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AUTHOR Ribezzi, Davide and Gueye, Marième and Florczak, Sammy and Dusi, Franziska and de Vos, Dieuwke and Manente, Francesca and Hierholzer, Andreas and Fussenegger, Martin and Caiazzo, Massimiliano and Blunk, Torsten and Malda, Jos and Levato, Riccardo
Title Shaping Synthetic Multicellular and Complex Multimaterial Tissues via Embedded Extrusion-Volumetric Printing of Microgels [Abstract]
Year 2023
Journal/Proceedings Advanced Materials
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Abstract In living tissues, cells express their functions following complex signals from their surrounding microenvironment. Capturing both hierarchical architectures at the micro- and macroscale, and anisotropic cell patterning remains a major challenge in bioprinting, and a bottleneck towards creating physiologically-relevant models. Addressing this limitation, we introduced a novel technique, termed Embedded Extrusion-Volumetric Printing (EmVP), converging extrusion-bioprinting and layer-less, ultra-fast volumetric bioprinting, allowing to spatially pattern multiple inks/cell types. Light-responsive microgels were developed for the first time as bioresins (μResins) for light-based volumetric bioprinting, providing a microporous environment permissive for cell homing and self-organization. Tuning the mechanical and optical properties of gelatin-based microparticles enables their use as support bath for suspended extrusion printing, in which features containing high cell densities can be easily introduced. μResins can be sculpted within seconds with tomographic light projections into centimetre-scale, granular hydrogel-based, convoluted constructs. Interstitial microvoids enhanced differentiation of multiple stem/progenitor cells (vascular, mesenchymal, neural), otherwise not possible with conventional bulk hydrogels. As proof-of-concept, EmVP was applied to create complex synthetic biology-inspired intercellular communication models, where adipocyte differentiation is regulated by optogenetic-engineered pancreatic cells. Overall, EmVP offers new avenues for producing regenerative grafts with biological functionality, and for developing engineered living systems and (metabolic) disease models. This article is protected by copyright. All rights reserved
AUTHOR Fanous, Marina and Gold, Sarah and Muller, Silvain and Hirsch, Stefan and Ogorka, Joerg and Imanidis, Georgios
Title Simplification of fused deposition modeling 3D-printing paradigm: Feasibility of 1-step direct powder printing for immediate release dosage form production [Abstract]
Year 2020
Journal/Proceedings International Journal of Pharmaceutics
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Direct powder three-dimensional (3D)-printing (DPP) of tablets to simplify fused deposition modelling (FDM) was explored. The FDM paradigm involving hot-melt extrusion for making 3D-printable drug-loaded filaments as intermediate products for tablet manufacturing has been gaining attention for the decentralized on-site production of personalized dosage forms. For direct 3D-printing, powder blends were loaded into a cartridge-like head and were successfully printed with honeycomb design following heating of the extrusion cartridge. This 1-step DPP with incorporation of in-built porosity providing higher surface area served as proof of concept for manufacture of rapid release dosage forms. Water soluble hydroxypropylcellulose SSL was chosen as matrix former and caffeine as model drug. The effect of PEG4000 as plasticizer/pore former and Kollidon VA64 as rapidly dissolving polymer on DPP processability and dissolution rate was investigated. Directly 3D-printed tablets with low (30%) infill density showed rapid dissolution independently of the formulation, whereas for high (80%) infill density a combination of PEG4000 and Kollidon VA64 was required to achieve rapid release. The obtained tablets demonstrated good uniformity of percent drug content but had variable weight. Caffeine was present in crystalline state and in the stable polymorph in the tablets. Hence, DPP feasibility for immediate release dosage form manufacture was demonstrated. This technique might create an opportunity to avoid hot-melt extrusion allowing 3D-printing independently of mechanical properties of a filament and potentially prolonging product shelf life by reducing thermal stress.
AUTHOR Laternser, Sandra and Keller, Hansjoerg and Leupin, Olivier and Rausch, Martin and Graf-Hausner, Ursula and Rimann, Markus
Title A Novel Microplate 3D Bioprinting Platform for the Engineering of Muscle and Tendon Tissues [Abstract]
Year 2018
Journal/Proceedings SLAS TECHNOLOGY: Translating Life Sciences Innovation
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Two-dimensional (2D) cell cultures do not reflect the in vivo situation, and thus it is important to develop predictive three-dimensional (3D) in vitro models with enhanced reliability and robustness for drug screening applications. Treatments against muscle-related diseases are becoming more prominent due to the growth of the aging population worldwide. In this study, we describe a novel drug screening platform with automated production of 3D musculoskeletal-tendon-like tissues. With 3D bioprinting, alternating layers of photo-polymerized gelatin-methacryloyl-based bioink and cell suspension tissue models were produced in a dumbbell shape onto novel postholder cell culture inserts in 24-well plates. Monocultures of human primary skeletal muscle cells and rat tenocytes were printed around and between the posts. The cells showed high viability in culture and good tissue differentiation, based on marker gene and protein expressions. Different printing patterns of bioink and cells were explored and calcium signaling with Fluo4-loaded cells while electrically stimulated was shown. Finally, controlled co-printing of tenocytes and myoblasts around and between the posts, respectively, was demonstrated followed by co-culture and co-differentiation. This screening platform combining 3D bioprinting with a novel microplate represents a promising tool to address musculoskeletal diseases.
AUTHOR Khaled, Shaban A. and Burley, Jonathan C. and Alexander, Morgan R. and Yang, Jing and Roberts, Clive J.
Title 3D printing of five-in-one dose combination polypill with defined immediate and sustained release profiles [Abstract]
Year 2015
Journal/Proceedings Journal of Controlled Release
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Abstract We have used three dimensional (3D) extrusion printing to manufacture a multi-active solid dosage form or so called polypill. This contains five compartmentalised drugs with two independently controlled and well-defined release profiles. This polypill demonstrates that complex medication regimes can be combined in a single personalised tablet. This could potentially improve adherence for those patients currently taking many separate tablets and also allow ready tailoring of a particular drug combination/drug release for the needs of an individual. The polypill here represents a cardiovascular treatment regime with the incorporation of an immediate release compartment with aspirin and hydrochlorothiazide and three sustained release compartments containing pravastatin, atenolol, and ramipril. X-ray powder diffraction (XRPD) and Attenuated Total Reflectance Fourier Transform Infrared Spectroscopy (ATR-FTIR) were used to assess drug-excipient interaction. The printed polypills were evaluated for drug release using {USP} dissolution testing. We found that the polypill showed the intended immediate and sustained release profiles based upon the active/excipient ratio used.
AUTHOR Zhang, Danwei and Jonhson, Win and Herng, Tun Seng and Ang, Yong Quan and Yang, Lin and Tan, Swee Ching and Peng, Erwin and He, Hui and Ding, Jun
Title A 3D-printing method of fabrication for metals{,} ceramics{,} and multi-materials using a universal self-curable technique for robocasting [Abstract]
Year 2019
Journal/Proceedings Materials Horizons
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Ceramics and metals are important materials that modern technologies are constructed from. The capability to produce such materials in a complex geometry with good mechanical properties can revolutionize the way we engineer our devices. Current curing techniques pose challenges such as high energy requirements{,} limitations of materials with high refractive index{,} tedious post-processing heat treatment processes{,} uneven drying shrinkages{,} and brittleness of green bodies. In this paper{,} a novel modified self-curable epoxide–amine 3D printing system is proposed to print a wide range of ceramics (metal oxides{,} nitrides{,} and carbides) and metals without the need for an external curing source. Through this technique{,} complex multi-material structures (with metal–ceramic and ceramic–ceramic combinations) can also be realized. Tailoring and matching the sintering temperatures of different materials through sintering additives and dopants{,} combined with a structural design providing maximum adhesion between interfaces{,} allow us to successfully obtain superior quality sintered multi-material structures. High-quality ceramic and metallic materials have been achieved (e.g.{,} zirconia with >98% theoretical density). Also{,} highly conductive metals and magnetic ceramics were printed and shaped uniquely without the need for a sacrificial support. With the addition of low molecular weight plasticizers and a multi-stage heat treatment process{,} crack-free and dense high-quality integrated multi-material structures fabricated by 3D printing can thus be a reality in the near future.
AUTHOR Khaled, Shaban A. and Burley, Jonathan C. and Alexander, Morgan R. and Yang, Jing and Roberts, Clive J.
Title 3D printing of tablets containing multiple drugs with defined release profiles [Abstract]
Year 2015
Journal/Proceedings International Journal of Pharmaceutics
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Abstract We have employed three-dimensional (3D) extrusion-based printing as a medicine manufacturing technique for the production of multi-active tablets with well-defined and separate controlled release profiles for three different drugs. This ‘polypill’ made by a 3D additive manufacture technique demonstrates that complex medication regimes can be combined in a single tablet and that it is viable to formulate and ‘dial up’ this single tablet for the particular needs of an individual. The tablets used to illustrate this concept incorporate an osmotic pump with the drug captopril and sustained release compartments with the drugs nifedipine and glipizide. This combination of medicines could potentially be used to treat diabetics suffering from hypertension. The room temperature extrusion process used to print the formulations used excipients commonly employed in the pharmaceutical industry. Attenuated Total Reflectance Fourier Transform Infrared Spectroscopy (ATR-FTIR) and X-ray powder diffraction (XRPD) were used to assess drug–excipient interaction. The printed formulations were evaluated for drug release using {USP} dissolution testing. We found that the captopril portion showed the intended zero order drug release of an osmotic pump and noted that the nifedipine and glipizide portions showed either first order release or Korsmeyer–Peppas release kinetics dependent upon the active/excipient ratio used.
AUTHOR Zhang, Danwei and Peng, Erwin and Borayek, Ramadan and Ding, Jun
Title Controllable Ceramic Green-Body Configuration for Complex Ceramic Architectures with Fine Features [Abstract]
Year 2019
Journal/Proceedings Advanced Functional Materials
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Abstract Fabrication of dense ceramic articles with intricate fine features and geometrically complex morphology by using a relatively simple and the cost-effective process still remains a challenge. Ceramics, either in its green- or sintered-form, are known for being hard yet brittle which limits further shape reconfiguration. In this work, a combinatorial process of ceramic robocasting and photopolymerization is demonstrated to produce either flexible and/or stretchable ceramic green-body (Flex-Body or Stretch-Body) that can undergo a postprinting reconfiguration process. Secondary shaping may proceed through: i) self-assembly-assisted shaping and ii) mold-assisted shaping process, which allows a well-controlled ceramic structure morphology. With a proposed well-controlled thermal heating process, the ceramic Sintered-Body can achieve >99.0% theoretical density with good mechanical rigidity. Complex and dense ceramic articles with fine features down to 65 μm can be fabricated. When combined with a multi-nozzle deposition process, i) self-shaping ceramic structures can be realized through anisotropic shrinkage induced by suspensions' composition variation and ii) technical and functional multiceramic structures can be fabricated. The simplicity of the proposed technique and its inexpensive processing cost make it an attractive approach for fabricating geometrically complex ceramic articles with unique macrostructures, which complements the existing state of-the-art ceramic additive manufacturing techniques.
AUTHOR Cianciosi, Alessandro and Simon, Jonas and Bartolf-Kopp, Michael and Grausgruber, Heinrich and Dargaville, Tim R. and Forget, Aurélien and Groll, Jürgen and Jungst, Tomasz and Beaumont, Marco
Title Direct ink writing of multifunctional nanocellulose and allyl-modified gelatin biomaterial inks for the fabrication of mechanically and functionally graded constructs [Abstract]
Year 2023
Journal/Proceedings Carbohydrate Polymers
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Recreating the intricate mechanical and functional gradients found in natural tissues through additive manufacturing poses significant challenges, including the need for precise control over time and space and the availability of versatile biomaterial inks. In this proof-of-concept study, we developed a new biomaterial ink for direct ink writing, allowing the creation of 3D structures with tailorable functional and mechanical gradients. Our ink formulation combined multifunctional cellulose nanofibrils (CNFs), allyl-functionalized gelatin (0.8–2.0 wt%), and polyethylene glycol dithiol (3.0–7.5 wt%). The CNF served as a rheology modifier, whereas a concentration of 1.8 w/v % in the inks was chosen for optimal printability and shape fidelity. In addition, CNFs were functionalized with azido groups, enabling the spatial distribution of functional moieties within a 3D structure. These functional groups were further modified using a spontaneous click chemistry reaction. Through additive manufacturing and a readily available static mixer, we successfully demonstrated the fabrication of mechanical gradients – ranging from 3 to 6 kPa in indentation strength – and functional gradients. Additionally, we introduced dual gradients by combining gradient printing with an anisotropic photocrosslinking step. The developed biomaterial ink opens up possibilities for printing intricate multigradient structures, resembling the complex hierarchical organization seen in living tissues.
AUTHOR Cojocaru, Elena and Ghitman, Jana and Pircalabioru, Gratiela Gradisteanu and Zaharia, Anamaria and Iovu, Horia and Sarbu, Andrei
Title Electrospun/3D-Printed Bicomponent Scaffold Co-Loaded with a Prodrug and a Drug with Antibacterial and Immunomodulatory Properties [Abstract]
Year 2023
Journal/Proceedings Polymers
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This work reports the construction of a bicomponent scaffold co-loaded with both a prodrug and a drug (BiFp@Ht) as an efficient platform for wound dressing, by combining the electrospinning and 3D-printing technologies. The outer component consisted of a chitosan/polyethylene oxide-electrospun membrane loaded with the indomethacin–polyethylene glycol–indomethacin prodrug (Fp) and served as a support for printing the inner component, a gelatin methacryloyl/sodium alginate hydrogel loaded with tetracycline hydrochloride (Ht). The different architectural characteristics of the electrospun and 3D-printed layers were very well highlighted in a morphological analysis performed by Scanning Electron Microscopy (SEM). In vitro release profile studies demonstrated that both Fp and Ht layers were capable to release the loaded therapeutics in a controlled and sustained manner. According to a quantitative in vitro biological assessment, the bicomponent BiFp@Ht scaffold showed a good biocompatibility and no cytotoxic effect on HeLa cell cultures, while the highest proliferation level was noted in the case of HeLa cells seeded onto an Fp nanofibrous membrane. Furthermore, the BiFp@Ht scaffold presented an excellent antimicrobial activity against the E. coli and S. aureus bacterial strains, along with promising anti-inflammatory and proangiogenic activities, proving its potential to be used for wound dressing.
AUTHOR Katcharava, Zviadi and Marinow, Anja and Bhandary, Rajesh and Binder, Wolfgang H.
Title 3D Printable Composite Polymer Electrolytes: Influence of SiO2 Nanoparticles on 3D-Printability [Abstract]
Year 2022
Journal/Proceedings Nanomaterials
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We here demonstrate the preparation of composite polymer electrolytes (CPEs) for Li-ion batteries, applicable for 3D printing process via fused deposition modeling. The prepared composites consist of modified poly(ethylene glycol) (PEG), lithium bis(trifluoromethylsulfonyl)imide (LiTFSI) and SiO2-based nanofillers. PEG was successfully end group modified yielding telechelic PEG containing either ureidopyrimidone (UPy) or barbiturate moieties, capable to form supramolecular networks via hydrogen bonds, thus introducing self-healing to the electrolyte system. Silica nanoparticles (NPs) were used as a filler for further adjustment of mechanical properties of the electrolyte to enable 3D-printability. The surface functionalization of the NPs with either ionic liquid (IL) or hydrophobic alkyl chains is expected to lead to an improved dispersion of the NPs within the polymer matrix. Composites with different content of NPs (5%, 10%, 15%) and LiTFSI salt (EO/Li+ = 5, 10, 20) were analyzed via rheology for a better understanding of 3D printability, and via Broadband Dielectric Spectroscopy (BDS) for checking their ionic conductivity. The composite electrolyte PEG 1500 UPy2/LiTFSI (EO:Li 5:1) mixed with 15% NP-IL was successfully 3D printed, revealing its suitability for application as printable composite electrolytes.
AUTHOR Jonhson, Win and Xu, Xi and Bian, Ka and Xun, Yanran and Tan, Yong Hao and Chen, Zhe and Zhang, Danwei and Ding, Jun
Title 3D-Printed Hierarchical Ceramic Architectures for Ultrafast Emulsion Treatment and Simultaneous Oil-Water Filtration [Abstract]
Year 2022
Journal/Proceedings ACS Materials Lett.
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There is a critical need for energy-efficient water treatment processes as the world seeks to limit global warming below 1.5 °C. Gravity-driven mesh filtration presents a sustainable solution to treating oily wastewater and emulsions, which are byproducts of many human activities. The promise of a green alternative is getting closer with the development of 3D printing combined with reusable, recyclable, and ubiquitous materials such as silica to produce durable and recyclable filters with controllable mesh spacing. In this work, several filters were fabricated to separate oily water mixtures with a separation efficiency of 99% at high flow flux by coating 3D porous ceramic architectures with organosilanes. The proposed ceramic filters can also treat oil-in-water and water-in-oil surfactant-stabilized emulsions with high flow flux. This strategy to functionalize the 3D printed silica surface to form either hydrophobic or hydrophilic surfaces can open a new possibility for gravity-driven simultaneous oil-water separation. The first gravity-driven hierarchical auto-oil-water separator (HAOS) was introduced to separate an oily water mixture into two different containers using a combination of 3D printed hierarchical hydrophilic and hydrophobic filters without an additional postseparation step.
AUTHOR Cao, Chuanliang and Huang, Pengren and Prasopthum, Aruna and Parsons, Andrew J. and Ai, Fanrong and Yang, Jing
Title Characterisation of bone regeneration in 3D printed ductile PCL/PEG/hydroxyapatite scaffolds with high ceramic microparticle concentrations [Abstract]
Year 2022
Journal/Proceedings Biomater. Sci.
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3D printed bioactive glass or bioceramic particle reinforced composite scaffolds for bone tissue engineering currently suffer from low particle concentration (100% breaking strain) by adding poly(ethylene glycol) which is biocompatible and FDA approved. The scaffolds require no post-printing washing to remove hazardous components. More exposure of HA microparticles on strut surfaces is enabled by incorporating higher HA concentrations. Compared to scaffolds with 72 wt% HA{,} scaffolds with higher HA content (90 wt%) enhance matrix formation but not new bone volume after 12 weeks implantation in rat calvarial defects. Histological analyses demonstrate that bone regeneration within the 3D printed scaffolds is via intramembranous ossification and starts in the central region of pores. Fibrous tissue that resembles non-union tissue within bone fractures is formed within pores that do not have new bone. The amount of blood vessels is similar between scaffolds with mainly fibrous tissue and those with more bone tissue{,} suggesting vascularization is not a deciding factor for determining the type of tissues regenerated within the pores of 3D printed scaffolds. Multinucleated immune cells are commonly present in all scaffolds surrounding the struts{,} suggesting a role of managing inflammation in bone regeneration within 3D printed scaffolds.
AUTHOR Da Silva, Aruã Clayton and Akbar, Teuku Fawzul and Paterson, Thomas Edward and Werner, Carsten and Tondera, Christoph and Minev, Ivan Rusev
Title Electrically Controlled Click-Chemistry for Assembly of Bioactive Hydrogels on Diverse Micro- and Flexible Electrodes [Abstract]
Year 2022
Journal/Proceedings Macromolecular Rapid Communications
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Abstract The seamless integration of electronics with living matter requires advanced materials with programmable biological and engineering properties. Here electrochemical methods to assemble semi-synthetic hydrogels directly on electronically conductive surfaces are explored. Hydrogels consisting of poly (ethylene glycol) (PEG) and heparin building blocks are polymerized by spatially controlling the click reaction between their thiol and maleimide moieties. The gels are grown as conformal coatings or 2D patterns on ITO, gold, and PtIr. This study demonstrates that such coatings significantly influence the electrochemical properties of the metal-electrolyte interface, likely due to space charge effects in the gels. Further a promising route toward engineering and electrically addressable extracellular matrices by printing arrays of gels with binary cell adhesiveness on flexible conductive surfaces is highlighted.
AUTHOR Wang, Chenmin and Honiball, John Robert and Lin, Junyu and Xia, Xingyu and Lau, Dzi Shing Aaron and Chen, Bo and Deng, Lianfu and Lu, William Weijia
Title Infiltration from Suspension Systems Enables Effective Modulation of 3D Scaffold Properties in Suspension Bioprinting [Abstract]
Year 2022
Journal/Proceedings ACS Appl. Mater. Interfaces
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Bioprinting is a biofabrication technology which allows efficient and large-scale manufacture of 3D cell culture systems. However, the available biomaterials for bioinks used in bioprinting are limited by their printability and biological functionality. Fabricated constructs are often homogeneous and have limited complexity in terms of current 3D cell culture systems comprising multiple cell types. Inspired by the phenomenon that hydrogels can exchange liquids under the infiltration action, infiltration-induced suspension bioprinting (IISBP), a novel printing technique based on a hyaluronic acid (HA) suspension system to modulate the properties of the printed scaffolds by infiltration action, was described in this study. HA served as a suspension system due to its shear-thinning and self-healing rheological properties, simplicity of preparation, reusability, and ease of adjustment to osmotic pressure. Changes in osmotic pressure were able to direct the swelling or shrinkage of 3D printed gelatin methacryloyl (GelMA)-based bioinks, enabling the regulation of physical properties such as fiber diameter, micromorphology, mechanical strength, and water absorption of 3D printed scaffolds. Human umbilical vein endothelial cells (HUVEC) were applied as a cell culture model and printed within cell-laden scaffolds at high resolution and cell viability with the IISBP technique. Herein, the IISBP technique had been realized as a reliable hydrogel-based bioprinting technique, which enabled facile modulation of 3D printed hydrogel scaffolds properties, being expected to meet the scaffolds requirements of a wide range of cell culture conditions to be utilized in bioprinting applications.
AUTHOR Kim, Jieun and Lee, Joohyung
Title Liquid-Suspended and Liquid-Bridged Liquid Metal Microdroplets [Abstract]
Year 2022
Journal/Proceedings Small
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Abstract Liquid metals (LMs) and alloys are attracting increasing attention owing to their combined advantages of high conductivity and fluidity, and have shown promising results in various emerging applications. Patterning technologies using LMs are being actively researched; among them, direct ink writing is considered a potentially viable approach for efficient LM additive manufacturing. However, true LM additive manufacturing with arbitrary printing geometries remains challenging because of the intrinsically low rheological strength of LMs. Herein, colloidal suspensions of LM droplets amenable to additive manufacturing (or “3D printing”) are realized using formulations containing minute amounts of liquid capillary bridges. The resulting LM suspensions exhibit exceptionally high rheological strength with yield stress values well above 103 Pa, attributed to inter-droplet capillary attraction mediated by the liquid bridges adsorbed on the oxide skin of the LM droplets. Such liquid-bridged LM suspensions, as extrudable ink-type filaments, are based on uncurable continuous-phase liquid media, have a long pot-life and outstanding shear-thinning properties, and shape retention, demonstrating excellent rheological processability suitable for 3D printing. These findings will enable the emergence of a variety of new advanced applications that necessitate LM patterning into highly complicated multidimensional structures.
AUTHOR Rupp, Harald and Bhandary, Rajesh and Kulkarni, Amit and Binder, Wolfgang
Title Printable Electrolytes: Tuning 3D-Printing by Multiple Hydrogen Bonds and Added Inorganic Lithium-Salts [Abstract]
Year 2022
Journal/Proceedings Advanced Materials Technologies
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Abstract 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 Zhang, Xiao and Liu, Yang and Zuo, Qiang and Wang, Qingyun and Li, Zuxi and Yan, Kai and Yuan, Tao and Zhang, Yi and Shen, Kai and Xie, Rui and Fan, Weimin
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)
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Recently, 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 Zhang, Xiao and Liu, Yang and Luo, Chunyang and Zhai, Chenjun and Li, Zuxi and Zhang, Yi and Yuan, Tao and Dong, Shilei and Zhang, Jiyong and Fan, Weimin
Title Crosslinker-free silk/decellularized extracellular matrix porous bioink for 3D bioprinting-based cartilage tissue engineering [Abstract]
Year 2021
Journal/Proceedings Materials Science and Engineering: C
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As cartilage tissue lacks the innate ability to mount an adequate regeneration response, damage to it is detrimental to the quality of life of the subject. The emergence of three-dimensional bioprinting (3DBP) technology presents an opportunity to repair articular cartilage defects. However, widespread adoption of this technique has been impeded by difficulty in preparing a suitable bioink and the toxicity inherent in the chemical crosslinking process of most bioinks. Our objective was to develop a crosslinker-free bioink with the same biological activity as the original cartilage extracellular matrix (ECM) and good mechanical strength. We prepared bioinks containing different concentrations of silk fibroin and decellularized extracellular matrix (SF-dECM bioinks) mixed with bone marrow mesenchymal stem cells (BMSCs) for 3D bioprinting. SF and dECM interconnect with each other through physical crosslinking and entanglement. A porous structure was formed by removing the polyethylene glycol from the SF-dECM bioink. The results showed the SF-dECM construct had a suitable mechanical strength and degradation rate, and the expression of chondrogenesis-specific genes was found to be higher than that of the SF control construct group. Finally, we confirmed that a SF-dECM construct that was designed to release TGF-β3 had the ability to promote chondrogenic differentiation of BMSCs and provided a good cartilage repair environment, suggesting it is an ideal scaffold for cartilage tissue engineering.
AUTHOR Chen, Shengyang and Shi, Qian and Jang, Taesik and Ibrahim, Mohammed Shahrudin Bin and Deng, Jingyu and Ferracci, Gaia and Tan, Wen See and Cho, Nam-Joon and Song, Juha
Title Engineering Natural Pollen Grains as Multifunctional 3D Printing Materials [Abstract]
Year 2021
Journal/Proceedings Advanced Functional Materials
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Abstract The development of multifunctional 3D printing materials from sustainable natural resources is a high priority in additive manufacturing. Using an eco-friendly method to transform hard pollen grains into stimulus-responsive microgel particles, we engineered a pollen-derived microgel suspension that can serve as a functional reinforcement for composite hydrogel inks and as a supporting matrix for versatile freeform 3D printing systems. The pollen microgel particles enabled the printing of composite inks and improved the mechanical and physiological stabilities of alginate and hyaluronic acid hydrogel scaffolds for 3D cell culture applications. Moreover, the particles endowed the inks with stimulus-responsive controlled release properties. The suitability of the pollen microgel suspension as a supporting matrix for freeform 3D printing of alginate and silicone rubber inks was demonstrated and optimized by tuning the rheological properties of the microgel. Compared with other classes of natural materials, pollen grains have several compelling features, including natural abundance, renewability, affordability, processing ease, monodispersity, and tunable rheological features, which make them attractive candidates to engineer advanced materials for 3D printing applications.
AUTHOR Zhang, Danwei and Jonhson, Win and Herng, Tun Seng and Xu, Xi and Liu, Xiaojing and Pan, Liang-ming and He, Hui and Ding, Jun
Title High Temperature Co-firing of 3D-Printed Al-ZnO/Al2O3 Multi-Material Two-Phase Flow Sensor [Abstract]
Year 2021
Journal/Proceedings Journal of Materiomics
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Sensors are crucial in the understanding of machines working under high temperatures and high-pressure conditions. Current devices utilize polymeric materials as electrical insulators which pose a challenge in the device’s lifespan. Ceramics, on the other hand, is robust and able to withstand high temperature and pressure. For such applications, a co-fired ceramic device which can provide both electrical conductivity and insulation is beneficial and acts as a superior candidate for sensor devices. In this paper, we propose a novel fabrication technique of complex multi-ceramics structures via 3D printing. This fabrication methodology increases both the geometrical complexity and the device’s shape precision. Structural ceramics (alumina) was employed as the electrical insulator whilst providing mechanical rigidity while a functional ceramic (alumina-doped zinc oxide) was employed as the electrically conductive material. The addition of sintering additives, tailoring the printing pastes’ solid loadings and heat treatment profile resolves multi-materials printing challenges such as shrinkage disparity and densification matching. Through high-temperature co-firing of ceramics (HTCC) technology, dense high quality functional multi-ceramics structures are achieved. The proposed fabrication methodology paves the way for multi-ceramics sensors to be utilized in high temperature and pressure systems in the near future.
AUTHOR Lotz, Benedict and Bothe, Friederike and Deubel, Anne-Kathrin and Hesse, Eliane and Renz, Yvonne and Werner, Carsten and Schäfer, Simone and Böck, Thomas and Groll, Jürgen and von Rechenberg, Brigitte and Richter, Wiltrud and Hagmann, Sebastien
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
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Abstract
Reinforced 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 Li, Zuxi and Zhang, Xiao and Yuan, Tao and Zhang, Yi and Luo, Chunyang and Zhang, Jiyong and Liu, Yang and Fan, Weimin
Title Addition of Platelet-Rich Plasma to Silk Fibroin Hydrogel Bioprinting for Cartilage Regeneration [Abstract]
Year 2020
Journal/Proceedings Tissue Engineering Part A
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Abstract
The recent advent of 3D bioprinting of biopolymers provides a novel method for fabrication of tissue-engineered scaffolds and also offers a potentially promising avenue in cartilage regeneration. Silk fibroin (SF) is one of the most popular biopolymers used for 3D bioprinting, but further application of SF is hindered by its limited biological activities. Incorporation of growth factors (GFs) has been identified as a solution to improve biological function. Platelet-rich plasma (PRP) is an autologous resource of GFs, which has been widely used in clinic. In this study, we have developed SF-based bioinks incorporated with different concentrations of PRP (12.5%, 25%, and 50%; vol/vol). Release kinetic studies show that SF-PRP bioinks could achieve controlled release of GFs. Subsequently, SF-PRP bioinks were successfully fabricated into scaffolds by bioprinting. Our results revealed that SF-PRP scaffolds possessed proper internal pore structure, good biomechanical properties, and a suitable degradation rate for cartilage regeneration. Live/dead staining showed that 3D, printed SF-PRP scaffolds were biocompatible. Moreover, in vitro studies revealed that tissue-engineered cartilage from the SF-PRP group exhibited improved qualities compared with the pure SF controls, according to histological and immunohistochemical findings. Biochemical evaluations confirmed that SF-PRP (50% PRP, v/v) scaffolds allowed the largest increases in collagen and glycosaminoglycan concentrations, when compared with the pure SF group. These findings suggest that 3D, printed SF-PRP scaffolds could be potential candidates for cartilage tissue engineering.
AUTHOR Steier, Anke and Schmieg, Barbara and Irtel von Brenndorff, Yannic and Meier, Manuel and Nirschl, Hermann and Franzreb, Matthias and Lahann, Joerg
Title Enzyme Scaffolds with Hierarchically Defined Properties via 3D Jet Writing [Abstract]
Year 2020
Journal/Proceedings Macromolecular Bioscience
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Abstract
Abstract The immobilization of enzymes into polymer hydrogels is a versatile approach to improve their stability and utility in biotechnological and biomedical applications. However, these systems typically show limited enzyme activity, due to unfavorable pore dimensions and low enzyme accessibility. Here, 3D jet writing of water-based bioinks, which contain preloaded enzymes, is used to prepare hydrogel scaffolds with well-defined, tessellated micropores. After 3D jet writing, the scaffolds are chemically modified via photopolymerization to ensure mechanical stability. Enzyme loading and activity in the hydrogel scaffolds is fully retained over 3 d. Important structural parameters of the scaffolds such as pore size, pore geometry, and wall diameter are controlled with micrometer resolution to avoid mass-transport limitations. It is demonstrated that scaffold pore sizes between 120 µm and 1 mm can be created by 3D jet writing approaching the length scales of free diffusion in the hydrogels substrates and resulting in high levels of enzyme activity (21.2% activity relative to free enzyme). With further work, a broad range of applications for enzyme-laden hydrogel scaffolds including diagnostics and enzymatic cascade reactions is anticipated.
AUTHOR Abu Awwad, Hosam Al-Deen M. and Thiagarajan, Lalitha and Kanczler, Janos M. and Amer, Mahetab H. and Bruce, Gordon and Lanham, Stuart and Rumney, Robin M. H. and Oreffo, Richard O. C. and Dixon, James E.
Title Genetically-programmed, mesenchymal stromal cell-laden & mechanically strong 3D bioprinted scaffolds for bone repair [Abstract]
Year 2020
Journal/Proceedings Journal of Controlled Release
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Abstract
Additive manufacturing processes used to create regenerative bone tissue engineered implants are not biocompatible, thereby restricting direct use with stem cells and usually require cell seeding post-fabrication. Combined delivery of stem cells with the controlled release of osteogenic factors, within a mechanically-strong biomaterial combined during manufacturing would replace injectable defect fillers (cements) and allow personalized implants to be rapidly prototyped by 3D bioprinting. Through the use of direct genetic programming via the sustained release of an exogenously delivered transcription factor RUNX2 (delivered as recombinant GET-RUNX2 protein) encapsulated in PLGA microparticles (MPs), we demonstrate that human mesenchymal stromal (stem) cells (hMSCs) can be directly fabricated into a thermo-sintered 3D bioprintable material and achieve effective osteogenic differentiation. Importantly we observed osteogenic programming of gene expression by released GET-RUNX2 (8.2-, 3.3- and 3.9-fold increases in OSX, RUNX2 and OPN expression, respectively) and calcification (von Kossa staining) in our scaffolds. The developed biodegradable PLGA/PEG paste formulation augments high-density bone development in a defect model (~2.4-fold increase in high density bone volume) and can be used to rapidly prototype clinically-sized hMSC-laden implants within minutes using mild, cytocompatible extrusion bioprinting. The ability to create mechanically strong 'cancellous bone-like’ printable implants for tissue repair that contain stem cells and controlled-release of programming factors is innovative, and will facilitate the development of novel localized delivery approaches to direct cellular behaviour for many regenerative medicine applications including those for personalized bone repair.
AUTHOR Cernecu, Alexandra and Lungu, Adriana and Stancu, Izabela Cristina and Vasile, Eugeniu and Iovu, Horia
Title Polysaccharide-Based 3D Printing Inks Supplemented with Additives
Year 2020
Journal/Proceedings University Politechnica of Bucharest Scientific Bulletin
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AUTHOR Rupp, Harald and Döhler, Diana and Hilgeroth, Philipp and Mahmood, Nasir and Beiner, Mario and Binder, Wolfgang H.
Title 3D Printing of Supramolecular Polymers: Impact of Nanoparticles and Phase Separation on Printability [Abstract]
Year 2019
Journal/Proceedings Macromolecular Rapid Communications
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Abstract
Abstract 3D printing of linear and three-arm star supramolecular polymers with attached hydrogen bonds and their nanocomposites is reported. The concept is based on hydrogen-bonded supramolecular polymers, known to form nano-sized micellar clusters. Printability is based on reversible thermal- and shear-induced dissociation of a supramolecular polymer network, which generates stable and self-supported structures after printing, as checked via melt-rheology and X-ray scattering. The linear and three-arm star poly(isobutylene)s PIB-B2 (Mn = 8500 g mol −1), PIB-B3 (Mn = 16 000 g mol −1), and linear poly(ethylene glycol)s PEG-B2 (Mn = 900 g mol−1, 8500 g mol −1) are prepared and then probed by melt-rheology to adjust the viscosity to address the proper printing window. The supramolecular PIB polymers show a rubber-like behavior and are able to form self-supported 3D printed objects at room temperature and below, reaching polymer strand diameters down to 200–300 µm. Nanocomposites of PIB-B2 with silica nanoparticles (12 nm, 5–15 wt%) are generated, in turn leading to an improvement of their shape persistence. A blend of the linear polymer PIB-B2 and the three-arm star polymer PIB-B3 (ratio ≈ 3/1 mol) reaches an even higher structural stability, able to build free-standing structures.
AUTHOR Shen, Jie and Wang, Wenhao and Zhai, Xinyun and Chen, Bo and Qiao, Wei and Li, Wan and Li, Penghui and Zhao, Ying and Meng, Yuan and Qian, Shi and Liu, Xuanyong and Chu, Paul K. and Yeung, Kelvin W. K.
Title 3D-printed nanocomposite scaffolds with tunable magnesium ionic microenvironment induce in situ bone tissue regeneration [Abstract]
Year 2019
Journal/Proceedings Applied Materials Today
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Abstract
Local tissue microenvironment is able to regulate cell-to-cell interaction that leads to effective tissue repair. This study aims to demonstrate a tunable magnesium ionic (Mg2+) microenvironment in bony tissue that can significantly induce bone defect repair. The concept can be realized by using a newly fabricated nanocomposite comprising of custom-made copolymer polycaprolactone-co-poly(ethylene glycol)-co-polycaprolactone (PCL-PEG-PCL) and surface-modified magnesium oxide (MgO) nanoparticles. In this study, additive manufacturing (AM) technology had been adopted to help design the porous three-dimensional (3D) scaffolds with tunable Mg2+ microenvironment. We found that the wettability and printability of new copolymer had been improved as compared with that of PCL polymer. Additionally, when MgO nanoparticles incorporated into the newly synthesized hydrophilic copolymer matrix, it could lead to increased compressive moduli significantly. In the in vitro studies, the fabricated nanocomposite scaffold with low concentration of Mg2+ microenvironment not only demonstrated better cytocompatibility, but also remarkably enhanced osteogenic differentiation in vitro as compared with the pure PCL and PCL-PEG-PCL co-polymer controls. In the animal studies, we also found that superior and early bone formation and tissue mineralization could be observed in the same 3D printed scaffold. However, the nanocomposite scaffold with high concentration of Mg2+ jeopardized the in situ bony tissue regeneration capability due to excessive magnesium ions in bone tissue microenvironment. Lastly, this study demonstrates that the nanocomposite 3D scaffold with controlled magnesium concentration in bone tissue microenvironment can effectively promote bone defect repair.
AUTHOR Aied, Ahmed and Song, Wenhui and Wang, Wenxin and Baki, Abdulrahman and Sigen, A.
Title 3D Bioprinting of stimuli-responsive polymers synthesised from DE-ATRP into soft tissue replicas [Abstract]
Year 2018
Journal/Proceedings Bioprinting
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Abstract
Synthetic polymers possess more reproducible physical and chemical properties than their naturally occurring counterparts. They have also emerged as an important alternative for fabricating tissue substitutes because they can be molecularly tailored to have vast array of molecular weights, block structures, active functional groups, and mechanical properties. To this date however, there has been very few successful and fully functional synthetic tissue and organ substitutes and with the rapidly spreading 3D printing technology beginning to reshape the tissue engineering and regenerative field, the need for an effective, safe, and bio printable biomaterial is becoming more and more urgent. Here, we have developed a synthetic polymer from controlled living radical polymerisation that can be printed into well-defined structures. The polymer showed low cytotoxicity before and after printing. Additionally, the incorporation of gelatine-methacrylate coated PLGA microparticles within the hydrogel provided cell adhesion surfaces for cell proliferation. The results point to possible application of the microparticle seeded, synthetic hydrogel as a direct printable tissue or organ substitute.
AUTHOR García-Lizarribar, Andrea and Fernández-Garibay, Xiomara and Velasco-Mallorquí, Ferran and G. Castaño, Albert and Samitier, Josep and Ramón-Azcón, Javier
Title Composite Biomaterials as Long-Lasting Scaffolds for 3D Bioprinting of Highly Aligned Muscle Tissue
Year 2018
Journal/Proceedings Macromolecular Bioscience
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AUTHOR Schmieg, Barbara and Schimek, Adrian and Franzreb, Matthias
Title Development and performance of a 3D‐printable Polyethylenglycol‐Diacrylate hydrogel suitable for enzyme entrapment and long‐term biocatalytic applications [Abstract]
Year 2018
Journal/Proceedings Engineering in Life Sciences
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Abstract
Physical entrapment of enzymes within a porous matrix is a fast and gentle process to immobilize biocatalysts to enable their recycling and long‐term use. This study introduces the development of a biocompatible 3D‐printing material suitable for enzyme entrapment, while having good rheological and UV‐hardening properties. Three different viscosity‐enhancing additives have been tested in combination with a polyethylenglycol‐diacrylate‐based hydrogel system. The addition of polyxanthan or hectorite clay particles results in hydrogels that degrade over hours or days, releasing entrapped compounds. In contrast, the addition of nanometer‐sized silicate particles ensures processability while preventing disintegration of the hydrogel. Lattice structures with a total height of 6 mm consisting of 40 layers were 3D‐printed with all materials and characterized by image analysis. Rheological measurements identified a shear stress window of 200 < τ < 500 Pa at shear rates of 25 s−1 and 25°C for well‐defined geometries with an extrusion‐based printhead. Enzymes immobilized in these long‐term stable hydrogel structures retained an effective activity of approximately 10% compared to the free enzyme in solution. It could be shown that the reduction of effective activity isn't caused by a significant reduction of the intrinsic enzyme activity but by mass transfer limitations within the printed hydrogel structures. This article is protected by copyright. All rights reserved
AUTHOR Kumari, Sushma and Bargel, Hendrik and Anby, Mette U. and Lafargue, David and Scheibel, Thomas
Title Recombinant Spider Silk Hydrogels for Sustained Release of Biologicals [Abstract]
Year 2018
Journal/Proceedings ACS Biomaterials Science and Engineering
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Abstract
Therapeutic biologics (i.e., proteins) have been widely recognized for the treatment, prevention, and cure of a variety of human diseases and syndromes. However, design of novel protein-delivery systems to achieve a nontoxic, constant, and efficient delivery with minimal doses of therapeutic biologics is still challenging. Here, recombinant spider silk-based materials are employed as a delivery system for the administration of therapeutic biologicals. Hydrogels made of the recombinant spider silk protein eADF4(C16) were used to encapsulate the model biologicals BSA, HRP, and LYS by direct loading or through diffusion, and their release was studied. Release of model biologicals from eADF4(C16) hydrogels is in part dependent on the electrostatic interaction between the biological and the recombinant spider silk protein variant used. In addition, tailoring the pore sizes of eADF4(C16) hydrogels strongly influenced the release kinetics. In a second approach, a particles-in-hydrogel system was used, showing a prolonged release in comparison with that of plain hydrogels (from days to week). The particle-enforced spider silk hydrogels are injectable and can be 3D printed. These initial studies indicate the potential of recombinant spider silk proteins to design novel injectable hydrogels that are suitable for delivering therapeutic biologics.
AUTHOR Ribeiro, Alexandre and Blokzijl, Maarten Michiel and Levato, Riccardo and Visser, Claas Willem and Castilho, Miguel and Hennink, Wim E. and Vermonden, Tina and Malda, Jos
Title Assessing bioink shape fidelity to aid material development in 3D bioprinting [Abstract]
Year 2017
Journal/Proceedings Biofabrication
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Abstract
Abstract During extrusion-based bioprinting, the deposited bioink filaments are subjected to deformations, such as collapse of overhanging filaments, which compromises the ability to stack several layers of bioink, and fusion between adjacent filaments, which compromises the resolution and maintenance of a desired pore structure. When developing new bioinks, approaches to assess their shape fidelity after printing would be beneficial to evaluate the degree of deformation of the deposited filament and to estimate how similar the final printed construct would be to the design. However, shape fidelity has been prevalently assessed qualitatively through visual inspection after printing, hampering the direct comparison of the printability of different bioinks. In this technical note, we propose a quantitative evaluation for shape fidelity of bioinks based on testing the filament collapse on overhanging structures and the filament fusion of parallel printed strands. Both tests were applied on a hydrogel platform based on poloxamer 407 and poly(ethylene glycol) (PEG) blends, providing a library of hydrogels with different yield stresses. The presented approach is an easy way to assess bioink shape fidelity, applicable to any filament-based bioprinting system and able to quantitatively evaluate this aspect of printability , based on the degree of deformation of the printed filament. In addition, we built a simple theoretical model that relates filament collapse with bioink yield stress. The results of both shape fidelity tests underline the role of yield stress as one of the parameters influencing the printability of a bioink. The presented quantitative evaluation will allow for reproducible comparisons between different bioink platforms.
AUTHOR Mouser, V. H. M. and Abbadessa, A. and Levato, R. and Hennink, W. E. and Vermonden, T. and Gawlitta, D. and Malda, J.
Title Development of a thermosensitive HAMA-containing bio-ink for the fabrication of composite cartilage repair constructs [Abstract]
Year 2017
Journal/Proceedings Biofabrication
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Abstract
Fine-tuning of bio-ink composition and material processing parameters is crucial for the development of biomechanically relevant cartilage constructs. This study aims to design and develop cartilage constructs with tunable internal architectures and relevant mechanical properties. More specifically, the potential of methacrylated hyaluronic acid (HAMA) added to thermosensitive hydrogels composed of methacrylated poly[ N -(2-hydroxypropyl)methacrylamide mono/dilactate] (pHPMA-lac)/polyethylene glycol (PEG) triblock copolymers, to optimize cartilage-like tissue formation by embedded chondrocytes, and enhance printability was explored. Additionally, co-printing with polycaprolactone (PCL) was performed for mechanical reinforcement. Chondrocyte-laden hydrogels composed of pHPMA-lac-PEG and different concentrations of HAMA (0%–1% w/w) were cultured for 28 d in vitro and subsequently evaluated for the presence of cartilage-like matrix. Young’s moduli were determined for hydrogels with the different HAMA concentrations. Additionally, hydrogel/PCL constructs with different internal architectures were co-printed and analyzed for their mechanical properties. The results of this study demonstrated a dose-dependent effect of HAMA concentration on cartilage matrix synthesis by chondrocytes. Glycosaminoglycan (GAG) and collagen type II content increased with intermediate HAMA concentrations (0.25%–0.5%) compared to HAMA-free controls, while a relatively high HAMA concentration (1%) resulted in increased fibrocartilage formation. Young’s moduli of generated hydrogel constructs ranged from 14 to 31 kPa and increased with increasing HAMA concentration. The pHPMA-lac-PEG hydrogels with 0.5% HAMA were found to be optimal for cartilage-like tissue formation. Therefore, this hydrogel system was co-printed with PCL to generate porous or solid constructs with different mesh sizes. Young’s moduli of these composite constructs were in the range of native cartilage (3.5–4.6 MPa). Interestingly, the co-printing procedure influenced the mechanical properties of the final constructs. These findings are relevant for future bio-ink development, as they demonstrate the importance of selecting proper HAMA concentrations, as well as appropriate print settings and construct designs for optimal cartilage matrix deposition and final mechanical properties of constructs, respectively.
AUTHOR Abbadessa, Anna and Landín, Mariana and Oude Blenke, Erik and Hennink, Wim E. and Vermonden, Tina
Title Two-component thermosensitive hydrogels: Phase separation affecting rheological behavior [Abstract]
Year 2017
Journal/Proceedings European Polymer Journal
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Abstract
Abstract Extracellular matrices are mainly composed of a mixture of different biopolymers and therefore the use of two or more building blocks for the development of tissue-mimicking hydrogels is nowadays an attractive strategy in tissue-engineering. Multi-component hydrogel systems may undergo phase separation, which in turn can lead to new, unexpected material properties. The aim of this study was to understand the role of phase separation on the mechanical properties and 3D printability of hydrogels composed of triblock copolymers of polyethylene glycol (PEG) and methacrylated poly(N-(2-hydroxypropyl) methacrylamide-mono/dilactate) (pHPMAlac) blended with methacrylated hyaluronic acid (HAMA). To this end, hydrogels composed of different concentrations of PEG/pHPMAlac and HAMA, were analyzed for phase behavior and rheological properties. Subsequently, phase separation and rheological behavior as function of the two polymer concentrations were mathematically processed to generate a predictive model. Results showed that PEG/pHPMAlac/HAMA hydrogels were characterized by hydrophilic, HAMA-richer internal domains dispersed in a more hydrophobic continuous phase, composed of PEG/pHPMAlac, and that the volume fraction of the dispersed phase increased by increasing HAMA concentration. Storage modulus, yield stress and viscosity increased with increasing HAMA concentration for low/medium HAMA contents (≤0.75% w/w), while a further increase of HAMA resulted in a decrease of the mentioned properties. On the other hand, by increasing the concentration of PEG/pHPMAlac these rheological properties were enhanced. The generated models showed a good fitting with experimental data, and were used to identify an exemplary 3D printability window for PEG/pHPMAlac/HAMA hydrogels, which was verified by rheological characterization and preparation of 3D printed scaffolds. In conclusion, a clear relationship between phase separation and rheological behavior in these two-component hydrogels can be described by complex functions of the two polymer concentrations. The predictive model generated in this study can be used as a valid tool for the identification of hydrogel compositions with desired, selected characteristics.
AUTHOR Daly, Andrew C. and Cunniffe, Gr{'{a}}inne M. and Sathy, Binulal N. and Jeon, Oju and Alsberg, Eben and Kelly, Daniel J.
Title 3D Bioprinting of Developmentally Inspired Templates for Whole Bone Organ Engineering [Abstract]
Year 2016
Journal/Proceedings Advanced Healthcare Materials
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Abstract
The ability to print defined patterns of cells and extracellular-matrix components in three dimensions has enabled the engineering of simple biological tissues; however, bioprinting functional solid organs is beyond the capabilities of current biofabrication technologies. An alternative approach would be to bioprint the developmental precursor to an adult organ, using this engineered rudiment as a template for subsequent organogenesis in vivo. This study demonstrates that developmentally inspired hypertrophic cartilage templates can be engineered in vitro using stem cells within a supporting gamma-irradiated alginate bioink incorporating Arg-Gly-Asp adhesion peptides. Furthermore, these soft tissue templates can be reinforced with a network of printed polycaprolactone fibers, resulting in a ≈350 fold increase in construct compressive modulus providing the necessary stiffness to implant such immature cartilaginous rudiments into load bearing locations. As a proof-of-principal, multiple-tool biofabrication is used to engineer a mechanically reinforced cartilaginous template mimicking the geometry of a vertebral body, which in vivo supported the development of a vascularized bone organ containing trabecular-like endochondral bone with a supporting marrow structure. Such developmental engineering approaches could be applied to the biofabrication of other solid organs by bioprinting precursors that have the capacity to mature into their adult counterparts over time in vivo.
AUTHOR Daly, Andrew C. and Critchley, Susan E. and Rencsok, Emily M. and Kelly, Daniel J.
Title A comparison of different bioinks for 3D bioprinting of fibrocartilage and hyaline cartilage [Abstract]
Year 2016
Journal/Proceedings Biofabrication
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Abstract
Cartilage is a dense connective tissue with limited self-repair capabilities. Mesenchymal stem cell (MSC) laden hydrogels are commonly used for fibrocartilage and articular cartilage tissue engineering, however they typically lack the mechanical integrity for implantation into high load bearing environments. This has led to increased interested in 3D bioprinting of cell laden hydrogel bioinks reinforced with stiffer polymer fibres. The objective of this study was to compare a range of commonly used hydrogel bioinks (agarose, alginate, GelMA and BioINK™) for their printing properties and capacity to support the development of either hyaline cartilage or fibrocartilage in vitro . Each hydrogel was seeded with MSCs, cultured for 28 days in the presence of TGF- β 3 and then analysed for markers indicative of differentiation towards either a fibrocartilaginous or hyaline cartilage-like phenotype. Alginate and agarose hydrogels best supported the development of hyaline-like cartilage, as evident by the development of a tissue staining predominantly for type II collagen. In contrast, GelMA and BioINK ™ (a PEGMA based hydrogel) supported the development of a more fibrocartilage-like tissue, as evident by the development of a tissue containing both type I and type II collagen. GelMA demonstrated superior printability, generating structures with greater fidelity, followed by the alginate and agarose bioinks. High levels of MSC viability were observed in all bioinks post-printing (∼80%). Finally we demonstrate that it is possible to engineer mechanically reinforced hydrogels with high cell viability by co-depositing a hydrogel bioink with polycaprolactone filaments, generating composites with bulk compressive moduli comparable to articular cartilage. This study demonstrates the importance of the choice of bioink when bioprinting different cartilaginous tissues for musculoskeletal applications.
AUTHOR Abbadessa, Anna and Mouser, Vivian H. M. and Blokzijl, Maarten M. and Gawlitta, Debby and Dhert, Wouter J. A. and Hennink, Wim E. and Malda, Jos and Vermonden, Tina
Title A Synthetic Thermosensitive Hydrogel for Cartilage Bioprinting and Its Biofunctionalization with Polysaccharides [Abstract]
Year 2016
Journal/Proceedings Biomacromolecules
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Abstract
Hydrogels based on triblock copolymers of polyethylene glycol and partially methacrylated poly[N-(2-hydroxypropyl) methacrylamide mono/dilactate] make up an attractive class of biomaterials because of their biodegradability, cytocompatibility, and tunable thermoresponsive and mechanical properties. If these properties are fine-tuned, the hydrogels can be three-dimensionally bioprinted, to generate, for instance, constructs for cartilage repair. This study investigated whether hydrogels based on the polymer mentioned above with a 10% degree of methacrylation (M10P10) support cartilage formation by chondrocytes and whether the incorporation of methacrylated chondroitin sulfate (CSMA) or methacrylated hyaluronic acid (HAMA) can improve the mechanical properties, long-term stability, and printability. Chondrocyte-laden M10P10 hydrogels were cultured for 42 days to evaluate chondrogenesis. M10P10 hydrogels with or without polysaccharides were evaluated for their mechanical properties (before and after UV photo-cross-linking), degradation kinetics, and printability. Extensive cartilage matrix production occurred in M10P10 hydrogels, highlighting their potential for cartilage repair strategies. The incorporation of polysaccharides increased the storage modulus of polymer mixtures and decreased the degradation kinetics in cross-linked hydrogels. Addition of HAMA to M10P10 hydrogels improved printability and resulted in three-dimensional constructs with excellent cell viability. Hence, this novel combination of M10P10 with HAMA forms an interesting class of hydrogels for cartilage bioprinting.
AUTHOR Abbadessa, A. and Blokzijl, M. M. and Mouser, V. H. M. and Marica, P. and Malda, J. and Hennink, W. E. and Vermonden, T.
Title A thermo-responsive and photo-polymerizable chondroitin sulfate-based hydrogel for 3D printing applications [Abstract]
Year 2016
Journal/Proceedings Carbohydrate Polymers
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Abstract
Abstract The aim of this study was to design a hydrogel system based on methacrylated chondroitin sulfate (CSMA) and a thermo-sensitive poly(N-(2-hydroxypropyl) methacrylamide-mono/dilactate)-polyethylene glycol triblock copolymer (M15P10) as a suitable material for additive manufacturing of scaffolds. {CSMA} was synthesized by reaction of chondroitin sulfate with glycidyl methacrylate (GMA) in dimethylsulfoxide at 50 °C and its degree of methacrylation was tunable up to 48.5%, by changing reaction time and {GMA} feed. Unlike polymer solutions composed of {CSMA} alone (20% w/w), mixtures based on 2% w/w of {CSMA} and 18% of {M15P10} showed strain-softening, thermo-sensitive and shear-thinning properties more pronounced than those found for polymer solutions based on {M15P10} alone. Additionally, they displayed a yield stress of 19.2 ± 7.0 Pa. The 3D printing of this hydrogel resulted in the generation of constructs with tailorable porosity and good handling properties. Finally, embedded chondrogenic cells remained viable and proliferating over a culture period of 6 days. The hydrogel described herein represents a promising biomaterial for cartilage 3D printing applications.
AUTHOR Kesti, Matti and Fisch, Philipp and Pensalfini, Marco and Mazza, Edoardo and Zenobi-Wong, Marcy
Title Guidelines for standardization of bioprinting: a systematic study of process parameters and their effect on bioprinted structures [Abstract]
Year 2016
Journal/Proceedings BioNanoMaterials
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Abstract
Biofabrication techniques including three-dimensional bioprinting could be used one day to fabricate living, patient-specific tissues and organs for use in regenerative medicine. Compared to traditional casting and molding methods, bioprinted structures can be much more complex, containing for example multiple materials and cell types in controlled spatial arrangement, engineered porosity, reinforcement structures and gradients in mechanical properties. With this complexity and increased function, however, comes the necessity to develop guidelines to standardize the bioprinting process, so printed grafts can safely enter the clinics. The bioink material must firstly fulfil requirements for biocompatibility and flow. Secondly, it is important to understand how process parameters affect the final mechanical properties of the printed graft. Using a gellan-alginate physically crosslinked bioink as an example, we show shear thinning and shear recovery properties which allow good printing resolution. Printed tensile specimens were used to systematically assess effect of line spacing, printing direction and crosslinking conditions. This standardized testing allowed direct comparison between this bioink and three commercially-available products. Bioprinting is a promising, yet complex fabrication method whose outcome is sensitive to a range of process parameters. This study provides the foundation for highly needed best practice guidelines for reproducible and safe bioprinted grafts.
AUTHOR Rimann, Markus and Bono, Epifania and Annaheim, Helene and Bleisch, Matthias and Graf-Hausner, Ursula
Title Standardized 3D Bioprinting of Soft Tissue Models with Human Primary Cells. [Abstract]
Year 2015
Journal/Proceedings Journal of laboratory automation
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Abstract
Cells grown in 3D are more physiologically relevant than cells cultured in 2D. To use 3D models in substance testing and regenerative medicine, reproducibility and standardization are important. Bioprinting offers not only automated standardizable processes but also the production of complex tissue-like structures in an additive manner. We developed an all-in-one bioprinting solution to produce soft tissue models. The holistic approach included (1) a bioprinter in a sterile environment, (2) a light-induced bioink polymerization unit, (3) a user-friendly software, (4) the capability to print in standard labware for high-throughput screening, (5) cell-compatible inkjet-based printheads, (6) a cell-compatible ready-to-use BioInk, and (7) standard operating procedures. In a proof-of-concept study, skin as a reference soft tissue model was printed. To produce dermal equivalents, primary human dermal fibroblasts were printed in alternating layers with BioInk and cultured for up to 7 weeks. During long-term cultures, the models were remodeled and fully populated with viable and spreaded fibroblasts. Primary human dermal keratinocytes were seeded on top of dermal equivalents, and epidermis-like structures were formed as verified with hematoxylin and eosin staining and immunostaining. However, a fully stratified epidermis was not achieved. Nevertheless, this is one of the first reports of an integrative bioprinting strategy for industrial routine application.