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AUTHOR Browning, James R. and Derr, Paige and Derr, Kristy and Doudican, Nicole and Michael, Sam and Lish, Samantha R. and Taylor, Nicholas A. and Krueger, James G. and Ferrer, Marc and Carucci, John A. and Gareau, Daniel S.
Title A 3D biofabricated cutaneous squamous cell carcinoma tissue model with multi-channel confocal microscopy imaging biomarkers to quantify antitumor effects of chemotherapeutics in tissue [Abstract]
Year 2020
Journal/Proceedings Oncotarget; Vol 11, No 27
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// James R. Browning 1 , Paige Derr 2 , Kristy Derr 2 , Nicole Doudican 3 , Sam Michael 2 , Samantha R. Lish 1 , Nicholas A. Taylor 3 , James G. Krueger 1 , Marc Ferrer 2 , John A. Carucci 3 and Daniel S. Gareau 1 1 Laboratory for Investigative Dermatology, The Rockefeller University, New York, New York, USA 2 National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USA 3 The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New York, USA Correspondence to: Daniel S. Gareau, email: dgareau@rockefeller.edu Keywords: squamous cell carcinoma; screening; 3D printing; in vitro model; confocal microscopy Received: January 05, 2020     Accepted: April 03, 2020     Published: July 07, 2020 ABSTRACT Cutaneous squamous cell carcinoma (cSCC) causes approximately 10,000 deaths annually in the U. S. Current therapies are largely ineffective against metastatic and locally advanced cSCC. There is a need to identify novel, effective, and less toxic small molecule cSCC therapeutics. We developed a 3-dimensional bioprinted skin (3DBPS) model of cSCC tumors together with a microscopy assay to test chemotherapeutic effects in tissue. The full thickness SCC tissue model was validated using hematoxylin and eosin (H&E) and immunohistochemical histological staining, confocal microscopy, and cDNA microarray analysis. A nondestructive, 3D fluorescence confocal imaging assay with tdTomato-labeled A431 SCC and ZsGreen-labeled keratinocytes was developed to test efficacy and general toxicity of chemotherapeutics. Fluorescence-derived imaging biomarkers indicated that 50% of cancer cells were killed in the tissue after 1?M 5-Fluorouracil 48-hour treatment, compared to a baseline of 12% for untreated controls. The imaging biomarkers also showed that normal keratinocytes were less affected by treatment (11% killed) than the untreated tissue, which had no significant killing effect. Data showed that 5-Fluorouracil selectively killed cSCC cells more than keratinocytes. Our 3DBPS assay platform provides cellular-level measurement of cell viability and can be adapted to achieve nondestructive high-throughput screening (HTS) in bio-fabricated tissues.
AUTHOR Wei, Zhengxi and Liu, Xue and Ooka, Masato and Zhang, Li and Song, Min Jae and Huang, Ruili and Kleinstreuer, Nicole C. and Simeonov, Anton and Xia, Menghang and Ferrer, Marc
Title Two-Dimensional Cellular and Three-Dimensional Bio-Printed Skin Models to Screen Topical-Use Compounds for Irritation Potential [Abstract]
Year 2020
Journal/Proceedings Frontiers in Bioengineering and Biotechnology
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Assessing skin irritation potential is critical for the safety evaluation of topical drugs and other consumer products such as cosmetics. The use of advanced cellular models, as an alternative to replace animal testing in the safety evaluation for both consumer products and ingredients, is already mandated by law in the European Union (EU) and other countries. However, there has not yet been a large-scale comparison of the effects of topical-use compounds in different cellular skin models. This study assesses the irritation potential of topical-use compounds in different cellular models of the skin that are compatible with high throughput screening (HTS) platforms. A set of 451 topical-use compounds were first tested for cytotoxic effects using two-dimensional (2D) monolayer models of primary neonatal keratinocytes and immortalized human keratinocytes. Forty-six toxic compounds identified from the initial screen with the monolayer culture systems were further tested for skin irritation potential on reconstructed human epidermis (RhE) and full thickness skin (FTS) three-dimensional (3D) tissue model constructs. Skin irritation potential of the compounds was assessed by measuring tissue viability, trans-epithelial electrical resistance (TEER), and secretion of cytokines interleukin 1 alpha (IL-1α) and interleukin 18 (IL-18). Among known irritants, high concentrations of methyl violet and methylrosaniline decreased viability, lowered TEER, and increased IL-1α secretion in both RhE and FTS models, consistent with irritant properties. However, at low concentrations, these two compounds increased IL-18 secretion without affecting levels of secreted IL-1α, and did not reduce tissue viability and TEER, in either RhE or FTS models. This result suggests that at low concentrations, methyl violet and methylrosaniline have an allergic potential without causing irritation. Using both HTS-compatible 2D cellular and 3D tissue skin models, together with irritation relevant activity endpoints, we obtained data to help assess the irritation effects of topical-use compounds and identify potential dermal hazards.
AUTHOR Derr, Kristy and Zou, Jinyun and Luo, Keren and Song, Min Jae and Sittampalam, G. Sitta and Zhou, Chao and Michael, Samuel and Ferrer, Marc and Derr, Paige
Title Fully 3D Bioprinted Skin Equivalent Constructs with Validated Morphology and Barrier Function [Abstract]
Year 2019
Journal/Proceedings Tissue Engineering Part C: Methods
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Development of high throughput, reproducible, three-dimensional bioprinted skin equivalents that are morphologically and functionally comparable to native skin tissue is advancing research in skin diseases, and providing a physiologically relevant platform for the development of therapeutics, transplants for regenerative medicine, and testing of skin products like cosmetics. Current protocols for the production of engineered skin rafts are limited in their ability to control three dimensional geometry of the structure and contraction leading to variability of skin function between constructs. Here we describe a method for the biofabrication of skin equivalents that are fully bioprinted using an open market bioprinter, made with commercially available primary cells and natural hydrogels. The unique hydrogel formulation allows for the production of a human-like skin equivalent with minimal lateral tissue contraction in a multiwell plate format, thus making them suitable for high throughput bioprinting in a single print with fast print and relatively short incubation times. The morphology and barrier function of the fully three-dimensional bioprinted skin equivalents are validated by immunohistochemistry staining, optical coherence tomography, and permeation assays.
AUTHOR Silberman, Eric and Oved, Hadas and Namestnikov, Michael and Shapira, Assaf and Dvir, Tal
Title Post-Maturation Reinforcement of 3d-Printed Vascularized Cardiac Tissues [Abstract]
Year 2023
Journal/Proceedings Advanced Materials
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Abstract Despite advances in biomaterials engineering, a large gap remains between the weak mechanical properties that can be achieved with natural materials and the strength of synthetic materials. Here, we present a method for reinforcing an engineered cardiac tissue fabricated from differentiated iPSCs and an ECM-based hydrogel in a manner that is fully biocompatible. The reinforcement occurs as a post-fabrication step, which allows for the use of 3D printing technology to generate thick, fully cellularized, and vascularized cardiac tissues. After tissue assembly and during the maturation process in a soft hydrogel, a small, tissue-penetrating reinforcer is deployed, leading to a significant increase in the tissue's mechanical properties. The tissue's robustness is demonstrated by injecting the tissue in a simulated minimally invasive procedure and showing that the tissue is functional and undamaged at the nano-, micro-, and macro-scales. This article is protected by copyright. All rights reserved
AUTHOR Liu, Xue and Michael, Samuel and Bharti, Kapil and Ferrer, Marc and Song, Min Jae
Title A biofabricated vascularized skin model of atopic dermatitis for preclinical studies [Abstract]
Year 2020
Journal/Proceedings Biofabrication
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Three-dimensional (3D) biofabrication techniques enable the production of multicellular tissue models as assay platforms for drug screening. The increased cellular and physiological complexity in these 3D tissue models should recapitulate the relevant biological environment found in the body. Here we describe the use of 3D bioprinting techniques to fabricate skin equivalent tissues of varying physiological complexity, including human epidermis, non-vascularized and vascularized full-thickness skin tissue equivalents, in a multi-well platform to enable drug screening. Human keratinocytes, fibroblasts, and pericytes, and induced pluripotent stem cell (iPSC)-derived endothelial cells were used in the biofabrication process to produce the varying complexity. The skin equivalents exhibit the correct structural markers of dermis and epidermis stratification, with physiological functions of the skin barrier. The robustness, versatility and reproducibility of the biofabrication techniques are further highlighted by the generation of atopic dermatitis (AD)-disease like tissues. These AD models demonstrate several clinical hallmarks of the disease, including: (i) spongiosis and hyperplasia; (ii) early and terminal expression of differentiation proteins; and (iii) increases in levels of pro-inflammatory cytokines. We show the pre-clinical relevance of the biofabricated AD tissue models to correct disease phenotype by testing the effects of dexamethasone, an anti-inflammatory corticosteroid, and three Janus Kinase inhibitors from clinical trials for AD. This study demonstrates the development of a versatile and reproducible bioprinting approach to create human skin equivalents with a range of cellular complexity for disease modelling. In addition, we establish several assay readouts that are quantifiable, robust, AD relevant, and can be scaled up for compound screening. The results show that the cellular complexity of the tissues develops a more physiologically relevant AD disease model. Thus, the skin models in this study offer an in vitro approach for the rapid understanding of pathological mechanisms, and testing for efficacy of action and toxic effects of drugs.
AUTHOR Kajtez, Janko and Wesseler, Milan Finn and Birtele, Marcella and Khorasgani, Farinaz Riyahi and Rylander Ottosson, Daniella and Heiskanen, Arto and Kamperman, Tom and Leijten, Jeroen and Martínez-Serrano, Alberto and Larsen, Niels B. and Angelini, Thomas E. and Parmar, Malin and Lind, Johan U. and Emnéus, Jenny
Title Embedded 3D Printing in Self-Healing Annealable Composites for Precise Patterning of Functionally Mature Human Neural Constructs [Abstract]
Year 2022
Journal/Proceedings Advanced Science
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Abstract Human in vitro models of neural tissue with tunable microenvironment and defined spatial arrangement are needed to facilitate studies of brain development and disease. Towards this end, embedded printing inside granular gels holds great promise as it allows precise patterning of extremely soft tissue constructs. However, granular printing support formulations are restricted to only a handful of materials. Therefore, there has been a need for novel materials that take advantage of versatile biomimicry of bulk hydrogels while providing high-fidelity support for embedded printing akin to granular gels. To address this need, Authors present a modular platform for bioengineering of neuronal networks via direct embedded 3D printing of human stem cells inside Self-Healing Annealable Particle-Extracellular matrix (SHAPE) composites. SHAPE composites consist of soft microgels immersed in viscous extracellular-matrix solution to enable precise and programmable patterning of human stem cells and consequent generation mature subtype-specific neurons that extend projections into the volume of the annealed support. The developed approach further allows multi-ink deposition, live spatial and temporal monitoring of oxygen levels, as well as creation of vascular-like channels. Due to its modularity and versatility, SHAPE biomanufacturing toolbox has potential to be used in applications beyond functional modeling of mechanically sensitive neural constructs.
AUTHOR Petretta, Mauro and Villata, Simona and Scozzaro, Marika Pia and Roseti, Livia and Favero, Marta and Napione, Lucia and Frascella, Francesca and Pirri, Candido Fabrizio and Grigolo, Brunella and Olivotto, Eleonora
Title In Vitro Synovial Membrane 3D Model Developed by Volumetric Extrusion Bioprinting [Abstract]
Year 2023
Journal/Proceedings Applied Sciences
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(1) Background: Synovial tissue plays a fundamental role in inflammatory processes. Therefore, understanding the mechanisms regulating healthy and diseased synovium functions, as in rheumatic diseases, is crucial to discovering more effective therapies to minimize or prevent pathological progress. The present study aimed at developing a bioartificial synovial tissue as an in vitro model for drug screening or personalized medicine applications using 3D bioprinting technology. (2) Methods: The volumetric extrusion technique has been used to fabricate cell-laden scaffolds. Gelatin Methacryloyl (GelMA), widely applied in regenerative medicine and tissue engineering, was selected as a bioink and combined with an immortalized cell line of fibroblast-like synoviocytes (K4IM). (3) Results: Three different GelMA formulations, 7.5–10–12.5% w/v, were tested for the fabrication of the scaffold with the desired morphology and internal architecture. GelMA 10% w/v was chosen and combined with K4IM cells to fabricate scaffolds that showed high cell viability and negligible cytotoxicity for up to 14 days tested by Live & Dead and lactate dehydrogenase assays. (4) Conclusions: We successfully 3D bioprinted synoviocytes-laden scaffolds as a proof-of-concept (PoC) towards the fabrication of a 3D synovial membrane model suitable for in vitro studies. However, further research is needed to reproduce the complexity of the synovial microenvironment to better mimic the physiological condition.
AUTHOR Kopecká, Kateřina and Vítková, Lenka and Kroneková, Zuzana and Musilová, Lenka and Smolka, Petr and Mikulka, Filip and Melánová, Klára and Knotek, Petr and Humeník, Martin and Minařík, Antonín and Mráček, Aleš
Title Synthesis and Exfoliation of Calcium Organophosphonates for Tailoring Rheological Properties of Sodium Alginate Solutions: A Path toward Polysaccharide-Based Bioink [Abstract]
Year 2023
Journal/Proceedings Biomacromolecules
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Layered nanoparticles with surface charge are explored as rheological modifiers for extrudable materials, utilizing their ability to induce electrostatic repulsion and create a house-of-cards structure. These nanoparticles provide mechanical support to the polymer matrix, resulting in increased viscosity and storage modulus. Moreover, their advantageous aspect ratio allows for shear-induced orientation and decreased viscosity during flow. In this work, we present a synthesis and liquid-based exfoliation procedure of phenylphosphonate-phosphate particles with enhanced ability to be intercalated by hydrophilic polymers. These layered nanoparticles are then tested as rheological modifiers of sodium alginate. The effective rheological modification is proved as the viscosity increases from 101 up to 103 Pa·s in steady state. Also, shear-thinning behavior is observed. The resulting nanocomposite hydrogels show potential as an extrudable bioink for 3D printing in tissue engineering and other biomedical applications, with good shape fidelity, nontoxicity, and satisfactory cell viability confirmed through encapsulation and printing of mouse fibroblasts.
AUTHOR Cakal, Selgin D. and Radeke, Carmen and Alcala, Juan F. and Ellman, Ditte G. and Butdayev, Sarkhan and Andersen, Ditte C. and Calloe, Kirstine and Lind, Johan U.
Title A simple and scalable 3D printing methodology for generating aligned and extended human and murine skeletal muscle tissues [Abstract]
Year 2022
Journal/Proceedings Biomedical Materials
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Preclinical biomedical and pharmaceutical research on disease causes, drug targets, and side effects increasingly relies on in vitro models of human tissue. 3D printing offers unique opportunities for generating models of superior physiological accuracy, as well as for automating their fabrication. Towards these goals, we here describe a simple and scalable methodology for generating physiologically relevant models of skeletal muscle. Our approach relies on dual-material micro-extrusion of two types of gelatin hydrogel into patterned soft substrates with locally alternating stiffness. We identify minimally complex patterns capable of guiding the large-scale self-assembly of aligned, extended, and contractile human and murine skeletal myotubes. Interestingly, we find high-resolution patterning is not required, as even patterns with feature sizes of several hundred micrometers is sufficient. Consequently, the procedure is rapid and compatible with any low-cost extrusion-based 3D printer. The generated myotubes easily span several millimeters, and various myotube patterns can be generated in a predictable and reproducible manner. The compliant nature and adjustable thickness of the hydrogel substrates, serves to enable extended culture of contractile myotubes. The method is further readily compatible with standard cell-culturing platforms as well as commercially available electrodes for electrically induced exercise and monitoring of the myotubes.
AUTHOR Anand, Resmi and Amoli, Mehdi Salar and Huysecom, An-Sofie and Amorim, Paulo Alexandre and Agten, Hannah and Geris, Liesbet and Bloemen, Veerle
Title A tunable gelatin-hyaluronan dialdehyde/methacryloyl gelatin interpenetrating polymer network hydrogel for additive tissue manufacturing [Abstract]
Year 2022
Journal/Proceedings Biomedical Materials
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Methacryloyl gelatin (GelMA) is a versatile material for bioprinting because of its tunable physical properties and inherent bioactivity. Bioprinting of GelMA is often met with challenges such as lower viscosity of GelMA inks due to higher methacryloyl substitution and longer physical gelation time at room temperature. In this study, a tunable interpenetrating polymer network (IPN) hydrogel was prepared from gelatin-hyaluronan dialdehyde (Gel-HDA) Schiff’s polymer, and 100% methacrylamide substituted GelMA for biofabrication through extrusion based bioprinting. Temperature sweep rheology measurements show a higher sol-gel transition temperature for IPN (30 °C) compared to gold standard GelMA (27 °C). Furthermore, to determine the tunability of the IPN hydrogel, several IPN samples were prepared by combining different ratios of Gel-HDA and GelMA achieving a compressive modulus ranging from 20.6 ± 2.48 KPa to 116.7 ± 14.80 KPa. Our results showed that the mechanical properties and printability at room temperature could be tuned by adjusting the ratios of GelMA and Gel-HDA. To evaluate cell response to the material, MC3T3-E1 mouse pre-osteoblast cells were embedded in hydrogels and 3D-printed, demonstrating excellent cell viability and proliferation after 10 d of 3D in vitro culture, making the IPN an interesting bioink for the fabrication of 3D constructs for tissue engineering applications.
AUTHOR Song, Min Jae and Quinn, Russ and Nguyen, Eric and Hampton, Christopher and Sharma, Ruchi and Park, Tea Soon and Koster, Céline and Voss, Ty and Tristan, Carlos and Weber, Claire and Singh, Anju and Dejene, Roba and Bose, Devika and Chen, Yu-Chi and Derr, Paige and Derr, Kristy and Michael, Sam and Barone, Francesca and Chen, Guibin and Boehm, Manfred and Maminishkis, Arvydas and Singec, Ilyas and Ferrer, Marc and Bharti, Kapil
Title Bioprinted 3D outer retina barrier uncovers RPE-dependent choroidal phenotype in advanced macular degeneration [Abstract]
Year 2022
Journal/Proceedings Nature Methods
Reftype Song2022
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Age-related macular degeneration (AMD), a leading cause of blindness, initiates in the outer-blood-retina-barrier (oBRB) formed by the retinal pigment epithelium (RPE), Bruch’s membrane, and choriocapillaris. The mechanisms of AMD initiation and progression remain poorly understood owing to the lack of physiologically relevant human oBRB models. To this end, we engineered a native-like three-dimensional (3D) oBRB tissue (3D-oBRB) by bioprinting endothelial cells, pericytes, and fibroblasts on the basal side of a biodegradable scaffold and establishing an RPE monolayer on top. In this 3D-oBRB model, a fully-polarized RPE monolayer provides barrier resistance, induces choriocapillaris fenestration, and supports the formation of Bruch’s-membrane-like structure by inducing changes in gene expression in cells of the choroid. Complement activation in the 3D-oBRB triggers dry AMD phenotypes (including subRPE lipid-rich deposits called drusen and choriocapillaris degeneration), and HIF-α stabilization or STAT3 overactivation induce choriocapillaris neovascularization and type-I wet AMD phenotype. The 3D-oBRB provides a physiologically relevant model to studying RPE-choriocapillaris interactions under healthy and diseased conditions.
AUTHOR Cadle, Rachel and Rogozea, Dan and Moldovan, Leni and Moldovan, Nicanor I.
Title Design and Implementation of Anatomically Inspired Mesenteric and Intestinal Vascular Patterns for Personalized 3D Bioprinting [Abstract]
Year 2022
Journal/Proceedings Applied Sciences
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Recent progress in bioprinting has made possible the creation of complex 3D intestinal constructs, including vascularized villi. However, for their integration into functional units useful for experimentation or implantation, the next challenge is to endow them with a larger-scale, anatomically realistic vasculature. In general, the perfusion of bioprinted constructs has remained difficult, and the current solution is to provide them with mostly linear and simply branched channels. To address this limitation, here we demonstrated an image analysis-based workflow leading through computer-assisted design from anatomic images of rodent mesentery and colon to the actual printing of such patterns with paste and hydrogel bioinks. Moreover, we reverse-engineered the 2D intestinal image-derived designs into cylindrical objects, and 3D-printed them in a support hydrogel. These results open the path towards generation of more realistically vascularized tissue constructs for a variety of personalized medicine applications.
AUTHOR Cadle, Rachel and Rogozea, Dan and Moldovan, Leni and Moldovan, Nicanor I.
Title Design and Implementation of Anatomically Inspired Mesenteric and Intestinal Vascular Patterns for Personalized 3D Bioprinting [Abstract]
Year 2022
Journal/Proceedings Applied Sciences
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Recent progress in bioprinting has made possible the creation of complex 3D intestinal constructs, including vascularized villi. However, for their integration into functional units useful for experimentation or implantation, the next challenge is to endow them with a larger-scale, anatomically realistic vasculature. In general, the perfusion of bioprinted constructs has remained difficult, and the current solution is to provide them with mostly linear and simply branched channels. To address this limitation, here we demonstrated an image analysis-based workflow leading through computer-assisted design from anatomic images of rodent mesentery and colon to the actual printing of such patterns with paste and hydrogel bioinks. Moreover, we reverse-engineered the 2D intestinal image-derived designs into cylindrical objects, and 3D-printed them in a support hydrogel. These results open the path towards generation of more realistically vascularized tissue constructs for a variety of personalized medicine applications.
AUTHOR Cadle, Rachel and Rogozea, Dan and Moldovan, Leni and Moldovan, Nicanor I.
Title Design and Implementation of Anatomically Inspired Mesenteric and Intestinal Vascular Patterns for Personalized 3D Bioprinting [Abstract]
Year 2022
Journal/Proceedings Applied Sciences
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Recent progress in bioprinting has made possible the creation of complex 3D intestinal constructs, including vascularized villi. However, for their integration into functional units useful for experimentation or implantation, the next challenge is to endow them with a larger-scale, anatomically realistic vasculature. In general, the perfusion of bioprinted constructs has remained difficult, and the current solution is to provide them with mostly linear and simply branched channels. To address this limitation, here we demonstrated an image analysis-based workflow leading through computer-assisted design from anatomic images of rodent mesentery and colon to the actual printing of such patterns with paste and hydrogel bioinks. Moreover, we reverse-engineered the 2D intestinal image-derived designs into cylindrical objects, and 3D-printed them in a support hydrogel. These results open the path towards generation of more realistically vascularized tissue constructs for a variety of personalized medicine applications.
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 Rahimnejad, Maedeh and Adoungotchodo, Atma and Demarquette, Nicole R. and Lerouge, Sophie
Title FRESH bioprinting of biodegradable chitosan thermosensitive hydrogels [Abstract]
Year 2022
Journal/Proceedings Bioprinting
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Thermosensitive chitosan (CH)-based hydrogels prepared with a mix of sodium bicarbonate and β-glycerophosphate as gelling agents rapidly pass from a liquid at room temperature to a mechanically strong solid at body temperature without any crosslinker. They show excellent potential for tissue engineering applications and could be interesting candidates for bioprinting. Unfortunately, since gelation is not instantaneous, formulations compatible with cell encapsulation (chitosan concentrations around 2% or lower) lead to very poor resolution and fidelity due to filament spreading. Here, we investigate the FRESH bioprinting approach with a warm sacrificial support bath, to overcome these limitations and enhance their bioprintability. First, a support bath, made of Pluronic including sodium chloride salt as a rheology modifier agent, was designed to meet the specific physical state requirements (solid at 37 °C and liquid at room temperature) and rheological properties appropriate for bioprinting. This support bath presented yield stress of over 100 Pa, a shear thinning behavior, and fast self-healing during cyclic recovery tests. Three different chitosan hydrogels (CH2%w/v, CH3%w/v, and a mixture of CH and gelatin) were tested for their ability to form filament and 3D structures, with and without a support bath. Both the resolution and mechanical properties of the printed structure were drastically enhanced using the FRESH method, with an approximate four fold decrease of the filament diameter which is close to the needle diameter. The printed structures were easily harvested without altering their shape by cooling down the support bath, and do not swell when immersed in PBS. Live/dead assays confirmed that the viability of encapsulated mesenchymal stem cells was highest in CH2% and that the support bath-assisted bioprinting process did not adversely impact cell viability. This study demonstrates that using a warm FRESH-like approach drastically enhances the potential for bioprinting of the thermosensitive biodegradable chitosan hydrogels and opens up a wide range of applications for 3D models and tissue engineering.
AUTHOR Lai, Jiahui and Wang, Chong and Liu, Jia and Chen, Shangsi and Liu, Chaoyu and Huang, Xiangxuan and Wu, Jing and Pan, Yue and Xie, Yuancai and Wang, Min
Title Low temperature hybrid 3D printing of hierarchically porous bone tissue engineering scaffolds with in situ delivery of osteogenic peptide and mesenchymal stem cells [Abstract]
Year 2022
Journal/Proceedings Biofabrication
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Compared to other conventional scaffold fabrication techniques, three-dimensional (3D) printing is advantageous in producing bone tissue engineering scaffolds with customized shape, tailored pore size/porosity, required mechanical properties and even desirable biomolecule delivery capability. However, for scaffolds with a large volume, it is highly difficult to get seeded cells to migrate to the central region of the scaffolds, resulting in an inhomogeneous cell distribution and therefore lowering the bone forming ability. To overcome this major obstacle, in this study, cell-laden bone tissue engineering scaffolds consisting of osteogenic peptide (OP) loaded β-tricalcium phosphate (TCP)/poly(lactic-co-glycolic acid) (PLGA) (OP/TCP/PLGA, designated as OTP) nanocomposite struts and rat bone marrow derived mesenchymal stem cell (rBMSC)-laden gelatin/GelMA hydrogel rods were produced through ‘dual-nozzle’ low temperature hybrid 3D printing. The cell-laden scaffolds exhibited a bi-phasic structure and had a mechanical modulus of about 19.6 MPa, which was similar to that of human cancellous bone. OP can be released from the hybrid scaffolds in a sustained manner and achieved a cumulative release level of about 78% after 24 d. rBMSCs encapsulated in the hydrogel rods exhibited a cell viability of about 87.4% right after low temperature hybrid 3D printing and could be released from the hydrogel rods to achieve cell anchorage on the surface of adjacent OTP struts. The OP released from OTP struts enhanced rBMSCs proliferation. Compared to rBMSC-laden hybrid scaffolds without OP incorporation, the rBMSC-laden hybrid scaffolds incorporated with OP significantly up-regulated osteogenic differentiation of rBMSCs by showing a higher level of alkaline phosphatase expression and calcium deposition. This ‘proof-of-concept’ study has provided a facile method to form cell-laden bone tissue engineering scaffolds with not only required mechanical strength, biomimetic structure and sustained biomolecule release profile but also excellent cell delivery capability with uniform cell distribution, which can improve the bone forming ability in the body.
AUTHOR Paterson, T. E. and Hagis, N. and Boufidis, D. and Wang, Q. and Moore, S. R. and da Silva, A. C. and Mitchell, R. L. and Alix, J. J. P. and Minev, I. R.
Title Monitoring of hand function enabled by low complexity sensors printed on textile [Abstract]
Year 2022
Journal/Proceedings Flexible and Printed Electronics
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Development of inexpensive, disposable, use-at-home, personalised health wearables can revolutionise clinical trial design and clinical care. Recent approaches have focused on electronic skins, which are complex systems of sensors and wiring produced by integration of multiple materials and layers. The requirement for high-end clean room microfabrication techniques create challenges for the development of such devices. Drawing inspiration from the ancient art of henna tattoos, where an artist draws designs directly on the hand by extruding a decorative ink, we developed a simple strategy for direct writing (3D printing) of bioelectronic sensors on textile. The sensors are realised using a very limited set of low-cost inks composed only of graphite flakes and silicone. By adapting sensor architectures in two dimensions, we produced electromyography (EMG), strain and pressure sensors. The sensors are printed directly onto stretchable textile (cotton) gloves and function as an integrated multimodal monitoring system for hand function. Gloves demonstrated functionality and stability by recording simultaneous readings of pinch strength, thumb movement (flexion) and EMG of the abductor pollicis brevis muscle over 5 days of daily recordings. Our approach is targeted towards a home based monitoring of hand function, with potential applications across a range of neurological and musculoskeletal conditions.
AUTHOR Salar Amoli, Mehdi and Anand, Resmi and EzEldeen, Mostafa and Amorim, Paulo Alexandre and Geris, Liesbet and Jacobs, Reinhilde and Bloemen, Veerle
Title The development of a 3D printable chitosan-based copolymer with tunable properties for dentoalveolar regeneration [Abstract]
Year 2022
Journal/Proceedings Carbohydrate Polymers
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Dentoalveolar tissue engineering is an emerging yet challenging field, considering the lack of suitable materials and difficulty to produce patient-specific hydrogel scaffolds. The present paper aims to produce a 3D printable and tuneable biomaterial by copolymerizing a synthesized water-soluble chitosan derivative called maleic anhydride grafted chitosan (MA-C) with gelatin using genipin, a natural crosslinking agent. Development and testing of this material for 3D printing, degradation, and swelling demonstrated the ability to fabricate scaffolds with controlled physical properties based on pre-determined designs. The MA-C-gelatin copolymer demonstrated excellent biocompatibility, which was verified by analyzing the viability, growth and proliferation of human dental pulp stem cells seeded on MA-C-gelatin constructs through live/dead, alamar blue and DNA quantification assays. Based on the present findings, the proposed material might be a suitable candidate for dentoalveolar tissue engineering, while further research is required to achieve this goal.
AUTHOR Rachel Cadle and Dan Rogozea and Leni Moldovan and Patricia Parsons-Wingerter and Nicanor I. Moldovan
Title An image analysis-based workflow for 3D bioprinting of anatomically realistic retinal vascular patterns [Abstract]
Year 2021
Journal/Proceedings Bioprinting
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There is an enduring need for vascularization of bioprinted constructs with vascular networks optimized for distribution of nutrient-containing fluids, both for in vitro applications and in vivo implantation. However, most of the efforts in this field were directed so far towards generation of simple linear channels, often lined with endothelial cells only, and thus lacking the anatomical details of real vascular networks. To start addressing this need, here we explored the possibility of using actual vascular patterns derived from human ocular fundus for instructing the 3D printing activity. In order to assign to these patterns the organ-specific topology, and eventually vessel branch-defined cellular composition, we describe the use of the branching analysis program VESGEN 2D for planning a workflow that links the primary vascular images with their 3D printing with bioinks. To this end, we show how to process flat vascular images and, for an even more realistic representation, how to retro-engineer concave retinal patterns from flat images and to print them in a supporting hydrogel. This work opens the possibility of bioprinting more anatomically realistic vascular networks, and thus to eventually improve the vascularization of living tissue-engineered constructs.
AUTHOR Rachel Cadle and Dan Rogozea and Leni Moldovan and Patricia Parsons-Wingerter and Nicanor I. Moldovan
Title An image analysis-based workflow for 3D bioprinting of anatomically realistic retinal vascular patterns [Abstract]
Year 2021
Journal/Proceedings Bioprinting
Reftype
DOI/URL URL DOI
Abstract
There is an enduring need for vascularization of bioprinted constructs with vascular networks optimized for distribution of nutrient-containing fluids, both for in vitro applications and in vivo implantation. However, most of the efforts in this field were directed so far towards generation of simple linear channels, often lined with endothelial cells only, and thus lacking the anatomical details of real vascular networks. To start addressing this need, here we explored the possibility of using actual vascular patterns derived from human ocular fundus for instructing the 3D printing activity. In order to assign to these patterns the organ-specific topology, and eventually vessel branch-defined cellular composition, we describe the use of the branching analysis program VESGEN 2D for planning a workflow that links the primary vascular images with their 3D printing with bioinks. To this end, we show how to process flat vascular images and, for an even more realistic representation, how to retro-engineer concave retinal patterns from flat images and to print them in a supporting hydrogel. This work opens the possibility of bioprinting more anatomically realistic vascular networks, and thus to eventually improve the vascularization of living tissue-engineered constructs.
AUTHOR Rachel Cadle and Dan Rogozea and Leni Moldovan and Patricia Parsons-Wingerter and Nicanor I. Moldovan
Title An image analysis-based workflow for 3D bioprinting of anatomically realistic retinal vascular patterns [Abstract]
Year 2021
Journal/Proceedings Bioprinting
Reftype
DOI/URL URL DOI
Abstract
There is an enduring need for vascularization of bioprinted constructs with vascular networks optimized for distribution of nutrient-containing fluids, both for in vitro applications and in vivo implantation. However, most of the efforts in this field were directed so far towards generation of simple linear channels, often lined with endothelial cells only, and thus lacking the anatomical details of real vascular networks. To start addressing this need, here we explored the possibility of using actual vascular patterns derived from human ocular fundus for instructing the 3D printing activity. In order to assign to these patterns the organ-specific topology, and eventually vessel branch-defined cellular composition, we describe the use of the branching analysis program VESGEN 2D for planning a workflow that links the primary vascular images with their 3D printing with bioinks. To this end, we show how to process flat vascular images and, for an even more realistic representation, how to retro-engineer concave retinal patterns from flat images and to print them in a supporting hydrogel. This work opens the possibility of bioprinting more anatomically realistic vascular networks, and thus to eventually improve the vascularization of living tissue-engineered constructs.
AUTHOR Rachel Cadle and Dan Rogozea and Leni Moldovan and Patricia Parsons-Wingerter and Nicanor I. Moldovan
Title An image analysis-based workflow for 3D bioprinting of anatomically realistic retinal vascular patterns [Abstract]
Year 2021
Journal/Proceedings Bioprinting
Reftype
DOI/URL URL DOI
Abstract
There is an enduring need for vascularization of bioprinted constructs with vascular networks optimized for distribution of nutrient-containing fluids, both for in vitro applications and in vivo implantation. However, most of the efforts in this field were directed so far towards generation of simple linear channels, often lined with endothelial cells only, and thus lacking the anatomical details of real vascular networks. To start addressing this need, here we explored the possibility of using actual vascular patterns derived from human ocular fundus for instructing the 3D printing activity. In order to assign to these patterns the organ-specific topology, and eventually vessel branch-defined cellular composition, we describe the use of the branching analysis program VESGEN 2D for planning a workflow that links the primary vascular images with their 3D printing with bioinks. To this end, we show how to process flat vascular images and, for an even more realistic representation, how to retro-engineer concave retinal patterns from flat images and to print them in a supporting hydrogel. This work opens the possibility of bioprinting more anatomically realistic vascular networks, and thus to eventually improve the vascularization of living tissue-engineered constructs.
AUTHOR García-Astrain, Clara and Lenzi, Elisa and Jimenez de Aberasturi, Dorleta and Henriksen-Lacey, Malou and Binelli, Marco R. and Liz-Marzán, Luis M.
Title 3D-Printed Biocompatible Scaffolds with Built-In Nanoplasmonic Sensors [Abstract]
Year 2020
Journal/Proceedings Advanced Functional Materials
Reftype
DOI/URL DOI
Abstract
Abstract 3D printing strategies have acquired great relevance toward the design of 3D scaffolds with precise macroporous structures, for supported mammalian cell growth. Despite advances in 3D model designs, there is still a shortage of detection tools to precisely monitor in situ cell behavior in 3D, thereby allowing a better understanding of the progression of diseases or to test the efficacy of drugs in a more realistic microenvironment. Even if the number of available inks has exponentially increased, they do not necessarily offer the required functionalities to be used as internal sensors. Herein the potential of surface-enhanced Raman scattering (SERS) spectroscopy for the detection of biorelevant analytes within a plasmonic hydrogel-based, 3D-printed scaffold is demonstrated. Such SERS-active scaffolds allow for the 3D detection of model molecules, such as 4-mercaptobenzoic acid. Flexibility in the choice of plasmonic nanoparticles is demonstrated through the use of gold nanoparticles with different morphologies, gold nanorods showing the best balance between SERS enhancement and scaffold transparency. Detection of the biomarker adenosine is also demonstrated as a proof-of-concept toward the use of these plasmonic scaffolds for SERS sensing of cell-secreted molecules over extended periods of time.