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AbstractSelf-assembling peptides (SAPs) have emerged as a groundbreaking platform in regenerative medicine, offering innovative strategies for tissue engineering and repair. These biomolecules, designed to autonomously organize into nanofibers, mimic the natural extracellular matrix, providing essential structural support and biological cues for tissue regeneration. This review highlights the versatile applications of SAPs in regenerating diverse tissues, including bone, cartilage, cardiac, neural, and dermal structures, showcasing their potential to address a broad spectrum of medical challenges. The unique properties of SAPs, such as biocompatibility, biodegradability and specific cell receptor interaction capabilities, make them ideal for developing advanced therapeutic strategies. We discuss here the molecular design principles that allow for precise control over the nanofibers physical and chemical characteristics, facilitating the creation of scaffolds that promote cell attachment, proliferation, and differentiation. Additionally, the review covers the use of SAPs in drug delivery systems, emphasizing their ability to control the release of therapeutic agents, a critical aspect in enhancing tissue repair processes. Moreover, we address key considerations regarding the safety, biodegradability and potential immunogenicity of SAPs, underscoring the importance of thorough preclinical and clinical evaluations. The future directions and challenges in optimizing SAPs design and functionalization for maximizing regenerative outcomes are also explored. [ABSTRACT FROM AUTHOR]

Human mesenchymal stromal cells (hMSCs), whether used alone or together with three-dimensional scaffolds, are the best-studied postnatal stem cells in regenerative medicine. In this study, innovative composite scaffolds consisting of a core–shell architecture were seeded with bone-marrow-derived hMSCs (BM-hMSCs) and tested for their biocompatibility and remarkable capacity to promote and support bone regeneration and mineralization. The scaffolds were prepared by grafting three different amounts of gelatin–chitosan (CH) hydrogel into a 3D-printed polylactic acid (PLA) core (PLA-CH), and the mechanical and degradation properties were analyzed. The BM-hMSCs were cultured in the scaffolds with the presence of growth medium (GM) or osteogenic medium (OM) with differentiation stimuli in combination with fetal bovine serum (FBS) or human platelet lysate (hPL). The primary objective was to determine the viability, proliferation, morphology, and spreading capacity of BM-hMSCs within the scaffolds, thereby confirming their biocompatibility. Secondly, the BM-hMSCs were shown to differentiate into osteoblasts and to facilitate scaffold mineralization. This was evinced by a positive Von Kossa result, the modulation of differentiation markers (osteocalcin and osteopontin), an expression of a marker of extracellular matrix remodeling (bone morphogenetic protein-2), and collagen I. The results of the energy-dispersive X-ray analysis (EDS) clearly demonstrate the presence of calcium and phosphorus in the samples that were incubated in OM, in the presence of FBS and hPL, but not in GM. The chemical distribution maps of calcium and phosphorus indicate that these elements are co-localized in the same areas of the sections, demonstrating the formation of hydroxyapatite. In conclusion, our findings show that the combination of BM-hMSCs and PLA-CH, regardless of the amount of hydrogel content, in the presence of differentiation stimuli, can provide a construct with enhanced osteogenicity for clinically relevant bone regeneration. [ABSTRACT FROM AUTHOR]

Scaffolds for tissue engineering are expected to respond to a challenging combination of physical and mechanical requirements, guiding the research towards the development of novel hybrid materials. This study introduces innovative three-dimensional bioresorbable scaffolds, in which a stiff poly(lactic acid) lattice structure is meant to ensure temporary mechanical support, while a bioactive gelatin–chitosan hydrogel is incorporated to provide a better environment for cell adhesion and proliferation. The scaffolds present a core–shell structure, in which the lattice core is realized by additive manufacturing, while the shell is nested throughout the core by grafting and crosslinking a hydrogel forming solution. After subsequent freeze-drying, the hydrogel network forms a highly interconnected porous structure that completely envelops the poly(lactic acid) core. Thanks to this strategy, it is easy to tailor the scaffold properties for a specific target application by properly designing the lattice geometry and the core/shell ratio, which are found to significantly affect the scaffold mechanical performance and its bioresorption. Scaffolds with a higher core/shell ratio exhibit higher mechanical properties, whereas reducing the core/shell ratio results in higher values of bioactive hydrogel content. Hydrogel contents up to 25 wt% could be achieved while maintaining high compression stiffness (>200 MPa) and strength (>5 MPa), overall, within the range of values displayed by human bone tissue. In addition, mechanical properties remain stable after prolonged immersion in water at body temperature for several weeks. On the other hand, the hydrogel undergoes gradual and homogeneous degradation over time, but the core–shell integrity and structural stability are nevertheless maintained during at least 7-week hydrolytic degradation tests. In vitro experiments with human mesenchymal stromal cells reveal that the core–shell scaffolds are biocompatible, and their physical–mechanical properties and architecture are suitable to support cell growth and osteogenic differentiation, as demonstrated by hydroxyapatite formation. These results suggest that the bioresorbable core–shell scaffolds can be considered and further studied, in view of clinically relevant endpoints in bone regenerative medicine. [ABSTRACT FROM AUTHOR]

Human mesenchymal stromal cells (hMSCs), whether used alone or together with three-dimensional scaffolds, are the best-studied postnatal stem cells in regenerative medicine. In this study, innovative composite scaffolds consisting of a core–shell architecture were seeded with bone-marrow-derived hMSCs (BM-hMSCs) and tested for their biocompatibility and remarkable capacity to promote and support bone regeneration and mineralization. The scaffolds were prepared by grafting three different amounts of gelatin–chitosan (CH) hydrogel into a 3D-printed polylactic acid (PLA) core (PLA-CH), and the mechanical and degradation properties were analyzed. The BM-hMSCs were cultured in the scaffolds with the presence of growth medium (GM) or osteogenic medium (OM) with differentiation stimuli in combination with fetal bovine serum (FBS) or human platelet lysate (hPL). The primary objective was to determine the viability, proliferation, morphology, and spreading capacity of BM-hMSCs within the scaffolds, thereby confirming their biocompatibility. Secondly, the BM-hMSCs were shown to differentiate into osteoblasts and to facilitate scaffold mineralization. This was evinced by a positive Von Kossa result, the modulation of differentiation markers (osteocalcin and osteopontin), an expression of a marker of extracellular matrix remodeling (bone morphogenetic protein-2), and collagen I. The results of the energy-dispersive X-ray analysis (EDS) clearly demonstrate the presence of calcium and phosphorus in the samples that were incubated in OM, in the presence of FBS and hPL, but not in GM. The chemical distribution maps of calcium and phosphorus indicate that these elements are co-localized in the same areas of the sections, demonstrating the formation of hydroxyapatite. In conclusion, our findings show that the combination of BM-hMSCs and PLA-CH, regardless of the amount of hydrogel content, in the presence of differentiation stimuli, can provide a construct with enhanced osteogenicity for clinically relevant bone regeneration.

Piezoelectric scaffolds have been recently developed to explore their potential to enhance the bone regeneration process using the concept of piezoelectricity, which also inherently occurs in bone. In addition to providing mechanical support during bone healing, with a suitable design, they are supposed to produce electrical signals that ought to favor the cell responses. In this study, using finite element analysis (FEA), a piezoelectric scaffold was designed with the aim of providing favorable ranges of mechanical and electrical signals when implanted in a large bone defect in a large animal model, so that it could inform future pre-clinical studies. A parametric analysis was then performed to evaluate the effect of the scaffold design parameters with regard to the piezoelectric behavior of the scaffold. The designed scaffold consisted of a porous strut-like structure with piezoelectric patches covering its free surfaces within the scaffold pores. The results showed that titanium or PCL for the scaffold and barium titanate (BT) for the piezoelectric patches are a promising material combination to generate favorable ranges of voltage, as reported in experimental studies. Furthermore, the analysis of variance showed the thickness of the piezoelectric patches to be the most influential geometrical parameter on the generation of electrical signals in the scaffold. This study shows the potential of computer tools for the optimization of scaffold designs and suggests that patches of piezoelectric material, attached to the scaffold surfaces, can deliver favorable ranges of electrical stimuli to the cells that might promote bone regeneration.

Due to their excellent properties, triply periodic minimal surfaces (TPMS) have been applied to design scaffolds for bone tissue engineering applications. Predicting the mechanical response of bone scaffolds in different loading conditions is vital to designing scaffolds. The optimal mechanical properties can be achieved by tuning their geometrical parameters to mimic the mechanical properties of natural bone. In this study, we designed gyroid scaffolds of different user-specific pore and strut sizes using a combined TPMS and signed distance field (SDF) method to obtain varying architecture and porosities. The designed scaffolds were converted to various meshes such as surface, volume, and finite element (FE) volume meshes to create FE models with different boundary and loading conditions. The designed scaffolds under compressive loading were numerically evaluated using a finite element method (FEM) to predict and compare effective elastic moduli. The effective elastic moduli range from 0.05 GPa to 1.93 GPa was predicted for scaffolds of different architectures comparable to human trabecular bone. The results assert that the optimal mechanical properties of the scaffolds can be achieved by tuning their design and morphological parameters to match the mechanical properties of human bone. [ABSTRACT FROM AUTHOR]

The dual role of macrophages in the healing process depends on macrophage ability to polarize into phenotypes that can propagate inflammation or exert anti-inflammatory and tissue-remodeling functions. Controlling scaffold geometry has been proposed as a strategy to influence macrophage behavior and favor the positive host response to implants. Here, we fabricated Polycaprolactone (PCL) scaffolds by Melt Electrowriting (MEW) to investigate the ability of scaffold architecture to modulate macrophage polarization.Primary human macrophages unpolarized (M0) or polarized into M1, M2a, and M2c phenotypes were cultured on PCL films and MEW scaffolds with pore geometries (square, triangle, and rhombus grid) characterized by different angles.M0, M2a, and M2c macrophages wrapped along the fibers, while M1 macrophages formed clusters with rounded cells. Cell bridges were formed only for angles up to 90°. No relevant differences were found among PCL films and 3D scaffolds in terms of surface markers. CD206 and CD163 were highly expressed by M2a and M2c macrophages, with M2a macrophages presenting also high levels of CD86. M1 macrophages expressed moderate levels of all markers. The rhombus architecture promoted an increased release by M2a macrophages of IL10, IL13, and sCD163 compared to PCL films. The proangiogenic factor IL18 was also upregulated by the rhombus configuration in M0 and M2a macrophages compared to PCL films.The interesting findings obtained for the rhombus architecture represent a starting point for the design of scaffolds able to modulate macrophage phenotype, prompting investigations addressed to verify their ability to facilitate the healing process in vivo.

Objectives: The optimal healing of skin wounds, deep burns, and chronic ulcers is an important clinical problem. Attempts to solve it have been driving the search for skin equivalents based on synthetic or natural polymers. Methods: Consistent with this endeavor, we used regenerated silk fibroin (SF) from Bombyx mori to produce a novel compound scaffold by welding a 3D carded/hydroentangled SF-microfiber-based nonwoven layer (C/H-3D-SFnw; to support dermis engineering) to an electrospun 2D SF nanofiber layer (ESFN; a basal lamina surrogate). Next, we assessed—via scanning electron microscopy, attenuated total reflectance Fourier transform infrared spectroscopy, differential scanning calorimetry, mono- and co-cultures of HaCaT keratinocytes and adult human dermal fibroblasts (HDFs), dsDNA assays, exosome isolation, double-antibody arrays, and angiogenesis assays—whether the C/H-3D-SFnws/ESFNs would allow the reconstitution of a functional human skin analog in vitro. Results: Physical analyses proved that the C/H-3D-SFnws/ESFNs met the requirements for human soft-tissue-like implants. dsDNA assays revealed that co-cultures of HaCaTs (on the 2D ESFN surface) and HDFs (inside the 3D C/H-3D-SFnws) grew more intensely than did the respective monocultures. Double-antibody arrays showed that the CD9+/CD81+ exosomes isolated from the 14-day pooled growth media of HDF and/or HaCaT mono- or co-cultures conveyed 35 distinct angiogenic/growth factors (AGFs). However, versus monocultures' exosomes, HaCaT/HDF co-cultures' exosomes (i) transported larger amounts of 15 AGFs, i.e., PIGF, ANGPT-1, bFGF, Tie-2, Angiogenin, VEGF-A, VEGF-D, TIMP-1/-2, GRO-α/-β/-γ, IL-1β, IL-6, IL-8, MMP-9, and MCP-1, and (ii) significantly more strongly stimulated human dermal microvascular endothelial cells to migrate and assemble tubes/nodes in vitro. Conclusions: Our results showed that both cell–cell and cell–SF interactions boosted the exosomal release of AGFs from HaCaTs/HDFs co-cultured on C/H-3D-SFnws/ESFNs. Hence, such exosomes are an asset for prospective clinical applications as they advance cell growth and neoangiogenesis and consequently graft take and skin healing. Moreover, this new integument analog could be instrumental in preclinical and translational studies on human skin pathophysiology and regeneration. [ABSTRACT FROM AUTHOR]

Materials with an internal porous structure that replace damaged bone and serve as scaffolds for regenerative processes are a fundamental tool in bone tissue engineering. In recent years, research has been carried out on the internal geometry that scaffolding must have in order to respond to specific requirements. The objective of this review is to show the biomaterials and additive manufacturing methods that are used in the manufacture of scaffolds, the main geometric characteristics of the cells that make up the cellular materials, the ways that these cells are distributed in space, among others. For the systematic review, the Google Scholar database was consulted. For this, the terms in English were used: bone tissue engineering scaffold geometric design. The inclusion criteria were that the documents were in English and had been published from 2018 onwards. The first 200 results were reviewed and those that were review articles were prioritized. The importance of pore size and porosity percentage was highlighted as the geometric properties that most in- fluence the mechanical, biological and permeability properties of the scaffold. It shows how current research tends towards degradable biomaterials that can generate a response in the tissue that grows on them and the design of structures where the search for a required property guides the design of the scaffold through procedural or optimization methods, which represents a change compared to the study of one or more cells to establish if their properties conformed to what was required. [ABSTRACT FROM AUTHOR]

Scaffolds for tissue engineering are expected to respond to a challenging combination of physical and mechanical requirements, guiding the research towards the development of novel hybrid materials. This study introduces innovative three-dimensional bioresorbable scaffolds, in which a stiff poly(lactic acid) lattice structure is meant to ensure temporary mechanical support, while a bioactive gelatin–chitosan hydrogel is incorporated to provide a better environment for cell adhesion and proliferation. The scaffolds present a core–shell structure, in which the lattice core is realized by additive manufacturing, while the shell is nested throughout the core by grafting and crosslinking a hydrogel forming solution. After subsequent freeze-drying, the hydrogel network forms a highly interconnected porous structure that completely envelops the poly(lactic acid) core. Thanks to this strategy, it is easy to tailor the scaffold properties for a specific target application by properly designing the lattice geometry and the core/shell ratio, which are found to significantly affect the scaffold mechanical performance and its bioresorption. Scaffolds with a higher core/shell ratio exhibit higher mechanical properties, whereas reducing the core/shell ratio results in higher values of bioactive hydrogel content. Hydrogel contents up to 25 wt% could be achieved while maintaining high compression stiffness (>200 MPa) and strength (>5 MPa), overall, within the range of values displayed by human bone tissue. In addition, mechanical properties remain stable after prolonged immersion in water at body temperature for several weeks. On the other hand, the hydrogel undergoes gradual and homogeneous degradation over time, but the core–shell integrity and structural stability are nevertheless maintained during at least 7-week hydrolytic degradation tests. In vitro experiments with human mesenchymal stromal cells reveal that the core–shell scaffolds are biocompatible, and their physical–mechanical properties and architecture are suitable to support cell growth and osteogenic differentiation, as demonstrated by hydroxyapatite formation. These results suggest that the bioresorbable core–shell scaffolds can be considered and further studied, in view of clinically relevant endpoints in bone regenerative medicine.

This study aimed to fabricate and characterize bovine nanohydroxyapatite (nano-HAp) scaffolds at a low sintering temperature. The compact bone/starch systems were formed using the inorganic matrix of trabecular bone powder and achira isolated starch. To generate the macroporosity, 0, 10, 15, and 20% achira starch granules were added. To obtain nano-HAp scaffolds, the compact bone/starch systems were incinerated at 600 °C, removing organic material. The scaffolds exhibit the presence of Ca, P, Sr, Ba, Fe, Na, Mg, K, and Si came from the HAp with a slight K increase because of the mineral contribution of the starch. Infrared spectroscopy helped determine the elimination of organic materials and evidenced carbonated nano-HAp. X-ray diffraction allows to determine the presence of nano-HAp crystals. Moreover, the X-ray tomography revealed an increased macroporosity (30–38%) for the scaffolds as the starch percentage increased and scanning electron microscopy (SEM) average pore length size for HAp, HAp-A10, HAp-A15, and HAp-A20 were 356.71 ± 156.71, 548.91 ± 131.99, 620.94 ± 147.93, and 728.16 ± 160.98 μm, respectively. In the same way, SEM images of the scaffolds evidenced the presence of micro and nano porosities. The N 2 adsorption-desorption analysis corroborated the presence of mesoporosity with average pore diameters of 3.66 and 3.32 nm in the samples before and after the calcining process, respectively. Thus, thermal treatments did not significantly affect the mesoporous size. In addition, effective Young's modulus is governed by the intrinsic properties of HAp, while the porosity governs the plastic and breaking point. The coalescence phenomena create the scaffold macro architecture. [ABSTRACT FROM AUTHOR]

Due to their excellent properties, triply periodic minimal surfaces (TPMS) have been applied to design scaffolds for bone tissue engineering applications. Predicting the mechanical response of bone scaffolds in different loading conditions is vital to designing scaffolds. The optimal mechanical properties can be achieved by tuning their geometrical parameters to mimic the mechanical properties of natural bone. In this study, we designed gyroid scaffolds of different user-specific pore and strut sizes using a combined TPMS and signed distance field (SDF) method to obtain varying architecture and porosities. The designed scaffolds were converted to various meshes such as surface, volume, and finite element (FE) volume meshes to create FE models with different boundary and loading conditions. The designed scaffolds under compressive loading were numerically evaluated using a finite element method (FEM) to predict and compare effective elastic moduli. The effective elastic moduli range from 0.05 GPa to 1.93 GPa was predicted for scaffolds of different architectures comparable to human trabecular bone. The results assert that the optimal mechanical properties of the scaffolds can be achieved by tuning their design and morphological parameters to match the mechanical properties of human bone.

Novel investigations of how microgravity affects cellular and tissue development have recently been made possible by the multidisciplinary fusion of tissue engineering and space science. This review examines the intersection of cartilage tissue engineering (CTE) and space science, focusing on how microgravity affects cartilage development. Space microgravity induces distinct physiological changes in chondrocytes, including a 20-30% increase in cell diameter, a 1.5- to 2-fold increase in proliferation rates, and up to 3-fold increases in chondrogenic markers such as SOX9 and collagen type II. These cellular alterations impact extracellular matrix composition and tissue structure. Space-optimized bioreactors using dynamic culture methods replicate physiological conditions and enhance tissue growth, but the absence of gravity raises concerns about the mechanical properties of engineered cartilage. Key research areas include the role of growth factors in cartilage development under microgravity, biocompatibility and degradation of scaffold materials in space, and in situ experiments on space stations. This review highlights the opportunities and challenges in leveraging microgravity for CTE advancements, emphasizing the need for continued research to harness space environments for therapeutic applications in cartilage regeneration. The multidisciplinary fusion of tissue engineering and space science opens novel avenues for understanding and improving cartilage tissue engineering, with significant implications for the future of biomedical applications in space and on Earth., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Jeyaraman et al.)

Natural porous materials have exceptional properties-for example, light weight, mechanical resilience, and multi-functionality. Efforts to imitate their properties in engineered structures have limited success. This, in part, is caused by the complexity of multi-phase materials composites and by the lack of quantified understanding of each component's role in overall hierarchy. This challenge is twofold: 1) computational. because non-periodicity and defects render constructing design guidelines between geometries and mechanical properties complex and expensive and 2) experimental. because the fabrication and characterization of complex, often hierarchical and non-periodic 3D architectures is non-trivial., (© 2024 Wiley‐VCH GmbH.)

Objectives: The optimal healing of skin wounds, deep burns, and chronic ulcers is an important clinical problem. Attempts to solve it have been driving the search for skin equivalents based on synthetic or natural polymers. Methods: Consistent with this endeavor, we used regenerated silk fibroin (SF) from Bombyx mori to produce a novel compound scaffold by welding a 3D carded/hydroentangled SF-microfiber-based nonwoven layer (C/H-3D-SFnw; to support dermis engineering) to an electrospun 2D SF nanofiber layer (ESFN; a basal lamina surrogate). Next, we assessed—via scanning electron microscopy, attenuated total reflectance Fourier transform infrared spectroscopy, differential scanning calorimetry, mono- and co-cultures of HaCaT keratinocytes and adult human dermal fibroblasts (HDFs), dsDNA assays, exosome isolation, double-antibody arrays, and angiogenesis assays—whether the C/H-3D-SFnws/ESFNs would allow the reconstitution of a functional human skin analog in vitro. Results: Physical analyses proved that the C/H-3D-SFnws/ESFNs met the requirements for human soft-tissue-like implants. dsDNA assays revealed that co-cultures of HaCaTs (on the 2D ESFN surface) and HDFs (inside the 3D C/H-3D-SFnws) grew more intensely than did the respective monocultures. Double-antibody arrays showed that the CD9+/CD81+ exosomes isolated from the 14-day pooled growth media of HDF and/or HaCaT mono- or co-cultures conveyed 35 distinct angiogenic/growth factors (AGFs). However, versus monocultures’ exosomes, HaCaT/HDF co-cultures’ exosomes (i) transported larger amounts of 15 AGFs, i.e., PIGF, ANGPT-1, bFGF, Tie-2, Angiogenin, VEGF-A, VEGF-D, TIMP-1/-2, GRO-α/-β/-γ, IL-1β, IL-6, IL-8, MMP-9, and MCP-1, and (ii) significantly more strongly stimulated human dermal microvascular endothelial cells to migrate and assemble tubes/nodes in vitro. Conclusions: Our results showed that both cell–cell and cell–SF interactions boosted the exosomal release of AGFs from HaCaTs/HDFs co-cultured on C/H-3D-SFnws/ESFNs. Hence, such exosomes are an asset for prospective clinical applications as they advance cell growth and neoangiogenesis and consequently graft take and skin healing. Moreover, this new integument analog could be instrumental in preclinical and translational studies on human skin pathophysiology and regeneration.

Tissue engineering has garnered considerable attention within the broader field of regenerative medicine that utilizes naturally-occurring nanomaterials as fillers in polymeric scaffolds and as carriers for sustained, targeted drug delivery. These nanomaterials act as functional constructs for the recovery of defective tissues and organs, which may aid in overcoming the current challenges of donor organ shortage. The present article looks into the properties of naturally-occurring nanomaterials, including halloysite nanotubes (Hal), imogolite, and chrysotile, and their potential to improve both the mechanical and biological aspects of polymeric scaffolds in tissue engineering applications. While Hal is natively comprised of hydrous aluminosilicate (primarily in the form of hollow tubes), imogolites are comprised of silanol tetrahedrons and Al–OH octahedrons with typically narrower and shorter dimensions than Hal. Even so, both Hal and imogolites have been found to be highly biocompatible and with negligible cytotoxicities. Conversely, the extensively fibrous and smaller dimensions of chrysotile (compared to Hal and imogolites) have been associated with bioaccumulation and asbestosis, limiting chrysotile applications. Nevertheless, the electrostatically-charged lumens of these nanomaterials enable the encapsulation and sustained release of active agents into the surrounding tissues. Furthermore, the large surface areas and high aspect ratio of both Hal and imogolites greatly enhance the crosslinking and load-bearing capacities of composite polymeric scaffolds; while also providing accessible sites that facilitate cellular attachment and proliferation. This review contributes towards a better understanding of natural nanotube utilization in tissue engineering by highlighting their potential applications to polymer nanocomposites.

The absence of pharmacological treatments to reduce or retard the progression of cardiac valve diseases makes replacement with artificial prostheses (mechanical or bio-prosthetic) essential. Given the increasing incidence of cardiac valve pathologies, there is always a more stringent need for valve replacements that offer enhanced performance and durability. Unfortunately, surgical valve replacement with mechanical or biological substitutes still leads to disadvantages over time. In fact, mechanical valves require a lifetime anticoagulation therapy that leads to a rise in thromboembolic complications, while biological valves are still manufactured with non-living tissue, consisting of aldehyde-treated xenograft material (e.g., bovine pericardium) whose integration into the host fails in the mid- to long-term due to unresolved issues regarding immune-compatibility. While various solutions to these shortcomings are currently under scrutiny, the possibility to implant fully biologically compatible valve replacements remains elusive, at least for large-scale deployment. In this regard, the failure in translation of most of the designed tissue engineered heart valves (TEHVs) to a viable clinical solution has played a major role. In this review, we present a comprehensive overview of the TEHVs developed until now, and critically analyze their strengths and limitations emerging from basic research and clinical trials. Starting from these aspects, we will also discuss strategies currently under investigation to produce valve replacements endowed with a true ability to self-repair, remodel and regenerate. We will discuss these new developments not only considering the scientific/technical framework inherent to the design of novel valve prostheses, but also economical and regulatory aspects, which may be crucial for the success of these novel designs.

The aim of skeletal muscle tissue engineering is to replace or repair skeletal muscle functions that have been injured or lost part of their functions. Skeletal muscle tissue engineering is an important strategy for muscle injury repair. The previous review on skeletal muscle tissue engineering was limited to the discussion of seed cells, biological materials and growth factors. In recent years, research results in this field have continued to emerge. This paper first briefly introduces the anatomy of skeletal muscle, and then combines the latest domestic and foreign study, from the basic problems of tissue engineering skeletal muscle construction to its vascularization, neuralization, etc., to review the current research status of skeletal muscle tissue engineering using three-dimensional (3D) printing, and look forward to its research prospects. [ABSTRACT FROM AUTHOR]

Peripheral nerve injury (PNI) represents a serious clinical and public health problem due to its high incurrence and poor spontaneous recovery. Compared to autograft, which is still the best current practice for long-gap peripheral nerve defects in clinics, the use of polymer-based biodegradable nerve guidance conduits (NGCs) has been gaining momentum as an alternative to guide the repair of severe PNI without the need of secondary surgery and donor nerve tissue. However, simple hollow cylindrical tubes can barely outperform autograft in terms of the regenerative efficiency especially in critical sized PNI. With the rapid development of tissue engineering technology and materials science, various functionalized NGCs have emerged to enhance nerve regeneration over the past decades. From the aspect of scaffold design considerations, with a specific focus on biodegradable polymers, this review aims to summarize the recent advances in NGCs by addressing the onerous demands of biomaterial selections, structural designs, and manufacturing techniques that contributes to the biocompatibility, degradation rate, mechanical properties, drug encapsulation and release efficiency, immunomodulation, angiogenesis, and the overall nerve regeneration potential of NGCs. In addition, several commercially available NGCs along with their regulation pathways and clinical applications are compared and discussed. Lastly, we discuss the current challenges and future directions attempting to provide inspiration for the future design of ideal NGCs that can completely cure long-gap peripheral nerve defects., (© 2024 IOP Publishing Ltd.)

In this study, we propose a spatially patterned 3D-printed nanohydroxyapatite (nHA)/beta-tricalcium phosphate (β-TCP)/collagen composite scaffold incorporating human dental pulp-derived mesenchymal stem cells (hDP-MSCs) for bone regeneration in critical-sized defects. We investigated angiogenesis and osteogenesis in a rabbit critical-sized mandibular defect model treated with this engineered construct. The critical and synergistic role of collagen coating and incorporation of stem cells in the regeneration process was confirmed by including a cell-free uncoated 3D-printed nHA/β-TCP scaffold, a stem cell-loaded 3D-printed nHA/β-TCP scaffold, and a cell-free collagen-coated 3D-printed nHA/β-TCP scaffold in the experimental design, in addition to an empty defect. Posteuthanasia evaluations through X-ray analysis, histological assessments, immunohistochemistry staining, histomorphometry, and reverse transcription-polymerase chain reaction (RT-PCR) suggest the formation of substantial woven and lamellar bone in the cell-loaded collagen-coated 3D-printed nHA/β-TCP scaffolds. Histomorphometric analysis demonstrated a significant increase in osteoblasts, osteocytes, osteoclasts, bone area, and vascularization compared to that observed in the control group. Conversely, a significant decrease in fibroblasts/fibrocytes and connective tissue was observed in this group compared to that in the control group. RT-PCR indicated a significant upregulation in the expression of osteogenesis-related genes, including BMP2, ALPL, SOX9, Runx2, and SPP1. The findings suggest that the hDP-MSC-loaded 3D-printed nHA/β-TCP/collagen composite scaffold is promising for bone regeneration in critical-sized defects.

Recent advances in intestinal organoid technologies have paved the way for in vitro recapitulation of the homeostatic renewal of adult tissues, tissue or organ morphogenesis during development, and pathogenesis of many disorders. In vitro modelling of individual patient diseases using organoid systems have been considered key in establishing rational design of personalized treatment strategies and in improving therapeutic outcomes. In addition, the transplantation of organoids into diseased tissues represents a novel approach to treat currently incurable diseases. Emerging evidence from intensive studies suggests that organoid systems' development and functional maturation depends on the presence of an extracellular matrix with suitable biophysical properties, where advanced synthetic hydrogels open new avenues for theoretical control of organoid phenotypes and potential applications of organoids in therapeutic purposes. In this review, we discuss the status, applications, challenges and perspectives of intestinal organoid systems emphasising on hydrogels and their properties suitable for intestinal organoid culture. We provide an overview of hydrogels used for intestinal organoid culture and key factors regulating their biological activity. The comparison of different hydrogels would be a theoretical basis for establishing design principles of synthetic niches directing intestinal cell fates and functions. Intestinal organoid is an in vitro recapitulation of the gut, which self-organizes from intestinal stem cells and maintains many features of the native tissue. Since the development of this technology, intestinal organoid systems have made significant contribution to rapid progress in intestinal biology. Prevailing methodology for organoid culture, however, depends on animal-derived matrices and suffers from variability and potential risk for contamination of pathogens, limiting their therapeutic application. Synthetic scaffold matrices, hydrogels, might provide solutions to these issues and deepen our understanding on how intestinal cells sense and respond to key biophysical properties of the surrounding matrices. This review provides an overview of developing intestinal models and biomaterials, thereby leading to better understanding of current intestinal organoid systems for both biologists and materials scientists. [Display omitted] [ABSTRACT FROM AUTHOR]

In this study, the printing capability of two different additive manufacturing (3D printing) techniques, namely PolyJet and micro-stereolithography (µSLA), are investigated regarding the fabrication of bone scaffolds. The 3D-printed scaffold structures are used as supports in replacing and repairing fractured bone tissue. Printed bone scaffolds with complex structures produced using additive manufacturing technology can mimic the mechanical properties of natural human bone, providing lightweight structures with modifiable porosity levels. In this study, 3D scaffold structures are designed with different combinations of architectural parameters. The dimensional accuracy, permeability, and mechanical properties of complex 3D-printed scaffold structures are analyzed to compare the advantages and drawbacks associated with the two techniques. The fluid flow rates through the 3D-printed scaffold structures are measured and Darcy's law is applied to calculate the experimentally measured permeability. The Kozeny–Carman equation is applied for theoretical calculation of permeability. Compression tests were performed on the printed samples to observe the effects of the printing techniques on the mechanical properties of the 3D-printed scaffold structures. The effect of the printing direction on the mechanical properties of the 3D-printed scaffold structures is also analyzed. The scaffold structures printed with the µSLA printer demonstrate higher permeability and mechanical properties as compared to those printed using the PolyJet technique. It is demonstrated that both the µSLA and PolyJet printing techniques can be used to print 3D scaffold structures with controlled porosity levels, providing permeability in a similar range to human bone. [ABSTRACT FROM AUTHOR]

The optimal performance of scaffolds for tissue engineering relies on a proper combination of their constituent biomaterials and on the design of their structure. In this work, composite scaffolds with a core-shell architecture are realized by grafting a gelatin-chitosan hydrogel onto a 3D-printed polylactic acid (PLA) core, aiming in particular at bone regeneration. This hydrogel was recently found to sustain osteogenic differentiation of mesenchymal stromal cells, leading to new bone tissue formation. Here, the integration with rigid PLA lattice structures provides improved mechanical support and finer control of strength and stiffness. The core is prepared by fused deposition modeling with the specific aim to study several lattice structures and thereby better tune the scaffold mechanical properties. In fact, the core architecture dictates the scaffold strength and stiffness, which are seen to match those of different types of bone tissue. For all lattice types, the hydrogel is found to penetrate throughout the entire core and to present highly interconnected pores for cell colonization. By varying the void volume fraction in the core it is possible to significantly change the bioactive shell content, as well as the mechanical properties, over a wide range of values. Looking for design guidelines, relationships between stiffness/strength and density are here outlined for scaffolds featuring different lattice parameters. Moreover, by acting on the core strut arrangement, scaffolds are reinforced along specific directions, as evaluated under compressive and bending loading conditions. [ABSTRACT FROM AUTHOR]

Engineered heart tissues (EHTs) built from human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) showed promising results for cardiac function restoration following myocardial infarction. Nevertheless, human iPSC-CMs have longer action potential and lower cell-to-cell coupling than adult-like CMs. These immature electrophysiological properties favor arrhythmias due to the generation of electrophysiological gradients when hiPSC-CMs are injected in the cardiac tissue. Culturing hiPSC-CMs on three-dimensional (3D) scaffolds can promote their maturation and influence their alignment. However, it is still uncertain how on-scaffold culturing influences the overall electrophysiology of the in vitro and implanted EHTs, as it requires expensive and time consuming experimentation. Here, we computationally investigated the impact of the scaffold design on the EHT electrical depolarization and repolarization before and after engraftment on infarcted tissue. We first acquired and processed electrical recordings from in vitro EHTs, which we used to calibrate the modeling and simulation of in silico EHTs to replicate experimental outcomes. Next, we built in silico EHT models for a range of scaffold pore sizes, shapes (square, rectangular, auxetic, hexagonal) and thicknesses. In this setup, we found that scaffolds made of small (0.2 mm 2 ), elongated (30° half-angle) hexagons led to faster EHT activation and better mimicked the cardiac anisotropy. The scaffold thickness had a marginal role on the not engrafted EHT electrophysiology. Moreover, EHT engraftment on infarcted tissue showed that the EHT conductivity should be at least 5% of that in healthy tissue for bidirectional EHT-myocardium electrical propagation. For conductivities above such threshold, the scaffold made of small elongated hexagons led to the lowest activation time (AT) in the coupled EHT-myocardium. If the EHT conductivity was further increased and the hiPSC-CMs were uniformly oriented parallel to the epicardial cells, the total AT and the repolarization time gradient decreased substantially, thus minimizing the likelihood for arrhythmias after EHT transplantation., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Ligament tissues exhibit zone-specific anisotropic cell organization. The cells in ligament-proper are longitudinally oriented, whereas, the cells in epiligament are circumferentially oriented. Therefore, scaffolds developed to regenerate ligament tissues should possess adequate architectural features to govern ligament-mimetic bi-directional cell organization. The scaffold architectural features along with ligament-mimetic cell organization may ultimately yield neo-tissues with ligament-like extracellular matrix (ECM) structure and biomechanical properties. Towards this goal, we fabricated a silk/gelatin-based core-shell scaffold (csSG) with zone-specific anisotropic architectural features, wherein, the core of the scaffold possessed longitudinally aligned pores while the shell of the scaffold possessed parallel microgrooves that are aligned circumferentially around the surface of the scaffold. The ligament-mimetic architectural features significantly improved the mechanical properties of the scaffold. Moreover, architectural features of the csSG scaffold governed zone-specific anisotropic organization of cells. The cells in the core were longitudinally oriented as observed in the ligament-proper and the cells on the shell were circumferentially oriented as observed in epiligament. This bi-directional cell orientation partially mimicked the complex cellular network in native ligament tissue. Additionally, both the core and the shell individually supported fibrogenic differentiation of stem cells which further improved their potential for ligament tissue engineering. Further, the aligned pores of the core could govern unidirectional organization of ECM deposited by cells which is crucial for regenerating anisotropic tissues like ligaments. Finally, when implanted subcutaneously in mice, the scaffolds retained their anisotropic architecture for at least 2 weeks, were biocompatible, supported cell infiltration and governed anisotropic organization of cells and ECM. Taken together, the fabricated biomimetic csSG scaffold, through its zone-specific architectural features, could govern ligament-mimetic cellular and ECM organization which is ultimately expected to achieve regeneration of ligament tissues with native-like hierarchical structure and biomechanical properties. Consequently, this study introduces bi-directional structural parameters as design criteria for developing scaffolds for ligament tissue engineering., (© 2024 IOP Publishing Ltd.)

Repair or regeneration of load-bearing bones has long been an incentive for the tissue engineering community to develop a plethora of synthetic bone scaffolds. Despite the key role of physical forces and the mechanical environment in bone regeneration, the mechanotransduction concept has rarely been incorporated in structural design of bone tissue scaffolds, particularly those made of bioactive materials such as hydrogels and bioceramics. Herein, we introduce a modular design strategy to fabricate a load bearing device that can support a wide range of hydrogel- and ceramic-based scaffolds against complex in-vivo loading conditions to induce desirable mechanical strains for bone regeneration within the scaffolds. The device is comprised of a fenestrated polymeric shell and ceramic structural pillars arranged in a sophisticated configuration to provide ample internal space for the scaffold, also enabling it to purposely regulate the levels of strains and stresses within the scaffolds. Utilizing this top-down design approach, we demonstrate that the failure load of alginate hydrogels increases 3200-fold in compression, 300-fold in shear and 75-fold in impact, achieving the values that enable them to withstand physiological loads in weight-bearing sites, while allowing generation of osteoinductive strains (i.e., 0.2-0.4%) in the hydrogel. This modular design approach opens a broad range of opportunities to utilize various bioactive but mechanically weak scaffolds for the treatment of load-bearing defects and exploiting mechanobiology strategies to improve bone regeneration. Image, graphical abstract [ABSTRACT FROM AUTHOR]

Direct ink writing allows controlling the structure of tissue engineering scaffolds. The aim of this work was to study the effects of the in silico pattern design on the dimensional accuracy of tricalcium phosphate scaffolds and of the loading direction on the compressive strength and fracture modes. Regular and shifted scaffolds showed anisotropic shrinkage during drying and isotropic shrinkage during sintering. Shifted layers induced bending stresses when compressed longitudinally, resulting in lower compressive strength. The transverse Young's modulus and compressive strength were higher than the longitudinal ones for both regular and shifted structures. Strand deflections were more pronounced in shifted structures. Finite element modelling suggested that such deflections considerably increased the effective transverse modulus of the shifted scaffolds, thus increasing the related compressive strength. In conclusion, shifted scaffolds performed similarly to regular ones in the transverse direction but were less mechanically reliable under the longitudinal direction. [ABSTRACT FROM AUTHOR]

In bone tissue engineering, the structure of a scaffold is very important for cell growth and bone regeneration. It is better to make the scaffold resemble the native cancellous bone because natural cancellous bone can promote scaffold revascularization, which then accelerates cell proliferation. This study presents a parameterized design and fabrication method for cranial scaffold construction. A native human cranial sample was first scanned using micro computed tomography (CT), followed by 3D reconstruction, after which the internal structure of the bone trabecula was created. Based on an extracted negative bone trabecula model, the design components of "cavity", "connecting pipe" and "spatial framework" were proposed to describe the scaffold model. Then, by using the parameterized component model and an assembly and deformation algorithm, the bionic scaffold was designed. Its porous distribution, connection, porosity and area size were easily controlled. Finally, a biomaterial scaffold case was fabricated using a gelcasting process, and cell culture testing was performed in vitro to verify the scaffold's biocompatibility. The results show that the scaffold can promote cell growth and that cells accumulate in the form of a mass within three days. • A native human cranial sample was scanned to detect the bone trabecula structure. • The design components of "cavity", "connecting pipe" and "spatial framework" were proposed to describe the scaffold architecture. • The generated porous scaffold structure was highly similar to the native bone trabecula. • A gel-casting process for β-TCP was proposed to fabricate the scaffold successfully. • The scaffold and cell culture test showed that the biological properties were good, the scaffold was well fit for cell adhesion and growth. [ABSTRACT FROM AUTHOR]

As an emerging technology, intestinal organoids are promising new tools for basic and translational research in gastroenterology. Currently, culture of intestinal organoids relies mostly on a type of tumor‐derived scaffolds, namely Matrigel, which may pose tumorigenic risks to organoid implantation. Apart from the traditional detection methods, such as tissue slicing and fluorescence staining, the monitoring of intestinal organoids requires real‐time biosensors that can adapt to their three‐dimensional dynamic growth patterns. In this review, we summarized the recent advances in developing definite hydrogel scaffolds for intestinal organoid culture and identified key parameters for scaffold design. In addition, classified by different substrate compositions like pH, electrolytes, and functional proteins, we concluded the existing live‐imaging biosensors and elucidated their underlying mechanisms. We hope this review enhances the understanding of intestinal organoid culture and provides more practical approaches to investigate them. [ABSTRACT FROM AUTHOR]

The suitability of a scaffold for tissue engineering is determined by a number of interrelated factors. The biomaterial should be biocompatible and cell instructive, with a porosity and pore interconnectivity that facilitates cellular migration and the transport of nutrients and waste products into and out of the scaffolds. For the engineering of load bearing tissues, the scaffold may also be required to possess specific mechanical properties and/or ensure the transfer of mechanical stimuli to cells to direct their differentiation. Achieving these design goals is challenging, but could potentially be realised by integrating computational tools such as finite element (FE) modelling with three-dimensional (3D) printing techniques to assess how scaffold architecture and material properties influence the performance of the implant. In this study we first use Fused Deposition Modelling (FDM) to modulate the architecture of polycaprolactone (PCL) scaffolds, exploring the influence of varying fibre diameter, spacing and laydown pattern on the structural and mechanical properties of such scaffolds. We next demonstrate that a simple FE modelling strategy, which captures key aspects of the printed scaffold's actual geometry and material behaviour, can be used to accurately model the mechanical characteristics of such scaffolds. We then show the utility of this strategy by using FE modelling to help design 3D printed scaffolds with mechanical properties mimicking that of articular cartilage. In conclusion, this study demonstrates that a relatively simple FE modelling approach can be used to inform the design of 3D printed scaffolds to ensure their bulk mechanical properties mimic specific target tissues. [ABSTRACT FROM AUTHOR]

• Grid point density is introduced to achieve smooth topological boundaries. • Boundary error is proposed to control the distribution of intermediate elements. • Different levels of anisotropic elastic tensor of cancellous bone are considered. • The optimized cancellous bone scaffolds have good printability. In this paper, a topology optimization method is proposed to design bone scaffold structures that match the anisotropic elasticity tensors of cancellous bone. Grid point density and boundary error are introduced in the optimization model to achieve smooth boundaries of scaffold topology and control the distribution of intermediate elements. Combined with finite element analysis, the effects of scaffolds with different levels of elasticity tensors on the stress transfer and distribution of the scaffold-cancellous bone structure are investigated. It is found that scaffolds with the same or slightly lower elastic properties (0.9 times) than cancellous bone transmitted more uniform stresses into the cancellous bone. Finally, we demonstrate that optimized scaffolds can be fabricated by Stereolithography (SLA). [ABSTRACT FROM AUTHOR]

In this study, the printing capability of two different additive manufacturing (3D printing) techniques, namely PolyJet and micro-stereolithography (µSLA), are investigated regarding the fabrication of bone scaffolds. The 3D-printed scaffold structures are used as supports in replacing and repairing fractured bone tissue. Printed bone scaffolds with complex structures produced using additive manufacturing technology can mimic the mechanical properties of natural human bone, providing lightweight structures with modifiable porosity levels. In this study, 3D scaffold structures are designed with different combinations of architectural parameters. The dimensional accuracy, permeability, and mechanical properties of complex 3D-printed scaffold structures are analyzed to compare the advantages and drawbacks associated with the two techniques. The fluid flow rates through the 3D-printed scaffold structures are measured and Darcy’s law is applied to calculate the experimentally measured permeability. The Kozeny–Carman equation is applied for theoretical calculation of permeability. Compression tests were performed on the printed samples to observe the effects of the printing techniques on the mechanical properties of the 3D-printed scaffold structures. The effect of the printing direction on the mechanical properties of the 3D-printed scaffold structures is also analyzed. The scaffold structures printed with the µSLA printer demonstrate higher permeability and mechanical properties as compared to those printed using the PolyJet technique. It is demonstrated that both the µSLA and PolyJet printing techniques can be used to print 3D scaffold structures with controlled porosity levels, providing permeability in a similar range to human bone.

Piezoelectric scaffolds have been recently developed to explore their potential to enhance the bone regeneration process using the concept of piezoelectricity, which also inherently occurs in bone. In addition to providing mechanical support during bone healing, with a suitable design, they are supposed to produce electrical signals that ought to favor the cell responses. In this study, using finite element analysis (FEA), a piezoelectric scaffold was designed with the aim of providing favorable ranges of mechanical and electrical signals when implanted in a large bone defect in a large animal model, so that it could inform future pre-clinical studies. A parametric analysis was then performed to evaluate the effect of the scaffold design parameters with regard to the piezoelectric behavior of the scaffold. The designed scaffold consisted of a porous strut-like structure with piezoelectric patches covering its free surfaces within the scaffold pores. The results showed that titanium or PCL for the scaffold and barium titanate (BT) for the piezoelectric patches are a promising material combination to generate favorable ranges of voltage, as reported in experimental studies. Furthermore, the analysis of variance showed the thickness of the piezoelectric patches to be the most influential geometrical parameter on the generation of electrical signals in the scaffold. This study shows the potential of computer tools for the optimization of scaffold designs and suggests that patches of piezoelectric material, attached to the scaffold surfaces, can deliver favorable ranges of electrical stimuli to the cells that might promote bone regeneration., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Badali, Checa, Zehn, Marinkovic and Mohammadkhah.)

Protein tyrosine phosphatase 1B (PTP1B) has been identified as a promising drug target for the development of diabetes medications via an inhibition mechanism. Using a computational approach, this study investigates the binding mechanism of lead optimized natural compounds from Allium sativum against the human PTP1B. The molecular docking, induced-fit docking, and binding free energy calculations were analyzed using Schrödinger Suite 2021-2. MD simulation, and gene enrichment analysis was achieved via the Desmond module of Schrödinger to identify best compounds as inhibitors against PTP1B in diabetes management. The docking scores of the lead optimized compounds were good; 5280443_121 from apigenin had the best binding score of -9.345 kcal/mol, followed by 5280443_129 with a binding score of -9.200 kcal/mol, and 5280863_177 from kaempferol had a binding score of -8.528 kcal/mol, followed by 5280863_462 with a binding score of -8.338 kcal/mol. The top two lead optimized compounds, docked better than the standard PTP1B inhibitor (-7.155 kcal/mol), suggesting them as potent inhibitors than the standard PTP1B inhibitor. The outcomes of the induced-fit docking were consistent with the increased binding affinity used in the Glide computation of the five conformed poses between the derivatives (5280443_121, 5280443_129, 5280863_177, and 5280863_462) and the protein (PTP1B). Based on the binding fee energies (MM-GBSA), the lead optimized compounds from kaempferol exhibited more stability than those from apigenin. In the pharmacophore development, all the models exhibit good results across the different metrics. The best performing model with five of five matches on a 1.34 and 1.33 phase score was DDRRR_1, DDRRR_2, and DDDRR_1. The average BEDROC value (= 160.9) was 1, while the average EF 1% value across all models was 101. There were no substantial conformational modifications during the MD simulation process, indicating that the apigenin derivatives (5280443_121) was stable in the protein's active site in 100 ns. IGF1R, EGFR, INSR, PTPN1, SRC, JAK2, GRB2, BCAR1, and IRS1 are among the 11 potential targets found in the protein-protein interaction (PPI) of A. sativum against PTP1B that may be important in A. sativum' s defense against PTP1B. Sixty-four (64) pathways were found by KEGG pathway enrichment analysis to be potentially involved in the anti-PTP1B of A. sativum . Consequently, data obtained indicates the effectiveness of the in silico studies in identifying potential lead compounds in A. sativum against PTP1B target.Communicated by Ramaswamy H. Sarma.

Featured Application: Optimization of Scaffold Design and Flow Perfusion Culturing Conditions for Maximal Delivery of Oxygen to the Cells Embedded Deep Inside of Engineered Tissues. Tissue engineering has the potential for repairing large bone defects, which impose a heavy financial burden on the public health. However, difficulties with O2 delivery to the cells residing in the interior of tissue engineering scaffolds make it challenging to grow artificial tissues of clinically-relevant sizes. This study uses image-based simulation in order to provide insight into how to better optimize the scaffold manufacturing parameters, and the culturing conditions, in order to resolve the O2 bottleneck. To do this, high resolution 3D X-ray images of two common scaffold types (salt leached foam and non-woven fiber mesh) are fed into Lattice Boltzmann Method fluid dynamics and reactive Lagrangian Scalar Tracking mass transfer solvers. The obtained findings indicate that the scaffolds should have maximal surface area-to-solid volume ratios for higher chances of the molecular collisions with the cells. Furthermore, the cell culture media should be flown through the scaffold pores as fast as practically possible (without detaching or killing the cells). Finally, we have provided a parametric sweep that maps how the molecular transport within the scaffolds is affected by variations in rates of O2 consumption by the cells. Ultimately, the results of this study are expected to benefit the computer-assisted design of tissue engineering scaffolds and culturing experiments. [ABSTRACT FROM AUTHOR]

Cancer research uses in vitro studies for controllable analysis of tumor behavior and preclinical testing of therapeutics. Shortcomings of basic cell culture systems in recreating in vivo interactions have driven the development of more efficient and biomimetic in vitro environments for cancer research. Assimilation of certain developments in tissue engineering will accelerate and improve the design of these environments. With the continual improvement of the tumor engineering field, the next step is towards macroscopic systems such as scaffold-supported, flow-perfused macroscale tumor bioreactors. Surface modifications of synthetic scaffolds allow for targeted cell adhesion and improved ECM development. Flow perfusion has emerged as means to expose cancerous tissues to critical biomechanical forces for tumor progression while simultaneously improving nutrient and waste transport. Macroscale perfusable systems allow for non-destructive real-time monitoring using biosensors capable of improving understanding of in vitro tumor development at reduced cost and waste. The combination of macroscale perfusable systems, surface-modified synthetic scaffolds, and non-destructive real-time monitoring will provide advanced platforms for in vitro modeling of tumor development, with broad applications in basic tumor research and preclinical drug development. [ABSTRACT FROM AUTHOR]

Abstract The current research reports for the first time the use of blends of poly(ε-caprolactone) (PCL) and poly(ester amide) (PEA) for the fabrication of 3D additive manufactured scaffolds. Tailor made PEA was synthesized to afford fully miscible blends of PCL and PEA using different percentages (5, 10, 15 and 20% w/w). Stability, characteristic temperatures and material's compatibility were studied through thermal analyses (i.e., TGA, DSC). Even though DMTA and static compression tests demonstrated the possibility to improve the storage modulus, Young's modulus and maximum stress by increasing the amount of PEA, a decrease of hardness was found beyond a threshold concentration of PEA as the lowest values were achieved for PCL/PEA (20% w/w) scaffolds (from 0.39 ± 0.03 GPa to 0.21 ± 0.02 GPa in the analysed load range). The scaffolds presented a controlled morphology and a fully interconnected network of internal channels. The water contact angle measurements showed a clear increase of hydrophilicity resulting from the addition of PEA. This result was further corroborated with the improved adhesion and proliferation of human mesenchymal stem cells (hMSCs). The presence of PEA also influenced the cell morphology. Better cell spreading and a much higher and homogenous number of cells were observed for PCL/PEA scaffolds when compared to PCL ones. Highlights • The synthesis of PEA with a proper chemical structure was performed to obtain miscible blends. • Blends of poly(ε-caprolactone) (PCL) and poly(ester amide) (PEA) were prepared for the bioprinting of 3D scaffolds. • The chemical, physical and biological properties of 3D bioprinted PCL scaffolds were evaluated as a function of PEA addition. • The addition of PEA strongly enhanced hydrophilicity, mechanical response and cellular function of PCL scaffolds. [ABSTRACT FROM AUTHOR]

The in vivo evaluation of soft biomaterial implant remodeling routinely requires the surgical removal of the implant for subsequent histological assessment of tissue ingrowth and scaffold remodeling. This approach is very resource intensive, often destructive, and imposes practical limitations on how effectively these materials can be evaluated. MRI has the potential to non‐invasively monitor the remodeling of implanted collagen scaffolds in real time. This study investigated the development of a model system to characterize the cellular infiltration, void area fraction, and angiogenesis in collagen scaffold implants using T2 relaxation time and apparent diffusion coefficient (ADC) maps along with conventional histological techniques. Initial correlations found statistically significant relationships between the MRI and histological parameters for various regions of the implanted sponges: T2 versus cell density (r ≈ −0.83); T2 versus void area fraction (r ≈ +0.78); T2 versus blood vessel density (r ≈ +0.95); ADC versus cell density (r ≈ −0.77); and ADC versus void area fraction (r ≈ +0.84). This suggests that MRI is sensitive to specific remodeling parameters and has the potential to serve as a non‐invasive tool to monitor the remodeling of implanted collagen scaffolds, and to ultimately assess the ability of these scaffolds to regenerate the functional properties of damaged tissues such as tendons, ligaments, skin or skeletal muscle. For evaluating cellular responses to soft biomaterial implants, histological analyses are the current reference standard for assessing tissue ingrowth and scaffold remodeling. In this study, magnetic resonance imaging (MRI) was used to characterize the cellular infiltration, void area fraction, and angiogenesis in collagen scaffold implants using T2 relaxation time and apparent diffusion coefficient (ADC) maps. Initial correlations were found between the MRI and histological parameters suggesting that MRI is sensitive to specific remodeling parameters. [ABSTRACT FROM AUTHOR]

Optical coherence tomography based computational flow dynamic (CFD) modeling provides detailed information about the local flow behavior in stented/scaffolded vessel segments. Our aim is to investigate the in-vivo effect of strut thickness and strut protrusion on endothelial wall shear stress (ESS) distribution in ArterioSorb Absorbable Drug-Eluting Scaffold (ArterioSorb) and Absorb everolimus-eluting Bioresorbable Vascular Scaffold (Absorb) devices that struts with similar morphology (quadratic structure) but different thickness. In three animals, six coronary arteries were treated with ArterioSorb. At different six animals, six coronary arteries were treated with Absorb. Following three-dimensional(3D) reconstruction of the coronary arteries, Newtonian steady flow simulation was performed and the ESS were estimated. Mixed effects models were used to compare ESS distribution in the two devices. There were 4591 struts in the analyzed 477 cross-sections in Absorb (strut thickness = 157 µm) and 3105 struts in 429 cross-sections in ArterioSorb (strut thickness = 95 µm) for the protrusion analysis. In cross-section level analysis, there was significant difference between the scaffolds in the protrusion distances. The protrusion was higher in Absorb (97% of the strut thickness) than in ArterioSorb (88% of the strut thickness). ESS was significantly higher in ArterioSorb (1.52 ± 0.34 Pa) than in Absorb (0.73 ± 2.19 Pa) (p = 0.001). Low- and very-low ESS data were seen more often in Absorb than in ArterioSorb. ArterioSorb is associated with a more favorable ESS distribution compared to the Absorb. These differences should be attributed to different strut thickness/strut protrusion that has significant effect on shear stress distribution. [ABSTRACT FROM AUTHOR]