Publications by authors named "Su Ryon Shin"

104 Publications

Effects of electrically conductive nano-biomaterials on regulating cardiomyocyte behavior for cardiac repair and regeneration.

Acta Biomater 2021 Nov 21. Epub 2021 Nov 21.

Division of Engineering in Medicine, Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Cambridge, MA 02139, USA. Electronic address:

Myocardial infarction (MI) represents one of the most prevalent cardiovascular diseases, with a highly relevant and impactful role in public health. Despite the therapeutic advances of the last decades, MI still begets extensive death rates around the world. The pathophysiology of the disease correlates with cardiomyocyte necrosis, caused by an imbalance in the demand of oxygen to cardiac tissues, resulting from obstruction of the coronary flow. To alleviate the severe effects of MI, the use of various biomaterials exhibit vast potential in cardiac repair and regeneration, acting as native extracellular matrices. These hydrogels have been combined with nano sized or functional materials which possess unique electrical, mechanical, and topographical properties that play important roles in regulating phenotypes and the contractile function of cardiomyocytes even in adverse microenvironments. These nano-biomaterials' differential properties have led to substantial healing on in vivo cardiac injury models by promoting fibrotic scar reduction, hemodynamic function preservation, and benign cardiac remodeling. In this review, we discuss the interplay of the unique physical properties of electrically conductive nano-biomaterials, are able to manipulate the phenotypes and the electrophysiological behavior of cardiomyocytes in vitro, and can enhance heart regeneration in vivo. Consequently, the understanding of the decisive roles of the nano-biomaterials discussed in this review could be useful for designing novel nano-biomaterials in future research for cardiac tissue engineering and regeneration. STATEMENT OF SIGNIFICANCE: This study introduced and deciphered the understanding of the role of multimodal cues in recent advances of electrically conductive nano-biomaterials on cardiac tissue engineering. Compared with other review papers, which mainly describe these studies based on various types of electrically conductive nano-biomaterials, in this review paper we mainly discussed the interplay of the unique physical properties (electrical conductivity, mechanical properties, and topography) of electrically conductive nano-biomaterials, which would allow them to manipulate phenotypes and the electrophysiological behaviour of cardiomyocytes in vitro and to enhance heart regeneration in vivo. Consequently, understanding the decisive roles of the nano-biomaterials discussed in the review could help design novel nano-biomaterials in future research for cardiac tissue engineering and regeneration.
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http://dx.doi.org/10.1016/j.actbio.2021.11.022DOI Listing
November 2021

Nanoengineered Shear-Thinning Hydrogel Barrier for Preventing Postoperative Abdominal Adhesions.

Nanomicro Lett 2021 Oct 18;13(1):212. Epub 2021 Oct 18.

Biomaterials Innovation Research Center, Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, 02139, USA.

More than 90% of surgical patients develop postoperative adhesions, and the incidence of hospital re-admissions can be as high as 20%. Current adhesion barriers present limited efficacy due to difficulties in application and incompatibility with minimally invasive interventions. To solve this clinical limitation, we developed an injectable and sprayable shear-thinning hydrogel barrier (STHB) composed of silicate nanoplatelets and poly(ethylene oxide). We optimized this technology to recover mechanical integrity after stress, enabling its delivery though injectable and sprayable methods. We also demonstrated limited cell adhesion and cytotoxicity to STHB compositions in vitro. The STHB was then tested in a rodent model of peritoneal injury to determine its efficacy preventing the formation of postoperative adhesions. After two weeks, the peritoneal adhesion index was used as a scoring method to determine the formation of postoperative adhesions, and STHB formulations presented superior efficacy compared to a commercially available adhesion barrier. Histological and immunohistochemical examination showed reduced adhesion formation and minimal immune infiltration in STHB formulations. Our technology demonstrated increased efficacy, ease of use in complex anatomies, and compatibility with different delivery methods, providing a robust universal platform to prevent postoperative adhesions in a wide range of surgical interventions.
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http://dx.doi.org/10.1007/s40820-021-00712-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8523737PMC
October 2021

Recent trends in gelatin methacryloyl nanocomposite hydrogels for tissue engineering.

J Biomed Mater Res A 2021 Sep 24. Epub 2021 Sep 24.

Department of Mechanical and Manufacturing Engineering, Schulich School of Engineering, University of Calgary, Calgary, Alberta, Canada.

Gelatin methacryloyl (GelMA), a photocrosslinkable gelatin-based hydrogel, has been immensely used for diverse applications in tissue engineering and drug delivery. Apart from its excellent functionality and versatile mechanical properties, it is also suitable for a wide range of fabrication methodologies to generate tissue constructs of desired shapes and sizes. Despite its exceptional characteristics, it is predominantly limited by its weak mechanical strength, as some tissue types naturally possess high mechanical stiffness. The use of high GelMA concentrations yields high mechanical strength, but not without the compromise in its porosity, degradability, and three-dimensional (3D) cell attachment. Recently, GelMA has been blended with various natural and synthetic biomaterials to reinforce its physical properties to match with the tissue to be engineered. Among these, nanomaterials have been extensively used to form a composite with GelMA, as they increase its biological and physicochemical properties without affecting the unique characteristics of GelMA and also introduce electrical and magnetic properties. This review article presents the recent advances in the formation of hybrid GelMA nanocomposites using a variety of nanomaterials (carbon, metal, polymer, and mineral-based). We give an overview of each nanomaterial's characteristics followed by a discussion of the enhancement in GelMA's physical properties after its incorporation. Finally, we also highlight the use of each GelMA nanocomposite for different applications, such as cardiac, bone, and neural regeneration.
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http://dx.doi.org/10.1002/jbm.a.37310DOI Listing
September 2021

Tethering Cells via Enzymatic Oxidative Crosslinking Enables Mechanotransduction in Non-Cell-Adhesive Materials.

Adv Mater 2021 Oct 3;33(42):e2102660. Epub 2021 Sep 3.

Department of Developmental BioEngineering, Faculty of Science and Technology, Technical Medical Centre, University of Twente, Drienerlolaan 5, Enschede, 7522NB, The Netherlands.

Cell-matrix interactions govern cell behavior and tissue function by facilitating transduction of biomechanical cues. Engineered tissues often incorporate these interactions by employing cell-adhesive materials. However, using constitutively active cell-adhesive materials impedes control over cell fate and elicits inflammatory responses upon implantation. Here, an alternative cell-material interaction strategy that provides mechanotransducive properties via discrete inducible on-cell crosslinking (DOCKING) of materials, including those that are inherently non-cell-adhesive, is introduced. Specifically, tyramine-functionalized materials are tethered to tyrosines that are naturally present in extracellular protein domains via enzyme-mediated oxidative crosslinking. Temporal control over the stiffness of on-cell tethered 3D microniches reveals that DOCKING uniquely enables lineage programming of stem cells by targeting adhesome-related mechanotransduction pathways acting independently of cell volume changes and spreading. In short, DOCKING represents a bioinspired and cytocompatible cell-tethering strategy that offers new routes to study and engineer cell-material interactions, thereby advancing applications ranging from drug delivery, to cell-based therapy, and cultured meat.
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http://dx.doi.org/10.1002/adma.202102660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8530967PMC
October 2021

Synthesis and characterization of C2C12-laden gelatin methacryloyl (GelMA) from marine and mammalian sources.

Int J Biol Macromol 2021 Jul 7;183:918-926. Epub 2021 May 7.

LIBio, Université de Lorraine, F-54000 Nancy, France. Electronic address:

Gelatin methacryloyl (GelMA) is widely used for tissue engineering applications as an extracellular matrix (ECM) mimicking scaffold due to its cost-effectiveness, ease of synthesis, and high biocompatibility. GelMA is widely synthesized from porcine skin gelatin, which labors under clinical, religious, and economical restrictions. In order to overcome these limitations, GelMA can be produced from fish skin gelatin, which is eco-friendly as well. Here, we present a comparative study of the physicochemical (structural, thermal, water uptake, swelling, rheological, and mechanical) and biological (cell viability, proliferation, and spreading) properties of porcine and fish skin GelMA with low and high methacrylation degrees, before and after crosslinking, to check whether fish skin can replace porcine skin as the source of GelMA. Porcine and fish skin GelMA presented similar structural, thermal, and water uptake properties prior to crosslinking. However, subsequent to crosslinking, fish skin GelMA hydrogels exhibited a higher mass swelling ratio and a lower elastic and compressive Young's moduli than porcine skin GelMA hydrogels of similar methacrylation level. Both types of GelMA hydrogels showed great biocompatibility toward encapsulated mouse myoblast cells (C2C12), however, improved cell spreading was observed in fish skin GelMA hydrogels, and cell proliferation was only induced in low methacrylated GelMA. These results suggest that fish skin GelMA is a promising substitute for porcine skin GelMA for biomedical applications and that low methacrylated fish skin GelMA can be used as a potential scaffold for skeletal muscle tissue engineering.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.05.040DOI Listing
July 2021

3D bioprinted human iPSC-derived somatosensory constructs with functional and highly purified sensory neuron networks.

Biofabrication 2021 06 1;13(3). Epub 2021 Jun 1.

Division of Engineering in Medicine, Department of Medicine, Harvard Medical School, Brigham Women's Hospital, Cambridge, MA 02139, United States of America.

Engineering three-dimensional (3D) sensible tissue constructs, along with the complex microarchitecture wiring of the sensory nervous system, has been an ongoing challenge in the tissue engineering field. By combining 3D bioprinting and human pluripotent stem cell (hPSC) technologies, sensible tissue constructs could be engineered in a rapid, precise, and controllable manner to replicate 3D microarchitectures and mechanosensory functionalities of the native sensory tissue (e.g. response to external stimuli). Here, we introduce a biofabrication approach to create complex 3D microarchitecture wirings. We develop an hPSC-sensory neuron (SN) laden bioink using highly purified and functional SN populations to 3D bioprint microarchitecture wirings that demonstrate responsiveness to warm/cold sense-inducing chemicals and mechanical stress. Specifically, we tailor a conventional differentiation strategy to our purification method by utilizing p75 cell surface marker and DAPT treatment along with neuronal growth factors in order to selectively differentiate neural crest cells into SNs. To create spatial resolution in 3D architectures and grow SNs in custom patterns and directions, an induced pluripotent stem cell (iPSC)-SN-laden gelatin bioink was printed on laminin-coated substrates using extrusion-based bioprinting technique. Then the printed constructs were covered with a collagen matrix that guided SNs growing in the printed micropattern. Using a sacrificial bioprinting technique, the iPSC-SNs were seeded into the hollow microchannels created by sacrificial gelatin ink printed in the gelatin methacryloyl supporting bath, thereby demonstrating controllability over axon guidance in curved lines up to several tens of centimeters in length on 2D substrates and in straight microchannels in 3D matrices. Therefore, this biofabrication approach could be amenable to incorporate sensible SN networks into the engineered skin equivalents, regenerative skin implants, and augmented somatosensory neuro-prosthetics that have the potential to regenerate sensible functions by connecting host neuron systems in injured areas.
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http://dx.doi.org/10.1088/1758-5090/abff11DOI Listing
June 2021

Microfluidic integration of regeneratable electrochemical affinity-based biosensors for continual monitoring of organ-on-a-chip devices.

Nat Protoc 2021 05 28;16(5):2564-2593. Epub 2021 Apr 28.

Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, USA.

Organs-on-chips have emerged as viable platforms for drug screening and personalized medicine. While a wide variety of human organ-on-a-chip models have been developed, rarely have there been reports on the inclusion of sensors, which are critical in continually measuring the microenvironmental parameters and the dynamic responses of the microtissues to pharmaceutical compounds over extended periods of time. In addition, automation capacity is strongly desired for chronological monitoring. To overcome this major hurdle, in this protocol we detail the fabrication of electrochemical affinity-based biosensors and their integration with microfluidic chips to achieve in-line microelectrode functionalization, biomarker detection and sensor regeneration, allowing continual, in situ and noninvasive quantification of soluble biomarkers on organ-on-a-chip platforms. This platform is almost universal and can be applied to in-line detection of a majority of biomarkers, can be connected with existing organ-on-a-chip devices and can be multiplexed for simultaneous measurement of multiple biomarkers. Specifically, this protocol begins with fabrication of the electrochemically competent microelectrodes and the associated microfluidic devices (~3 d). The integration of electrochemical biosensors with the chips and their further combination with the rest of the platform takes ~3 h. The functionalization and regeneration of the microelectrodes are subsequently described, which require ~7 h in total. One cycle of sampling and detection of up to three biomarkers accounts for ~1 h.
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http://dx.doi.org/10.1038/s41596-021-00511-7DOI Listing
May 2021

Oxygen-Releasing Biomaterials: Current Challenges and Future Applications.

Trends Biotechnol 2021 Nov 16;39(11):1144-1159. Epub 2021 Feb 16.

Department of Developmental BioEngineering, Faculty of Science and Technology, Technical Medical Centre, University of Twente, Drienerlolaan 5, 7522 NB, Enschede, The Netherlands. Electronic address:

Oxygen is essential for the survival, function, and fate of mammalian cells. Oxygen tension controls cellular behaviour via metabolic programming, which in turn controls tissue regeneration, stem cell differentiation, drug metabolism, and numerous pathologies. Thus, oxygen-releasing biomaterials represent a novel and unique strategy to gain control over a variety of in vivo processes. Consequently, numerous oxygen-generating or carrying materials have been developed in recent years, which offer innovative solutions in the field of drug efficiency, regenerative medicine, and engineered living systems. In this review, we discuss the latest trends, highlight current challenges and solutions, and provide a future perspective on the field of oxygen-releasing materials.
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http://dx.doi.org/10.1016/j.tibtech.2021.01.007DOI Listing
November 2021

Suturable elastomeric tubular grafts with patterned porosity for rapid vascularization of 3D constructs.

Biofabrication 2021 Jan 22. Epub 2021 Jan 22.

ICPEES, University of Strasbourg, 25 rue Bécquerel, Strasbourg, 67087, FRANCE.

Vascularization is considered to be one of the key challenges in engineering functional 3D tissues. Engineering suturable vascular grafts containing pores with diameter of several tens of microns in tissue engineered constructs may provide an instantaneous blood perfusion through the grafts improving cell infiltration and thus, allowing rapid vascularization and vascular branching. The aim of this work was to develop suturable tubular scaffolds to be integrated in biofabricated constructs, enabling the direct connection of the biofabricated construct with the host blood stream, providing an immediate blood flow inside the construct. Here, tubular grafts with customizable shapes (tubes, Y-shape capillaries) and controlled diameter ranging from several hundreds of microns to few mm are fabricated based on poly(glycerol sebacate) (PGS) / poly(vinyl alcohol) (PVA) electrospun scaffolds. Furthermore, a network of pore channels of diameter in the order of 100 µm was machined by laser femtosecond ablation in the tube wall. Both non-machined and laser machined tubular scaffolds elongated more than 100% of their original size have shown suture retention, being 5.85 and 3.96 N/mm2 respectively. To demonstrate the potential of application, the laser machined porous grafts were embedded in gelatin methacryloyl (GelMA) hydrogels, resulting in elastomeric porous tubular graft/GelMA 3D constructs. These constructs were then co-seeded with osteoblast-like cells (MG-63) at the external side of the graft and endothelial cells (HUVEC) inside, forming a bone osteon model. The laser machined pore network allowed an immediate endothelial cell flow towards the osteoblasts enabling the osteoblasts and endothelial cells to interact and form 3D structures. This rapid vascularization approach could be applied, not only for bone tissue regeneration, but also for a variety of tissues and organs.
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http://dx.doi.org/10.1088/1758-5090/abdf1dDOI Listing
January 2021

Customizable Composite Fibers for Engineering Skeletal Muscle Models.

ACS Biomater Sci Eng 2020 02 9;6(2):1112-1123. Epub 2020 Jan 9.

Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, Massachusetts 02139, United States.

Engineering tissue-like scaffolds that can mimic the microstructure, architecture, topology, and mechanical properties of native tissues while offering an excellent environment for cellular growth has remained an unmet need. To address these challenges, multicompartment composite fibers are fabricated. These fibers can be assembled through textile processes to tailor tissue-level mechanical and electrical properties independent of cellular level components. Textile technologies also allow control of the distribution of different cell types and the microstructure of fabricated constructs and the direction of cellular growth within the 3D microenvironment. Here, we engineered composite fibers from biocompatible cores and biologically relevant hydrogel sheaths. The fibers are mechanically robust to being assembled using textile processes and could support adhesion, proliferation, and maturation of cell populations important for the engineering of skeletal muscles. We also demonstrated that the changes in the coating of the multicompartment fibers could potentially enhance myogenesis .
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http://dx.doi.org/10.1021/acsbiomaterials.9b00992DOI Listing
February 2020

Tissue Adhesives: From Research to Clinical Translation.

Nano Today 2021 Feb 20;36. Epub 2020 Dec 20.

Division of Engineering in Medicine, Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Cambridge, MA 02139, USA.

Sutures, staples, clips and skin closure strips are used as the gold standard to close wounds after an injury. In spite of being the present standard of care, the utilization of these conventional methods is precarious amid complicated and sensitive surgeries such as vascular anastomosis, ocular surgeries, nerve repair, or due to the high-risk components included. Tissue adhesives function as an interface to connect the surfaces of wound edges and prevent them from separation. They are fluid or semi-fluid mixtures that can be easily used to seal any wound of any morphology - uniform or irregular. As such, they provide alternatives to new and novel platforms for wound closure methods. In this review, we offer a background on the improvement of distinctive tissue adhesives focusing on the chemistry of some of these products that have been a commercial success from the clinical application perspective. This review is aimed to provide a guide toward innovation of tissue bioadhesive materials and their associated biomedical applications.
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http://dx.doi.org/10.1016/j.nantod.2020.101049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793024PMC
February 2021

Cell-Laden Gelatin Methacryloyl Bioink for the Fabrication of Z-Stacked Hydrogel Scaffolds for Tissue Engineering.

Polymers (Basel) 2020 Dec 17;12(12). Epub 2020 Dec 17.

Department of Stem Cell and Regenerative Biotechnology, KU Convergence Science and Technology Institute, Konkuk University, Seoul 05029, Korea.

Hydrogel-based scaffolds have been widely used to fabricate artificial tissues capable of replacing tissues and organs. However, several challenges inherent in fabricating tissues of large size and complex morphology using such scaffolds while ensuring cell viability remain. To address this problem, we synthesized gelatin methacryloyl (GelMA) based bioink with cells for fabricating a scaffold with superior characteristics. The bioink was grafted onto a Z-stacking bioprinter that maintained the cells at physiological temperature during the printing process, without exerting any physical pressure on the cells. Various parameters, such as the bioink composition and light exposure time, were optimized. The printing accuracy of the scaffolds was evaluated using photorheological studies. The internal morphology of the scaffolds at different time points was analyzed using electron microscopy. The Z-stacked scaffolds were fabricated using high-speed printing, with the conditions optimized to achieve high model reproducibility. Stable adhesion and high proliferation of cells encapsulated within the scaffold were confirmed. We introduced various strategies to improve the accuracy and reproducibility of Z-stack GelMA bioprinting while ensuring that the scaffolds facilitated cell adhesion, encapsulation, and proliferation. Our results demonstrate the potential of the present method for various applications in tissue engineering.
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http://dx.doi.org/10.3390/polym12123027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767119PMC
December 2020

Ferritin Nanocage Conjugated Hybrid Hydrogel for Tissue Engineering and Drug Delivery Applications.

ACS Biomater Sci Eng 2020 01 5;6(1):277-287. Epub 2019 Nov 5.

Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, Massachusetts 02139, United States.

Hydrogels have recently been attractive in various drug delivery and tissue engineering applications because of their structural similarities to the natural extracellular matrix. Despite enormous advances in the application of hydrogels, poor mechanical properties and lack of control for the release of drugs and biomolecules act as major barriers for widespread clinical applications. To overcome these challenges, we developed both physically and covalently conjugated nanocage-laden hydrogels between the surface of the nanocage and a gelatin methacryloyl (GelMA) hydrogel matrix. Ferritin and its empty-core equivalent apoferritin were used as nanocages that could be easily incorporated into a GelMA hydrogel via physical bonding. To fabricate covalently conjugated nanocage-laden GelMA hydrogels, ferritin and apoferritin were chemically modified to present the methacryloyl groups, ferritin methacryloyl (FerMA) and apoferritin methacryloyl (ApoMA), respectively. The covalently conjugated FerMA- and ApoMA-GelMA hydrogels offered a better ability to tune mechanical properties compared with those prepared by direct dispersion of ferritin and apoferritin into GelMA hydrogels with physical bonding, without affecting their porosity or cell growth. Furthermore, the ability of the nanocage to release small chemical compounds was confirmed by performing a cumulative release test on fluorescein isothiocyanate (FITC) encapsulated apoferritin and ApoMA incorporated GelMA hydrogels by pH stimulus. Thus, the nanocage incorporated hydrogels have emerged as excellent materials for drug delivery and tissue engineering applications.
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http://dx.doi.org/10.1021/acsbiomaterials.9b01482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725239PMC
January 2020

Injectable hydrogel derived from chitosan with tunable mechanical properties via hybrid-crosslinking system.

Carbohydr Polym 2021 Jan 6;251:117036. Epub 2020 Sep 6.

Department of Stem Cell and Regenerative Biotechnology, KU Convergence Science and Technology Institute, Konkuk University, Seoul, 05029, Republic of Korea. Electronic address:

Thermo-sensitive injectable hydrogels that spontaneously react to physiological temperature have been widely studied to be used in biomedical fields. However, several challenges on their unstable structures with large-sized pores and low mechanical strength under physiological conditions must be addressed to enable their practical applications. We synthesized the hydroxybutyl methacrylated chitosan (HBC-MA) hydrogel that possesses both thermo-sensitive and photo-crosslinkable properties. The HBC-MA showed effective sol-gel transition under physiological temperature as well as a sensitive photo-crosslinkable property with visible light capable of skin penetration. The co-nonsolvency property and thermo-sensitivity of HBC-MA prevented unintended loss of the hydrogel graft after being subcutaneously injected in mice. Subsequently applied visible light on the skin beneath which the hydrogel was injected significantly improved the mechanical strength and stability of the graft. The injectable HBC-MA hydrogel developed in this study can be applicable to a wide range of biomedical fields such as drug delivery system and tissue engineering.
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http://dx.doi.org/10.1016/j.carbpol.2020.117036DOI Listing
January 2021

A Heart-Breast Cancer-on-a-Chip Platform for Disease Modeling and Monitoring of Cardiotoxicity Induced by Cancer Chemotherapy.

Small 2021 04 23;17(15):e2004258. Epub 2020 Oct 23.

Division of Engineering in Medicine, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Cambridge, MA, 02139, USA.

Cardiotoxicity is one of the most serious side effects of cancer chemotherapy. Current approaches to monitoring of chemotherapy-induced cardiotoxicity (CIC) as well as model systems that develop in vivo or in vitro CIC platforms fail to notice early signs of CIC. Moreover, breast cancer (BC) patients with preexisting cardiac dysfunctions may lead to different incident levels of CIC. Here, a model is presented for investigating CIC where not only induced pluripotent stem cell (iPSC)-derived cardiac tissues are interacted with BC tissues on a dual-organ platform, but electrochemical immuno-aptasensors can also monitor cell-secreted multiple biomarkers. Fibrotic stages of iPSC-derived cardiac tissues are promoted with a supplement of transforming growth factor-β 1 to assess the differential functionality in healthy and fibrotic cardiac tissues after treatment with doxorubicin (DOX). The production trend of biomarkers evaluated by using the immuno-aptasensors well-matches the outcomes from conventional enzyme-linked immunosorbent assay, demonstrating the accuracy of the authors' sensing platform with much higher sensitivity and lower detection limits for early monitoring of CIC and BC progression. Furthermore, the versatility of this platform is demonstrated by applying a nanoparticle-based DOX-delivery system. The proposed platform would potentially help allow early detection and prediction of CIC in individual patients in the future.
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http://dx.doi.org/10.1002/smll.202004258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049959PMC
April 2021

Kappa-Carrageenan-Based Dual Crosslinkable Bioink for Extrusion Type Bioprinting.

Polymers (Basel) 2020 Oct 15;12(10). Epub 2020 Oct 15.

KU Convergence Science and Technology Institute, Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul 05029, Korea.

Bioink based 3D bioprinting is a promising new technology that enables fabrication of complex tissue structures with living cells. The printability of the bioink depends on the physical properties such as viscosity. However, the high viscosity bioink puts shear stress on the cells and low viscosity bioink cannot maintain complex tissue structure firmly after the printing. In this work, we applied dual crosslinkable bioink using Kappa-carrageenan (κ-CA) to overcome existing shortcomings. κ-CA has properties such as biocompatibility, biodegradability, shear-thinning and ionic gelation but the difficulty of controlling gelation properties makes it unsuitable for application in 3D bioprinting. This problem was solved by synthesizing methacrylated Kappa-carrageenan (MA-κ-CA), which can be dual crosslinked through ionic and UV (Ultraviolet) crosslinking to form hydrogel using NIH-3T3 cells. Through MA substitutions, the rheological properties of the gel could be controlled to reduce the shear stress. Moreover, bioprinting using the cell-laden MA-κ-CA showed cell compatibility with enhanced shape retention capability. The potential to control the physical properties through dual crosslinking of MA-κ-CA hydrogel is expected to be widely applied in 3D bioprinting applications.
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http://dx.doi.org/10.3390/polym12102377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602869PMC
October 2020

Nonmulberry Silk Based Ink for Fabricating Mechanically Robust Cardiac Patches and Endothelialized Myocardium-on-a-Chip Application.

Adv Funct Mater 2020 Mar 20;30(12). Epub 2020 Jan 20.

Division of Engineering in Medicine, Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Cambridge, MA 02139, USA.

Bioprinting holds great promise towards engineering functional cardiac tissue constructs for regenerative medicine and as drug test models. However, it is highly limited by the choice of inks that require maintaining a balance between the structure and functional properties associated with the cardiac tissue. In this regard, we have developed a novel and mechanically robust biomaterial-ink based on non-mulberry silk fibroin protein. The silk-based ink demonstrated suitable mechanical properties required in terms of elasticity and stiffness (~40 kPa) for developing clinically relevant cardiac tissue constructs. The ink allowed the fabrication of stable anisotropic scaffolds using a dual crosslinking method, which were able to support formation of aligned sarcomeres, high expression of gap junction proteins as connexin-43, and maintain synchronously beating of cardiomyocytes. The printed constructs were found to be non-immunogenic and . Furthermore, delving into an innovative method for fabricating a vascularized myocardial tissue-on-a-chip, the silk-based ink was used as supporting hydrogel for encapsulating human induced pluripotent stem cell derived cardiac spheroids (hiPSC-CSs) and creating perfusable vascularized channels via an embedded bioprinting technique. We confirmed the ability of silk-based supporting hydrogel towards maturation and viability of hiPSC-CSs and endothelial cells, and for applications in evaluating drug toxicity.
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http://dx.doi.org/10.1002/adfm.201907436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566555PMC
March 2020

Toward a neurospheroid niche model: optimizing embedded 3D bioprinting for fabrication of neurospheroid brain-like co-culture constructs.

Biofabrication 2020 Oct 15. Epub 2020 Oct 15.

Medicine, Harvard Medical School, Cambridge, Massachusetts, UNITED STATES.

A crucial step in creating reliable in vitro platforms for neural development and disorder studies is the reproduction of the multicellular three-dimensional (3D) brain microenvironment and the capturing of cell-cell interactions within the model. The power of self-organization of diverse cell types into brain spheroids could be harnessed to study mechanisms underlying brain development trajectory and diseases. A challenge of current 3D organoid and spheroid models grown in petri-dishes is the lack of control over cellular localization and diversity. To overcome this limitation, neural spheroids can be patterned into customizable 3D structures using microfabrication. We developed a 3D brain-like co-culture construct using embedded 3D bioprinting as a flexible solution for composing heterogenous neural populations with neurospheroids and glia. Specifically, neurospheroid-laden free-standing 3D structures were fabricated in an engineered astrocyte-laden support bath resembling a neural stem cell niche environment. A photo-crosslinkable bioink and a thermal-healing supporting bath were engineered to mimic the mechanical modulus of soft tissue while supporting the formation of self-organizing neurospheroids within elaborate 3D networks. Moreover, bioprinted neurospheroid-laden structures exhibited the capability to differentiate into neuronal cells. These brain-like co-cultures could provide a reproducible platform for modeling neurological diseases, neural regeneration, and drug development and repurposing.
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http://dx.doi.org/10.1088/1758-5090/abc1beDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387028PMC
October 2020

Designing Gelatin Methacryloyl (GelMA)-Based Bioinks for Visible Light Stereolithographic 3D Biofabrication.

Macromol Biosci 2021 01 11;21(1):e2000317. Epub 2020 Oct 11.

School of Engineering, The University of British Columbia, Kelowna, BC, V1V 1V7, Canada.

Bioinks play a key role in determining the capability of the biofabricatoin processes and the resolution of the printed constructs. Excellent biocompatibility, tunable physical properties, and ease of chemical or biological modifications of gelatin methacryloyl (GelMA) have made it an attractive choice as bioinks for biomanufacturing of various tissues or organs. However, the current preparation methods for GelMA-based bioinks lack the ability to tailor their physical properties for desired bioprinting methods. Inherently, GelMA prepolymer solution exhibits a fast sol-gel transition at room temperature, which is a hurdle for its use in stereolithography (SLA) bioprinting. Here, synthesis parameters are optimized such as solvents, pH, and reaction time to develop GelMA bioinks which have a slow sol-gel transition at room temperature and visible light crosslinkable functions. A total of eight GelMA combinations are identified as suitable for digital light processing (DLP)-based SLA (DLP-SLA) bioprinting through systematic characterizations of their physical and rheological properties. Out of various types of GelMA, those synthesized in reverse osmosis (RO) purified water (referred to as RO-GelMA) are regarded as most suitable to achieve high DLP-SLA printing resolution. RO-GelMA-based bioinks are also found to be biocompatible showing high survival rates of encapsulated cells in the photocrosslinked gels. Additionally, the astrocytes and fibroblasts are observed to grow and integrate well within the bioprinted constructs. The bioink's superior physical and photocrosslinking properties offer pathways of tuning the scaffold microenvironment and highlight the applicability of developed GelMA bioinks in various tissue engineering and regenerative medicine applications.
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http://dx.doi.org/10.1002/mabi.202000317DOI Listing
January 2021

Strategies to use fibrinogen as bioink for 3D bioprinting fibrin-based soft and hard tissues.

Acta Biomater 2020 11 16;117:60-76. Epub 2020 Sep 16.

Department of Biochemistry, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04039-032, Brazil.

Fibrin gel has been widely used for engineering various types of tissues due to its biocompatible nature, biodegradability, and tunable mechanical and nanofibrous structural properties. Despite their promising regenerative capacity and extensive biocompatibility with various tissue types, fibrin-based biomaterials are often notoriously known as burdensome candidates for 3D biofabrication and bioprinting. The high viscosity of fibrin (crosslinked form) hinders proper ink extrusion, and its pre-polymer form, fibrinogen, is not capable of maintaining shape fidelity. To overcome these limitations and empower fibrinogen-based bioinks for fibrin biomimetics and regenerative applications, different strategies can be practiced. The aim of this review is to report the strategies that bring fabrication compatibility to these bioinks through mixing fibrinogen with printable biomaterials, using supporting bath supplemented with crosslinking agents, and crosslinking fibrin in situ. Moreover, the review discusses some of the recent advances in 3D bioprinting of biomimetic soft and hard tissues using fibrinogen-based bioinks, and highlights the impacts of these strategies on fibrin properties, its bioactivity, and the functionality of the consequent biomimetic tissue. Statement of Significance Due to its biocompatible nature, biodegradability, and tunable mechanical and nanofibrous structural properties, fibrin gel has been widely employed in tissue engineering and more recently, used as in 3D bioprinting. The fibrinogen's poor printable properties make it difficult to maintain the 3D shape of bioprinted constructs. Our work describes the strategies employed in tissue engineering to allow the 3D bioprinting of fibrinogen-based bioinks, such as the combination of fibrinogen with printable biomaterials, the in situ fibrin crosslinking, and the use of supporting bath supplemented with crosslinking agents. Further, this review discuss the application of 3D bioprinting technology to biofabricate fibrin-based soft and hard tissues for biomedical applications, and discuss current limitations and future of such in vitro models.
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http://dx.doi.org/10.1016/j.actbio.2020.09.024DOI Listing
November 2020

Immune Organs and Immune Cells on a Chip: An Overview of Biomedical Applications.

Micromachines (Basel) 2020 Sep 12;11(9). Epub 2020 Sep 12.

Division of Engineering in Medicine, Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Cambridge, MA 02139, USA.

Understanding the immune system is of great importance for the development of drugs and the design of medical implants. Traditionally, two-dimensional static cultures have been used to investigate the immune system in vitro, while animal models have been used to study the immune system's function and behavior in vivo. However, these conventional models do not fully emulate the complexity of the human immune system or the human in vivo microenvironment. Consequently, many promising preclinical findings have not been reproduced in human clinical trials. Organ-on-a-chip platforms can provide a solution to bridge this gap by offering human micro-(patho)physiological systems in which the immune system can be studied. This review provides an overview of the existing immune-organs-on-a-chip platforms, with a special emphasis on interorgan communication. In addition, future challenges to develop a comprehensive immune system-on-chip model are discussed.
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http://dx.doi.org/10.3390/mi11090849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7570325PMC
September 2020

Engineering Smart Targeting Nanovesicles and Their Combination with Hydrogels for Controlled Drug Delivery.

Pharmaceutics 2020 Sep 7;12(9). Epub 2020 Sep 7.

Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139, USA.

Smart engineered and naturally derived nanovesicles, capable of targeting specific tissues and cells and delivering bioactive molecules and drugs into them, are becoming important drug delivery systems. Liposomes stand out among different types of self-assembled nanovesicles, because of their amphiphilicity and non-toxic nature. By modifying their surfaces, liposomes can become stimulus-responsive, releasing their cargo on demand. Recently, the recognized role of exosomes in cell-cell communication and their ability to diffuse through tissues to find target cells have led to an increase in their usage as smart delivery systems. Moreover, engineering "smarter" delivery systems can be done by creating hybrid exosome-liposome nanocarriers via membrane fusion. These systems can be loaded in naturally derived hydrogels to achieve sustained and controlled drug delivery. Here, the focus is on evaluating the smart behavior of liposomes and exosomes, the fabrication of hybrid exosome-liposome nanovesicles, and the controlled delivery and routes of administration of a hydrogel matrix for drug delivery systems.
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http://dx.doi.org/10.3390/pharmaceutics12090849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559099PMC
September 2020

Cellular Mechanisms of Rejection of Optic and Sciatic Nerve Transplants: An Observational Study.

Transplant Direct 2020 Aug 24;6(8):e589. Epub 2020 Jul 24.

Transplantation Research Center, Renal Division, Brigham and Women's Hospital/Harvard Medical School, Boston, MA.

Background: Organ transplantation is a standard therapeutic strategy for irreversible organ damage, but the utility of nerve transplantation remains generally unexplored, despite its potential benefit to a large patient population. Here, we aimed to establish a feasible preclinical mouse model for understanding the cellular mechanisms behind the rejection of peripheral and optic nerves.

Methods: We performed syngenic and allogenic transplantation of optic and sciatic nerves in mice by inserting the nerve grafts inside the kidney capsule, and we assessed the allografts for signs of rejection through 14 d following transplantation. Then, we assessed the efficacy of CTLA4 Ig, Rapamycin, and anti-CD3 antibody in suppressing immune cell infiltration of the nerve allografts.

Results: By 3 d posttransplantation, both sciatic and optic nerves transplanted from BALB/c mice into C57BL/6J recipients contained immune cell infiltrates, which included more CD11b macrophages than CD3 T cells or B220 B cells. Ex vivo immunogenicity assays demonstrated that sciatic nerves demonstrated higher alloreactivity in comparison with optic nerves. Interestingly, optic nerves contained higher populations of anti-inflammatory PD-L1 cells than sciatic nerves. Treatment with anti-CD3 antibody reduced immune cell infiltrates in the optic nerve allograft, but exerted no significant effect in the sciatic nerve allograft.

Conclusions: These findings establish the feasibility of a preclinical allogenic nerve transplantation model and provide the basis for future testing of directed, high-intensity immunosuppression in these mice.
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http://dx.doi.org/10.1097/TXD.0000000000001012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382554PMC
August 2020

Lymph node fibroblastic reticular cells deposit fibrosis-associated collagen following organ transplantation.

J Clin Invest 2020 08;130(8):4182-4194

Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Although the immune response within draining lymph nodes (DLNs) has been studied for decades, how their stromal compartment contributes to this process remains to be fully explored. Here, we show that donor mast cells were prominent activators of collagen I deposition by fibroblastic reticular cells (FRCs) in DLNs shortly following transplantation. Serial analysis of the DLN indicated that the LN stroma did not return to its baseline microarchitecture following organ rejection and that the DLN contained significant fibrosis following repetitive organ transplants. Using several FRC conditional-knockout mice, we show that induction of senescence in the FRCs of the DLN resulted in massive production of collagen I and a proinflammatory milieu within the DLN. Stimulation of herpes virus entry mediator (HVEM) on FRCs by its ligand LIGHT contributed chiefly to the induction of senescence in FRCs and overproduction of collagen I. Systemic administration of ex vivo-expanded FRCs to mice decreased DLN fibrosis and strengthened the effect of anti-CD40L in prolonging heart allograft survival. These data demonstrate that the transformation of FRCs into proinflammatory myofibroblasts is critically important for the maintenance of a proinflammatory milieu within a fibrotic DLN.
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http://dx.doi.org/10.1172/JCI136618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410068PMC
August 2020

Combinatorial screening of biochemical and physical signals for phenotypic regulation of stem cell-based cartilage tissue engineering.

Sci Adv 2020 May 22;6(21):eaaz5913. Epub 2020 May 22.

Department of Bioengineering, Henry Samueli School of Engineering and Applied Sciences, University of California, Los Angeles, Los Angeles, CA 90095, USA.

Despite great progress in biomaterial design strategies for replacing damaged articular cartilage, prevention of stem cell-derived chondrocyte hypertrophy and resulting inferior tissue formation is still a critical challenge. Here, by using engineered biomaterials and a high-throughput system for screening of combinatorial cues in cartilage microenvironments, we demonstrate that biomaterial cross-linking density that regulates matrix degradation and stiffness-together with defined presentation of growth factors, mechanical stimulation, and arginine-glycine-aspartic acid (RGD) peptides-can guide human mesenchymal stem cell (hMSC) differentiation into articular or hypertrophic cartilage phenotypes. Faster-degrading, soft matrices promoted articular cartilage tissue formation of hMSCs by inducing their proliferation and maturation, while slower-degrading, stiff matrices promoted cells to differentiate into hypertrophic chondrocytes through Yes-associated protein (YAP)-dependent mechanotransduction. in vitro and in vivo chondrogenesis studies also suggest that down-regulation of the Wingless and INT-1 (WNT) signaling pathway is required for better quality articular cartilage-like tissue production.
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http://dx.doi.org/10.1126/sciadv.aaz5913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244269PMC
May 2020

Hydrogel Production Platform with Dynamic Movement Using Photo-Crosslinkable/Temperature Reversible Chitosan Polymer and Stereolithography 4D Printing Technology.

Tissue Eng Regen Med 2020 08 21;17(4):423-431. Epub 2020 May 21.

Department of Stem Cell and Regenerative Biotechnology, KU Convergence Science and Technology Institute, Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul, 05029, Republic of Korea.

Background: Three-dimensional (3D) printing using hydrogel has made great strides when it comes to mimicking 3D artificial tissue in the medical field. However, most structures do not mimic the dynamic movement of the tissues. Without imitating dynamic movements, there are limitations on the extent to which the proper implementation of the tissue's own functions can be achieved.

Method: In this study, we intend to present an approach to solving this problem using hydroxybutyl methacrylated chitosan (HBC-MA), a photo-crosslinkable/temperature reversible chitosan polymer. In addition, stereolithography-3D (SLA-3D) printing technology was used, which is more likely to mimic the complex microstructure. As a control, a 3D structure made with pristine poly(ethylene glycol) dimethacrylate (PEG-DMA) was created, and a 4D structure was prepared by adding HBC-MA to poly(ethylene glycol) dimethacrylate (PEG-DMAP) resin.

Results: HBC-MA caused the expansion of water into the polymer matrix at low temperature, and the 4D structure resulted in expansion of the polymer volume, generating dynamic movement due to the expansion of water. Conversely, as the temperature rose, deswelling occurred, followed by a decrease in the volume, showing a shape memory property of returning to the existing structure. Morphological, swelling, and mechanical analysis further confirmed the principle of dynamic movement. In addition, parameters were provided through calculation of the bending ratio angle (θ).

Conclusion: Through this, it is suggested that HBC-MA can be applied as a core polymer for SLA-4D printing, and has high potential for realizing the dynamic movement of tissue.
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http://dx.doi.org/10.1007/s13770-020-00264-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392993PMC
August 2020

Novel Cell-Based and Tissue Engineering Approaches for Induction of Angiogenesis as an Alternative Therapy for Diabetic Retinopathy.

Int J Mol Sci 2020 May 15;21(10). Epub 2020 May 15.

Division of Engineering in Medicine, Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Cambridge, MA 02139, USA.

Diabetic retinopathy (DR) is the most frequent microvascular complication of long-term diabetes and the most common cause of blindness, increasing morbidity in the working-age population. The most effective therapies for these complications include laser photocoagulation and anti-vascular endothelial growth factor (VEGF) intravitreal injections. However, laser and anti-VEGF drugs are untenable as a final solution as they fail to address the underlying neurovascular degeneration and ischemia. Regenerative medicine may be a more promising approach, aimed at the repair of blood vessels and reversal of retinal ischemia. Stem cell therapy has introduced a novel way to reverse the underlying ischemia present in microvascular complications in diseases such as diabetes. The present review discusses current treatments, their side effects, and novel cell-based and tissue engineering approaches as a potential alternative therapeutic approach.
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http://dx.doi.org/10.3390/ijms21103496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278952PMC
May 2020

Materials and technical innovations in 3D printing in biomedical applications.

J Mater Chem B 2020 04 2;8(15):2930-2950. Epub 2020 Apr 2.

Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 65 Lansdowne Street, Cambridge, Massachusetts 02139, USA.

3D printing is a rapidly growing research area, which significantly contributes to major innovations in various fields of engineering, science, and medicine. Although the scientific advancement of 3D printing technologies has enabled the development of complex geometries, there is still an increasing demand for innovative 3D printing techniques and materials to address the challenges in building speed and accuracy, surface finish, stability, and functionality. In this review, we introduce and review the recent developments in novel materials and 3D printing techniques to address the needs of the conventional 3D printing methodologies, especially in biomedical applications, such as printing speed, cell growth feasibility, and complex shape achievement. A comparative study of these materials and technologies with respect to the 3D printing parameters will be provided for selecting a suitable application-based 3D printing methodology. Discussion of the prospects of 3D printing materials and technologies will be finally covered.
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http://dx.doi.org/10.1039/d0tb00034eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092991PMC
April 2020

Modular Fabrication of Intelligent Material-Tissue Interfaces for Bioinspired and Biomimetic Devices.

Prog Mater Sci 2019 Dec 17;106. Epub 2019 Jul 17.

Department of Biomedical Engineering, the University of Texas at Austin, Austin, Texas, USA.

One of the goals of biomaterials science is to reverse engineer aspects of human and nonhuman physiology. Similar to the body's regulatory mechanisms, such devices must transduce changes in the physiological environment or the presence of an external stimulus into a detectable or therapeutic response. This review is a comprehensive evaluation and critical analysis of the design and fabrication of environmentally responsive cell-material constructs for bioinspired machinery and biomimetic devices. In a bottom-up analysis, we begin by reviewing fundamental principles that explain materials' responses to chemical gradients, biomarkers, electromagnetic fields, light, and temperature. Strategies for fabricating highly ordered assemblies of material components at the nano to macro-scales via directed assembly, lithography, 3D printing and 4D printing are also presented. We conclude with an account of contemporary material-tissue interfaces within bioinspired and biomimetic devices for peptide delivery, cancer theranostics, biomonitoring, neuroprosthetics, soft robotics, and biological machines.
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http://dx.doi.org/10.1016/j.pmatsci.2019.100589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7079701PMC
December 2019

Bioinspired Soft Robot with Incorporated Microelectrodes.

J Vis Exp 2020 02 28(156). Epub 2020 Feb 28.

Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School;

Bioinspired soft robotic systems that mimic living organisms using engineered muscle tissue and biomaterials are revolutionizing the current biorobotics paradigm, especially in biomedical research. Recreating artificial life-like actuation dynamics is crucial for a soft-robotic system. However, the precise control and tuning of actuation behavior still represents one of the main challenges of modern soft robotic systems. This method describes a low-cost, highly scalable, and easy-to-use procedure to fabricate an electrically controllable soft robot with life-like movements that is activated and controlled by the contraction of cardiac muscle tissue on a micropatterned sting ray-like hydrogel scaffold. The use of soft photolithography methods makes it possible to successfully integrate multiple components in the soft robotic system, including micropatterned hydrogel-based scaffolds with carbon nanotubes (CNTs) embedded gelatin methacryloyl (CNT-GelMA), poly(ethylene glycol) diacrylate (PEGDA), flexible gold (Au) microelectrodes, and cardiac muscle tissue. In particular, the hydrogels alignment and micropattern are designed to mimic the muscle and cartilage structure of the sting ray. The electrically conductive CNT-GelMA hydrogel acts as a cell scaffold that improves the maturation and contraction behavior of cardiomyocytes, while the mechanically robust PEGDA hydrogel provides structural cartilage-like support to the whole soft robot. To overcome the hard and brittle nature of metal-based microelectrodes, we designed a serpentine pattern that has high flexibility and can avoid hampering the beating dynamics of cardiomyocytes. The incorporated flexible Au microelectrodes provide electrical stimulation across the soft robot, making it easier to control the contraction behavior of cardiac tissue.
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http://dx.doi.org/10.3791/60717DOI Listing
February 2020
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