Publications by authors named "Jinah Jang"

71 Publications

Neural stem cell delivery using brain-derived tissue-specific bioink for recovering from traumatic brain injury.

Biofabrication 2021 Sep 22. Epub 2021 Sep 22.

Department of Mechanical Engineering, Pohang University of Science and Technology, Pohang, Kyungbuk 790-784, KOREA, Pohang, 37673, Korea (the Republic of).

Traumatic brain injury is one of the leading causes of accidental death and disability. The loss of parts in a severely injured brain induces edema, neuronal apoptosis, and neuroinflammation. Recently, stem cell transplantation demonstrated regenerative efficacy in an injured brain. However, the efficacy of current stem cell therapy needs improvement to resolve issues such as low survival of implanted stem cells and low efficacy of differentiation into respective cells. We developed brain-derived decellularized extracellular matrix (BdECM) bioink that is printable and has native brain-like stiffness. This study aimed to fabricate injured cavity-fit scaffold with BdECM bioink and assessed the utility of BdECM bioink for stem cell delivery to a traumatically injured brain. Our BdECM bioink had shear thinning property for 3D-cell-printing and physical properties and fiber structures comparable to those of the native brain, which is important for tissue integration after implantation. The human neural stem cells (F3 cells) laden with BdECM bioink were found to be fully differentiated to neurons; the levels of markers for mature differentiated neurons were higher than those observed with collagen bioink in vitro. Moreover, the BdECM bioink demonstrated potential in defect-fit carrier fabrication with 3D cell-printing, based on the rheological properties and shape fidelity of the material. As F3 cell-laden BdECM bioink was transplanted into the motor cortex of a rat brain, high efficacy of differentiation into mature neurons was observed in the transplanted neural stem cells; notably increased level of MAP2, a marker of neuronal differentiation, was observed. Furthermore, the transplanted-cell bioink suppressed reactive astrogliosis and microglial activation that may impede regeneration of the injured brain. The brain-specific material reported here is favorable for neural stem cell differentiation and suppression of neuroinflammation and is expected to successfully support regeneration of a traumatically injured brain.
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http://dx.doi.org/10.1088/1758-5090/ac293fDOI Listing
September 2021

Employing Extracellular Matrix-Based Tissue Engineering Strategies for Age-Dependent Tissue Degenerations.

Int J Mol Sci 2021 Aug 29;22(17). Epub 2021 Aug 29.

School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology (POSTECH), Pohang 37673, Korea.

Tissues and organs are not composed of solely cellular components; instead, they converge with an extracellular matrix (ECM). The composition and function of the ECM differ depending on tissue types. The ECM provides a microenvironment that is essential for cellular functionality and regulation. However, during aging, the ECM undergoes significant changes along with the cellular components. The ECM constituents are over- or down-expressed, degraded, and deformed in senescence cells. ECM aging contributes to tissue dysfunction and failure of stem cell maintenance. Aging is the primary risk factor for prevalent diseases, and ECM aging is directly or indirectly correlated to it. Hence, rejuvenation strategies are necessitated to treat various age-associated symptoms. Recent rejuvenation strategies focus on the ECM as the basic biomaterial for regenerative therapies, such as tissue engineering. Modified and decellularized ECMs can be used to substitute aged ECMs and cell niches for culturing engineered tissues. Various tissue engineering approaches, including three-dimensional bioprinting, enable cell delivery and the fabrication of transplantable engineered tissues by employing ECM-based biomaterials.
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http://dx.doi.org/10.3390/ijms22179367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8431718PMC
August 2021

A 3D bioprinted hybrid encapsulation system for delivery of human pluripotent stem cell-derived pancreatic islet-like aggregates.

Biofabrication 2021 Sep 3. Epub 2021 Sep 3.

Department of Convergence IT Engineering, Pohang University of Science and Technology (POSTECH), 80, Jigok-ro, Nam-gu, Pohang, Gyeongsangbuk-do, 37666, Korea (the Republic of).

Islet transplantation is a promising treatment for Type 1 diabetes. However, treatment failure can result from loss of functional cells associated with cell dispersion, low viability, and severe immune response. To overcome these limitations, various islet encapsulation approaches have been introduced. Among them, macroencapsulation offers the advantages of delivering and retrieving a large volume of islets in one system. In this study, we developed a hybrid encapsulation system composed of a macroporous polymer capsule with stagger-type membrane and assemblable structure, and a nanoporous dECM hydrogel containing pancreatic islet-like aggregates using 3D bioprinting technique. The outer part (macroporous polymer capsule) was designed to have an interconnected porous architecture, which allows insulin-producing β cells encapsulated in the hybrid encapsulation system to maintain their cellular behaviors, including viability, cell proliferation, and insulin-producing function. The inner part (nanoporous dECM hydrogel), composed of the 3D biofabricated pancreatic islet-like aggregates, was simultaneously placed into the macroporous polymer capsule in one step. The developed hybrid encapsulation system exhibited biocompatibility in vitro and in vivo in terms of M1 macrophage polarization. Furthermore, by controlling the printing parameters, we generated islet-like aggregates, improving cell viability and functionality. Moreover, the 3D bioprinted pancreatic islet-like aggregates exhibited structural maturation and functional enhancement associated with intercellular interaction occurring at the β cell edges. In addition, we also investigated the therapeutic potential of a hybrid encapsulation system by integrating human pluripotent stem cell-derived insulin-producing cells, which are promising to overcome the donor shortage problem. In summary, these results demonstrated that the 3D bioprinting approach facilitates the fabrication of a hybrid islet encapsulation system with multiple materials and potentially improves the clinical outcomes by driving structural maturation and functional improvement of cells.
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http://dx.doi.org/10.1088/1758-5090/ac23acDOI Listing
September 2021

3D bioprinted tissue-specific spheroidal multicellular microarchitectures for advanced cell therapy.

Biofabrication 2021 09 3;13(4). Epub 2021 Sep 3.

Department of Convergence IT Engineering, Pohang University of Science and Technology (POSTECH), Pohang, Kyungbuk 37673, Republic of Korea.

Intercellular interaction is the most crucial factor in promoting cell viability and functionality in an engineered tissue system. Of the various shapes available for cell-laden constructs, spheroidal multicellular microarchitectures (SMMs) have been introduced as building blocks and injectable cell carriers with substantial cell-cell and cell-extracellular matrix (ECM) interactions. Here, we developed a precise and expeditious SMM printing method that can create a tissue-specific microenvironment and thus be potentially useful for cell therapy. This printing strategy is designed to manufacture SMMs fabricated with optimal bioink blended with decellularized ECM and alginate to enhance the functional performance of the encapsulated cells. Experimental results showed that the proposed method allowed for size controllability and mass production of SMMs with high cell viability. Moreover, SMMs co-cultured with endothelial cells promoted lineage-specific maturation and increased functionality compared to monocultured SMMs. Overall, it was concluded that SMMs have the potential for use in cell therapy due to their high cell retention and proliferation rate compared to single-cell injection, particularly for efficient tissue regeneration after myocardial infarction. This study suggests that utilizing microextrusion-based 3D bioprinting technology to encapsulate cells in cell-niche-standardized SMMs can expand the range of possible applications.
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http://dx.doi.org/10.1088/1758-5090/ac212eDOI Listing
September 2021

3D bioprinting of stem cell-laden cardiac patch: A promising alternative for myocardial repair.

APL Bioeng 2021 Sep 27;5(3):031508. Epub 2021 Jul 27.

Department of Convergence IT Engineering, POSTECH, 77 Cheongam-ro, Namgu, Pohang, Kyungbuk 37673, Republic of Korea.

Stem cell-laden three-dimensional (3D) bioprinted cardiac patches offer an alternative and promising therapeutic and regenerative approach for ischemic cardiomyopathy by reversing scar formation and promoting myocardial regeneration. Numerous studies have reported using either multipotent or pluripotent stem cells or their combination for 3D bioprinting of a cardiac patch with the sole aim of restoring cardiac function by faithfully rejuvenating the cardiomyocytes and associated vasculatures that are lost to myocardial infarction. While many studies have demonstrated success in mimicking cardiomyocytes' behavior, improving cardiac function and providing new hope for regenerating heart post-myocardial infarction, some others have reported contradicting data in apparent ways. Nonetheless, all investigators in the field are speed racing toward determining a potential strategy to effectively treat losses due to myocardial infarction. This review discusses various types of candidate stem cells that possess cardiac regenerative potential, elucidating their applications and limitations. We also brief the challenges of and an update on the implementation of the state-of-the-art 3D bioprinting approach to fabricate cardiac patches and highlight different strategies to implement vascularization and augment cardiac functional properties with respect to electrophysiological similarities to native tissue.
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http://dx.doi.org/10.1063/5.0030353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8318604PMC
September 2021

Promoting Long-Term Cultivation of Motor Neurons for 3D Neuromuscular Junction Formation of 3D In Vitro Using Central-Nervous-Tissue-Derived Bioink.

Adv Healthc Mater 2021 Sep 7;10(18):e2100581. Epub 2021 Aug 7.

School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology (POSTECH), 77 Cheongam-ro, Nam-gu, Pohang, Kyungbuk, 37673, Republic of Korea.

3D cell printing technology is in the spotlight for producing 3D tissue or organ constructs useful for various medical applications. In printing of neuromuscular tissue, a bioink satisfying all the requirements is a challenging issue. Gel integrity and motor neuron activity are two major characters because a harmonious combination of extracellular materials essential to motor neuron activity consists of disadvantages in mechanical properties. Here, a method for fabrication of 3D neuromuscular tissue is presented using a porcine central nervous system tissue decellularized extracellular matrix (CNSdECM) bioink. CNSdECM retains CNS tissue-specific extracellular molecules, provides rheological properties crucial for extrusion-based 3D cell printing, and reveals positive effects on the growth and maturity of axons of motor neurons compared with Matrigel. It also allows long-term cultivation of human-induced-pluripotent-stem-cell-derived lower motor neurons and sufficiently supports their cellular behavior to carry motor signals to muscle fibers. CNSdECM bioink holds great promise for producing a tissue-engineered motor system using 3D cell printing.
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http://dx.doi.org/10.1002/adhm.202100581DOI Listing
September 2021

3D bioprinted and integrated platforms for cardiac tissue modeling and drug testing.

Essays Biochem 2021 Aug;65(3):545-554

Department of Convergence IT Engineering, Pohang University of Science and Technology (POSTECH), 77 Cheongam-ro, Namgu, Pohang 37673, Kyungbuk, Republic of Korea.

Recent advances in biofabrication techniques, including 3D bioprinting, have allowed for the fabrication of cardiac models that are similar to the human heart in terms of their structure (e.g., volumetric scale and anatomy) and function (e.g., contractile and electrical properties). The importance of developing techniques for assessing the characteristics of 3D cardiac substitutes in real time without damaging their structures has also been emphasized. In particular, the heart has two primary mechanisms for transporting blood through the body: contractility and an electrical system based on intra and extracellular calcium ion exchange. This review introduces recent trends in 3D bioprinted cardiac tissues and the measurement of their structural, contractile, and electrical properties in real time. Cardiac models have also been regarded as alternatives to animal models as drug-testing platforms. Thus, perspectives on the convergence of 3D bioprinted cardiac tissues and their assessment for use in drug development are also presented.
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http://dx.doi.org/10.1042/EBC20200106DOI Listing
August 2021

Quantitative Photothermal Characterization with Bioprinted 3D Complex Tissue Constructs for Early-Stage Breast Cancer Therapy Using Gold Nanorods.

Adv Healthc Mater 2021 Sep 8;10(18):e2100636. Epub 2021 Jul 8.

Center for Scientific Instrumentation, Division of Scientific Instrumentation and Management, Korea Basic Science Institute (KBSI), Daejeon, 34133, Republic of Korea.

Plasmonic photothermal therapy (PPTT) using gold nanoparticles (AuNPs) has shown great potential for use in selective tumor treatment, because the AuNPs can generate destructive heat preferentially upon irradiation. However, PPTT using AuNPs has not been added to practice, owing to insufficient heating methods and tissue temperature measurement techniques, leading to unreliable and inaccurate treatments. Because the photothermal properties of AuNPs vary with laser power, particle optical density, and tissue depth, the accurate prediction of heat generation is indispensable for clinical treatment. In this report, bioprinted 3D complex tissue constructs comprising processed gel obtained from porcine skin and human decellularized adipose tissue are presented for characterization of the photothermal properties of gold nanorods (AuNRs) having an aspect ratio of 3.7 irradiated by a near-infrared laser. Moreover, an analytical function is suggested for achieving PPTT that can cause thermal damage selectively on early-stage human breast cancer by regulating the heat generation of the AuNRs in the tissue.
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http://dx.doi.org/10.1002/adhm.202100636DOI Listing
September 2021

3D Bioprinting-Based Vascularized Tissue Models Mimicking Tissue-Specific Architecture and Pathophysiology for Studies.

Front Bioeng Biotechnol 2021 31;9:685507. Epub 2021 May 31.

School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang, South Korea.

A wide variety of experimental models including 2D cell cultures, model organisms, and 3D models have been developed to understand pathophysiological phenomena and assess the safety and efficacy of potential therapeutics. In this sense, 3D models are an intermediate between 2D cell cultures and animal models, as they adequately reproduce 3D microenvironments and human physiology while also being controllable and reproducible. Particularly, recent advances in 3D biomimicry models, which can produce complex cell structures, shapes, and arrangements, can more similarly reflect conditions than 2D cell culture. Based on this, 3D bioprinting technology, which enables to place the desired materials in the desired locations, has been introduced to fabricate tissue models with high structural similarity to the native tissues. Therefore, this review discusses the recent developments in this field and the key features of various types of 3D-bioprinted tissues, particularly those associated with blood vessels or highly vascularized organs, such as the heart, liver, and kidney. Moreover, this review also summarizes the current state of the three categories: (1) chemical substance treatment, (2) 3D bioprinting of lesions, and (3) recapitulation of tumor microenvironments (TME) of 3D bioprinting-based disease models according to their disease modeling approach. Finally, we propose the future directions of 3D bioprinting approaches for the creation of more advanced biomimetic 3D tissues, as well as the translation of 3D bioprinted tissue models to clinical applications.
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http://dx.doi.org/10.3389/fbioe.2021.685507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201787PMC
May 2021

Application of 3D bioprinting in the prevention and the therapy for human diseases.

Signal Transduct Target Ther 2021 May 14;6(1):177. Epub 2021 May 14.

Department of Mechanical Engineering, Pohang University of Science and Technology (POSTECH), 77 Cheongam-Ro, Pohang, Kyungbuk, 37673, Korea.

Rapid development of vaccines and therapeutics is necessary to tackle the emergence of new pathogens and infectious diseases. To speed up the drug discovery process, the conventional development pipeline can be retooled by introducing advanced in vitro models as alternatives to conventional infectious disease models and by employing advanced technology for the production of medicine and cell/drug delivery systems. In this regard, layer-by-layer construction with a 3D bioprinting system or other technologies provides a beneficial method for developing highly biomimetic and reliable in vitro models for infectious disease research. In addition, the high flexibility and versatility of 3D bioprinting offer advantages in the effective production of vaccines, therapeutics, and relevant delivery systems. Herein, we discuss the potential of 3D bioprinting technologies for the control of infectious diseases. We also suggest that 3D bioprinting in infectious disease research and drug development could be a significant platform technology for the rapid and automated production of tissue/organ models and medicines in the near future.
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http://dx.doi.org/10.1038/s41392-021-00566-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119699PMC
May 2021

Tissue printing for engineering transplantable human parathyroid patch to improve parathyroid engraftment, integration, and hormone secretion.

Biofabrication 2021 04 26;13(3). Epub 2021 Apr 26.

Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.

During thyroid surgery, some parathyroid glands fail to maintain their function, therefore, they are unavoidably detached from the patient. For the purpose of re-preservation of the function, they are minced into small segments and transplanted into the fat or muscle layer. Yet, this method of auto-grafting the parathyroid glands is frequently unsuccessful due to its poor interaction and engraftment with the native tissue, eventually leading to the dysfunction of the parathyroid hormone (PTH) secretion. In this study, we suggest a methodology to restore parathyroid activity through the introduction of the 'tissue printing' concept. Parathyroid glands of patients with secondary hyperparathyroidism were minced into the fragments smaller than 0.5 × 0.5 mm, which is in common with the traditional surgical method. These parathyroid tissues (PTs) were uniformly mixed with the adipose-derived decellularized extracellular matrix (adECM) bioink that protects the PTs from hostileenvironments and promote initial engraftment. PTs-encapsulated adECM bioink (PTs-adECM) was then printed onto the pre-designed polycaprolactone (PCL) mesh to produce patch-type PTs construct, which functions as a mechanical support to further enhance long-termstability. The engineered patch was transplanted subcutaneously into rats and harvested after 4 weeks.results showed that the engineered patches were well engrafted and stabilized in their original position for 4 weeks as compared with PTs only. Immunohistochemistry results further revealed that the concentration of PTH was approximately 2.5-fold greater in rats engrafted in the patch. Taken together, we envision that the novel concept 'tissue printing' over cell printing could provide a closer step towards clinical applications of 3D bioprinting to solve the unmet need for parathyroid surgery method.
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http://dx.doi.org/10.1088/1758-5090/abf740DOI Listing
April 2021

Quadruple ultrasound, photoacoustic, optical coherence, and fluorescence fusion imaging with a transparent ultrasound transducer.

Proc Natl Acad Sci U S A 2021 03;118(11)

School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, 37673 Pohang, Republic of Korea;

Ultrasound and optical imagers are used widely in a variety of biological and medical applications. In particular, multimodal implementations combining light and sound have been actively investigated to improve imaging quality. However, the integration of optical sensors with opaque ultrasound transducers suffers from low signal-to-noise ratios, high complexity, and bulky form factors, significantly limiting its applications. Here, we demonstrate a quadruple fusion imaging system using a spherically focused transparent ultrasound transducer that enables seamless integration of ultrasound imaging with photoacoustic imaging, optical coherence tomography, and fluorescence imaging. As a first application, we comprehensively monitored multiparametric responses to chemical and suture injuries in rats' eyes in vivo, such as corneal neovascularization, structural changes, cataracts, and inflammation. As a second application, we successfully performed multimodal imaging of tumors in vivo, visualizing melanomas without using labels and visualizing 4T1 mammary carcinomas using PEGylated gold nanorods. We strongly believe that the seamlessly integrated multimodal system can be used not only in ophthalmology and oncology but also in other healthcare applications with broad impact and interest.
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http://dx.doi.org/10.1073/pnas.1920879118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980418PMC
March 2021

Controlling Cancer Cell Behavior by Improving the Stiffness of Gastric Tissue-Decellularized ECM Bioink With Cellulose Nanoparticles.

Front Bioeng Biotechnol 2021 17;9:605819. Epub 2021 Mar 17.

School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang, South Korea.

A physiologically relevant tumor microenvironment is favorable for the progression and growth of gastric cancer cells. To simulate the tumor-specific conditions of environments, several biomaterials engineering studies have investigated three-dimensional (3D) cultures. However, the implementation of such cultures remains limited because of challenges in outlining the biochemical and biophysical characteristics of the gastric cancer microenvironment. In this study, we developed a 3D cell printing-based gastric cancer model, using a combination of gastric tissue-specific bioinks and cellulose nanoparticles (CN) to provide adequate stiffness to gastric cancer cells. To create a 3D gastric tissue-specific microenvironment, we developed a decellularization process for a gastric tissue-derived decellularized extracellular matrix (g-dECM) bioink, and investigated the effect of the g-dECM bioink on promoting the aggressiveness of gastric cancer cells using histological and genetic validation methods. We found that incorporating CN in the matrix improves its mechanical properties, which supports the progression of gastric cancer. These mechanical properties are distinguishing characteristics that can facilitate the development of an gastric cancer model. Further, the CN-supplemented g-dECM bioink was used to print a variety of free-standing 3D shapes, including gastric rugae. These results indicate that the proposed model can be used to develop a physiologically relevant gastric cancer system that can be used in future preclinical trials.
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http://dx.doi.org/10.3389/fbioe.2021.605819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009980PMC
March 2021

Engineering of diseased human skin equivalent using 3D cell printing for representing pathophysiological hallmarks of type 2 diabetes in vitro.

Biomaterials 2021 05 24;272:120776. Epub 2021 Mar 24.

POSTECH-Catholic Biomedical Engineering Institute, POSTECH, Pohang, Kyungbuk, 37673, Republic of Korea; Department of Mechanical Engineering, POSTECH, 77 Cheongam-ro, Nam-gu, Pohang, Kyungbuk, 37673, Republic of Korea. Electronic address:

Despite many significant advances in 3D cell printing for skin, a disease model displaying the pathological processes present in the native skin has not been reported yet. Therefore, we were motivated for modeling a 3D diseased skin tissue with pathophysiological hallmarks of type 2 diabetes in vitro based on 3D cell printing technique. By stimulating epidermal-dermal intercellular crosstalk found in the native skin, it was hypothesized that normal keratinocytes would be differentiated as diabetic epidermis when interacting with the diabetic dermal compartment. To prove this, a novel wounded skin model was successfully devised during tissue maturation in vitro. Interestingly, the slow re-epithelization was observed in our diabetic model, which is a representative hallmark of diabetic skin. Using the versatility of 3D cell printing, the structural similarities and diabetic properties of the model were further augmented by addition of perfusable vascularized diabetic hypodermis. Insulin resistance, adipocyte hypertrophy, inflammatory reactions, and vascular dysfunction, as the typical hallmarks in diabetes, were found under hyperglycemia. Finally, the feasibility of this new disease model for drug development was successfully demonstrated through application of test drugs. We trust that this study provides a pioneering step towards 3D cell printing-based in vitro skin disease modeling.
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http://dx.doi.org/10.1016/j.biomaterials.2021.120776DOI Listing
May 2021

3D Cell-Printed Hypoxic Cancer-on-a-Chip for Recapitulating Pathologic Progression of Solid Cancer.

J Vis Exp 2021 01 5(167). Epub 2021 Jan 5.

Department of Mechanical Engineering, Pohang University of Science and Technology (POSTECH); Department of Rural and Biosystems Engineering, College of Agriculture and Life Sciences, Chonnam National University;

Cancer microenvironment has a significant impact on the progression of the disease. In particular, hypoxia is the key driver of cancer survival, invasion, and chemoresistance. Although several in vitro models have been developed to study hypoxia-related cancer pathology, the complex interplay of the cancer microenvironment observed in vivo has not been reproduced yet owing to the lack of precise spatial control. Instead, 3D biofabrication approaches have been proposed to create microphysiological systems for better emulation of cancer ecology and accurate anticancer treatment evaluation. Herein, we propose a 3D cell-printing approach to fabricate a hypoxic cancer-on-a-chip. The hypoxia-inducing components in the chip were determined based on a computer simulation of the oxygen distribution. Cancer-stroma concentric rings were printed using bioinks containing glioblastoma cells and endothelial cells to recapitulate a type of solid cancer. The resulting chip realized central hypoxia and aggravated malignancy in cancer with the formation of representative pathophysiological markers. Overall, the proposed approach for creating a solid-cancer-mimetic microphysiological system is expected to bridge the gap between in vivo and in vitro models for cancer research.
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http://dx.doi.org/10.3791/61945DOI Listing
January 2021

A Wearable Surface-Enhanced Raman Scattering Sensor for Label-Free Molecular Detection.

ACS Appl Mater Interfaces 2021 Jan 6;13(2):3024-3032. Epub 2021 Jan 6.

Department of Nano-Bio Convergence, Korea Institute of Materials Science (KIMS), Changwon, Gyeongnam 51508, Republic of Korea.

A wearable surface-enhanced Raman scattering (SERS) sensor has been developed as a patch type to utilize as a molecular sweat sensor. Here, the SERS patch sensor is designed to comprise a sweat-absorbing layer, which is an interface to the human skin, an SERS active layer, and a dermal protecting layer that prevents damage and contaminations. A silk fibroin protein film (SFF) is a basement layer that absorbs aqueous solutions and filtrates molecules larger than the nanopores created in the β-sheet matrix of the SFF. On the SFF layer, a plasmonic silver nanowire (AgNW) layer is formed to enhance the Raman signal of the molecules that penetrated through the SERS patch in a label-free method. A transparent dermal protecting layer (DP) allows laser penetration to the AgNW layer enabling Raman measurement through the SERS patch without its detachment from the surface. The molecular detection capability and time-dependent absorption properties of the SERS patch are investigated, and then, the feasibility of its use as a wearable drug detection sweat sensor is demonstrated using 2-fluoro-methamphetamine (2-FMA) on the human cadaver skin. It is believed that the developed SERS patch can be utilized as various flexible and wearable biosensors for healthcare monitoring.
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http://dx.doi.org/10.1021/acsami.0c18892DOI Listing
January 2021

Microphysiological Systems for Neurodegenerative Diseases in Central Nervous System.

Micromachines (Basel) 2020 Sep 16;11(9). Epub 2020 Sep 16.

Department of Mechanical Engineering, Pohang University of Science and Technology (POSTECH), 77 Chungam-ro, Nam-gu, Pohang 37673, Korea.

Neurodegenerative diseases are among the most severe problems in aging societies. Various conventional experimental models, including 2D and animal models, have been used to investigate the pathogenesis of (and therapeutic mechanisms for) neurodegenerative diseases. However, the physiological gap between humans and the current models remains a hurdle to determining the complexity of an irreversible dysfunction in a neurodegenerative disease. Therefore, preclinical research requires advanced experimental models, i.e., those more physiologically relevant to the native nervous system, to bridge the gap between preclinical stages and patients. The neural microphysiological system (neural MPS) has emerged as an approach to summarizing the anatomical, biochemical, and pathological physiology of the nervous system for investigation of neurodegenerative diseases. This review introduces the components (such as cells and materials) and fabrication methods for designing a neural MPS. Moreover, the review discusses future perspectives for improving the physiological relevance to native neural systems.
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http://dx.doi.org/10.3390/mi11090855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7570039PMC
September 2020

3D printing of drug-loaded multi-shell rods for local delivery of bevacizumab and dexamethasone: A synergetic therapy for retinal vascular diseases.

Acta Biomater 2020 10 11;116:174-185. Epub 2020 Sep 11.

School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology (POSTECH), Pohang, South Korea; Department of Mechanical Engineering, Pohang University of Science and Technology (POSTECH), Pohang, South Korea. Electronic address:

The clinical therapy for retinal vascular diseases requires repeated intravitreal injections of drugs owing to their short half-life, which imposes health and economic burdens on patients. Therefore, it is necessary to develop an advanced drug delivery system that can prolong the drug activity and minimize secondary complications. In this study, we developed a core/shell drug-loaded rod (drug rod) to deliver two types of drugs (bevacizumab (BEV) and dexamethasone (DEX)) from a single implant. The coaxial printing technique allowed BEV and DEX to be released with different kinetics at the same site by using a polymeric shell and a hydrogel core, respectively. The suggested printing technique facilitates the production of drug rods with various dimensions and drug concentrations, and the multi-layered design allows to adjust the release profile of dual drug-delivery system. The rod was injected in rat vitreous less invasively using a small-gauge needle. Further, we validated the efficacy of the implanted drug rods in inhibiting inflammatory responses and long-term suppression of neovascularization compared to the conventional intravitreal injection of BEV in animal model, indicating that the drug rods can be an alternative therapeutic approach for the treatment of various types of retinal vascular diseases.
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http://dx.doi.org/10.1016/j.actbio.2020.09.015DOI Listing
October 2020

Decellularized Extracellular Matrix-based Bioinks for Engineering Tissue- and Organ-specific Microenvironments.

Chem Rev 2020 10 31;120(19):10608-10661. Epub 2020 Jul 31.

Department of Mechanical Engineering, Pohang University of Science and Technology (POSTECH), 77 Cheongam-ro, Namgu, Pohang, Kyungbuk 37673, Republic of Korea.

Biomaterials-based biofabrication methods have gained much attention in recent years. Among them, 3D cell printing is a pioneering technology to facilitate the recapitulation of unique features of complex human tissues and organs with high process flexibility and versatility. Bioinks, combinations of printable hydrogel and cells, can be utilized to create 3D cell-printed constructs. The bioactive cues of bioinks directly trigger cells to induce tissue morphogenesis. Among the various printable hydrogels, the tissue- and organ-specific decellularized extracellular matrix (dECM) can exert synergistic effects in supporting various cells at any component by facilitating specific physiological properties. In this review, we aim to discuss a new paradigm of dECM-based bioinks able to recapitulate the inherent microenvironmental niche in 3D cell-printed constructs. This review can serve as a toolbox for biomedical engineers who want to understand the beneficial characteristics of the dECM-based bioinks and a basic set of fundamental criteria for printing functional human tissues and organs.
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http://dx.doi.org/10.1021/acs.chemrev.9b00808DOI Listing
October 2020

Multi-layered Free-form 3D Cell-printed Tubular Construct with Decellularized Inner and Outer Esophageal Tissue-derived Bioinks.

Sci Rep 2020 04 29;10(1):7255. Epub 2020 Apr 29.

Department of Creative IT Engineering, Pohang University of Science and Technology, San 31, Pohang, Gyeongbuk, Republic of Korea.

The incidences of various esophageal diseases (e.g., congenital esophageal stenosis, tracheoesophageal fistula, esophageal atresia, esophageal cancer) are increasing, but esophageal tissue is difficult to be recovered because of its weak regenerative capability. There are no commercialized off-the-shelf alternatives to current esophageal reconstruction and regeneration methods. Surgeons usually use ectopic conduit tissues including stomach and intestine, presumably inducing donor site morbidity and severe complications. To date, polymer-based esophageal substitutes have been studied as an alternative. However, the fabrication techniques are nearly limited to creating only cylindrical outer shapes with the help of additional apparatus (e.g., mandrels for electrospinning) and are unable to recapitulate multi-layered characteristic or complex-shaped inner architectures. 3D bioprinting is known as a suitable method to fabricate complex free-form tubular structures with desired pore characteristic. In this study, we developed a extrusion-based 3D printing technique to control the size and the shape of the pore in a single extrusion process, so that the fabricated structure has a higher flexibility than that fabricated in the conventional process. Based on this suggested technique, we developed a bioprinted 3D esophageal structure with multi-layered features and converged with biochemical microenvironmental cues of esophageal tissue by using decellularizedbioinks from mucosal and muscular layers of native esophageal tissues. The two types of esophageal tissue derived-decellularized extracellular matrix bioinks can mimic the inherent components and composition of original tissues with layer specificity. This structure can be applied to full-thickness circumferential esophageal defects and esophageal regeneration.
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http://dx.doi.org/10.1038/s41598-020-64049-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190629PMC
April 2020

Recapitulation of the accessible interface of biopsy-derived canine intestinal organoids to study epithelial-luminal interactions.

PLoS One 2020 17;15(4):e0231423. Epub 2020 Apr 17.

Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, United States of America.

Recent advances in canine intestinal organoids have expanded the option for building a better in vitro model to investigate translational science of intestinal physiology and pathology between humans and animals. However, the three-dimensional geometry and the enclosed lumen of canine intestinal organoids considerably hinder the access to the apical side of epithelium for investigating the nutrient and drug absorption, host-microbiome crosstalk, and pharmaceutical toxicity testing. Thus, the creation of a polarized epithelial interface accessible from apical or basolateral side is critical. Here, we demonstrated the generation of an intestinal epithelial monolayer using canine biopsy-derived colonic organoids (colonoids). We optimized the culture condition to form an intact monolayer of the canine colonic epithelium on a nanoporous membrane insert using the canine colonoids over 14 days. Transmission and scanning electron microscopy revealed a physiological brush border interface covered by the microvilli with glycocalyx, as well as the presence of mucin granules, tight junctions, and desmosomes. The population of stem cells as well as differentiated lineage-dependent epithelial cells were verified by immunofluorescence staining and RNA in situ hybridization. The polarized expression of P-glycoprotein efflux pump was confirmed at the apical membrane. Also, the epithelial monolayer formed tight- and adherence-junctional barrier within 4 days, where the transepithelial electrical resistance and apparent permeability were inversely correlated. Hence, we verified the stable creation, maintenance, differentiation, and physiological function of a canine intestinal epithelial barrier, which can be useful for pharmaceutical and biomedical researches.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0231423PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164685PMC
July 2020

In vivo priming of human mesenchymal stem cells with hepatocyte growth factor-engineered mesenchymal stem cells promotes therapeutic potential for cardiac repair.

Sci Adv 2020 03 25;6(13):eaay6994. Epub 2020 Mar 25.

Department of Medical Life Science, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 137701, Republic of Korea.

The clinical use of human bone marrow-derived mesenchymal stem cells (BM-MSCs) has been hampered by their poor performance after transplantation into failing hearts. Here, to improve the therapeutic potential of BM-MSCs, we developed a strategy termed in vivo priming in which BM-MSCs are primed in vivo in myocardial infarction (MI)-induced hearts through genetically engineered hepatocyte growth factor-expressing MSCs (HGF-eMSCs) that are encapsulated within an epicardially implanted 3D cardiac patch. Primed BM-MSCs through HGF-eMSCs exhibited improved vasculogenic potential and cell viability, which ultimately enhanced vascular regeneration and restored cardiac function to the MI hearts. Histological analyses further demonstrated that the primed BM-MSCs survived longer within a cardiac patch and conferred cardioprotection evidenced by substantially higher numbers of viable cardiomyocytes in the MI hearts. These results provide compelling evidence that this in vivo priming strategy can be an effective means to enhance the cardiac repair of MI hearts.
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http://dx.doi.org/10.1126/sciadv.aay6994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141892PMC
March 2020

3D cell printing of islet-laden pancreatic tissue-derived extracellular matrix bioink constructs for enhancing pancreatic functions.

J Mater Chem B 2019 03 16;7(10):1773-1781. Epub 2019 Jan 16.

Department of Mechanical Engineering, Pohang University of Science and Technology (POSTECH), Pohang, Korea.

Type 1 diabetes mellitus (T1DM) is a form of diabetes that inhibits or halts insulin production in the pancreas. Although various therapeutic options are applied in clinical settings, not all patients are treatable with such methods due to the instability of the T1DM or the unawareness of hypoglycemia. Islet transplantation using a tissue engineering-based approach may mark a clinical significance, but finding ways to increase the function of islets in 3D constructs is a major challenge. In this study, we suggest pancreatic tissue-derived extracellular matrix as a potential candidate to recapitulate the native microenvironment in transplantable 3D pancreatic tissues. Notably, insulin secretion and the maturation of insulin-producing cells derived from human pluripotent stem cells were highly up-regulated when cultured in pdECM bioink. In addition, co-culture with human umbilical vein-derived endothelial cells decreased the central necrosis of islets under 3D culture conditions. Through the convergence of 3D cell printing technology, we validated the possibility of fabricating 3D constructs of a therapeutically applicable transplant size that can potentially be an allogeneic source of islets, such as patient-induced pluripotent stem cell-derived insulin-producing cells.
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http://dx.doi.org/10.1039/c8tb02787kDOI Listing
March 2019

3D Bioprinting Strategies for the Regeneration of Functional Tubular Tissues and Organs.

Bioengineering (Basel) 2020 Mar 31;7(2). Epub 2020 Mar 31.

Department of Mechanical Engineering, Wonkwang University, 54538, Iksan-daero 460, Iksan-si, Jeollabuk-do, Korea.

It is difficult to fabricate tubular-shaped tissues and organs (e.g., trachea, blood vessel, and esophagus tissue) with traditional biofabrication techniques (e.g., electrospinning, cell-sheet engineering, and mold-casting) because these have complicated multiple processes. In addition, the tubular-shaped tissues and organs have their own design with target-specific mechanical and biological properties. Therefore, the customized geometrical and physiological environment is required as one of the most critical factors for functional tissue regeneration. 3D bioprinting technology has been receiving attention for the fabrication of patient-tailored and complex-shaped free-form architecture with high reproducibility and versatility. Printable biocomposite inks that can facilitate to build tissue constructs with polymeric frameworks and biochemical microenvironmental cues are also being actively developed for the reconstruction of functional tissue. In this review, we delineated the state-of-the-art of 3D bioprinting techniques specifically for tubular tissue and organ regeneration. In addition, this review described biocomposite inks, such as natural and synthetic polymers. Several described engineering approaches using 3D bioprinting techniques and biocomposite inks may offer beneficial characteristics for the physiological mimicry of human tubular tissues and organs.
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http://dx.doi.org/10.3390/bioengineering7020032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357036PMC
March 2020

A 3-Dimensional Bioprinted Scaffold With Human Umbilical Cord Blood-Mesenchymal Stem Cells Improves Regeneration of Chronic Full-Thickness Rotator Cuff Tear in a Rabbit Model.

Am J Sports Med 2020 03;48(4):947-958

Department and Research Institute of Rehabilitation Medicine, College of Medicine, Yonsei University, Seoul, Republic of Korea.

Background: Chronic full-thickness rotator cuff tears (FTRCTs) represent a major clinical concern because they show highly compromised healing capacity.

Purpose: To evaluate the efficacy of using a 3-dimensional (3D) bioprinted scaffold with human umbilical cord blood (hUCB)-mesenchymal stem cells (MSCs) for regeneration of chronic FTRCTs in a rabbit model.

Study Design: Controlled laboratory study.

Methods: A total of 32 rabbits were randomly assigned to 4 treatment groups (n = 8 per group) at 6 weeks after a 5-mm FTRCT was created on the supraspinatus tendon. Group 1 (G1-SAL) was transplanted with normal saline. Group 2 (G2-MSC) was transplanted with hUCB-MSCs (0.2 mL, 1 × 10) into FTRCTs. Group 3 (G3-3D) was transplanted with a 3D bioprinted construct without MSCs, and group 4 (G4-3D+MSC) was transplanted with a 3D bioprinted construct containing hUCB-MSCs (0.2 mL, 1 × 10 cells) into FTRCTs. All 32 rabbits were euthanized at 4 weeks after treatment. Examination of gross morphologic changes and histologic results was performed on all rabbits after sacrifice. Motion analysis was also performed before and after treatment.

Results: In G4-3D+MSC, newly regenerated collagen type 1 fibers, walking distance, fast walking time, and mean walking speed were greater than those in G2-MSC based on histochemical and motion analyses. In addition, when compared with G3-3D, G4-3D+MSC showed more prominent regenerated tendon fibers and better parameters of motion analysis. However, there was no significant difference in gross tear size among G2-MSC, G3-3D, and G4-3D+MSC, although these groups showed significant decreases in tear size as compared with the control group (G1-SAL).

Conclusion: Findings of this study show that a tissue engineering strategy based on a 3D bioprinted scaffold filled with hUCB-MSCs can improve the microenvironment for regenerative processes of FTRCT without any surgical repair.

Clinical Relevance: In the case of rotator cuff tear, the cell loss of the external MSCs can be increased by exposure to synovial fluid. Therefore, a 3D bioprinted scaffold in combination with MSCs without surgical repair may be effective in increasing cell retention in FTRCT.
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http://dx.doi.org/10.1177/0363546520904022DOI Listing
March 2020

The bioprinting roadmap.

Biofabrication 2020 02 6;12(2):022002. Epub 2020 Feb 6.

Department of Mechanical Engineering and Mechanics, College of Engineering, Drexel University, 3141 Chestnut Street, Philadelphia, PA 19104, United States of America. Department of Mechanical Engineering, Tsinghua University, Beijing 100084, People's Republic of China.

This bioprinting roadmap features salient advances in selected applications of the technique and highlights the status of current developments and challenges, as well as envisioned advances in science and technology, to address the challenges to the young and evolving technique. The topics covered in this roadmap encompass the broad spectrum of bioprinting; from cell expansion and novel bioink development to cell/stem cell printing, from organoid-based tissue organization to bioprinting of human-scale tissue structures, and from building cell/tissue/organ-on-a-chip to biomanufacturing of multicellular engineered living systems. The emerging application of printing-in-space and an overview of bioprinting technologies are also included in this roadmap. Due to the rapid pace of methodological advancements in bioprinting techniques and wide-ranging applications, the direction in which the field should advance is not immediately clear. This bioprinting roadmap addresses this unmet need by providing a comprehensive summary and recommendations useful to experienced researchers and newcomers to the field.
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http://dx.doi.org/10.1088/1758-5090/ab5158DOI Listing
February 2020

Visibility of Bioresorbable Vascular Scaffold in Intravascular Ultrasound Imaging.

IEEE Trans Ultrason Ferroelectr Freq Control 2020 06 7;67(6):1090-1101. Epub 2020 Jan 7.

Bioresorbable vascular scaffold (BVS) has recently been spotlighted for its unique characteristics of absorbing into blood vessels and eventually disappearing. Although intravascular ultrasound (IVUS) is the most common guiding tool for stent deployment, the echogenicity of BVS struts has changed as the center of stent lumen and scanning rotation is not concentric, which may cause a critical erroneous measurement in practice. This study investigated the physical conditions for dimming the stent brightness in IVUS images using a finite-difference method (FDM) to numerically solve acoustic wave propagation through nonhomogeneous medium. The dimmed brightness is caused by an angled rectangular cross section of a strut and its similar acoustic impedance with water. Imaging frequency is not a major cause. However, the angle between the acoustic beam and the BVS surface is the major cause of the dimmed brightness. As a solution, an approach using a frequency compounding method with signal polarity comparator was proposed to recover the reduced brightness without sacrificing spatial resolutions. Based on the simulation study, the signal level from BVS can be attenuated down by 17 dB when the angle between the acoustic beamline and the surface of BVS is more than 45°. With the proposed frequency compounding approach, the reduced signal can be recovered by 6 dB. In the experimental BVS IVUS imaging, strut brightness was reduced by 18 dB with an angled strut position and recovered by 5 dB with the proposed frequency compounding method. A pig coronary was imaged to demonstrate the performance of the proposed method.
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http://dx.doi.org/10.1109/TUFFC.2020.2964322DOI Listing
June 2020

Pancreatic Tissue-Derived Extracellular Matrix Bioink for Printing 3D Cell-Laden Pancreatic Tissue Constructs.

J Vis Exp 2019 12 13(154). Epub 2019 Dec 13.

Department of Mechanical Engineering, Pohang University of Science and Technology; School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology; Department of Creative IT Engineering, Pohang University of Science and Technology;

The transplantation of pancreatic islets is a promising treatment for patients who suffer from type 1 diabetes accompanied by hypoglycemia and secondary complications. However, islet transplantation still has several limitations such as the low viability of transplanted islets due to poor islet engraftment and hostile environments. In addition, the insulin-producing cells differentiated from human pluripotent stem cells have limited ability to secrete sufficient hormones that can regulate the blood glucose level; therefore, improving the maturation by culturing cells with proper microenvironmental cues is strongly required. In this article, we elucidate protocols for preparing a pancreatic tissue-derived decellularized extracellular matrix (pdECM) bioink to provide a beneficial microenvironment that can increase glucose sensitivity of pancreatic islets, followed by describing the processes for generating 3D pancreatic tissue constructs using a microextrusion-based bioprinting technique.
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http://dx.doi.org/10.3791/60434DOI Listing
December 2019

Accelerated Bone Regeneration via Three-Dimensional Cell-Printed Constructs Containing Human Nasal Turbinate-Derived Stem Cells as a Clinically Applicable Therapy.

ACS Biomater Sci Eng 2019 Nov 31;5(11):6171-6185. Epub 2019 Oct 31.

Department of Otolaryngology-Head and Neck Surgery, Seoul St. Mary's Hospital, The Catholic University of Korea, 222 Banpo-Daero, Seocho-gu, Seoul 06591, Republic of Korea.

Stem cell transplantation is a promising therapeutic strategy that includes both cell therapy and tissue engineering for the treatment of many regenerative diseases; however, the efficacy and safety of stem cell therapy depend on the cell type used in therapeutic and translational applications. In this study, we validated the hypothesis that human nasal turbinate-derived mesenchymal stem cells (hTMSCs) are a potential therapeutic source of adult stem cells for clinical use in bone tissue engineering using three-dimensional (3D) cell-printing technology. hTMSCs were cultured and evaluated for clinical use according to their cell growth, cell size, and preclinical safety and were then incorporated into a multicompositional 3D bioprinting system and investigated for bone tissue regeneration in vitro and in vivo. Finally, hTMSCs were compared with human bone marrow-derived MSCs (hBMSCs), which are the most common stem cell type used in regenerative medicine. hTMSCs from three different donors showed greater and faster cell growth than hBMSCs from two different donors when cultured. The hTMSCs were smaller in size than the hBMSCs. Furthermore, the hTMSCs did not exhibit safety issues in immunodeficient mice. hTMSCs in 3D-printed constructs (3D-hTMSC) showed much greater viability, growth, and osteogenic differentiation potential in vitro than hBMSCs in 3D-printed constructs (3D-hBMSC). Likewise, 3D-hTMSC showed better cell survival and alkaline phosphatase activity and greater osteogenic protein expression than 3D-hBMSC upon subcutaneous implantation into the dorsal region of nude mice. Notably, in an orthotopic model involving implantation into a tibial defect in rats, implantation of 3D-hTMSC led to greater bone matrix formation and enhanced bone healing to a greater degree than implantation of 3D-hBMSC. The clinically reliable evidence provided by these results is underlined by the potential for rapid tissue regeneration and ambulation in bone fracture patients implanted with 3D-hTMSC.
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http://dx.doi.org/10.1021/acsbiomaterials.9b01356DOI Listing
November 2019

Directed differential behaviors of multipotent adult stem cells from decellularized tissue/organ extracellular matrix bioinks.

Biomaterials 2019 12 12;224:119496. Epub 2019 Sep 12.

Department of Mechanical Engineering, Pohang University of Science and Technology, Pohang, 37673, Republic of Korea. Electronic address:

The decellularized tissue/organ extracellular matrix (dECM) is a naturally derived biomaterial that inherits various functional components from the native tissue or organ. Recently, various kinds of tissue/organ dECM bioinks capable of encapsulating cells, combined with 3D cell printing, have enabled remarkable progress in tissue engineering and regenerative medicine. However, the way in which the dECM component compositions of each tissue of different origins interact with cells and dictate tissue-specific cell behavior in the 3D microenvironment remains mostly unknown. To address this issue, in-depth differential proteomic analyses of four porcine dECMs were performed. Specifically, the differential variations of matrisome protein composition in each decellularized tissue type were also uncovered, which can play a significant role by affecting the resident cells in specific tissues. Furthermore, microarray analyses of human bone marrow mesenchymal stem cells (hBMMSCs) printed with various dECM bioinks were conducted to reveal the effect of compositional variations in a tissue-specific manner at the cellular level depending on the multipotency of MSCs. Through whole transcriptome analysis, differential expression patterns of genes were observed in a tissue-specific manner, and this research provides strong evidence of the tissue-specific functionalities of dECM bioinks.
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http://dx.doi.org/10.1016/j.biomaterials.2019.119496DOI Listing
December 2019
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