirmed significance level is 95% or higher.Conclusion. Pathomorphological data of biopsies were studied using an ANN mathematical model, built on a softwarehardware system, which allowed analyzing all microscope fields of view of a histological slide, bypassing random samples, as well as the evaluation by a pathologist of individual microscope fields of view, to exclude the possibility of unrepresentative sampling and the influence of human factor, which significantly increases the significance of the received results.

Negative pressure wound therapy (NPWT) is used clinically to promote tissue formation and wound closure. In this study, a porcine wound model was used to further investigate the mechanisms as to how NPWT modulates wound healing via utilization of a form of NPWT called the vacuum-assisted closure. To observe the effect of NPWT more accurately, non-NPWT control wounds containing GranuFoam™ dressings, without vacuum exposure, were utilized. In situ histological analysis revealed that NPWT enhanced plasma protein adsorption throughout the GranuFoam™, resulting in increased cellular colonization and tissue ingrowth. Gram staining revealed that NPWT decreased bacterial dissemination to adjacent tissue with greater bacterial localization within the GranuFoam™. Genomic analysis demonstrated the significant changes in gene expression across a number of genes between wounds treated with non-NPWT and NPWT when compared against baseline tissue. However, minimal differences were noted between non-NPWT and NPWT wounds, including no significant differences in expression of collagen, angiogenic, or key inflammatory genes. Similarly, significant increases in immune cell populations were observed from day 0 to day 9 for both non-NPWT and NPWT wounds, though no differences were noted between non-NPWT and NPWT wounds. Furthermore, histological analysis demonstrated the presence of a foreign body response (FBR), with giant cell formation and encapsulation of GranuFoam™ particles. The unique in situ histological evaluation and genomic comparison of non-NPWT and NPWT wounds in this pilot study provided a never-before-shown perspective, offering novel insights into the physiological processes of NPWT and the potential role of a FBR in NPWT clinical outcomes.

In general, matrices for tissue engineering must maintain structural integrity during the process of tissue formation and promote vascularization of developing tissue. Therefore, collagen sponges, manufactured by an approach that offers the potential of unidirectional pore size, were seeded with human umbilical vein endothelial cells (HUVEC) to demonstrate a positive effect on cell proliferation. In addition, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) have been used to promote proliferation of HUVEC on optimized collagen sponges. Growth and viability of the cells were evaluated. Potential unidirectional pore structure demonstrated an improvement of both, endothelial cell growth and viability. Supplementation of growth factors showed an additional increase of endothelial cell growth on collagen sponges, which confirmed the high potential of combining this biomaterial with growth factors. The results suggest that a collagen sponge with a potential specific pore size could be a suitable scaffold for endothelial cells and might be a promising implantable biomaterial with enhanced angiogenic capabilities for future clinical applications.

Transforming growth factor beta (TGFβ) signaling is required for in vitro chondrogenesis. In animal models of osteoarthritis (OA), TGFβ receptor alterations are detected in chondrocytes in severe O...

Cells sense and respond to scaffold pore geometry and mechanical stimuli. Many fabrication methods used in bone tissue engineering render structures with poorly controlled pore geometries. Given that cell-scaffold interactions are complex, drawing a conclusion on how cells sense and respond to uncontrolled scaffold features under mechanical loading is difficult. Here, monodisperse templated scaffolds (MTSC) were fabricated and used as a well-defined porous scaffolds to study the effect of dynamic culture conditions on bone-like tissue formation. Human bone marrow derived stromal cells were cultured on MTSC or conventional salt-leached scaffolds (SLSC) for up to 7 weeks, either under static or dynamic conditions (wall shear stress (WSS) using spinner flask bioreactors). The influence of controlled spherical pore geometry of MTSC subjected to static or dynamic conditions on osteoblast cells differentiation, bone-like tissue formation, structure and distribution was investigated. WSS generated within the two idealized geometrical scaffold features was assessed. Distinct response to fluid flow in osteoblast cell differentiation were shown to be dependent on scaffold pore geometry. As revealed by collagen staining and micro-computed tomography images, dynamic conditions promoted a more regular extracellular matrix (ECM) formation and mineral distribution in both scaffold types compared to static conditions. The results showed that regulation of bone-related genes and the amount and the structure of mineralized ECM were dependent on scaffold pore geometry and the mechanical cues provided by the two different culture conditions. Under dynamic conditions, SLSC favored osteoblast cell differentiation and ECM formation, while MTSC enhanced ECM mineralization. The spherical pore shape in MTSC supported a more trabecular bone-like structure under dynamic conditions compared to MTSC statically cultured or to SLSC under either static or dynamic conditions. These results suggest that cell activity and bone-like tissue formation is driven not only by the pore geometry but also by the mechanical environment. This should be taken into account in the future design of complex scaffolds, which should favor cell differentiation while guiding the formation, structure and distribution of the engineered bone tissue. This could help to mimic the anatomical complexity of the bone tissue structure and to adapt to each bone defect needs.Impact statementAging of the human population leads to an increasing need for medical implants with high success rate. We provide evidence that cell activity and the amount and structure of bone-like tissue formation is dependent on the scaffold pore geometry and on the mechanical environment. Fabrication of complex scaffolds comprising concave and planar pore geometries might represent a promising direction towards the tunability and mimicry the structural complexity of the bone tissue. Moreover, the use of fabrication methods that allow a systematic fabrication of reproducible and geometrically controlled structures would simplify scaffold design optimization.

Porosity parameters are one of the structural properties of the extracellular microenvironment that have been shown to have a great impact on the cellular phenotype and various biological activities such as diffusion of fluid, initial protein adsorption, permeability, cell penetration and migration, ECM deposition, angiogenesis, and rate and pattern of new tissue formation. The heterogeneity of the study protocols and research methodologies do not allow reliable meta-analysis for definite findings. As such, despite the huge available literature, no generally accepted consensus is defined for the porosity requirements of specific tissue engineering applications. However, based on the biomimetic approach, the biological substitutes should replicate the 3D local microenvironment of the recipient site with matching porosity parameters to best support local cells during tissue regeneration. Ideally, the porosity of biomaterials should mimic the porosity of the substituting natural tissue and match the clinical requirements. Careful analysis of the impact of architectures (i.e., porosity) on biophysical, biochemical, and biological behaviors will support designing smart biomaterials with customized architectural and functional properties that are patient and defect site-specific.

Appropriate biomimetic scaffolds created via 3D bioprinting are promising methods for treating damaged menisci. However, given the unique anatomical structure and complex stress environment of the meniscus, many studies have adopted various techniques to take full advantage of different materials, such as the printing combined with infusion, or electrospining, to chase the biomimetic meniscus, which makes the process complicated to some extent. Some researchers have tried to tackle the challenges only by 3D biopringting, while its alternative materials and models have been constrained. In this study, based on a multilayer biomimetic strategy, we optimized the preparation of meniscus-derived bioink, gelatin methacrylate (GelMA)/meniscal extracellular matrix (MECM), to take printability and cytocompatibility into account together. Subsequently, a customized 3D bioprinting system featuring a dual nozzle + multitemperature printing was used to integrate the advantages of polycaprolactone (PCL) and meniscal fibrocartilage chondrocytes (MFCs)-laden GelMA/MECM bioink to complete the biomimetic meniscal scaffold, which had the best biomimetic features in terms of morphology and components. Furthermore, cell viability, mechanics, biodegradation and tissue formation in vivo were performed to ensure that the scaffold had sufficient feasibility and functionality, thereby providing a reliable basis for its application in tissue engineering., Graphical abstract Image 1, Highlights • We have optimized the preparation of meniscus-derived bioink with good printability and cytocompatibility. • A customized printing system for biomimetic meniscus, the dual-nozzle + multitemperature printing system was developed. • We have achieved multilayer meniscal biomimetic strategy, especially the best biomimetics of morphology and components. • Focusing on application prospect, we designed a few experiments to verity the feasibility and functionality of the scaffold.

Due to the integration of recent advances in stem cell biology, materials science, and engineering, the field of cardiac tissue engineering has been rapidly progressing toward developing more accurate functional 3D cardiac microtissues from human cell sources. These engineered tissues enable screening of cardiotoxic drugs, disease modeling (eg, by using cells from specific genetic backgrounds or modifying environmental conditions) and can serve as novel drug development platforms. This concise review presents the most recent advances and improvements in cardiac tissue formation, including cardiomyocyte maturation and disease modeling.

Collective cell migration is often seen in many biological processes like embryogenesis, cancer metastasis, and wound healing. Despite extensive experimental and theoretical research, the unified mechanism responsible for collective cell migration is not well known. Most of the studies have investigated artificial model wound to study the collective cell migration in an epithelial monolayer. These artificial model wounds possess a high cell number density compared to the physiological scenarios like wound healing (cell damage due to applied cut) and cancer metastasis (smaller cell clusters). Therefore, both systems may not completely relate to each other, and further investigation is needed to understand the collective cell migration in physiological scenarios. In an effort to fill this existing knowledge gap, we investigated the freely expanding monolayer that closely represented the physiological scenarios and compared it with the artificially created model wound. In the present work, we report the effect of initial boundary conditions (free and confined) on the collective cell migration of the epithelial cell monolayer. The expansion and migration aspects of the freely expanding and earlier-confined monolayer were investigated at the tissue and cellular levels. The freely expanding monolayer showed significantly higher expansion and lower migration in comparison to the earlier-confined monolayer. The expansion and migration rate of the monolayer exhibited a strong negative correlation. The study highlights the importance of initial boundary conditions in the collective cell migration of the expanding tissue and provides useful insights that might be helpful in the future to tune the collective cell migration in wound healing, cancer metastasis, and tissue formation.

Pendahuluan: Stunting di Indonesia masih tergolong tinggi. Salah satu faktor risikonya adalah kejadian berat badan lahir rendah pada bayi. Jika tidak diatasi, kualitas sumber daya manusia di Indonesia menjadi rendah. Maka, pemberian Lipid-based Nutrient Supplements (LNS), yang telah dilakukan oleh beberapa negara tetangga dalam rangka mengoptimalkan berat badan lahir rendah dan daya kognitif bayi, perlu dilakukan penelitian. Penelitian ini bertujuan untuk mengumpulkan dan menganalisis artikel yang berhubungan dengan pengaruh pemberian LNS pada ibu hamil terhadap berat badan lahir dan daya kognitif pada bayi. Metode: Desain yang digunakan adalah literature review, artikel dikumpulkan dengan menggunakan mesin pencari Google melalui beberapa sumber data seperti Pubmed, Science Direct, Proquest, Kemenkes, dan BPS RI. Kriteria artikel yang digunakan adalah jurnal penelitian dengan metode Randomized Controlled Trial dan Systematic Review yang diterbitkan pada tahun 2015 – 2020. Pembahasan: Berdasarkan artikel yang dikumpulkan, hasilnya menunjukan bahwa LNS yang diberikan pada ibu hamil dapat meningkatkan massa tubuh dan meningkatkan volume otak pada bayi. Hal ini disebabkan oleh Brain Specific Fatty Acid yang meliputi docosahexaenoic acid (DHA) and arachidonic acid (ARA) yang menunjang pembentukan jaringan, imunitas, dan perkembangan saraf. Simpulan: Pemberian LNS pada di daerah yang prevalensi stunting masih tinggi dapat menjadi solusi atas permasalahan stunting di daerah tersebut. Saran dari penelitian ini adalah untuk dibuat suatu program LNS, khususnya di daerah yang prevalensi stunting masih tinggi.

Cellular senescence is a state of permanent cell cycle arrest accompanied by unique secretory actions, which influences tissue formation, tumor suppression and aging in vivo. Recent evidences suggest that metabolic and epigenomic reprogram cooperatively creates phenotypic differences of senescent cells, which may provide new clues to control aging processes.

The demand for artificial organs has greatly increased because of various aging-associated diseases and the wide need for organ transplants. A recent trend in tissue engineering is the precise reconstruction of tissues by the growth of cells adhering to bioscaffolds, which are three-dimensional (3D) structures that guide tissue and organ formation. Bioscaffolds used to fabricate bionic tissues should be able to not only guide cell growth but also regulate cell behaviors. Common regulation methods include biophysical and biochemical stimulations. Biophysical stimulation cues include matrix hardness, external stress and strain, surface topology, and electromagnetic field and concentration, whereas biochemical stimulation cues include growth factors, proteins, kinases, and magnetic nanoparticles. This review discusses bioink preparation, 3D bioprinting (including extrusion-based, inkjet, and ultraviolet-assisted 3D bioprinting), and regulation of cell behaviors. In particular, it provides an overview of state-of-the-art methods and devices for regulating cell growth and tissue formation and the effects of biophysical and biochemical stimulations on cell behaviors. In addition, the fabrication of bioscaffolds embedded with regulatory modules for biomimetic tissue preparation is explained. Finally, challenges in cell growth regulation and future research directions are presented., Graphical abstract The functions of different simulations on cells, including biophysical simulations and biochemical simulations are expounded. The regulatory methods for cell growth and tissue formation are organized mainly by three points, bioinks, 3D bioprinting methods, the effects of different simulations on cell behavior regulation. Also, the limitation of biological printing and regulation process and future research matters, are pointed out. We envisage this approach will offer an effective way to tissue reconstruction.Image 1, Highlights • The state of the art on scaffolds in regulating cell behaviors is reviewed. • The functions of different stimulations on cells are expounded. • The limitation of regulatory techniques and future directions, are presented. • The method of synergetic regulation for cell behaviors, are proposed.

The studies were carried out with the aim of revealing histological reactions in the shoots of remontant raspberries as an aspect of the growth-stimulating effect of pre-planting treatment of the root system of seedlings with strains of saprotrophic bacteria of the genus Bacillus. The observations in the model experiment were carried out in 2017-2018 in the production plantings of remontant raspberries of the agricultural artel “Sady Sibiri” in the Novosibirsk Region. Plants were treated before planting by soaking the root system in a working fluid containing a bioagent at a concentration of 1×105 CFU / ml. In terms of the totality of growth-stimulating effects, the most effective complex effect on remontant raspberry plants was provided by pre-planting treatment with B subtilis strain VKPM B-10641 and a mixture preparation Fitop 8.67. The number of replacement shoots increased by 45–69%, the length of replacement shoots - by 16–20%, the amount internodes - 1.2 times relative to control. Under the influence of the same bacterial bioagents in the shoots of remontant raspberries, an increase in the thickness of the peridermis by 20–25% relative to the control, an increase in the number of peridermal layers by 12–35%, suberinized (matured) layers of the peridermis by 30–48%, and the thickness of xylem by 12 –22% was observed. B subtilis VKPM B-10641 strain and Fitop 8.67 influence raspberry plants, the regularity of simultaneous stimulation of growth processes in the replacement shoots and the formation of mature peridermis. So it acts as an immunological barrier against phytopathogens, pests and abiotic stress factors. So the research proved it.

Objective: In tissue engineering, biomaterials create a 3D scaffold for cell-to-cell adhesion, proliferation and tissue formation. Because of their similarity to extracellular matrix and architectural adaptability, nanofibers are of particular interest in tissue engineering. Electrospinning is a well-documented technique for nanofiber production for tissue engineering scaffolds. Here we present literature on the applications of electrospinning in the field of otolaryngology. Review Methods: A PubMed database search was performed to isolate articles published about applications of electrospun nanofibers for tissue engineering in otolaryngology. Study design, size, material tested, site of application within the head and neck, and outcomes were obtained for each study. Results: Almost all data on electrospinning in otolaryngology was published in the last 6 years (84%), highlighting its novelty. A total of 25 pre-clinical studies were identified: 9 in vitro studies, 5 in vivo animal studies, and 11 combination studies. Sites of application included: tracheal reconstruction (n = 16), tympanic membrane repair (n = 3), cranial nerve regeneration (n = 3), mastoid osteogenesis (n = 1) and ear/nose chondrogenesis (n = 2). Implications for Practice: Tissue engineering is a burgeoning field, with recent innovative applications in the field of otolaryngology. Electrospun nanofibers specifically have relevant applications in the field of otolaryngology, due in part to their similarity to native extracellular matrix, with emerging areas of interest being tympanic membrane repair, cranial nerve regeneration and tracheal reconstruction.

A mechanical stimulation device for cell-seeded scaffolds was designed and manufactured to provide control of dynamic compressive loading on biomimetic 3D neo-tissue constructs for enhanced tissue regeneration. Despite emerging evidence implicating the importance of mechanical forces in directing cellular differentiation and dental tissue formation, the role of variable mechanical stimuli in developing dental tissue has not been fully investigated. The device described here was designed to be easily cleanable by technicians and scientists between individual tests providing repeatable displacement of gels for their experiments. Increased extracellular matrix production of temporomandibular joints (TMJ – the joints that connect the jawbone to the skull) was observed while under loading by the device and the device is capable of providing compression as low as 0.01 mm of the desired displacement. Force calibration and sterilization testing were also performed to validate the functional requirements and device performance. The preliminary results show that the resulting device can deliver up to 2 kPa of dynamic compressive pressure to bioengineer cell-based constructs, and that ethanol sterilization is sufficient to maintain a sterile environment in long term tissue culture. In this paper, we introduce a device to mechanically stimulate bioengineered tissue formation, which could be used for a variety of applications in regenerative medicine.

Significance Many questions about how stem cells communicate with neighboring cells and self-organize to initiate tissue formation remain unanswered. We uncovered mechanisms employed by embryonic stem cells (ESCs) and trophoblast stem cells (TSCs) to coform embryo-like structures. We describe ESC-generated cytonemes that react to self-renewal–promoting Wnt ligands secreted by TSCs. We identified glutamatergic activity upon formation of ESC–TSC interaction. This cellular connection is required for the transmission of Wnt signals to ESCs for Wnt/β-catenin pathway activation, a process that regulates morphogenesis. Given that many stem cell types express glutamate receptors and rely on niche-secreted Wnt ligands for self-renewal, we propose that Wnt and glutamatergic signaling crosstalk may prove prevalent in various mammalian tissues to regulate stem cell–niche interactions., Spatial cellular organization is fundamental for embryogenesis. Remarkably, coculturing embryonic stem cells (ESCs) and trophoblast stem cells (TSCs) recapitulates this process, forming embryo-like structures. However, mechanisms driving ESC–TSC interaction remain elusive. We describe specialized ESC-generated cytonemes that react to TSC-secreted Wnts. Cytoneme formation and length are controlled by actin, intracellular calcium stores, and components of the Wnt pathway. ESC cytonemes select self-renewal–promoting Wnts via crosstalk between Wnt receptors, activation of ionotropic glutamate receptors (iGluRs), and localized calcium transients. This crosstalk orchestrates Wnt signaling, ESC polarization, ESC–TSC pairing, and consequently synthetic embryogenesis. Our results uncover ESC–TSC contact–mediated signaling, reminiscent of the glutamatergic neuronal synapse, inducing spatial self-organization and embryonic cell specification.

Regenerative medicine is a promising new area of research that offers potential to treat diseased and injured tissue. In particular, the development of new biomaterial-based approaches shows promise for the treatment of challenging bone and cartilage injuries. Recent trends have focused on the development of biofunctional materials that have bioactive properties and are capable of supporting and promoting new tissue formation during the tissue repair process. This article discusses current biomaterial-based approaches for bone and cartilage repair and highlights emerging material functionalization methodologies including surface modification, growth factor delivery, cell-seeding strategies and gene therapy.

Zebrafish caudal fin rays are used as a model system for regeneration because of their high regenerative ability, but studies on the regeneration polarity of the fin ray are limited. To investigate this regeneration polarity, we made a hole to excise part of the fin ray and analyzed the regeneration process. We confirmed that the fin rays always regenerated from the proximal margin toward the distal margin, as previously reported, however, regeneration-related genes were expressed at both the proximal and distal edges of the hole in the early stage of regeneration, suggesting that the regenerative response also occurs at the distal edge. One difference between the proximal and distal margins is a sheet-like tissue that is formed on the apical side of the regenerated tissue at the proximal margin. This sheet-like tissue was not observed at the distal edge. To investigate whether the distal margin was also capable of forming this sheet-like tissue and subsequent regeneration, we kept the distal margin separated from the proximal margin by manipulation. Consequently, the sheet-like tissue was formed at the distal margin and regeneration of the fin ray was also induced. The regenerated fin rays from the distal margin protruded laterally from the caudal fin and then bent distally, and their ends showed the same characteristics as those of the normal fin rays. These results suggest that fin rays have an ability to regenerate in both directions, however, under normal conditions, regeneration is restricted to the proximal margin because the sheet-like tissue is preferentially formed on the apical side of the regenerating tissue from the proximal margin.

Vascularization is a key event and also still a challenge in tissue engineering. Many efforts have been devoted to the development of vascularization based on cells, growth factors, and porous scaffolds in the past decades. Among these efforts, the architecture features of pores in scaffolds played important roles for vascularization, which have attracted increasing attention. It has been known that the open macro pores in scaffolds could facilitate cell migration, nutrient, and oxygen diffusion, which then could promote new tissue formation and vascularization. The pore parameters are the important factors affecting cells response and vessel formation. Thus, this review will give an overview of the current advances in the effects of pore parameters on vascularization in tissue engineering, mainly including pore size, interconnectivity, pore size distribution, pore shape (channel structure), and the micro/nano-surface topography of pores.

The fundamental life-defining processes in living cells, such as replication, division, adaptation, and tissue formation, take place via intertwined metabolic reaction networks orchestrating downstream signal processing in a confined, crowded environment with high precision. Hence, it is crucial to understand and reenact some of these functions in wholly synthetic cell-like entities (protocells) to envision designing soft-materials with life-like traits. Herein, we report on a programmable all-DNA protocell (PC) composed of a liquid DNA interior and a hydrogel-like shell, harboring DNAzyme active sites in the interior whose catalytic bond-cleaving activity leads to a downstream phenotype change in the protocells, as well as triggers prototissue formation. In this regard, we coupled several tools of DNA nanoscience, such as RNA cleavage, dynamic strand displacement reactions, and multivalent palindromic interactions, in a synchronize pathway so that the input signal can be processed inside the protocells and generate downstream cues giving rise to metabolic adaptive behavior. For example, the compartmentalized DNAzyme catalyzes the bond-cleavage of a substrate that releases a DNA strand in situ to trigger a strand displacement reaction at the shell of the protocells leading to a change in color resembling a “phenotype-like” change in cells, and finally to establish communication with other protocells via multivalent interactions.

Introduction The formation of superimposed tissue (SIT), a layer on top of the original valve leaflet, has been described in patients with mitral regurgitation, as a major contributor of valve thickening and probably secondary to increased valve mechanical stress. However, little is known whether SIT formation also occurs in aortic valve disease. Both in the case of aortic stenosis or aortic regurgitation, the aortic valve (AV) is subjected to increased mechanical stresses, although different in type, extent and location. Purpose To characterize SIT formation in aortic stenosis and regurgitation. Methods Human diseased AV leaflets (n=31) were obtained from patients undergoing aortic valve replacement because of aortic stenosis (n=17) or aortic regurgitation (n=14). Histological analysis was performed and elastin staining was used to distinguish the SIT from the original leaflet. Alpha-smooth muscle actin (SMA) staining was performed to identify myofibroblasts and Masson's Trichrome staining to identify collagen fibres. Results In both regurgitant leaflets (RL) and stenotic leaflets (SL) SIT was found at both the ventricular and aortic side (94% of SL, 93% of RL) and could reach up to 50% of total leaflet thickness (Fig. A-C). Although the average SIT thickness did not differ between SL and RL (0.30 mm, standard error of the mean (SEM): ±0.04 for SL vs 0.38 mm, SEM: ±0.05 for RL; p=0.61), the distribution of SIT differed. The SIT at the free edge of the aortic valve was significantly thicker in the RL (0.39 mm, SEM: ±0.06 for SL vs 0.88 mm, SEM: ± 0.07 for RL; p Conclusions Both in aortic stenosis and aortic regurgitation, the AV is characterized by SIT formation but with difference in distribution and composition. These observations suggest the involvement of hemodynamic and mechanical stresses in the regulation of SIT formation of the AV. Understanding the formation of SIT might provide new insights in pathology of AV disease. Funding Acknowledgement Type of funding sources: None.

Increasing numbers of endoscopically implantable devices are implanted in the airways, such as airway stents, one-way valves and coils, to treat both malignant and benign diseases. They significantly improve patient outcomes, but their long-term effectiveness and sustainability is hampered by the reaction of the formation of granulation tissue. Factors including procedural-related tissue injury; micro-organism presence; device-related factors, such as the material, design and sizing in relation to the airway; and patient-related factors, including genetic susceptibility, comorbidities and medication use, might all effect the severity of the tissue response and the subsequent degree of granulation tissue formation. However, research into the underlying mechanism and risk factors is scarce and therefore our knowledge is limited. Joint efforts from the scientific community, both pre-clinical and clinical, are needed to gain a deeper understanding and eventually improve the long-term treatment effectiveness of lung-implantable devices.

The challenges to accommodate multiple tissue formation metrics in conventional bioreactors have resulted in an increased interest to explore novel bioreactor designs. Bioreactors allow researchers to isolate variables in controlled environments to quantify cell response. While current bioreactor designs can effectively provide either mechanical, electrical, or chemical stimuli to the controlled environment, these systems lack the ability to combine all these stimuli simultaneously to better recapitulate the physiological environment. Introducing a dynamic and systematic combination of biomimetic stimuli bioreactor systems could tremendously enhance its clinical relevance in research. Thus, cues from different tissue responses should be studied collectively and included in the design of a biomimetic bioreactor platform. This review begins by providing a summary on the progression of bioreactors from simple to complex designs, focusing on the major advances in bioreactor technology and the approaches employed to better simulate in vivo conditions. The current state of bioreactors in terms of their clinical relevance is also analyzed. Finally, this review provides a comprehensive overview of individual biophysical stimuli and their role in establishing a biomimetic microenvironment for tissue engineering. To date, the most advanced bioreactor designs only incorporate one or two stimuli. Thus, the cell response measured is likely unrelated to the actual clinical performance. Integrating clinically relevant stimuli in bioreactor designs to study cell response can further advance the understanding of physical phenomenon naturally occurring in the body. In the future, the clinically informed biomimetic bioreactor could yield more efficiently translatable results for improved patient care.

Summary Many organs are formed through folding of an epithelium. This change in shape is usually attributed to tissue heterogeneities, for example, local apical contraction. In contrast, compressive stresses have been proposed to fold a homogeneous epithelium by buckling. While buckling is an appealing mechanism, demonstrating that it underlies folding requires measurement of the stress field and the material properties of the tissue, which are currently inaccessible in vivo. Here, we show that monolayers of identical cells proliferating on the inner surface of elastic spherical shells can spontaneously fold. By measuring the elastic deformation of the shell, we infer the forces acting within the monolayer and its elastic modulus. Using analytical and numerical theories linking forces to shape, we find that buckling quantitatively accounts for the shape changes of our monolayers. Our study shows that forces arising from epithelial growth in three-dimensional confinement are sufficient to drive folding by buckling., Graphical Abstract, Highlights • A proliferating epithelium encapsulated in a hollow sphere spontaneously invaginates • Epithelial proliferation generates compressive stresses that deform the elastic shell • Coupling between stress and folding shape shows that folding arises from buckling • Epithelial elastic moduli are inferred from buckling theory and experiments, Force-driven buckling was proposed to cause epithelial folding. Trushko et al. test this hypothesis by measuring the force (or stress) arising during spontaneous folding of an epithelium grown in an elastic shell. Coupling between stress and folding shape provides evidence that folding occurs by buckling.

The mechanisms that govern cell interactions during organ formation are not fully understood. In this issue of Developmental Cell, Miao et al. demonstrate a channel-independent role for gap junction proteins in the establishment of contacts between three cell types that build up the micropyle during oocyte development in Drosophila.

Aim The aim of this study was to evaluate the platelet rich fibrin as a scaffold for revascularization of immature root canals in dogs. Study design Sixteen double rooted teeth divided into two main groups A and B (contaminated and non-contaminated). Each group included two sub groups, one experimental (platelet rich fibrin subgroup) and the other is control (calcium hydroxide subgroup). After six months, dogs were sacrificed and histological evaluation of prepared sections was done for apical closure, internal root thickness and new vital pulp tissue formation. Results In contaminated root canals regarding all parameters used (apical closure, internal root thickness and new vital pulp tissue formation), PRF subgroup showed higher values than control subgroup with significant difference only in hard tissue formation in internal root surface. Non-contaminated PRF treated root canals showed better results than control subgroup and significant difference was in new intra canal vital pulp tissue formation only. No significant difference was clear between the two main groups. Conclusion Platelet rich fibrin is a good intra-canal scaffold for revascularization of immature permanent teeth.

Morphological changes during development, tissue repair, and disease largely rely on coordinated cell movements and are controlled by the tissue environment. Epithelial cell sheets are often subjected to large scale deformation during tissue formation. The active mechanical environment in which epithelial cells operate have the ability to promote collective oscillations, but how these cellular movements are generated and relate to collective migration remains unclear. Here, combining in vitro experiments and computational modelling we describe a novel mode of collective oscillations in confined epithelial tissues where the oscillatory motion is the dominant contribution to the cellular movements. We show that epithelial cells exhibit large-scale coherent oscillations when constrained within micro-patterns of varying shapes and sizes, and that their period and amplitude are set by the smallest confinement dimension. Using molecular perturbations, we then demonstrate that force transmission at cell-cell junctions and its coupling to cell polarity are pivotal for the generation of these collective movements. We find that the resulting tissue deformations are sufficient to trigger mechanotransduction within cells, potentially affecting a wide range of cellular processes.

Vitamins play important roles in bone health, and vitamin supplementation has been recommended to prevent osteoporosis and to reduce fracture risk in the elderly. However, the benefits of vitamin intake for bone health are still controversial. The aim of the review is to examine the relationship between vitamins and bone health and how vitamins function in osteoblasts and osteoclasts. A broad literature search with the PubMed database was performed. The results of human clinical studies are inconsistent due to differences in the study design, race, genetic factors, and the population. Vitamin K, E, or C intake seems to benefit for bone health as well as vitamin D. Recent findings did not support the benefit of the vitamin B complex for bone health. Furthermore, both the excess and deficiency of vitamin A might be involved in compromised bone health. The well-balanced and adequate amounts of vitamins should be ensured to prevent adverse effects on bone health.