Publications by authors named "Dong-Woo Cho"

164 Publications

Development of 3D Printed Bruch's Membrane-Mimetic Substance for the Maturation of Retinal Pigment Epithelial Cells.

Int J Mol Sci 2021 Jan 22;22(3). Epub 2021 Jan 22.

Department of Mechanical Engineering, Pohang University of Science and Technology (POSTECH), Pohang 37673, Korea.

Retinal pigment epithelium (RPE) is a monolayer of the pigmented cells that lies on the thin extracellular matrix called Bruch's membrane. This monolayer is the main component of the outer blood-retinal barrier (BRB), which plays a multifunctional role. Due to their crucial roles, the damage of this epithelium causes a wide range of diseases related to retinal degeneration including age-related macular degeneration, retinitis pigmentosa, and Stargardt disease. Unfortunately, there is presently no cure for these diseases. Clinically implantable RPE for humans is under development, and there is no practical examination platform for drug development. Here, we developed porcine Bruch's membrane-derived bioink (BM-ECM). Compared to conventional laminin, the RPE cells on BM-ECM showed enhanced functionality of RPE. Furthermore, we developed the Bruch's membrane-mimetic substrate (BMS) via the integration of BM-ECM and 3D printing technology, which revealed structure and extracellular matrix components similar to those of natural Bruch's membrane. The developed BMS facilitated the appropriate functions of RPE, including barrier and clearance functions, the secretion of anti-angiogenic growth factors, and enzyme formation for phototransduction. Moreover, it could be used as a basement frame for RPE transplantation. We established BMS using 3D printing technology to grow RPE cells with functions that could be used for an in vitro model and RPE transplantation.
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http://dx.doi.org/10.3390/ijms22031095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865340PMC
January 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

Application of Gelatin Bioinks and Cell-Printing Technology to Enhance Cell Delivery Capability for 3D Liver Fibrosis-on-a-Chip Development.

ACS Biomater Sci Eng 2020 Apr 4;6(4):2469-2477. Epub 2020 Mar 4.

Department of Mechanical Engineering, Pohang University of Science and Technology (POSTECH), 77 Cheongam-ro, Hyogok-dong, Nam-gu, Pohang-si, Gyeongsangbuk-do, 37673, South Korea.

Liver fibrosis is a critical liver disease which can lead to liver cirrhosis, cancer, and liver failure. Among various etiological factors, activated stellate cells are a major factor that can induce liver fibrosis. Several studies have presented models to identify drugs for liver fibrosis; however, there are still limitations in terms of the 2D culture conditions, random co-culture of liver cells, and lack of extracellular matrix components. Therefore, a 3D liver fibrosis-on-a-chip was developed with three liver cell types (hepatocytes, activated stellate cells, and endothelial cells) using a novel cell-printing technique with gelatin bioinks, which were used to deliver each nonparenchymal liver cell type as a multilayer construct. Liver fibrosis-specific gene expression, collagen accumulation, cell apoptosis, and reduced liver functions caused by activated stellate cells were also evaluated. Furthermore, previously reported chemicals were added to the 3D liver fibrosis-on-a-chip to examine the downregulation of activated hepatic stellate cells. In conclusion, the developed 3D liver fibrosis-on-a-chip could be used as a potential model in the research field.
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http://dx.doi.org/10.1021/acsbiomaterials.9b01735DOI Listing
April 2020

3D cell-printing of tendon-bone interface using tissue-derived extracellular matrix bioinks for chronic rotator cuff repair.

Biofabrication 2020 Dec 7. Epub 2020 Dec 7.

Department of Mechanical Engineering, Pohang University of Science and Technology, 77 Cheongam-ro, Nam-gu, Pohang, Gyeongsangbuk-do, 37673, Korea (the Republic of).

The tendon-bone interface (TBI) in rotator cuffs exhibits a structural and compositional gradient integrated through the fibrocartilaginous transition. Owing to restricted healing capacity, functional regeneration of the TBI is considered a great clinical challenge. Here, we establish a novel therapeutic platform based on 3D cell-printing and tissue-specific bioinks to achieve spatially-graded physiology for functional TBI regeneration. The 3D cell-printed TBI patch constructs are created via a spatial arrangement of cell-laden tendon and bone-specific bioinks in a graded manner, approximating a multi-tissue fibrocartilaginous interface. This TBI patch offers a cell favorable microenvironment, including high cell viability, proliferative capacity, and zonal-specific differentiation of encapsulated stem cells for TBI formation in vitro. Furthermore, in vivo application of spatially-graded TBI patches with stem cells demonstrates their regenerative potential, indicating that repair with 3D cell-printed TBI patch significantly accelerates and promotes TBI healing in a rat chronic tear model. Therefore, our findings propose a new therapeutic strategy for functional TBI regeneration using 3D cell-printing and tissue-specific decellularized extracellular matrix (dECM) bioink-based approach.
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http://dx.doi.org/10.1088/1758-5090/abd159DOI Listing
December 2020

Flexible Adipose-Vascular Tissue Assembly Using Combinational 3D Printing for Volume-Stable Soft Tissue Reconstruction.

Adv Healthc Mater 2020 Nov 25:e2001693. Epub 2020 Nov 25.

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

A new concept, assembling cell-laden tissue modules, is for the first time proposed for soft tissue engineering. Adipose-vascular tissue modules composed of a synthetic polymer-based substructure and customized bioinks using planar 3D cell printing are engineered. Such tissue modules are systematically assembled into a synthetic polymer-based module holder fabricated with rotational 3D printing, resulting in the development of a flexible and volumetric tissue assembly. Whereas most of the previous studies about the construction of adipose tissue are limited to hypoxia, poor vascularization, rapid resorption, and mismatch in mechanical properties, it is aimed to realize the construction of nonhypoxic, flexible, and volume-stable tissue assembly in this study. The significance of engineered tissue assembly is proven through various in vitro and in vivo evaluations. In particular, stable volume and remarkable neovascularization/adipogenesis are observed in the implanted assembly over four weeks. Interestingly, the size of newly formed lipid droplets and the remodeled morphology in the assembly are comparable to those in native adipose tissue. As far as it is known, this work is a first report suggesting a cell printing-based tissue assembly for functional reconstruction of soft tissue.
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http://dx.doi.org/10.1002/adhm.202001693DOI Listing
November 2020

3D cell-printing of biocompatible and functional meniscus constructs using meniscus-derived bioink.

Biomaterials 2021 Jan 20;267:120466. Epub 2020 Oct 20.

Department of Mechanical Engineering, Pohang University of Science and Technology, 77 Cheongam-ro, Nam-gu, Pohang, 37673, Kyungbuk, South Korea; Postech-Catholic Biomedical Engineering Institute, Pohang University of Science and Technology, 77 Cheongam-ro, Nam-gu, Pohang, 37673, Kyungbuk, South Korea; Institute of Convergence Science, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, South Korea. Electronic address:

Meniscus injuries are prevalent in orthopedic diagnosis. The reconstruction of the structural inhomogeneity and anisotropy of the meniscus is a major challenge in clinical practice. Meniscal tissue engineering has emerged as a potential alternative for the treatment of various meniscal diseases and injuries. In this study, we developed three-dimensional (3D) cell-printed meniscus constructs using a mixture of polyurethane and polycaprolactone polymers and cell-laden decellularized meniscal extracellular matrix (me-dECM) bioink with high controllability and durable architectural integrity. The me-dECM bioink provided 3D cell-printed meniscus constructs with a conducive biochemical environment that supported growth and promoted the proliferation and differentiation of encapsulated stem cells toward fibrochondrogenic commitment. In addition, we investigated the in vivo performance of the 3D cell-printed meniscus constructs, which exhibited biocompatibility, excellent mechanical properties, and improved biological functionality. These attributes were similar to those of the native meniscus. Collectively, the 3D cell-printing technology and me-dECM bioink facilitate the recapitulation of meniscus tissue specificity in the aspect of the shape and microenvironment for meniscus regeneration. Further, the developed constructs can potentially be applied in clinical practice.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120466DOI Listing
January 2021

Therapeutic effect of decellularized extracellular matrix-based hydrogel for radiation esophagitis by 3D printed esophageal stent.

Biomaterials 2021 Jan 19;266:120477. Epub 2020 Oct 19.

Department of Mechanical Engineering, Pohang University of Science and Technology, Pohang, South Korea; School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang, South Korea; Center for Rapid Prototyping based 3D Tissue/Organ Printing, Pohang University of Science and Technology, Pohang, South Korea; Postech-Catholic Biomedical Engineering Institute, Pohang University of Science and Technology, Pohang, South Korea; Institute of Convergence Science, Yonsei University, Seoul, South Korea. Electronic address:

Radiation esophagitis, the most common acute adverse effect of radiation therapy, leads to unwanted consequences including discomfort, pain, an even death. However, no direct cure exists for patients suffering from this condition, with the harmful effect of ingestion and acid reflux on the damaged esophageal mucosa remaining an unresolved problem. Through the delivery of the hydrogel with stent platform, we aimed to evaluate the regenerative capacity of a tissue-specific decellularized extracellular matrix (dECM) hydrogel on damaged tissues. For this, an esophagus-derived dECM (EdECM) was developed and shown to have superior biofunctionality and rheological properties, as well as physical stability, potentially providing a better microenvironment for tissue development. An EdECM hydrogel-loaded stent was sequentially fabricated using a rotating rod combined 3D printing system that showed structural stability and protected a loaded hydrogel during delivery. Finally, following stent implantation, the therapeutic effect of EdECM was examined in a radiation esophagitis rat model. Our findings demonstrate that EdECM hydrogel delivery via a stent platform can rapidly resolve an inflammatory response, thus promoting a pro-regenerative microenvironment. The results suggest a promising therapeutic strategy for the treatment of radiation esophagitis.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120477DOI Listing
January 2021

3D Cell Printing of Tissue/Organ-Mimicking Constructs for Therapeutic and Drug Testing Applications.

Int J Mol Sci 2020 Oct 20;21(20). Epub 2020 Oct 20.

Department of Mechanical Engineering, Pohang University of Science and Technology (POSTECH), Pohang 37673, Korea.

The development of artificial tissue/organs with the functional maturity of their native equivalents is one of the long-awaited panaceas for the medical and pharmaceutical industries. Advanced 3D cell-printing technology and various functional bioinks are promising technologies in the field of tissue engineering that have enabled the fabrication of complex 3D living tissue/organs. Various requirements for these tissues, including a complex and large-volume structure, tissue-specific microenvironments, and functional vasculatures, have been addressed to develop engineered tissue/organs with native relevance. Functional tissue/organ constructs have been developed that satisfy such criteria and may facilitate both in vivo replenishment of damaged tissue and the development of reliable in vitro testing platforms for drug development. This review describes key developments in technologies and materials for engineering 3D cell-printed constructs for therapeutic and drug testing applications.
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http://dx.doi.org/10.3390/ijms21207757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589604PMC
October 2020

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

Scenarios of energy reduction potential of zero energy building promotion in the Asia-Pacific region to year 2050.

Energy (Oxf) 2020 Dec 10;213:118792. Epub 2020 Sep 10.

China Academy of Building Research, Beijing, 100013, China.

Building energy consumption in the Asia-Pacific region continues to rise. It is important to understand the energy use and future trends of 21 members of Asia-Pacific Economic Cooperation (APEC) and to find more effective ways to achieve APEC's dual goals of reducing energy intensity by 45% of 2005 levels by 2035 and doubling the share of renewable energy in the energy mix between 2010 and 2030. Recently, promoting building toward ultra-low energy, nearly zero energy and zero energy is becoming a consensus trend. This paper aims to explore how zero energy building promotion could influence the total energy demand in the mid to long term. An EUPP (Economic, Urbanization, Population and Purchasing power parity) model was established to show the relationship between building energy consumption and its influencing factors, and the potential development path of building energy consumption in APEC was predicted by using the model. The results show that in the Business As Usual (BAU) model, building energy demand will increase from 1387.4 Mtoe in 2016 to 2456.8 Mtoe in 2050 while in the CAP model, building energy demand will be constrained to under 2000 Mtoe before 2050. In the ZEB promotion model, 897.8 to 1945.3 Mtoe could be saved separately. The share of end demand supplied by onsite renewable energy production could reach 11%-54%. The building sector has the potential to become the largest contributor to achieve the APEC energy goal and thus to the climate change goal.
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http://dx.doi.org/10.1016/j.energy.2020.118792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481845PMC
December 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 Oct 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

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

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

Correction to: Graft immaturity and safety concerns in transplanted human kidney organoids.

Exp Mol Med 2020 Jan;52(1):180

Cell Death Disease Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s12276-019-0366-4DOI Listing
January 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

Three-dimensional cell-printing of advanced renal tubular tissue analogue.

Biomaterials 2020 02 26;232:119734. Epub 2019 Dec 26.

Department of Mechanical Engineering, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea; Institute for Convergence Research and Education in Advanced Technology, Yonsei University, Seoul, Republic of Korea; Postech-Catholic Biomedical Engineering Institute, Pohang Uiniversity of Science and Technology, Pohang, Republic of Korea. Electronic address:

Despite significant progress in the development of renal tissue, recapitulation of perfusable complex renal tubular tissue with clinically relevant cellular heterogeneity is still remaining a challenge. In this study, using coaxial 3D cell-printing technique, we present microfluidic hollow tubes to realize tubular/vascular renal parenchyma composed of renal tubular epithelial and endothelial cells, respectively. We developed a functional hybrid bioink that inherits microenvironments for vascularized native kidney tissue with rapidly crosslinkable character to optimize cell functionality and retain the predefined hollow tubular structure. In addition, the novel bioink and 3D coaxial cell-printing technique provided a complex tube with tunable feature of monolayer and bilayer structure across the length of printed tube. Through prototyping a vascularized renal proximal tubule-on-a-chip, we showed its applicability to novel microfluidic renal tissue models. The renal subcapsular transplantation of the hollow tubes showed a long-term graft survival with the therapeutic capability of the tubular constructs in in vivo model of renal disease, which serves their applicability in regenerative medicine.
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http://dx.doi.org/10.1016/j.biomaterials.2019.119734DOI Listing
February 2020

Graft immaturity and safety concerns in transplanted human kidney organoids.

Exp Mol Med 2019 11 28;51(11):1-13. Epub 2019 Nov 28.

Cell Death Disease Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea.

For chronic kidney disease, regeneration of lost nephrons with human kidney organoids derived from induced pluripotent stem (iPS) cells is proposed to be an attractive potential therapeutic option. It remains unclear, however, whether organoids transplanted into kidneys in vivo would be safe or functional. Here, we purified kidney organoids and transplanted them beneath the kidney capsules of immunodeficient mice to test their safety and maturity. Kidney organoid grafts survived for months after transplantation and became vascularized from host mouse endothelial cells. Nephron-like structures in grafts appeared more mature than kidney organoids in vitro, but remained immature compared with the neighboring mouse kidney tissue. Ultrastructural analysis revealed filtration barrier-like structures, capillary lumens, and tubules with brush border in the transplanted kidney organoids, which were more mature than those of the kidney organoids in vitro but not as organized as adult mammalian kidneys. Immaturity was a common feature of three separate differentiation protocols by immunofluorescence analysis and single cell RNA sequencing. Stroma of transplanted kidney organoid grafts were filled with vimentin-positive mesenchymal cells, and chondrogenesis, cystogenesis, and stromal expansion were observed in the long term. Transcription profiles showed that long-term maintenance after kidney organoid transplantation induced transcriptomic reprogramming with prominent suppression of cell-cycle-related genes and upregulation of extracellular matrix organization. Our data suggest that kidney organoids derived from iPS cells may be transplantable but strategies to improve nephron differentiation and purity are required before they can be applied in humans as a therapeutic option.
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http://dx.doi.org/10.1038/s12276-019-0336-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881327PMC
November 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

Compressed collagen intermixed with cornea-derived decellularized extracellular matrix providing mechanical and biochemical niches for corneal stroma analogue.

Mater Sci Eng C Mater Biol Appl 2019 Oct 30;103:109837. Epub 2019 May 30.

Department of Mechanical Engineering, Pohang University of Science and Technology (POSTECH), 77 Cheongam-ro, Pohang, Gyeongbuk 37673, South Korea. Electronic address:

Compressed collagen is a promising scaffold for corneal stroma analogue due to its facile incorporation of keratocytes while mimicking the mechanical niche of a native cornea with dense collagen fibrillar structures. However, it does not offer the sufficient biochemical niche crucial for in vivo-like quiescent keratocyte phenotype. In this study, we engineered a scaffold for a corneal stroma analogue that mimics both the mechanical and biochemical niches of the corneal stroma by introducing cornea-derived decellularized extracellular matrix (Co-dECM) to the collagen compression process. The compressed collagen intermixed with Co-dECM (COLEM; Co-dECM content, <50 wt%) maintained a uniform structure and showed an elastic modulus and tensile strength on the order of 100 kPa, which is comparable with that of conventional compressed collagen. The COLEM with the 50 wt% Co-dECM content was found to possess 2-fold higher amount of the glycosaminoglycans as compared to the compressed collagen. The biochemical components of Co-dECM in the COLEM were verified to significantly promote the expression of quiescent keratocyte-specific genes, i.e., KERA and ALDH3A1, while improving the optical transmittance of the COLEM by reducing the diameter of collagen fibrils. The ability of the COLEM to construct multicellular in vitro corneal tissue was demonstrated by an additional corneal epithelial cell culture. The results support the hypothesis that COLEM has strong potential use in the development of corneal equivalent for in vitro models and tissue transplantation.
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http://dx.doi.org/10.1016/j.msec.2019.109837DOI Listing
October 2019

Dual stem cell therapy synergistically improves cardiac function and vascular regeneration following myocardial infarction.

Nat Commun 2019 07 16;10(1):3123. Epub 2019 Jul 16.

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

Since both myocardium and vasculature in the heart are excessively damaged following myocardial infarction (MI), therapeutic strategies for treating MI hearts should concurrently target both so as to achieve true cardiac repair. Here we demonstrate a concomitant method that exploits the advantages of cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) and human mesenchymal stem cell-loaded patch (hMSC-PA) to amplify cardiac repair in a rat MI model. Epicardially implanted hMSC-PA provide a complimentary microenvironment which enhances vascular regeneration through prolonged secretion of paracrine factors, but more importantly it significantly improves the retention and engraftment of intramyocardially injected hiPSC-CMs which ultimately restore the cardiac function. Notably, the majority of injected hiPSC-CMs display adult CMs like morphology suggesting that the secretomic milieu of hMSC-PA constitutes pleiotropic effects in vivo. We provide compelling evidence that this dual approach can be a promising means to enhance cardiac repair on MI hearts.
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http://dx.doi.org/10.1038/s41467-019-11091-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635499PMC
July 2019

Biocompatibility evaluation of bioprinted decellularized collagen sheet implanted in vivo cornea using swept-source optical coherence tomography.

J Biophotonics 2019 11 23;12(11):e201900098. Epub 2019 Jul 23.

School of Electronic Engineering, College of IT Engineering, Kyungpook National University, Daegu, South Korea.

Corneal transplantation by full-thickness penetrating keratoplasty with human donor tissue is a widely accepted treatment for damaged or diseased corneas. Although corneal transplantation has a high success rate, a shortage of high-quality donor tissue is a considerable limitation. Therefore, bioengineered corneas could be an effective solution for this limitation, and a decellularized extracellular matrix comprises a promising scaffold for their fabrication. In this study, three-dimensional bioprinted decellularized collagen sheets were implanted into the stromal layer of the cornea of five rabbits. We performed in vivo noninvasive monitoring of the rabbit corneas using swept-source optical coherence tomography (OCT) after implanting the collagen sheets. Anterior segment OCT images and averaged amplitude-scans were acquired biweekly to monitor corneal thickness after implantation for 1 month. The averaged cornea thickness in the control images was 430.3 ± 5.9 μm, while the averaged thickness after corneal implantation was 598.5 ± 11.8 μm and 564.5 ± 12.5 μm at 2 and 4 weeks, respectively. The corneal thickness reduction of 34 μm confirmed the biocompatibility through the image analysis of the depth-intensity profile base. Moreover, hematoxylin and eosin staining supported the biocompatibility evaluation of the bioprinted decellularized collagen sheet implantation. Hence, the developed bioprinted decellularized collagen sheets could become an alternative solution to human corneal donor tissue, and the proposed image analysis procedure could be beneficial to confirm the success of the surgery.
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http://dx.doi.org/10.1002/jbio.201900098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065634PMC
November 2019

A bioprinted human-glioblastoma-on-a-chip for the identification of patient-specific responses to chemoradiotherapy.

Nat Biomed Eng 2019 07 18;3(7):509-519. Epub 2019 Mar 18.

Department of Mechanical Engineering, POSTECH, Pohang, Korea.

Patient-specific ex vivo models of human tumours that recapitulate the pathological characteristics and complex ecology of native tumours could help determine the most appropriate cancer treatment for individual patients. Here, we show that bioprinted reconstituted glioblastoma tumours consisting of patient-derived tumour cells, vascular endothelial cells and decellularized extracellular matrix from brain tissue in a compartmentalized cancer-stroma concentric-ring structure that sustains a radial oxygen gradient, recapitulate the structural, biochemical and biophysical properties of the native tumours. We also show that the glioblastoma-on-a-chip reproduces clinically observed patient-specific resistances to treatment with concurrent chemoradiation and temozolomide, and that the model can be used to determine drug combinations associated with superior tumour killing. The patient-specific tumour-on-a-chip model might be useful for the identification of effective treatments for glioblastoma patients resistant to the standard first-line treatment.
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http://dx.doi.org/10.1038/s41551-019-0363-xDOI Listing
July 2019

Shear-induced alignment of collagen fibrils using 3D cell printing for corneal stroma tissue engineering.

Biofabrication 2019 05 7;11(3):035017. Epub 2019 May 7.

Department of Mechanical Engineering, Pohang University of Science and Technology, 77 Cheongam-ro, Pohang, Gyeongbuk, 37673, Republic of Korea.

The microenvironments of tissues or organs are complex architectures comprised of structural proteins including collagen. Particularly, the cornea is organized in a lattice pattern of collagen fibrils which play a significant role in its transparency. This paper introduces a transparent bioengineered corneal structure for transplantation. The structure is fabricated by inducing shear stress to a corneal stroma-derived decellularized extracellular matrix bioink based on a 3D cell printing technique. The printed structure recapitulates the native macrostructure of the cornea with aligned collagen fibrils which results in the construction of a highly matured and transparent cornea stroma analog. The level of shear stress, controlled by the various size of the printing nozzle, manipulates the arrangement of the fibrillar structure. With proper parameter selection, the printed cornea exhibits high cellular alignment capability, indicating a tissue-specific structural organization of collagen fibrils. In addition, this structural regulation enhances critical cellular events in the assembly of collagen over time. Interestingly, the collagen fibrils that remodeled along with the printing path create a lattice pattern similar to the structure of native human cornea after 4 weeks in vivo. Taken together, these results establish the possibilities and versatility of fabricating aligned collagen fibrils; this represents significant advances in corneal tissue engineering.
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http://dx.doi.org/10.1088/1758-5090/ab1a8bDOI Listing
May 2019

Decellularized extracellular matrix bioinks and the external stimuli to enhance cardiac tissue development in vitro.

Acta Biomater 2019 09 12;95:188-200. Epub 2019 Apr 12.

Department of Creative IT Engineering, Pohang University of Science and Technology (POSTECH), 77 Cheongam-ro, Namgu, Pohang, Kyungbuk 37673, Republic of Korea; Department of Mechanical Engineering, Pohang University of Science and Technology (POSTECH), 77 Cheongam-ro, Namgu, Pohang, Kyungbuk 37673, Republic of Korea; School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology (POSTECH), 77 Cheongam-ro, Namgu, Pohang, Kyungbuk 37673, Republic of Korea. Electronic address:

Engineered heart tissue (EHT) has ample potential as a model for in vitro tissue modeling or tissue regeneration. Using 3D cell printing technology, various hydrogels have been utilized as bioinks to fabricate EHT to date. However, its efficacy has remained limited due to poor functional properties of the cultured cardiomyocytes stemming from a lack of proper microenvironmental cues. Specifically, the surrounding matrix plays a key role in modulating cardiomyocyte differentiation and maturation. Recently, the use of heart tissue-derived extracellular matrix (hdECM) bioink has come to be seen as one of the most promising candidates due to its functional and structural similarities to native tissue. Here, we demonstrated a correlation between the synthesis of cardiomyocyte-specific proteins and the surrounding microenvironment irrespective of the similar material chemistry. Primary cardiomyocytes isolated from neonatal rats were encapsulated in different composition and concentration of bioinks (hdECM and collagen). The bioinks were sequentially printed using an extrusion-based 3D bioprinter and cultured either statically or dynamically. Qualitative and quantitative evaluation revealed enhanced maturation of cardiomyocytes in hdECM, unlike the collagen group under similar culture conditions. Specifically, 3D-printed EHT using a low concentration of hdECM promoted early differentiation of cardiomyocytes. Hence, the present study provides experimental insights regarding the establishment of a 3D-printed cardiac tissue model, highlighting that the matrix and the culture microenvironment can be decisive factors for cell-material interactions that affect cardiomyocyte maturation. STATEMENT OF SIGNIFICANCE: The regulation of signal transduction and responses to extracellular matrices (ECMs) is of particular relevance in tissue maturation. In particular, there is a clear need to understand the structural and phenotypical modulation in cardiomyocytes with respect to the surrounding microenvironment. Exploration of the key regulators, such as the compositional and the biophysical properties of bioinks associated directly with cell-cell and cell-matrix interactions would assist with the fabrication of cardiac tissue constructs with enhanced functionality. Hence, we documented the synergistic effects of surrounding matrices and culture conditions on the maturation of cardiomyocytes. Additionally, we highlighted the potential of using 3D bioprinting techniques to fabricate uniformly aligned cardiac constructs for mid- to high-throughput drug testing platforms that have great reproducibility and versatility.
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http://dx.doi.org/10.1016/j.actbio.2019.04.026DOI Listing
September 2019

A 3D cell printed muscle construct with tissue-derived bioink for the treatment of volumetric muscle loss.

Biomaterials 2019 06 27;206:160-169. Epub 2019 Mar 27.

Department of Mechanical Engineering, Pohang University of Science and Technology (POSTECH), 77 Cheongam-ro, Nam-gu, Pohang, Kyungbuk, 37673, South Korea. Electronic address:

Volumetric muscle loss (VML) is an irrecoverable injury associated with muscle loss greater than 20%. Although hydrogel-based 3D engineered muscles and the decellularized extracellular matrix (dECM) have been considered for VML treatment, they have shown limited efficacy. We established a novel VML treatment with dECM bioink using 3D cell printing technology. Volumetric muscle constructs composed of cell-laden dECM bioinks were generated with a granule-based printing reservoir. The 3D cell printed muscle constructs exhibited high cell viability without generating hypoxia and enhanced de novo muscle formation in a VML rat model. To improve functional recovery, prevascularized muscle constructs that mimic the hierarchical architecture of vascularized muscles were fabricated through coaxial nozzle printing with muscle and vascular dECM bioinks. Spatially printing tissue-specific dECM bioinks offers organized microenvironmental cues for the differentiation of each cell and improves vascularization, innervation, and functional recovery. Our present results suggest that a 3D cell printing and tissue-derived bioink-based approach could effectively generate biomimetic engineered muscles to improve the treatment of VML injuries.
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http://dx.doi.org/10.1016/j.biomaterials.2019.03.036DOI Listing
June 2019

3D Bioprinted BioMask for Facial Skin Reconstruction.

Bioprinting 2018 Jun 20;10. Epub 2018 Aug 20.

Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

Skin injury to the face remains one of the greatest challenges in wound care due to the varied contours and complex movement of the face. Current treatment strategies for extensive facial burns are limited to the use of autografts, allografts, and skin substitutes, and these often result in scarring, infection, and graft failure. Development of an effective treatment modality will greatly improve the quality of life and social integration of the affected individuals. In this proof of concept study, we developed a novel strategy, called "BioMask", which is a customized bioengineered skin substitute combined with a wound dressing layer that snugly fits onto the facial wounds. To achieve this goal, three-dimensional (3D) bioprinting principle was used to fabricate the BioMask that could be customized by patients' clinical images such as computed tomography (CT) data. Based on a face CT image, a wound dressing material and cell-laden hydrogels were precisely dispensed and placed in a layer-by-layer fashion by the control of air pressure and 3-axis stage. The resulted miniature BioMask consisted of three layers; a porous polyurethane (PU) layer, a keratinocyte-laden hydrogel layer, and a fibroblast-laden hydrogel layer. To validate this novel concept, the bioprinted BioMask was applied to a skin wound on a pre-fabricated face-shaped structure in mice. Through this study using the 3D BioMask, skin contraction and histological examination showed the regeneration of skin tissue, consisting of epidermis and dermis layers, on the complex facial wounds. Consequently, effective and rapid restoration of aesthetic and functional facial skin would be a significant improvement to the current issues a facial wound patient experience.
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http://dx.doi.org/10.1016/j.bprint.2018.e00028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6430133PMC
June 2018