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- Bioprinting Technologies
AUTHOR
Title
Bioprinting of structurally organized meniscal tissue within anisotropic melt electrowritten scaffolds
[Abstract]
Year
2023
Journal/Proceedings
Acta Biomaterialia
Reftype
Groups
AbstractThe meniscus is characterised by an anisotropic collagen fibre network which is integral to its biomechanical functionality. The engineering of structurally organized meniscal grafts that mimic the anisotropy of the native tissue remains a significant challenge. In this study, inkjet bioprinting was used to deposit a cell-laden bioink into additively manufactured scaffolds of differing architectures to engineer fibrocartilage grafts with user defined collagen architectures. Polymeric scaffolds consisting of guiding fibre networks with varying aspect ratios (1:1; 1:4; 1:16) were produced using either fused deposition modelling (FDM) or melt electrowriting (MEW), resulting in scaffolds with different internal architectures and fibre diameters. Scaffold architecture was found to influence the spatial organization of the collagen network laid down by the jetted cells, with higher aspect ratios (1:4 and 1:16) supporting the formation of structurally anisotropic tissues. The MEW scaffolds supported the development of a fibrocartilaginous tissue with compressive mechanical properties similar to that of native meniscus, while the anisotropic tensile properties of these constructs could be tuned by altering the fibre network aspect ratio. This MEW framework was then used to generate scaffolds with spatially distinct fibre patterns, which in turn supported the development of heterogenous tissues consisting of isotropic and anisotropic collagen networks. Such bioprinted tissues could potentially form the basis of new treatment options for damaged and diseased meniscal tissue. Statement of significance This study describes a multiple tool biofabrication strategy which enables the engineering of spatially organized fibrocartilage tissues. The architecture of MEW scaffolds can be tailored to not only modulate the directionality of the collagen fibres laid down by cells, but also to tune the anisotropic tensile mechanical properties of the resulting constructs, thereby enabling the engineering of biomimetic meniscal-like tissues. Furthermore, the inherent flexibility of MEW enables the development of zonally defined and potentially patient-specific implants.
AUTHOR
Title
Melt electrowriting onto anatomically relevant biodegradable substrates: Resurfacing a diarthrodial joint
[Abstract]
Year
2020
Journal/Proceedings
Materials & Design
Reftype
Groups
AbstractThree-dimensional printed hydrogel constructs with well-organized melt electrowritten (MEW) fibre-reinforcing scaffolds have been demonstrated as a promising regenerative approach to treat small cartilage defects. Here, we investige how to translate the fabrication of small fibre-reinforced structures on flat surfaces to anatomically relevant structures. In particular, the accurate deposition of MEW-fibres onto curved surfaces of conductive and non-conductive regenerative biomaterials is studied. This study reveals that clinically relevant materials with low conductivities are compatible with resurfacing with organized MEW fibres. Importantly, accurate patterning on non-flat surfaces was successfully shown, provided that a constant electrical field strength and an electrical force normal to the substrate material is maintained. Furthermore, the application of resurfacing the geometry of the medial human femoral condyle is confirmed by the fabrication of a personalised osteochondral implant. The implant composed of an articular cartilage-resident chondroprogenitor cells (ACPCs)-laden hydrogel reinforced with a well-organized MEW scaffold retained its personalised shape, improved its compressive properties and supported neocartilage formation after 28 days in vitro culture. Overall, this study establishes the groundwork for translating MEW from planar and non-resorbable material substrates to anatomically relevant geometries and regenerative materials that the regenerative medicine field aims to create.
AUTHOR
Title
Biofabrication of spatially organised tissues by directing the growth of cellular spheroids within 3D printed polymeric microchambers
[Abstract]
Year
2019
Journal/Proceedings
Biomaterials
Reftype
Groups
AbstractSuccessful tissue engineering requires the generation of human scale implants that mimic the structure, composition and mechanical properties of native tissues. Here, we report a novel biofabrication strategy that enables the engineering of structurally organised tissues by guiding the growth of cellular spheroids within arrays of 3D printed polymeric microchambers. With the goal of engineering stratified articular cartilage, inkjet bioprinting was used to deposit defined numbers of mesenchymal stromal cells (MSCs) and chondrocytes into pre-printed microchambers. These jetted cell suspensions rapidly underwent condensation within the hydrophobic microchambers, leading to the formation of organised arrays of cellular spheroids. The microchambers were also designed to provide boundary conditions to these spheroids, guiding their growth and eventual fusion, leading to the development of stratified cartilage tissue with a depth-dependant collagen fiber architecture that mimicked the structure of native articular cartilage. Furthermore, the composition and biomechanical properties of the bioprinted cartilage was also comparable to the native tissue. Using multi-tool biofabrication, we were also able to engineer anatomically accurate, human scale, osteochondral templates by printing this microchamber system on top of a hypertrophic cartilage region designed to support endochondral bone formation and then maintaining the entire construct in long-term bioreactor culture to enhance tissue development. This bioprinting strategy provides a versatile and scalable approach to engineer structurally organised cartilage tissues for joint resurfacing applications.
AUTHOR
Title
Pore-forming bioinks to enable Spatio-temporally defined gene delivery in bioprinted tissues
[Abstract]
Year
2019
Journal/Proceedings
Journal of Controlled Release
Reftype
Groups
AbstractThe regeneration of complex tissues and organs remains a major clinical challenge. With a view towards bioprinting such tissues, we developed a new class of pore-forming bioink to spatially and temporally control the presentation of therapeutic genes within bioprinted tissues. By blending sacrificial and stable hydrogels, we were able to produce bioinks whose porosity increased with time following printing. When combined with amphipathic peptide-based plasmid DNA delivery, these bioinks supported enhanced non-viral gene transfer to stem cells in vitro. By modulating the porosity of these bioinks, it was possible to direct either rapid and transient (pore-forming bioinks), or slower and more sustained (solid bioinks) transfection of host or transplanted cells in vivo. To demonstrate the utility of these bioinks for the bioprinting of spatially complex tissues, they were next used to zonally position stem cells and plasmids encoding for either osteogenic (BMP2) or chondrogenic (combination of TGF-β3, BMP2 and SOX9) genes within networks of 3D printed thermoplastic fibers to produce mechanically reinforced, gene activated constructs. In vivo, these bioprinted tissues supported the development of a vascularised, bony tissue overlaid by a layer of stable cartilage. When combined with multiple-tool biofabrication strategies, these gene activated bioinks can enable the bioprinting of a wide range of spatially complex tissues.
AUTHOR
Title
Three-Dimensional Bioprinting of Polycaprolactone Reinforced Gene Activated Bioinks for Bone Tissue Engineering
[Abstract]
Year
2017
Journal/Proceedings
Tissue Engineering Part A
Reftype
DOI/URL
DOI
Groups
AbstractRegeneration of complex bone defects remains a significant clinical challenge. Multi-tool biofabrication has permitted the combination of various biomaterials to create multifaceted composites with tailorable mechanical properties and spatially controlled biological function. In this study we sought to use bioprinting to engineer nonviral gene activated constructs reinforced by polymeric micro-filaments. A gene activated bioink was developed using RGD-g-irradiated alginate and nano-hydroxyapatite (nHA) complexed to plasmid DNA (pDNA). This ink was combined with bonemarrow-derived mesenchymal stemcells (MSCs) and then co-printed with a polycaprolactone supporting mesh to provide mechanical stability to the construct. Reporter genes were first used to demonstrate successful cell transfection using this system, with sustained expression of the transgene detected over 14 days postbioprinting. Delivery of a combination of therapeutic genes encoding for bone morphogenic protein and transforming growth factor promoted robust osteogenesis of encapsulated MSCs in vitro, with enhanced levels of matrix deposition and mineralization observed following the incorporation of therapeutic pDNA. Gene activated MSC-laden constructs were then implanted subcutaneously, directly postfabrication, and were found to support superior levels of vascularization andmineralization compared to cell-free controls. These results validate the use of a gene activated bioink to impart biological functionality to three-dimensional bioprinted constructs.
AUTHOR
Title
Fluidic integrated 3D bioprinting system to sustain cell viability towards larynx fabrication
[Abstract]
Year
2022
Journal/Proceedings
Bioengineering & Translational Medicine
Reftype
DOI/URL
DOI
Groups
AbstractAbstract Herein, we report the first study to create a three-dimensional (3D) bioprinted artificial larynx for whole-laryngeal replacement. Our 3D bio-printed larynx was generated using extrusion-based 3D bioprinter with rabbit's chondrocyte-laden gelatin methacryloyl (GelMA)/glycidyl-methacrylated hyaluronic acid (GMHA) hybrid bioink. We used a polycaprolactone (PCL) outer framework incorporated with pores to achieve the structural strength of printed constructs, as well as to provide a suitable microenvironment to support printed cells. Notably, we established a novel fluidics supply (FS) system that simultaneously supplies basal medium together with a 3D bioprinting process, thereby improving cell survival during the printing process. Our results showed that the FS system enhanced post-printing cell viability, which enabled the generation of a large-scale cell-laden artificial laryngeal framework. Additionally, the incorporation of the PCL outer framework with pores and inner hydrogel provides structural stability and sufficient nutrient/oxygen transport. An animal study confirmed that the transplanted 3D bio-larynx successfully maintained the airway. With further development, our new strategy holds great potential for fabricating human-scale larynxes with in vivo-like biological functions for laryngectomy patients.
AUTHOR
Title
3D bioprinting spatiotemporally defined patterns of growth factors to tightly control tissue regeneration
[Abstract]
Year
2020
Journal/Proceedings
Science Advances
Reftype
Groups
AbstractTherapeutic growth factor delivery typically requires supraphysiological dosages, which can cause undesirable off-target effects. The aim of this study was to 3D bioprint implants containing spatiotemporally defined patterns of growth factors optimized for coupled angiogenesis and osteogenesis. Using nanoparticle functionalized bioinks, it was possible to print implants with distinct growth factor patterns and release profiles spanning from days to weeks. The extent of angiogenesis in vivo depended on the spatial presentation of vascular endothelial growth factor (VEGF). Higher levels of vessel invasion were observed in implants containing a spatial gradient of VEGF compared to those homogenously loaded with the same total amount of protein. Printed implants containing a gradient of VEGF, coupled with spatially defined BMP-2 localization and release kinetics, accelerated large bone defect healing with little heterotopic bone formation. This demonstrates the potential of growth factor printing, a putative point of care therapy, for tightly controlled tissue regeneration.
AUTHOR
Title
Crystal Growth of 3D Poly(ε-caprolactone) Based Bone Scaffolds and Its Effects on the Physical Properties and Cellular Interactions
[Abstract]
Year
2022
Journal/Proceedings
Advanced Science
Reftype
Groups
AbstractAbstract Extrusion additive manufacturing is widely used to fabricate polymer-based 3D bone scaffolds. However, the insight views of crystal growths, scaffold features and eventually cell-scaffold interactions are still unknown. In this work, melt and solvent extrusion additive manufacturing techniques are used to produce scaffolds considering highly analogous printing conditions. Results show that the scaffolds produced by these two techniques present distinct physiochemical properties, with melt-printed scaffolds showing stronger mechanical properties and solvent-printed scaffolds showing rougher surface, higher degradation rate, and faster stress relaxation. These differences are attributed to the two different crystal growth kinetics, temperature-induced crystallization (TIC) and strain-induced crystallization (SIC), forming large/integrated spherulite-like and a small/fragmented lamella-like crystal regions respectively. The stiffer substrate of melt-printed scaffolds contributes to higher ratio of nuclear Yes-associated protein (YAP) allocation, favoring cell proliferation and differentiation. Faster relaxation and degradation of solvent-printed scaffolds result in dynamic surface, contributing to an early-stage faster osteogenesis differentiation.
AUTHOR
Title
A culture model to analyze the acute biomaterial-dependent reaction of human primary neutrophils in vitro
[Abstract]
Year
2023
Journal/Proceedings
Bioactive Materials
Reftype
Groups
AbstractNeutrophils play a pivotal role in orchestrating the immune system response to biomaterials, the onset and resolution of chronic inflammation, and macrophage polarization. However, the neutrophil response to biomaterials and the consequent impact on tissue engineering approaches is still scarcely understood. Here, we report an in vitro culture model that comprehensively describes the most important neutrophil functions in the light of tissue repair. We isolated human primary neutrophils from peripheral blood and exposed them to a panel of hard, soft, naturally- and synthetically-derived materials. The overall trend showed increased neutrophil survival on naturally derived constructs, together with higher oxidative burst, decreased myeloperoxidase and neutrophil elastase and decreased cytokine secretion compared to neutrophils on synthetic materials. The culture model is a step to better understand the immune modulation elicited by biomaterials. Further studies are needed to correlate the neutrophil response to tissue healing and to elucidate the mechanism triggering the cell response and their consequences in determining inflammation onset and resolution.
AUTHOR
Title
Accelerated Degradation of Poly-ε-caprolactone Composite Scaffolds for Large Bone Defects
[Abstract]
Year
2023
Journal/Proceedings
Polymers
Reftype
Groups
AbstractThis research investigates the accelerated hydrolytic degradation process of both anatomically designed bone scaffolds with a pore size gradient and a rectangular shape (biomimetically designed scaffolds or bone bricks). The effect of material composition is investigated considering poly-ε-caprolactone (PCL) as the main scaffold material, reinforced with ceramics such as hydroxyapatite (HA), β-tricalcium phosphate (TCP) and bioglass at a concentration of 20 wt%. In the case of rectangular scaffolds, the effect of pore size (200 μm, 300 μm and 500 μm) is also investigated. The degradation process (accelerated degradation) was investigated during a period of 5 days in a sodium hydroxide (NaOH) medium. Degraded bone bricks and rectangular scaffolds were measured each day to evaluate the weight loss of the samples, which were also morphologically, thermally, chemically and mechanically assessed. The results show that the PCL/bioglass bone brick scaffolds exhibited faster degradation kinetics in comparison with the PCL, PCL/HA and PCL/TCP bone bricks. Furthermore, the degradation kinetics of rectangular scaffolds increased by increasing the pore size from 500 μm to 200 μm. The results also indicate that, for the same material composition, bone bricks degrade slower compared with rectangular scaffolds. The scanning electron microscopy (SEM) images show that the degradation process was faster on the external regions of the bone brick scaffolds (600 μm pore size) compared with the internal regions (200 μm pore size). The thermal gravimetric analysis (TGA) results show that the ceramic concentration remained constant throughout the degradation process, while differential scanning calorimetry (DSC) results show that all scaffolds exhibited a reduction in crystallinity (Xc), enthalpy (Δm) and melting temperature (Tm) throughout the degradation process, while the glass transition temperature (Tg) slightly increased. Finally, the compression results show that the mechanical properties decreased during the degradation process, with PCL/bioglass bone bricks and rectangular scaffolds presenting higher mechanical properties with the same design in comparison with the other materials.
AUTHOR
Year
2023
Journal/Proceedings
Science Advances
Reftype
DOI/URL
DOI
Groups
AbstractGlass is ubiquitous in life and widely used in various fields. However, there is an urgent need to develop biodegradable and biorecyclable glasses that have a minimal environmental footprint toward a sustainable society and a circular materials economy. Here, we report a family of eco-friendly glasses of biological origin fabricated using biologically derived amino acids or peptides through the classic heating-quenching procedure. Amino acids and peptides with chemical modification at their ends are found able to form a supercooled liquid before decomposition and eventually glass upon quenching. These developed glasses exhibit excellent glass-forming ability and optical characteristics and are amenable to three-dimensional–printed additive manufacturing and mold casting. Crucially, the glasses show biocompatibility, biodegradability, and biorecyclability beyond the currently used commercial glasses and plastic materials. Biodegradable and biorecyclable glasses developed from amino acids exhibit functionality and sustainability.
AUTHOR
Title
Composite grafts made of polycaprolactone fiber mats and oil-based calcium phosphate cement pastes for the reconstruction of cranial and maxillofacial defects
[Abstract]
Year
2023
Journal/Proceedings
Clinical Oral Investigations
Reftype
Fuchs2023
DOI/URL
DOI
Groups
AbstractSynthetic bone substitutes which can be adapted preoperatively and patient specific may be helpful in various bony defects in the field of oral- and maxillofacial surgery. For this purpose, composite grafts made of self-setting and oil-based calcium phosphate cement (CPC) pastes, which were reinforced with 3D-printed polycaprolactone (PCL) fiber mats were manufactured.
AUTHOR
Title
Early In Vivo Osteogenic and Inflammatory Response of 3D Printed Polycaprolactone/Carbon Nanotube/Hydroxyapatite/Tricalcium Phosphate Composite Scaffolds
[Abstract]
Year
2023
Journal/Proceedings
Polymers
Reftype
Groups
AbstractThe development of advanced biomaterials and manufacturing processes to fabricate biologically and mechanically appropriate scaffolds for bone tissue is a significant challenge. Polycaprolactone (PCL) is a biocompatible and degradable polymer used in bone tissue engineering, but it lacks biofunctionalization. Bioceramics, such as hydroxyapatite (HA) and β tricalcium phosphate (β-TCP), which are similar chemically to native bone, can facilitate both osteointegration and osteoinduction whilst improving the biomechanics of a scaffold. Carbon nanotubes (CNTs) display exceptional electrical conductivity and mechanical properties. A major limitation is the understanding of how PCL-based scaffolds containing HA, TCP, and CNTs behave in vivo in a bone regeneration model. The objective of this study was to evaluate the use of three-dimensional (3D) printed PCL-based composite scaffolds containing CNTs, HA, and β-TCP during the initial osteogenic and inflammatory response phase in a critical bone defect rat model. Gene expression related to early osteogenesis, the inflammatory phase, and tissue formation was evaluated using quantitative real-time PCR (RT-qPCR). Tissue formation and mineralization were assessed by histomorphometry. The CNT+HA/TCP group presented higher expression of osteogenic genes after seven days. The CNT+HA and CNT+TCP groups stimulated higher gene expression for tissue formation and mineralization, and pro- and anti-inflammatory genes after 14 and 30 days. Moreover, the CNT+TCP and CNT+HA/TCP groups showed higher gene expressions related to M1 macrophages. The association of CNTs with ceramics at 10wt% (CNT+HA/TCP) showed lower expressions of inflammatory genes and higher osteogenic, presenting a positive impact and balanced cell signaling for early bone formation. The association of CNTs with both ceramics promoted a minor inflammatory response and faster bone tissue formation.
AUTHOR
Title
Electrical Stimulation Therapy and HA/TCP Composite Scaffolds Modulate the Wnt Pathways in Bone Regeneration of Critical-Sized Defects
[Abstract]
Year
2023
Journal/Proceedings
Bioengineering
Reftype
Groups
AbstractCritical bone defects are the most difficult challenges in the area of tissue repair. Polycaprolactone (PCL) scaffolds, associated with hydroxyapatite (HA) and tricalcium phosphate (TCP), are reported to have an enhanced bioactivity. Moreover, the use of electrical stimulation (ES) has overcome the lack of bioelectricity at the bone defect site and compensated the endogenous electrical signals. Such treatments could modulate cells and tissue signaling pathways. However, there is no study investigating the effects of ES and bioceramic composite scaffolds on bone tissue formation, particularly in the view of cell signaling pathway. This study aims to investigate the application of HA/TCP composite scaffolds and ES and their effects on the Wingless-related integration site (Wnt) pathway in critical bone repair. Critical bone defects (25 mm2) were performed in rats, which were divided into four groups: PCL, PCL + ES, HA/TCP and HA/TCP + ES. The scaffolds were grafted at the defect site and applied with the ES application twice a week using 10 µA of current for 5 min. Bone samples were collected for histomorphometry, immunohistochemistry and molecular analysis. At the Wnt canonical pathway, HA/TCP and HA/TCP + ES groups showed higher Wnt1 and β-catenin gene expression levels, especially HA/TCP. Moreover, HA/TCP + ES presented higher Runx2, Osterix and Bmp-2 levels. At the Wnt non-canonical pathway, HA/TCP group showed higher voltage-gated calcium channel (Vgcc), calmodulin-dependent protein kinase II, and Wnt5a genes expression, while HA/TCP + ES presented higher protein expression of VGCC and calmodulin (CaM) at the same period. The decrease in sclerostin and osteopontin genes expressions and the lower bone sialoprotein II in the HA/TCP + ES group may be related to the early bone remodeling. This study shows that the use of ES modulated the Wnt pathways and accelerated the osteogenesis with improved tissue maturation.
AUTHOR
Title
Flexible 3D printed microwires and 3D microelectrodes for heart-on-a-chip engineering
[Abstract]
Year
2023
Journal/Proceedings
Biofabrication
Reftype
DOI/URL
DOI
Groups
AbstractWe developed a heart-on-a-chip platform that integrates highly flexible, vertical, 3D micropillar electrodes for electrophysiological recording and elastic microwires for the tissue’s contractile force assessment. The high aspect ratio microelectrodes were 3D-printed into the device using a conductive polymer, poly(3,4-ethylenedioxythiophene): poly(styrene sulfonate) (PEDOT:PSS). A pair of flexible, quantum dots/thermoplastic elastomer nanocomposite microwires were 3D printed to anchor the tissue and enable continuous contractile force assessment. The 3D microelectrodes and flexible microwires enabled unobstructed human iPSC-based cardiac tissue formation and contraction, suspended above the device surface, under both spontaneous beating and upon pacing with a separate set of integrated carbon electrodes. Recording of extracellular field potentials using the PEDOT:PSS micropillars was demonstrated with and without epinephrine as a model drug, non-invasively, along with in situ monitoring of tissue contractile properties and calcium transients. Uniquely, the platform provides integrated profiling of electrical and contractile tissue properties, which is critical for proper evaluation of complex, mechanically and electrically active tissues, such as the heart muscle under both physiological and pathological conditions.
AUTHOR
Title
iPSC-derived tenocytes seeded on microgrooved 3D printed scaffolds for Achilles Tendon Regeneration
[Abstract]
Year
2023
Journal/Proceedings
Journal of Orthopaedic Research
Reftype
DOI/URL
DOI
Groups
AbstractAbstractTendons and ligaments have a poor innate healing capacity, yet account for 50% of musculoskeletal injuries in the US. Full structure and function restoration post-injury remains an unmet clinical need. This study aimed to assess the application of novel 3D printed scaffolds and induced pluripotent stem cell-derived mesenchymal stem cells (iMSCs) overexpressing the transcription factor Scleraxis (SCX, iMSCSCX+) as a new strategy for tendon defect repair. The polycaprolactone (PCL) scaffolds were fabricated by extrusion through a patterned nozzle or conventional round nozzle. Scaffolds were seeded with iMSCSCX+ and outcomes were assessed in vitro via gene expression analysis and immunofluorescence. In vivo, rat Achilles tendon defects were repaired with iMSCSCX+-seeded microgrooved scaffolds, microgrooved scaffolds only, or suture only and assessed via gait, gene expression, biomechanical testing, histology, and immunofluorescence.iMSCSCX+-seeded on microgrooved scaffolds showed upregulation of tendon markers and increased organization and linearity of cells compared to non-patterned scaffolds in vitro. In vivo gait analysis showed improvement in the Scaffold+iMSCSCX+-treated group compared to the controls. Tensile testing of the tendons demonstrated improved biomechanical properties of the Scaffold+iMSCSCX+ group compared to the controls. Histology and immunofluorescence demonstrated more regular tissue formation in the Scaffold+iMSCSCX+ group.This article is protected by copyright. All rights reserved.
AUTHOR
Year
2023
Journal/Proceedings
RSC Adv.
Reftype
DOI/URL
DOI
Groups
AbstractPolymer electrolytes (PEs) are a promising alternative to overcome shortcomings of conventional lithium ion batteries (LiBs) and make them safer for users. Introduction of self-healing features in PEs additionally leads to prolonged life-time of LIBs{,} thus tackling cost and environmental issues. We here present solvent free{,} self-healable{,} reprocessable{,} thermally stable{,} conductive poly(ionic liquid) (PIL) consisting of pyrrolidinium-based repeating units. PEO-functionalized styrene was used as a co-monomer for improving mechanical properties and introducing pendant OH groups in the polymer backbone to act as a transient crosslinking site for boric acid{,} leading to the formation of dynamic boronic ester bonds{,} thus forming a vitrimeric material. Dynamic boronic ester linkages allow reprocessing (at 40 °C){,} reshaping and self-healing ability of PEs. A series of vitrimeric PILs by varying both monomers ratio and lithium salt (LiTFSI) content was synthesized and characterized. The conductivity reached 10−5 S cm−1 at 50 °C in the optimized composition. Moreover{,} the PILs rheological properties fit the required melt flow behavior (above 120 °C) for 3D printing via fused deposition modeling (FDM){,} offering the possibility to design batteries with more complex and diverse architectures.
AUTHOR
Title
Study on 3D-Printed Emodin/Nano-Hydroxyapatite Scaffolds Promoting Bone Regeneration by Supporting Osteoblast Proliferation and Macrophage M2 Polarization
[Abstract]
Year
2023
Journal/Proceedings
ACS Appl. Polym. Mater.
Reftype
DOI/URL
DOI
Groups
AbstractThe treatment of bone defects caused by diseases, trauma, or tumor has always been a great clinical challenge. Implantation of bone biomaterials into bone defect areas is an effective method for bone injury repair. In this study, we used three-dimensional (3D) printing technology to prepare nano-hydroxyapatite (nHA)/sodium alginate (SA)/gelatin (Gel) hydrogel scaffolds loaded with different ratios (0, 0.13, 0.26, 0.39, 0.53, and 0.79‰) of emodin (EM) (EM/nHA/SA/Gel). Scanning electron microscopy showed that the scaffolds had a smooth surface without fracture and nHA was evenly distributed on the surface. The cell proliferation and migration results showed that the 0.39‰ EM group, in particular, could significantly promote the proliferation and migration of mouse embryonic osteoblast precursor (MC3T3-E1) cells and significantly increase the mRNA expression of osteogenic differentiation-related genes (bone morphogenetic protein/BMP-2, BMP-9, osteocalcin). In addition, the 0.39‰ EM group exhibited the best effect on osteogenic differentiation-related proteins (alkaline phosphatase, Runx 2, OSX). The expression of M2 polarization-related genes (arginase-1, CD206) also significantly increased after the treatment with the 0.39‰ EM group. Micro-CT showed that in the rat skull defect model, the EM/nHA/SA/Gel scaffold group significantly promoted bone regeneration after being implanted into the skull for 30 days. Our results indicate that the EM/nHA/SA/Gel hydrogel scaffolds can not only directly promote the proliferation and differentiation of osteoblasts but also indirectly promote osteogenic differentiation by supporting M2 polarization of macrophages. EM/nHA/SA/Gel hydrogel scaffolds are potential bone tissue engineering materials for bone regeneration.
AUTHOR
Year
2022
Journal/Proceedings
Acta Biomaterialia
Reftype
Groups
AbstractDamaged or diseased bone can be treated using autografts or a range of different bone grafting biomaterials, however limitations with such approaches has motivated increased interest in developmentally inspired bone tissue engineering (BTE) strategies that seek to recapitulate the process of endochondral ossification (EO) as a means of regenerating critically sized defects. The clinical translation of such strategies will require the engineering of scaled-up, geometrically defined hypertrophic cartilage grafts that can be rapidly vascularised and remodelled into bone in mechanically challenging defect environments. The goal of this study was to 3D bioprint mechanically reinforced cartilaginous templates and to assess their capacity to regenerate critically sized femoral bone defects. Human mesenchymal stem/stromal cells (hMSCs) were incorporated into fibrin based bioinks and bioprinted into polycaprolactone (PCL) frameworks to produce mechanically reinforced constructs. Chondrogenic priming of such hMSC laden constructs was required to support robust vascularisation and graft mineralisation in vivo following their subcutaneous implantation into nude mice. With a view towards maximising their potential to support endochondral bone regeneration, we next explored different in vitro culture regimes to produce chondrogenic and early hypertrophic engineered grafts. Following their implantation into femoral bone defects within transiently immunosuppressed rats, such bioprinted constructs were rapidly remodelled into bone in vivo, with early hypertrophic constructs supporting higher levels of vascularisation and bone formation compared to the chondrogenic constructs. Such early hypertrophic bioprinted constructs also supported higher levels of vascularisation and spatially distinct patterns of new formation compared to BMP-2 loaded collagen scaffolds (here used as a positive control). In conclusion, this study demonstrates that fibrin based bioinks support chondrogenesis of hMSCs in vitro, which enables the bioprinting of mechanically reinforced hypertrophic cartilaginous templates capable of supporting large bone defect regeneration. These results support the use of 3D bioprinting as a strategy to scale-up the engineering of developmentally inspired templates for BTE. Statement of significance Despite the promise of developmentally inspired tissue engineering strategies for bone regeneration, there are still challenges that need to be addressed to enable clinical translation. This work reports the development and assessment (in vitro and in vivo) of a 3D bioprinting strategy to engineer mechanically-reinforced cartilaginous templates for large bone defect regeneration using human MSCs. Using distinct in vitro priming protocols, it was possible to generate cartilage grafts with altered phenotypes. More hypertrophic grafts, engineered in vitro using TGF-β3 and BMP-2, supported higher levels of blood vessel infiltration and accelerated bone regeneration in vivo. This study also identifies some of the advantages and disadvantages of such endochondral bone TE strategies over the direct delivery of BMP-2 from collagen-based scaffolds.
AUTHOR
Title
3D printing of complex architected metamaterial structures by simple material extrusion for bone tissue engineering
[Abstract]
Year
2022
Journal/Proceedings
Materials Today Communications
Reftype
Groups
AbstractTriply periodic minimal surfaces (TPMS) are gaining popularity as scaffolds for bioapplications due to their unique structure, offering strong mechanical properties and biomorphic surfaces which enhance cell attachment and proliferation. In this work, polymer TPMS sheet lattices were printed using a well-known yet unprecedented technique of manufacturing such structures; which is material extrusion (specifically, pneumatic melt extrusion). This method offers a one step, straightforward yet reliable way to print complex porous structures while retaining design accuracy and significantly simplifying the process. Multiple primitive, gyroid and cubic structures were designed using MSLattice and Solidworks with 70% porosity and 2×2×3 unit cells. The scaffolds were printed by melt extrusion of polycaprolactone (PCL) at different parameters to establish the optimal settings. Morphological features (pore size and strut thickness) were determined using scanning electron microscopy (SEM) and the accuracy of print was determined by comparing to the design, showing high print accuracy and minimal percentage errors of less than 15% in all prints. Uniaxial compression testing was used to demonstrate the different deformation processes of the scaffolds and evaluate their mechanical properties, with primitive having the highest modulus and gyroid the highest yield strength. Finally, cell viability was quantified by alamar blue cell viability assay and visualized by SEM, displaying significant increase in cell proliferation and attachment, specifically in the primitive structure. Herein we will explain the challenges faced with design and print optimization and how we overcame them, making this work the first of its kind in material extrusion (pneumatic melt extrusion) printing of TPMS scaffolds.
AUTHOR
Title
3D Printing of Triamcinolone Acetonide in Triblock Copolymers of Styrene–Isobutylene–Styrene as a Slow-Release System
[Abstract]
Year
2022
Journal/Proceedings
Polymers
Reftype
Groups
AbstractAdditive manufacturing has a wide range of applications and has opened up new methods of drug formulation, in turn achieving attention in medicine. We prepared styrene–isobutylene–styrene triblock copolymers (SIBS; Mn = 10 kDa–25 kDa, PDI 1,3–1,6) as a drug carrier for triamcinolone acetonide (TA), further processed by fused deposition modeling to create a solid drug release system displaying improved bioavailability and applicability. Living carbocationic polymerization was used to exert control over block length and polymeric architecture. Thermorheological properties of the SIBS polymer (22.3 kDa, 38 wt % S) were adjusted to the printability of SIBS/TA mixtures (1–5% of TA), generating an effective release system effective for more than 60 days. Continuous drug release and morphological investigations were conducted to probe the influence of the 3D printing process on the drug release, enabling 3D printing as a formulation method for a slow-release system of Triamcinolone.
AUTHOR
Title
3D-printing of the polymer/insect-repellent system poly(l-lactic acid)/ethyl butylacetylaminopropionate (PLLA/IR3535)
[Abstract]
Year
2022
Journal/Proceedings
International Journal of Pharmaceutics
Reftype
Groups
AbstractThe polymer/solvent system poly(l-lactic acid)/ethyl butylacetylaminopropionate (PLLA/IR3535) is regarded as an insect-repellent-delivery system, serving, e.g., for fighting mosquito-borne tropical diseases. In such systems the solid polymer hosts the liquid repellent, with the latter slowly released to the environment, expelling mosquitoes. As a new approach, exceeding prior work about application of different technologies to obtain such devices, in this work, samples of the polymer/repellent system PLLA/IR3535 were prepared by 3D-printing. The experiments showed that it is possible to print 3D-parts containing up to 25 m% repellent, with an only minor loss of repellent during the printing process. For samples containing low amount of repellent, crystallization of PLLA was suppressed due to the rather fast cooling step and the low bed temperature of around 25 °C, being lower than the glass transition temperature of the homogeneous polymer/repellent strands. At higher repellent concentration, due to the lowering of the glass transition temperature to near or even below ambient temperature, the crystallinity slowly increased during storage after printing. For all samples, regardless of the initial repellent concentration, the repellent-release rate increases with temperature, and at ambient temperature the release-time constant is in the order of 10 days. The study successfully proved the applicability of the technology of extrusion-based 3D-printing for the preparation of polymer parts with a specific shape/design containing mosquito-repellent at a concentration which raises the expectation to be used as a repellent delivery-device.
AUTHOR
Title
Bone Bricks: The Effect of Architecture and Material Composition on the Mechanical and Biological Performance of Bone Scaffolds
[Abstract]
Year
2022
Journal/Proceedings
ACS Omega
Reftype
DOI/URL
DOI
Groups
AbstractLarge bone loss injuries require high-performance scaffolds with an architecture and material composition resembling native bone. However, most bone scaffold studies focus on three-dimensional (3D) structures with simple rectangular or circular geometries and uniform pores, not able to recapitulate the geometric characteristics of the native tissue. This paper addresses this limitation by proposing novel anatomically designed scaffolds (bone bricks) with nonuniform pore dimensions (pore size gradients) designed based on new lay-dawn pattern strategies. The gradient design allows one to tailor the properties of the bricks and together with the incorporation of ceramic materials allows one to obtain structures with high mechanical properties (higher than reported in the literature for the same material composition) and improved biological characteristics.
AUTHOR
Title
Deferoxamine/magnesium modified β-tricalcium phosphate promotes the bone regeneration in osteoporotic rats
[Abstract]
Year
2022
Journal/Proceedings
Journal of Biomaterials Applications
Reftype
DOI/URL
DOI
Groups
AbstractRecently, Deferoxamine (DFO) and magnesium (Mg) have been identified as critical factors for angiogenesis and bone formation. However, in current research studies, there is a lack of focus on whether DFO plus Mg can affect the regeneration of β-tricalcium phosphate (β-TCP) in osteoporosis and through what biological mechanisms. Therefore, the present work was aimed to preparation and evaluate the effect of Deferoxamine/magnesium modified β-tricalcium phosphate promotes (DFO/Mg-TCP) in ovariectomized rats model and preliminary exploration of possible mechanisms. The MC3T3-E1 cells were co-cultured with the exudate of DFO/Mg-TCP and induced to osteogenesis, and the cell viability, osteogenic activity were observed by Cell Counting Kit-8(CCK-8), Alkaline Phosphatase (ALP) staining, Alizarin Red Staining (RES) and Western Blot. In vitro experiments, CCK-8, ALP and ARS staining results show that the mineralization and osteogenic activity of MC3T3-E1increased significantly after intervention by DFO/Mg-TCP, as well as a higher levels of protein expressions including VEGF, OC, Runx-2 and HIF-1α. In vivo experiment, Micro-CT and Histological analysis evaluation show that DFO/Mg-TCP treatment presented the stronger effect on bone regeneration, bone mineralization and biomaterial degradation, when compared with OVX+Mg-TCP group and OVX+TCP group, as well as a higher VEGF, OC, Runx-2 and HIF-1α gene expression. The present study indicates that treatment with DFO/Mg-TCP was associated with increased regeneration by enhancing the function of osteoblasts in an OVX rat.
AUTHOR
Year
2022
Journal/Proceedings
The Journal of Vascular Access
Reftype
DOI/URL
DOI
Groups
AbstractBackground:The two ends of arteriovenous graft (AVG) are anastomosed to the upper limb vessels by surgery for hemodialysis therapy. However, the size of upper limb vessels varies to a large extent among different individuals.Methods:According to the shape and size of neck vessels quantified from the preoperative computed tomography angiographic scan, the ethylene-vinyl acetate (EVA)-based AVG was produced in H-shape by the three-dimensional (3D) printer and then sterilized. This study investigated the function of this novel 3D-printed AVG in vitro and in vivo.Results:This 3D-printed AVG can be implanted in the rabbit’s common carotid artery and common jugular vein with ease and functions in vivo. The surgical procedure was quick, and no suture was required. The blood loss was minimal, and no hematoma was noted at least 1 week after the surgery. The blood flow velocity within the implanted AVG was 14.9 ± 3.7 cm/s. Additionally, the in vitro characterization experiments demonstrated that this EVA-based biomaterial is biocompatible and possesses a superior recovery property than ePTFE after hemodialysis needle cannulation.Conclusions:Through the 3D printing technology, the EVA-based AVG can be tailor-made to fit the specific vessel size. This kind of 3D-printed AVG is functioning in vivo, and our results realize personalized vascular implants. Further large-animal studies are warranted to examine the long-term patency.
AUTHOR
Title
In Vivo Investigation of Polymer-Ceramic PCL/HA and PCL/β-TCP 3D Composite Scaffolds and Electrical Stimulation for Bone Regeneration
[Abstract]
Year
2022
Journal/Proceedings
Polymers
Reftype
Groups
AbstractCritical bone defects are a major clinical challenge in reconstructive bone surgery. Polycaprolactone (PCL) mixed with bioceramics, such as hydroxyapatite (HA) and tricalcium phosphate (TCP), create composite scaffolds with improved biological recognition and bioactivity. Electrical stimulation (ES) aims to compensate the compromised endogenous electrical signals and to stimulate cell proliferation and differentiation. We investigated the effects of composite scaffolds (PCL with HA; and PCL with β-TCP) and the use of ES on critical bone defects in Wistar rats using eight experimental groups: untreated, ES, PCL, PCL/ES, HA, HA/ES, TCP, and TCP/ES. The investigation was based on histomorphometry, immunohistochemistry, and gene expression analysis. The vascular area was greater in the HA/ES group on days 30 and 60. Tissue mineralization was greater in the HA, HA/ES, and TCP groups at day 30, and TCP/ES at day 60. Bmp-2 gene expression was higher in the HA, TCP, and TCP/ES groups at day 30, and in the TCP/ES and PCL/ES groups at day 60. Runx-2, Osterix, and Osteopontin gene expression were also higher in the TCP/ES group at day 60. These results suggest that scaffolds printed with PCL and TCP, when paired with electrical therapy application, improve bone regeneration.
AUTHOR
Title
Investigation of polycaprolactone for bone tissue engineering scaffolds: in vitro degradation and biological studies
[Abstract]
Year
2022
Journal/Proceedings
Materials & Design
Reftype
Groups
AbstractPolycaprolactone (PCL) is one of the most recognized polymeric materials used for bone tissue engineering scaffold fabrication. This study aims to evaluate the effects of the molecular weight (Mn) of PCL on the degradation kinematics, surface, microstructural, thermal, mechanical, and biological properties of 3D printed bone scaffolds. Surface properties were investigated considering water-in-air contact angle and nanoindentation tests, while morphological characteristics and degradation kinematics (accelerated degradation tests) were examined using scanning electron microscopy (SEM), pairing with thermal and mechanical properties monitored at each considered time point. A set of mathematical equations describing the variation of fiber diameter, porosity, mechanical properties, and weight, as a function of molecular weight and degradation time, were obtained based on the experimental results. Human adipose-derived stem cells (hADSCs) proliferation and differentiation tests were also conducted using in vitro colorimetric assay. All results indicated that molecular weight had impacts on the surface, mechanical and biological properties of PCL scaffolds, while no significant effects were observed on the degradation rate. Scaffolds with lower molecular weight presented better bio-mechanical properties. These findings provide useful information for the design of polymeric bone tissue engineering scaffolds.
AUTHOR
Year
2022
Journal/Proceedings
ACS Appl. Bio Mater.
Reftype
DOI/URL
DOI
Groups
AbstractHuman mesenchymal stem cells (HMSCs) are important for cell-based therapies. However, the success of HMSC therapy requires large-scale in vitro expansion of these multipotent cells. The traditional expansion of HMSCs on tissue-culture-treated stiff polystyrene induces significant changes in their shape, multipotency, and secretome, leading to early senescence and subdued paracrine activity. To enhance their therapeutic potential, here, we have developed two-dimensional soft hydrogels with imprinted microscale aligned grooves for use as HMSC culture substrates. We showed that, depending on the dimensions of the topographical features, these substrates led to lower cellular spreading and cytoskeletal tension, maintaining multipotency and osteogenic and adipogenic differentiate potential, while lowering cellular senescence. We also observed a greater capacity of HMSCs to produce anti-inflammatory cytokines after short-term priming on these hydrogel substrates. Overall, these soft hydrogels with unique surface topography have shown great promise as in vitro culture substrates to maximize the therapeutic potential of HMSCs.
AUTHOR
Year
2022
Journal/Proceedings
Polymers
Reftype
Groups
AbstractThe design of scaffolds with optimal biomechanical properties for load-bearing applications is an important topic of research. Most studies have addressed this problem by focusing on the material composition and not on the coupled effect between the material composition and the scaffold architecture. Polymer–bioglass scaffolds have been investigated due to the excellent bioactivity properties of bioglass, which release ions that activate osteogenesis. However, material preparation methods usually require the use of organic solvents that induce surface modifications on the bioglass particles, compromising the adhesion with the polymeric material thus compromising mechanical properties. In this paper, we used a simple melt blending approach to produce polycaprolactone/bioglass pellets to construct scaffolds with pore size gradient. The results show that the addition of bioglass particles improved the mechanical properties of the scaffolds and, due to the selected architecture, all scaffolds presented mechanical properties in the cortical bone region. Moreover, the addition of bioglass indicated a positive long-term effect on the biological performance of the scaffolds. The pore size gradient also induced a cell spreading gradient.
AUTHOR
Title
Printable Electrolytes: Tuning 3D-Printing by Multiple Hydrogen Bonds and Added Inorganic Lithium-Salts
[Abstract]
Year
2022
Journal/Proceedings
Advanced Materials Technologies
Reftype
DOI/URL
DOI
Groups
AbstractAbstract Here, the 3D-printing of supramolecular polymer electrolytes is reported, able to be manufactured via 3D-printing processes, additionally dynamically compensating for volume changes. A careful mechanical design, in addition to rheological effects observed for different additives to the electrolyte, is investigated and adjusted, in order to achieve printability via an extrusion process to generate a conductive electrode material. Qudruple-hydrogen bonds (UPy) act as supramolecular entities for the desired dynamic properties to adjust printability, in addition to added LiTFSi-salts to achieve ionic conductivities of ≈10–4 S cm–1 at T = 80 °C. Three different telechelic UPy-PEO/PPO-UPy-polymers with molecular weights ranging from Mn = 600–1500 g mol−1 were investigated in view of their 3D-printability by FDM-processes. It is found that there are three effects counterbalancing the rheological properties of the polymers: besides temperatures, which can be used as a known tool to adjust melt-rheology, also the addition of lithium-salts in junction with the polymers crystallinity exerts a major toolbox to 3D-print these electrolytes. Using specific compositions with Li/EO-ratios from 20:1, 10:1, and 5:1, the rheological profile can be adjusted to reach the required printability window. AT-IR-investigations clearly indicate a weakening of the UPy-bonds by the added Li+ ions, in addition to a reduction of the crystallinity of the PEO-units, further changing the rheological profile. The so generated electrolytes are printable systems for novel electrolytes.
AUTHOR
Title
Scaffold microarchitecture regulates angiogenesis and the regeneration of large bone defects
[Abstract]
Year
2022
Journal/Proceedings
Biofabrication
Reftype
DOI/URL
DOI
Groups
AbstractEmerging 3D printing technologies can provide exquisite control over the external shape and internal architecture of scaffolds and tissue engineered constructs, enabling systematic studies to explore how geometric design features influence the regenerative process. Here we used fused deposition modelling (FDM) and melt electrowriting (MEW) to investigate how scaffold microarchitecture influences the healing of large bone defects. FDM was used to fabricate scaffolds with relatively large fibre diameters and low porosities, while MEW was used to fabricate scaffolds with smaller fibre diameters and higher porosities, with both scaffolds being designed to have comparable surface areas. Scaffold microarchitecture significantly influenced the healing response following implantation into critically sized femoral defects in rats, with the FDM scaffolds supporting the formation of larger bone spicules through its pores, while the MEW scaffolds supported the formation of a more round bone front during healing. After 12 weeks in vivo, both MEW and FDM scaffolds supported significantly higher levels of defect vascularisation compared to empty controls, while the MEW scaffolds supported higher levels of new bone formation. Somewhat surprisingly, this superior healing in the MEW group did not correlate with higher levels of angiogenesis, with the FDM scaffold supporting greater total vessel formation and the formation of larger vessels, while the MEW scaffold promoted the formation of a dense microvasculature with minimal evidence of larger vessels infiltrating the defect region. To conclude, the small fibre diameter, high porosity and high specific surface area of the MEW scaffold proved beneficial for osteogenesis and bone regeneration, demonstrating that changes in scaffold architecture enabled by this additive manufacturing technique can dramatically modulate angiogenesis and tissue regeneration without the need for complex exogenous growth factors. These results provide a valuable insight into the importance of 3D printed scaffold architecture when developing new bone tissue engineering strategies.
AUTHOR
Title
Spatial patterning of phenotypically distinct microtissues to engineer osteochondral grafts for biological joint resurfacing
[Abstract]
Year
2022
Journal/Proceedings
Biomaterials
Reftype
Groups
AbstractModular biofabrication strategies using microtissues or organoids as biological building blocks have great potential for engineering replacement tissues and organs at scale. Here we describe the development of a biofabrication strategy to engineer osteochondral tissues by spatially localising phenotypically distinct cartilage microtissues within an instructive 3D printed polymer framework. We first demonstrate that immature cartilage microtissues can spontaneously fuse to form homogeneous macrotissues, and that combining less cellular microtissues results in superior fusion and the generation of a more hyaline-like cartilage containing higher levels of sulphated glycosaminoglycans and type II collagen. Furthermore, temporally exposing developing microtissues to transforming growth factor-β accelerates their volumetric growth and subsequent capacity to fuse into larger hyaline cartilage grafts. Next, 3D printed polymeric frameworks are used to further guide microtissue fusion and the subsequent self-organisation process, resulting in the development of a macroscale tissue with zonal collagen organisation analogous to the structure seen in native articular cartilage. To engineer osteochondral grafts, hypertrophic cartilage microtissues are engineered as bone precursor tissues and spatially localised below phenotypically stable cartilage microtissues. Implantation of these engineered grafts into critically-sized caprine osteochondral defects results in effective defect stabilisation and histologically supports the restoration of a more normal articular surface after 6 months in vivo. These findings support the use of such modular biofabrication strategies for biological joint resurfacing.
AUTHOR
Title
Standard in vitro evaluations of engineered bone substitutes are not sufficient to predict in vivo preclinical model outcomes
[Abstract]
Year
2022
Journal/Proceedings
Acta Biomaterialia
Reftype
Groups
AbstractUnderstanding the optimal conditions required for bone healing can have a substantial impact to target the problem of non–unions and large bone defects. The combination of bioactive factors, regenerative progenitor cells and biomaterials to form a tissue engineered (TE) complex is a promising solution but translation to the clinic has been slow. We hypothesized the typical material testing algorithm used is insufficient and leads to materials being mischaracterized as promising. In the first part of this study, human bone marrow – derived mesenchymal stromal cells (hBM-MSCs) were embedded in three commonly used biomaterials (hyaluronic acid methacrylate, gelatin methacrylate and fibrin) and combined with relevant bioactive osteogenesis factors (dexamethasone microparticles and polyphosphate nanoparticles) to form a TE construct that underwent in vitro osteogenic differentiation for 28 days. Gene expression of relevant transcription factors and osteogenic markers, and von Kossa staining were performed. In the second and third part of this study, the same combination of TE constructs were implanted subcutaneously (cell containing) in T cell-deficient athymic Crl:NIH-Foxn1rnu rats for 8 weeks or cell free in an immunocompetent New Zealand white rabbit calvarial model for 6 weeks, respectively. Osteogenic performance was investigated via MicroCT imaging and histology staining. The in vitro study showed enhanced upregulation of relevant genes and significant mineral deposition within the three biomaterials, generally considered as a positive result. Subcutaneous implantation indicates none to minor ectopic bone formation. No enhanced calvarial bone healing was detected in implanted biomaterials compared to the empty defect. The reasons for the poor correlation of in vitro and in vivo outcomes are unclear and needs further investigation. This study highlights the discrepancy between in vitro and in vivo outcomes, demonstrating that in vitro data should be interpreted with extreme caution. In vitro models with higher complexity are necessary to increase value for translational studies. Statement of significance Preclinical testing of newly developed biomaterials is a crucial element of the development cycle. Despite this, there is still significant discrepancy between in vitro and in vivo test results. Within this study we investigate multiple combinations of materials and osteogenic stimulants and demonstrate a poor correlation between the in vitro and in vivo data. We propose rationale for why this may be the case and suggest a modified testing algorithm.
AUTHOR
Title
The efficacy of a paeoniflorin-sodium alginate-gelatin skin scaffold for the treatment of diabetic wound: An in vivo study in a rat model
[Abstract]
Year
2022
Journal/Proceedings
Biomedicine & Pharmacotherapy
Reftype
Groups
AbstractObjective To investigate the efficacy of a paeoniflorin-sodium alginate (SA)-gelatin skin scaffold for treating diabetic wound in a rat model. Methods Bioinks were prepared using various percentages of paeoniflorin in the total weight of a solution containing SA and gelatin. Skin scaffolds containing 0%, 1%, 3%, 5%, and 10% paeoniflorin were printed using 3D bioprinting technology, and scaffold microstructure was observed with scanning electron microscopy. Skin scaffolds were then used in rats with diabetic wounds. H&E staining, Masson staining, and immunohistochemical staining for IL-1β and CD31 were performed on days 7 and 14. Results All skin scaffolds had a mesh-like structure with uniform pore distribution. Wounds healed well in each group, with the 1% and 3% groups demonstrating the most complete healing. H&E staining showed that skin accessory organs had appeared in each group. On day 7, collagen deposition in the 3% group was higher than in the other groups (P<0.05), and IL-1β infiltration was lower in the 10% group than in the 3% group (P = 0.002). On day 14, IL-1β infiltration was not significantly different between the 10% and 3% groups (P = 0.078). The CD31 level was higher in the 3% group than in the other groups on days 7 and 14 (P<0.05). Conclusion A 3% paeoniflorin-SA-gelatin skin scaffold promoted the healing of diabetic wounds in rats. This scaffold promoted collagen deposition and microvascular regeneration and demonstrated anti-inflammatory properties, suggesting that this scaffold type could be used to treat diabetic wounds.
AUTHOR
Title
3D Bioprinting of Biomimetic Bilayered Scaffold Consisting of Decellularized Extracellular Matrix and Silk Fibroin for Osteochondral Repair
[Abstract]
Year
2021
Journal/Proceedings
International Journal of Bioprinting; Vol 7, No 4 (2021)
Reftype
Groups
AbstractRecently, three-dimensional (3D) bioprinting technology is becoming an appealing approach for osteochondral repair. However, it is challenging to develop a bilayered scaffold with anisotropic structural properties to mimic a native osteochondral tissue. Herein, we developed a bioink consisting of decellularized extracellular matrix and silk fibroin to print the bilayered scaffold. The bilayered scaffold mimics the natural osteochondral tissue by controlling the composition, mechanical properties, and growth factor release in each layer of the scaffold. The in vitro results show that each layer of scaffolds had a suitable mechanical strength and degradation rate. Furthermore, the scaffolds encapsulating transforming growth factor-beta (TGF-β) and bone morphogenetic protein-2 (BMP-2) can act as a controlled release system and promote directed differentiation of bone marrow-derived mesenchymal stem cells. Furthermore, the in vivo experiments suggested that the scaffolds loaded with growth factors promoted osteochondral regeneration in the rabbit knee joint model. Consequently, the biomimetic bilayered scaffold loaded with TGF-β and BMP-2 would be a promising strategy for osteochondral repair.
AUTHOR
Title
3D Bioprinting of prevascularised implants for the repair of critically-sized bone defects
[Abstract]
Year
2021
Journal/Proceedings
Acta Biomaterialia
Reftype
Groups
AbstractFor 3D bioprinted tissues to be scaled-up to clinically relevant sizes, effective prevascularisation strategies are required to provide the necessary nutrients for normal metabolism and to remove associated waste by-products. The aim of this study was to develop a bioprinting strategy to engineer prevascularised tissues in vitro and to investigate the capacity of such constructs to enhance the vascularisation and regeneration of large bone defects in vivo. From a screen of different bioinks, a fibrin-based hydrogel was found to best support human umbilical vein endothelial cell (HUVEC) sprouting and the establishment of a microvessel network. When this bioink was combined with HUVECs and supporting human bone marrow stem/stromal cells (hBMSCs), these microvessel networks persisted in vitro. Furthermore, only bioprinted tissues containing both HUVECs and hBMSCs, that were first allowed to mature in vitro, supported robust blood vessel development in vivo. To assess the therapeutic utility of this bioprinting strategy, these bioinks were used to prevascularise 3D printed polycaprolactone (PCL) scaffolds, which were subsequently implanted into critically-sized femoral bone defects in rats. Microcomputed tomography (µCT) angiography revealed increased levels of vascularisation in vivo, which correlated with higher levels of new bone formation. Such prevascularised constructs could be used to enhance the vascularisation of a range of large tissue defects, forming the basis of multiple new bioprinted therapeutics. Statement of Significance This paper demonstrates a versatile 3D bioprinting technique to improve the vascularisation of tissue engineered constructs and further demonstrates how this method can be incorporated into a bone tissue engineering strategy to improve vascularisation in a rat femoral defect model.
AUTHOR
Title
3D printing of PCL/nano-hydroxyapatite scaffolds derived from biogenic sources for bone tissue engineering
[Abstract]
Year
2021
Journal/Proceedings
Sustainable Materials and Technologies
Reftype
Groups
AbstractBioactive composites made of ∽85 wt% poly(ε-caprolactone) (PCL) and ∽15 wt% nanometric hydroxyapatite (HA) produced from biogenic sources were 3D printed by an extrusion-based process to obtain porous scaffolds suitable for bone regeneration. Three different composite formulations were considered by using HA synthesized from three distinct natural sources, which were collected as food wastes: cuttlefish bones, mussel shells and chicken eggshells. Composition and thermal properties of the materials were analysed by thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and x-ray spectroscopy (XRD), while the morphological and mechanical properties of the 3D scaffolds were studied by means of electron microscopy (SEM) and compression tests. Bioactivity was tested by seeding human osteoblast cell line (MG63) onto the scaffolds which were analysed by confocal microscopy and Alamar Blue and PicoGreen® tests after 1 to 7 culture days. The elastic modulus (177–316 MPa) is found to be within the range reported for typical trabecular bones being increased by the presence of the bio-HA particles. Moreover, cells adhesion, viability and proliferation are largely promoted in the scaffolds containing nanometric HA with respect to pure PCL, the best results being revealed when mussel shell-derived HA is used. Indeed, different biological sources result in different cell proliferation rates, pointing that the biological origin has an impact on the cells-scaffold interaction. In general, the results show that PCL/bio-HA scaffolds possess improved mechanical properties and enhanced bioactivity when compared with pure PCL ones.
AUTHOR
Title
3D printing of silk microparticle reinforced polycaprolactone scaffolds for tissue engineering applications
[Abstract]
Year
2021
Journal/Proceedings
Materials Science and Engineering: C
Reftype
Groups
AbstractPolycaprolactone (PCL) scaffolds have been widely investigated for tissue engineering applications, however, they exhibit poor cell adhesion and mechanical properties. Subsequently, PCL composites have been produced to improve the material properties. This study utilises a natural material, Bombyx mori silk microparticles (SMP) prepared by milling silk fibre, to produce a composite to enhance the scaffolds properties. Silk is biocompatible and biodegradable with excellent mechanical properties. However, there are no studies using SMPs as a reinforcing agent in a 3D printed thermoplastic polymer scaffold. PCL/SMP (10, 20, 30 wt%) composites were prepared by melt blending. Rheological analysis showed that SMP loading increased the shear thinning and storage modulus of the material. Scaffolds were fabricated using a screw-assisted extrusion-based additive manufacturing system. Scanning electron microscopy and X-ray microtomography was used to determine scaffold morphology. The scaffolds had high interconnectivity with regular printed fibres and pore morphologies within the designed parameters. Compressive mechanical testing showed that the addition of SMP significantly improved the compressive Young's modulus of the scaffolds. The scaffolds were more hydrophobic with the inclusion of SMP which was linked to a decrease in total protein adsorption. Cell behaviour was assessed using human adipose derived mesenchymal stem cells. A cytotoxic effect was observed at higher particle loading (30 wt%) after 7 days of culture. By day 21, 10 wt% loading showed significantly higher cell metabolic activity and proliferation, high cell viability, and cell migration throughout the scaffold. Calcium mineral deposition was observed on the scaffolds during cell culture. Large calcium mineral deposits were observed at 30 wt% and smaller calcium deposits were observed at 10 wt%. This study demonstrates that SMPs incorporated into a PCL scaffold provided effective mechanical reinforcement, improved the rate of degradation, and increased cell proliferation, demonstrating potential suitability for bone tissue engineering applications.
AUTHOR
Title
Biofabrication of a shape-stable auricular structure for the reconstruction of ear deformities
[Abstract]
Year
2021
Journal/Proceedings
Materials Today Bio
Reftype
Groups
AbstractBioengineering of the human auricle remains a significant challenge, where the complex and unique shape, the generation of high-quality neocartilage, and shape preservation are key factors. Future regenerative medicine–based approaches for auricular cartilage reconstruction will benefit from a smart combination of various strategies. Our approach to fabrication of an ear-shaped construct uses hybrid bioprinting techniques, a recently identified progenitor cell population, previously validated biomaterials, and a smart scaffold design. Specifically, we generated a 3D-printed polycaprolactone (PCL) scaffold via fused deposition modeling, photocrosslinked a human auricular cartilage progenitor cell–laden gelatin methacryloyl (gelMA) hydrogel within the scaffold, and cultured the bioengineered structure in vitro in chondrogenic media for 30 days. Our results show that the fabrication process maintains the viability and chondrogenic phenotype of the cells, that the compressive properties of the combined PCL and gelMA hybrid auricular constructs are similar to native auricular cartilage, and that biofabricated hybrid auricular structures exhibit excellent shape fidelity compared with the 3D digital model along with deposition of cartilage-like matrix in both peripheral and central areas of the auricular structure. Our strategy affords an anatomically enhanced auricular structure with appropriate mechanical properties, ensures adequate preservation of the auricular shape during a dynamic in vitro culture period, and enables chondrogenically potent progenitor cells to produce abundant cartilage-like matrix throughout the auricular construct. The combination of smart scaffold design with 3D bioprinting and cartilage progenitor cells holds promise for the development of clinically translatable regenerative medicine strategies for auricular reconstruction.
AUTHOR
Title
Biofabrication of Prevascularised Hypertrophic Cartilage Microtissues for Bone Tissue Engineering
[Abstract]
Year
2021
Journal/Proceedings
Frontiers in Bioengineering and Biotechnology
Reftype
DOI/URL
DOI
Groups
AbstractBone tissue engineering (TE) has the potential to transform the treatment of challenging musculoskeletal pathologies. To date, clinical translation of many traditional TE strategies has been impaired by poor vascularisation of the implant. Addressing such challenges has motivated research into developmentally inspired TE strategies, whereby implants mimicking earlier stages of a tissue’s development are engineered in vitro and then implanted in vivo to fully mature into the adult tissue. The goal of this study was to engineer in vitro tissues mimicking the immediate developmental precursor to long bones, specifically a vascularised hypertrophic cartilage template, and to then assess the capacity of such a construct to support endochondral bone formation in vivo. To this end, we first developed a method for the generation of large numbers of hypertrophic cartilage microtissues using a microwell system, and encapsulated these microtissues into a fibrin-based hydrogel capable of supporting vasculogenesis by human umbilical vein endothelial cells (HUVECs). The microwells supported the formation of bone marrow derived stem/stromal cell (BMSC) aggregates and their differentiation toward a hypertrophic cartilage phenotype over 5 weeks of cultivation, as evident by the development of a matrix rich in sulphated glycosaminoglycan (sGAG), collagen types I, II, and X, and calcium. Prevascularisation of these microtissues, undertaken in vitro 1 week prior to implantation, enhanced their capacity to mineralise, with significantly higher levels of mineralised tissue observed within such implants after 4 weeks in vivo within an ectopic murine model for bone formation. It is also possible to integrate such microtissues into 3D bioprinting systems, thereby enabling the bioprinting of scaled-up, patient-specific prevascularised implants. Taken together, these results demonstrate the development of an effective strategy for prevascularising a tissue engineered construct comprised of multiple individual microtissue “building blocks,” which could potentially be used in the treatment of challenging bone defects.
AUTHOR
Title
Bioprinting of biomimetic self-organised cartilage with a supporting joint fixation device
[Abstract]
Year
2021
Journal/Proceedings
Biofabrication
Reftype
DOI/URL
DOI
Groups
AbstractDespite sustained efforts, engineering truly biomimetic articular cartilage (AC) via traditional top-down approaches remains challenging. Emerging biofabrication strategies, from 3D bioprinting to scaffold-free approaches that leverage principles of cellular self-organisation, are generating significant interest in the field of cartilage tissue engineering as a means of developing biomimetic tissue analogues in vitro. Although such strategies have advanced the quality of engineered cartilage, recapitulation of many key structural features of native AC, in particular a collagen network mimicking the tissue’s ‘Benninghoff arcade’, remains elusive. Additionally, a complete solution to fixating engineered cartilages in situ within damaged synovial joints has yet to be identified. This study sought to address both of these key challenges by engineering biomimetic AC within a device designed to anchor the tissue within a synovial joint defect. We first designed and fabricated a fixation device capable of anchoring engineered cartilage into the subchondral bone. Next, we developed a strategy for inkjet printing porcine mesenchymal stem/stromal cells (MSCs) into this supporting fixation device, which was also designed to provide instructive cues to direct the self-organisation of MSC condensations towards a stratified engineered AC. We found that a higher starting cell-density supported the development of a more zonally defined collagen network within the engineered tissue. Dynamic culture was implemented to further enhance the quality of this engineered tissue, resulting in an approximate 3 fold increase in glycosaminoglycan and collagen accumulation. Ultimately this strategy supported the development of AC that exhibited near-native levels of glycosaminoglycan accumulation (>5% WW), as well as a biomimetic collagen network organisation with a perpendicular to a parallel fibre arrangement (relative to the tissue surface) from the deep to superficial zones via arcading fibres within the middle zone of the engineered tissue. Collectively, this work demonstrates the successful convergence of novel biofabrication methods, bioprinting strategies and culture regimes to engineer a hybrid implant suited to resurfacing AC defects.
AUTHOR
Title
Composite Scaffolds for Bone Tissue Regeneration Based on PCL and Mg-Containing Bioactive Glasses
[Abstract]
Year
2021
Journal/Proceedings
Biology
Reftype
DOI/URL
DOI
Groups
AbstractPolycaprolactone (PCL) is widely used in additive manufacturing for the construction of scaffolds for tissue engineering because of its good bioresorbability, biocompatibility, and processability. Nevertheless, its use is limited by its inadequate mechanical support, slow degradation rate and the lack of bioactivity and ability to induce cell adhesion and, thus, bone tissue regeneration. In this study, we fabricated 3D PCL scaffolds reinforced with a novel Mg-doped bioactive glass (Mg-BG) characterized by good mechanical properties and biological reactivity. An optimization of the printing parameters and scaffold fabrication was performed; furthermore, an extensive microtopography characterization by scanning electron microscopy and atomic force microscopy was carried out. Nano-indentation tests accounted for the mechanical properties of the scaffolds, whereas SBF tests and cytotoxicity tests using human bone-marrow-derived mesenchymal stem cells (BM-MSCs) were performed to evaluate the bioactivity and in vitro viability. Our results showed that a 50/50 wt% of the polymer-to-glass ratio provides scaffolds with a dense and homogeneous distribution of Mg-BG particles at the surface and roughness twice that of pure PCL scaffolds. Compared to pure PCL (hardness H = 35 ± 2 MPa and Young’s elastic modulus E = 0.80 ± 0.05 GPa), the 50/50 wt% formulation showed H = 52 ± 11 MPa and E = 2.0 ± 0.2 GPa, hence, it was close to those of trabecular bone. The high level of biocompatibility, bioactivity, and cell adhesion encourages the use of the composite PCL/Mg-BG scaffolds in promoting cell viability and supporting mechanical loading in the host trabecular bone.
AUTHOR
Title
Green Synthesis of Silver Nanoparticles Using Extract of Cilembu Sweet Potatoes (Ipomoea batatas L var. Rancing) as Potential Filler for 3D Printed Electroactive and Anti-Infection Scaffolds
[Abstract]
Year
2021
Journal/Proceedings
Molecules
Reftype
Groups
AbstractElectroactive biomaterials are fascinating for tissue engineering applications because of their ability to deliver electrical stimulation directly to cells, tissue, and organs. One particularly attractive conductive filler for electroactive biomaterials is silver nanoparticles (AgNPs) because of their high conductivity, antibacterial activity, and ability to promote bone healing. However, production of AgNPs involves a toxic reducing agent which would inhibit biological scaffold performance. This work explores facile and green synthesis of AgNPs using extract of Cilembu sweet potato and studies the effect of baking and precursor concentrations (1, 10 and 100 mM) on AgNPs’ properties. Transmission electron microscope (TEM) results revealed that the smallest particle size of AgNPs (9.95 ± 3.69 nm) with nodular morphology was obtained by utilization of baked extract and ten mM AgNO3. Polycaprolactone (PCL)/AgNPs scaffolds exhibited several enhancements compared to PCL scaffolds. Compressive strength was six times greater (3.88 ± 0.42 MPa), more hydrophilic (contact angle of 76.8 ± 1.7°), conductive (2.3 ± 0.5 × 10−3 S/cm) and exhibited anti-bacterial properties against Staphylococcus aureus ATCC3658 (99.5% reduction of surviving bacteria). Despite the promising results, further investigation on biological assessment is required to obtain comprehensive study of this scaffold. This green synthesis approach together with the use of 3D printing opens a new route to manufacture AgNPs-based electroactive with improved anti-bacterial properties without utilization of any toxic organic solvents.
AUTHOR
Title
In vivo investigation of 3D printed polycaprolactone/graphene electro-active bone scaffolds
[Abstract]
Year
2021
Journal/Proceedings
Bioprinting
Reftype
Groups
AbstractAdditive manufactured scaffolds are widely used as 3D support structures for tissue engineering. This paper investigates the mechanisms behind bone regeneration due to the combined use of 3D printed poly (ϵ-caprolactone)/graphene (PCL/G) electro-active scaffolds and electrical stimulation. A comprehensive in vivo study was conducted to assess the proposed approach, using a rat model. Results show that the combined use of electro-active scaffolds and electrical stimulation therapy accelerates the bone regeneration process and the formation of more organized new bone, through fast angiogenesis, and a rapid transition to the mineralization and bone remodelling phase. The mechanism is investigated and explained.
AUTHOR
Title
In vivo study of conductive 3D printed PCL/MWCNTs scaffolds with electrical stimulation for bone tissue engineering
[Abstract]
Year
2021
Journal/Proceedings
Bio-Design and Manufacturing
Reftype
e Silva2021
DOI/URL
DOI
Groups
AbstractCritical bone defects are considered one of the major clinical challenges in reconstructive bone surgery. The combination of 3D printed conductive scaffolds and exogenous electrical stimulation (ES) is a potential favorable approach for bone tissue repair. In this study, 3D conductive scaffolds made with biocompatible and biodegradable polycaprolactone (PCL) and multi-walled carbon nanotubes (MWCNTs) were produced using the extrusion-based additive manufacturing to treat large calvary bone defects in rats. Histology results show that the use of PCL/MWCNTs scaffolds and ES contributes to thicker and increased bone tissue formation within the bone defect. Angiogenesis and mineralization are also significantly promoted using high concentration of MWCNTs (3 wt%) and ES. Moreover, scaffolds favor the tartrate-resistant acid phosphatase (TRAP) positive cell formation, while the addition of MWCNTs seems to inhibit the osteoclastogenesis but present limited effects on the osteoclast functionalities (receptor activator of nuclear factor κβ ligand (RANKL) and osteoprotegerin (OPG) expressions). The use of ES promotes the osteoclastogenesis and RANKL expressions, showing a dominant effect in the bone remodeling process. These results indicate that the combination of 3D printed conductive PCL/MWCNTs scaffold and ES is a promising strategy to treat critical bone defects and provide a cue to establish an optimal protocol to use conductive scaffolds and ES for bone tissue engineering.
AUTHOR
Title
Increased Osteogenic Potential of Pre-Osteoblasts on Three-Dimensional Printed Scaffolds Compared to Porous Scaffolds for Bone Regeneration
[Abstract]
Year
2021
Journal/Proceedings
Iranian Biomedical Journal
Reftype
Groups
AbstractBackground: One of the main challenges with conventional scaffold fabrication methods is the inability to control scaffold architecture. Recently, scaffolds with controlled shape and architecture have been fabricated using three-dimensional printing (3DP). Herein, we aimed to determine whether the much tighter control of microstructure of 3DP poly(lactic-co-glycolic) acid/β-tricalcium phosphate (PLGA/β-TCP) scaffolds is more effective in promoting osteogenesis than porous scaffolds produced by solvent casting/porogen leaching. Methods: Physical and mechanical properties of porous and 3DP scaffolds were studied. The response of pre-osteoblasts to the scaffolds was analyzed after 14 days. Results: The 3DP scaffolds had a smoother surface (Ra: 22 ± 3 µm) relative to the highly rough surface of porous scaffolds (Ra: 110 ± 15 µm). Water contact angle was 112 ± 4° on porous and 76 ± 6° on 3DP scaffolds. Porous and 3DP scaffolds had the pore size of 408 ± 90 and 315 ± 17 µm and porosity of 85 ± 5% and 39 ± 7%, respectively. Compressive strength of 3DP scaffolds (4.0 ± 0.3 MPa) was higher than porous scaffolds (1.7 ± 0.2 MPa). Collagenous matrix deposition was similar on both scaffolds. Cells proliferated from day 1 to day 14 by fourfold in porous and by 3.8-fold in 3DP scaffolds. Alkaline phosphatase (ALP) activity was 21-fold higher in 3DP scaffolds than porous scaffolds. Conclusion: The 3DP scaffolds show enhanced mechanical properties and ALP activity compared to porous scaffolds in vitro, suggesting that 3DP PLGA/β-TCP scaffolds are possibly more favorable for bone formation.
AUTHOR
Title
Investigating the Influence of Architecture and Material Composition of 3D Printed Anatomical Design Scaffolds for Large Bone Defects
[Abstract]
Year
2021
Journal/Proceedings
International Journal of Bioprinting; Vol 7, No 2 (2021)
Reftype
DOI/URL
URL
Groups
AbstractThere is a significant unmet clinical need to prevent amputations due to large bone loss injuries. We are addressing this problem by developing a novel, cost-effective osseointegrated prosthetic solution based on the use of modular pieces, bone bricks, made with biocompatible and biodegradable materials that fit together in a Lego-like way to form the prosthesis. This paper investigates the anatomical designed bone bricks with different architectures, pore size gradients, and material compositions. Polymer and polymer-composite 3D printed bone bricks are extensively morphological, mechanical, and biological characterized. Composite bone bricks were produced by mixing polycaprolactone (PCL) with different levels of hydroxyapatite (HA) and β-tri-calcium phosphate (TCP). Results allowed to establish a correlation between bone bricks architecture and material composition and bone bricks performance. Reinforced bone bricks showed improved mechanical and biological results. Best mechanical properties were obtained with PCL/TCP bone bricks with 38 double zig-zag filaments and 14 spiral-like pattern filaments, while the best biological results were obtained with PCL/HA bone bricks based on 25 double zig-zag filaments and 14 spiral-like pattern filaments.
AUTHOR
Title
Investigations of Graphene and Nitrogen-Doped Graphene Enhanced Polycaprolactone 3D Scaffolds for Bone Tissue Engineering
[Abstract]
Year
2021
Journal/Proceedings
Nanomaterials
Reftype
Groups
AbstractScaffolds play a key role in tissue engineering applications. In the case of bone tissue engineering, scaffolds are expected to provide both sufficient mechanical properties to withstand the physiological loads, and appropriate bioactivity to stimulate cell growth. In order to further enhance cell–cell signaling and cell–material interaction, electro-active scaffolds have been developed based on the use of electrically conductive biomaterials or blending electrically conductive fillers to non-conductive biomaterials. Graphene has been widely used as functioning filler for the fabrication of electro-active bone tissue engineering scaffolds, due to its high electrical conductivity and potential to enhance both mechanical and biological properties. Nitrogen-doped graphene, a unique form of graphene-derived nanomaterials, presents significantly higher electrical conductivity than pristine graphene, and better surface hydrophilicity while maintaining a similar mechanical property. This paper investigates the synthesis and use of high-performance nitrogen-doped graphene as a functional filler of poly(ɛ-caprolactone) (PCL) scaffolds enabling to develop the next generation of electro-active scaffolds. Compared to PCL scaffolds and PCL/graphene scaffolds, these novel scaffolds present improved in vitro biological performance.
AUTHOR
Title
Multifunctional 3D-Printed Magnetic Polycaprolactone/Hydroxyapatite Scaffolds for Bone Tissue Engineering
[Abstract]
Year
2021
Journal/Proceedings
Polymers
Reftype
Groups
AbstractMultifunctional and resistant 3D structures represent a great promise and a great challenge in bone tissue engineering. This study addresses this problem by employing polycaprolactone (PCL)-based scaffolds added with hydroxyapatite (HAp) and superparamagnetic iron oxide nanoparticles (SPION), able to drive on demand the necessary cells and other bioagents for a high healing efficiency. PCL-HAp-SPION scaffolds with different concentrations of the superparamagnetic component were developed through the 3D-printing technology and the specific topographical features were detected by Atomic Force and Magnetic Force Microscopy (AFM-MFM). AFM-MFM measurements confirmed a homogenous distribution of HAp and SPION throughout the surface. The magnetically assisted seeding of cells in the scaffold resulted most efficient for the 1% SPION concentration, providing good cell entrapment and adhesion rates. Mesenchymal Stromal Cells (MSCs) seeded onto PCL-HAp-1% SPION showed a good cell proliferation and intrinsic osteogenic potential, indicating no toxic effects of the employed scaffold materials. The performed characterizations and the collected set of data point on the inherent osteogenic potential of the newly developed PCL-HAp-1% SPION scaffolds, endorsing them towards next steps of in vitro and in vivo studies and validations.
AUTHOR
Title
Novel Shape-Stabilized Phase Change Material with Cascade Character: Synthesis, Performance and Shaping Evaluation
[Abstract]
Year
2021
Journal/Proceedings
Energies
Reftype
Groups
AbstractThermal Energy Storage (TES) materials, such as Phase Change Materials (PCMs) are proven to enhance the energy efficiency in many fields, such as automotive and building sectors, which correspond to the most energy intensive ones. Shape-stabilized PCM and cascade PCM are procedures to overcome the most important barriers when PCMs are applied since PCMs need to be encapsulated for their technical use: the leakage of the liquid phase, corrosion, low heat transfer and narrow temperature of application. In the present study, a novel shape stabilized PCM with cascade performance (cascade shape stabilized phase change material, CSS-PCM) is synthesized via dissolution, which allows up to 60 wt.% of a paraffin-PCM in the final composition. The novel CSS-PCM is based on a biopolymer, the polycaprolactone (PCL), a low melting temperature polyester as polymeric matrix and RT27 and Micronal DS 5040 acting as PCM. To evaluate the performance of the new TES materials developed, several techniques have been used: Differential Scanning Calorimetry (DSC), and Fourier-Transformed Infrared (FT-IR) spectroscopy were used to evaluate the thermophysical properties and the chemical properties of the different formulations. The CSS-PCM show an increment of storage capacity by increasing the PCM content, and the thermal reliability was also tested: some of the CSS-PCM formulations were stable for up to 500 thermal cycles. Finally, as a potential application of the new polymeric-based PCM 3D, a printing attempt was performed in order to analyze the viability of the formulations to be used as 3D printing material as a first proof of concept.
AUTHOR
Title
Potential of Melt Electrowritten Scaffolds Seeded with Meniscus Cells and Mesenchymal Stromal Cells
[Abstract]
Year
2021
Journal/Proceedings
International Journal of Molecular Sciences
Reftype
Groups
AbstractMeniscus injury and meniscectomy are strongly related to osteoarthritis, thus there is a clinical need for meniscus replacement. The purpose of this study is to create a meniscus scaffold with micro-scale circumferential and radial fibres suitable for a one-stage cell-based treatment. Poly-caprolactone-based scaffolds with three different architectures were made using melt electrowriting (MEW) technology and their in vitro performance was compared with scaffolds made using fused-deposition modelling (FDM) and with the clinically used Collagen Meniscus Implants® (CMI®). The scaffolds were seeded with meniscus and mesenchymal stromal cells (MSCs) in fibrin gel and cultured for 28 d. A basal level of proteoglycan production was demonstrated in MEW scaffolds, the CMI®, and fibrin gel control, yet within the FDM scaffolds less proteoglycan production was observed. Compressive properties were assessed under uniaxial confined compression after 1 and 28 d of culture. The MEW scaffolds showed a higher Young’s modulus when compared to the CMI® scaffolds and a higher yield point compared to FDM scaffolds. This study demonstrates the feasibility of creating a wedge-shaped meniscus scaffold with MEW using medical-grade materials and seeding the scaffold with a clinically-feasible cell number and -type for potential translation as a one-stage treatment.
AUTHOR
Title
Preclinical Testing of New Hydrogel Materials for Cartilage Repair: Overcoming Fixation Issues in a Large Animal Model
[Abstract]
Year
2021
Journal/Proceedings
International Journal of Biomaterials
Reftype
DOI/URL
DOI
Groups
AbstractReinforced hydrogels represent a promising strategy for tissue engineering of articular cartilage. They can recreate mechanical and biological characteristics of native articular cartilage and promote cartilage regeneration in combination with mesenchymal stromal cells. One of the limitations of in vivo models for testing the outcome of tissue engineering approaches is implant fixation. The high mechanical stress within the knee joint, as well as the concave and convex cartilage surfaces, makes fixation of reinforced hydrogel challenging. Methods. Different fixation methods for full-thickness chondral defects in minipigs such as fibrin glue, BioGlue®, covering, and direct suturing of nonenforced and enforced constructs were compared. Because of insufficient fixation in chondral defects, superficial osteochondral defects in the femoral trochlea, as well as the femoral condyle, were examined using press-fit fixation. Two different hydrogels (starPEG and PAGE) were compared by 3D-micro-CT (μCT) analysis as well as histological analysis. Results. Our results showed fixation of below 50% for all methods in chondral defects. A superficial osteochondral defect of 1 mm depth was necessary for long-term fixation of a polycaprolactone (PCL)-reinforced hydrogel construct. Press-fit fixation seems to be adapted for a reliable fixation of 95% without confounding effects of glue or suture material. Despite the good integration of our constructs, especially in the starPEG group, visible bone lysis was detected in micro-CT analysis. There was no significant difference between the two hydrogels (starPEG and PAGE) and empty control defects regarding regeneration tissue and cell integration. However, in the starPEG group, more cell-containing hydrogel fragments were found within the defect area. Conclusion. Press-fit fixation in a superficial osteochondral defect in the medial trochlear groove of adult minipigs is a promising fixation method for reinforced hydrogels. To avoid bone lysis, future approaches should focus on multilayered constructs recreating the zonal cartilage as well as the calcified cartilage and the subchondral bone plate.
AUTHOR
Title
3D bioprinting of a stem cell-laden, multi-material tubular composite: An approach for spinal cord repair
[Abstract]
Year
2020
Journal/Proceedings
Materials Science and Engineering: C
Reftype
Groups
AbstractDevelopment of a biomimetic tubular scaffold capable of recreating developmental neurogenesis using pluripotent stem cells offers a novel strategy for the repair of spinal cord tissues. Recent advances in 3D printing technology have facilitated biofabrication of complex biomimetic environments by precisely controlling the 3D arrangement of various acellular and cellular components (biomaterials, cells and growth factors). Here, we present a 3D printing method to fabricate a complex, patterned and embryoid body (EB)-laden tubular scaffold composed of polycaprolactone (PCL) and hydrogel (alginate or gelatine methacrylate (GelMA)). Our results revealed 3D printing of a strong, macro-porous PCL/hydrogel tubular scaffold with a high capacity to control the porosity of the PCL scaffold, wherein the maximum porosity in the PCL wall was 15%. The method was equally employed to create spatiotemporal protein concentration within the scaffold, demonstrating its ability to generate linear and opposite gradients of model molecules (fluorescein isothiocyanate-conjugated bovine serum albumin (FITC-BSA) and rhodamine). 3D bioprinting of EBs-laden GelMA was introduced as a novel 3D printing strategy to incorporate EBs in a hydrogel matrix. Cell viability and proliferation were measured post-printing. Following the bioprinting of EBs-laden 5% GelMA hydrogel, neural differentiation of EBs was induced using 1 μM retinoic acid (RA). The differentiated EBs contained βIII-tubulin positive neurons displaying axonal extensions and cells migration. Finally, 3D bioprinting of EBs-laden PCL/GelMA tubular scaffold successfully supported EBs neural differentiation and patterning in response to co-printing with 1 μM RA. 3D printing of a complex heterogeneous tubular scaffold that can encapsulate EBs, spatially controlled protein concentration and promote neuronal patterning will help in developing more biomimetic scaffolds capable of replicating the neural patterning which occurs during neural tube development.
AUTHOR
Title
3D Printing of Core–Shell Capsule Composites for Post-Reactive and Damage Sensing Applications
[Abstract]
Year
2020
Journal/Proceedings
Advanced Materials Technologies
Reftype
DOI/URL
DOI
Groups
AbstractAbstract 3D printing of multicomponent materials as an advantageous method over traditional mold casting methods is demonstrated, developing small core–shell capsule composites fabricated by a two-step 3D printing process. Using a two-print-head system (fused deposition modeling extruder and a liquid inkjet print head), micro-sized capsules are manufactured in sizes ranging from 100 to 800 µm. The thermoplastic polymer poly(ε-caprolactone) (PCL) is chosen as matrix/shell material due to its optimal interaction with the embedded hydrophobic liquids. First, the core–shell capsules are printed with model liquids and pure PCL to optimize the printing parameters and to ensure fully enclosed capsules inside the polymer. As a proof of concept, novel “click” reaction systems, used in self-healing and stress-detection applications, are manufactured in which PCL composites with nano- and micro-fillers are combined with reactive, encapsulated liquids. The so generated 3D printed core–shell capsule composite can be used for post-printing reactions and damage sensing when combined with a fluorogenic dye.
AUTHOR
Title
3D printing of fibre-reinforced cartilaginous templates for the regeneration of osteochondral defects
[Abstract]
Year
2020
Journal/Proceedings
Acta Biomaterialia
Reftype
Groups
AbstractSuccessful osteochondral defect repair requires regenerating the subchondral bone whilst simultaneously promoting the development of an overlying layer of articular cartilage that is resistant to vascularization and endochondral ossification. During skeletal development articular cartilage also functions as a surface growth plate, which postnatally is replaced by a more spatially complex bone-cartilage interface. Motivated by this developmental process, the hypothesis of this study is that bi-phasic, fibre-reinforced cartilaginous templates can regenerate both the articular cartilage and subchondral bone within osteochondral defects created in caprine joints. To engineer mechanically competent implants, we first compared a range of 3D printed fibre networks (PCL, PLA and PLGA) for their capacity to mechanically reinforce alginate hydrogels whilst simultaneously supporting mesenchymal stem cell (MSC) chondrogenesis in vitro. These mechanically reinforced, MSC-laden alginate hydrogels were then used to engineer the endochondral bone forming phase of bi-phasic osteochondral constructs, with the overlying chondral phase consisting of cartilage tissue engineered using a co-culture of infrapatellar fat pad derived stem/stromal cells (FPSCs) and chondrocytes. Following chondrogenic priming and subcutaneous implantation in nude mice, these bi-phasic cartilaginous constructs were found to support the development of vascularised endochondral bone overlaid by phenotypically stable cartilage. These fibre-reinforced, bi-phasic cartilaginous templates were then evaluated in clinically relevant, large animal (caprine) model of osteochondral defect repair. Although the quality of repair was variable from animal-to-animal, in general more hyaline-like cartilage repair was observed after 6 months in animals treated with bi-phasic constructs compared to animals treated with commercial control scaffolds. This variability in the quality of repair points to the need for further improvements in the design of 3D bioprinted implants for joint regeneration. Statement of Significance Successful osteochondral defect repair requires regenerating the subchondral bone whilst simultaneously promoting the development of an overlying layer of articular cartilage. In this study, we hypothesised that bi-phasic, fibre-reinforced cartilaginous templates could be leveraged to regenerate both the articular cartilage and subchondral bone within osteochondral defects. To this end we used 3D printed fibre networks to mechanically reinforce engineered transient cartilage, which also contained an overlying layer of phenotypically stable cartilage engineered using a co-culture of chondrocytes and stem cells. When chondrogenically primed and implanted into caprine osteochondral defects, these fibre-reinforced bi-phasic cartilaginous grafts were shown to spatially direct tissue development during joint repair. Such developmentally inspired tissue engineering strategies, enabled by advances in biofabrication and 3D printing, could form the basis of new classes of regenerative implants in orthopaedic medicine.
AUTHOR
Title
3D Printing of Polycaprolactone-Polyaniline Electroactive Scaffolds for Bone Tissue Engineering.
[Abstract]
Year
2020
Journal/Proceedings
Materials
Reftype
DOI/URL
DOI
Groups
AbstractElectrostimulation and electroactive scaffolds can positively influence and guide cellular behaviour and thus has been garnering interest as a key tissue engineering strategy. The development of conducting polymers such as polyaniline enables the fabrication of conductive polymeric composite scaffolds. In this study, we report on the initial development of a polycaprolactone scaffold incorporating different weight loadings of a polyaniline microparticle filler. The scaffolds are fabricated using screw-assisted extrusion-based 3D printing and are characterised for their morphological, mechanical, conductivity, and preliminary biological properties. The conductivity of the polycaprolactone scaffolds increases with the inclusion of polyaniline. The in vitro cytocompatibility of the scaffolds was assessed using human adipose-derived stem cells to determine cell viability and proliferation up to 21 days. A cytotoxicity threshold was reached at 1% wt. polyaniline loading. Scaffolds with 0.1% wt. polyaniline showed suitable compressive strength (6.45 ± 0.16 MPa) and conductivity (2.46 ± 0.65 × 10(-4) S/cm) for bone tissue engineering applications and demonstrated the highest cell viability at day 1 (88%) with cytocompatibility for up to 21 days in cell culture.
AUTHOR
Title
3D-printed poly(Ɛ-caprolactone) scaffold with gradient mechanical properties according to force distribution in the mandible for mandibular bone tissue engineering
[Abstract]
Year
2020
Journal/Proceedings
Journal of the Mechanical Behavior of Biomedical Materials
Reftype
Groups
AbstractIn bone tissue engineering, prediction of forces induced to the native bone during normal functioning is important in the design, fabrication, and integration of a scaffold with the host. The aim of this study was to customize the mechanical properties of a layer-by-layer 3D-printed poly(ϵ-caprolactone) (PCL) scaffold estimated by finite element (FE) modeling in order to match the requirements of the defect, to prevent mechanical failure, and ensure optimal integration with the surrounding tissue. Forces and torques induced on the mandibular symphysis during jaw opening and closing were predicted by FE modeling. Based on the predicted forces, homogeneous-structured PCL scaffolds with 3 different void sizes (0.3, 0.6, and 0.9 mm) were designed and 3D-printed using an extrusion based 3D-bioprinter. In addition, 2 gradient-structured scaffolds were designed and 3D-printed. The first gradient scaffold contained 2 regions (0.3 mm and 0.6 mm void size in the upper and lower half, respectively), whereas the second gradient scaffold contained 3 regions (void sizes of 0.3, 0.6, and 0.9 mm in the upper, middle and lower third, respectively). Scaffolds were tested for their compressive and tensile strength in the upper and lower halves. The actual void size of the homogeneous scaffolds with designed void size of 0.3, 0.6, and 0.9 mm was 0.20, 0.59, and 0.95 mm, respectively. FE modeling showed that during opening and closing of the jaw, the highest force induced on the symphysis was a compressive force in the transverse direction. The compressive force was induced throughout the symphyseal line and reduced from top (362.5 N, compressive force) to bottom (107.5 N, tensile force) of the symphysis. Compressive and tensile strength of homogeneous scaffolds decreased by 1.4-fold to 3-fold with increasing scaffold void size. Both gradient scaffolds had higher compressive strength in the upper half (2 region-gradient scaffold: 4.9 MPa; 3 region-gradient scaffold: 4.1 MPa) compared with the lower half (2 region-gradient scaffold: 2.5 MPa; 3 region-gradient scaffold: 2.7 MPa) of the scaffold. 3D-printed PCL scaffolds had higher compressive strength in the scaffold layer-by-layer building direction compared with the side direction, and a very low tensile strength in the scaffold layer-by-layer building direction. Fluid shear stress and fluid pressure distribution in the gradient scaffolds were more homogeneous than in the 0.3 mm void size scaffold and similar to the 0.6 mm and 0.9 mm void size scaffolds. In conclusion, these data show that the mechanical properties of 3D-printed PCL scaffolds can be tailored based on the predicted forces on the mandibular symphysis. These 3D-printed PCL scaffolds had different mechanical properties in scaffold building direction compared with the side direction, which should be taken into account when placing the scaffold in the defect site. Our findings might have implications for improved performance and integration of scaffolds with native tissue.
AUTHOR
Title
A composite hydrogel-3D printed thermoplast osteochondral anchor as example for a zonal approach to cartilage repair: in vivo performance in a long-term equine model
[Abstract]
Year
2020
Journal/Proceedings
Biofabrication
Reftype
DOI/URL
DOI
Groups
AbstractRecent research has been focusing on the generation of living personalized osteochondral constructs for joint repair. Native articular cartilage has a zonal structure, which is not reflected in current constructs and which may be a cause of the frequent failure of these repair attempts. Therefore, we investigated the performance of a composite implant that further reflects the zonal distribution of cellular component both in vitro and in vivo in a long-term equine model. Constructs constituted of a 3D-printed poly(ϵ-caprolactone) (PCL) bone anchor from which reinforcing fibers protruded into the chondral part of the construct over which two layers of a thiol-ene cross-linkable hyaluronic acid/poly(glycidol) hybrid hydrogel (HA-SH/P(AGE-co-G)) were fabricated. The top layer contained Articular Cartilage Progenitor Cells (ACPCs) derived from the superficial layer of native cartilage tissue, the bottom layer contained mesenchymal stromal cells (MSCs). The chondral part of control constructs were homogeneously filled with MSCs. After six months in vivo, microtomography revealed significant bone growth into the anchor. Histologically, there was only limited production of cartilage-like tissue (despite persistency of hydrogel) both in zonal and non-zonal constructs. There were no differences in histological scoring; however, the repair tissue was significantly stiffer in defects repaired with zonal constructs. The sub-optimal quality of the repair tissue may be related to several factors, including early loss of implanted cells, or inappropriate degradation rate of the hydrogel. Nonetheless, this approach may be promising and research into further tailoring of biomaterials and of construct characteristics seems warranted.
AUTHOR
Title
A Preliminary Evaluation of the Pro-Chondrogenic Potential of 3D-Bioprinted Poly(ester Urea) Scaffolds
Year
2020
Journal/Proceedings
Polymers
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DOI/URL
DOI
AUTHOR
Title
Aligned multi-walled carbon nanotubes with nanohydroxyapatite in a 3D printed polycaprolactone scaffold stimulates osteogenic differentiation
[Abstract]
Year
2020
Journal/Proceedings
Materials Science and Engineering: C
Reftype
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