Browsing by Author "Skardal, Aleksander"
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- Immersion Bioprinting of Tumor Organoids in Multi-Well Plates for Increasing Chemotherapy Screening ThroughputMaloney, Erin; Clark, Casey; Sivakumar, Hemamylammal; Yoo, KyungMin; Aleman, Julio; Rajan, Shiny A. P.; Forsythe, Steven; Mazzocchi, Andrea R.; Laxton, Adrian W.; Tatter, Stephen B.; Strowd, Roy E.; Votanopoulos, Konstantinos I.; Skardal, Aleksander (MDPI, 2020-02-18)The current drug development pipeline takes approximately fifteen years and $2.6 billion to get a new drug to market. Typically, drugs are tested on two-dimensional (2D) cell cultures and animal models to estimate their efficacy before reaching human trials. However, these models are often not representative of the human body. The 2D culture changes the morphology and physiology of cells, and animal models often have a vastly different anatomy and physiology than humans. The use of bioengineered human cell-based organoids may increase the probability of success during human trials by providing human-specific preclinical data. They could also be deployed for personalized medicine diagnostics to optimize therapies in diseases such as cancer. However, one limitation in employing organoids in drug screening has been the difficulty in creating large numbers of homogeneous organoids in form factors compatible with high-throughput screening (e.g., 96- and 384-well plates). Bioprinting can be used to scale up deposition of such organoids and tissue constructs. Unfortunately, it has been challenging to 3D print hydrogel bioinks into small-sized wells due to well–bioink interactions that can result in bioinks spreading out and wetting the well surface instead of maintaining a spherical form. Here, we demonstrate an immersion printing technique to bioprint tissue organoids in 96-well plates to increase the throughput of 3D drug screening. A hydrogel bioink comprised of hyaluronic acid and collagen is bioprinted into a viscous gelatin bath, which blocks the bioink from interacting with the well walls and provides support to maintain a spherical form. This method was validated using several cancerous cell lines, and then applied to patient-derived glioblastoma (GBM) and sarcoma biospecimens for drug screening.
- In Situ Bioprinting of Autologous Skin Cells Accelerates Wound Healing of Extensive Excisional Full-Thickness WoundsAlbanna, Mohammed; Binder, Kyle W.; Murphy, Sean V.; Kim, Jaehyun; Qasem, Shadi A.; Zhao, Weixin; Tan, Josh; El-Amin, Idris B.; Dice, Dennis D.; Marco, Julie; Green, Jason; Xu, Tao; Skardal, Aleksander; Holmes, James H.; Jackson, John D.; Atala, Anthony; Yoo, James J. (Springer Nature, 2019-02-21)The early treatment and rapid closure of acute or chronic wounds is essential for normal healing and prevention of hypertrophic scarring. The use of split thickness autografts is often limited by the availability of a suitable area of healthy donor skin to harvest. Cellular and non-cellular biological skin-equivalents are commonly used as an alternative treatment option for these patients, however these treatments usually involve multiple surgical procedures and associated with high costs of production and repeated wound treatment. Here we describe a novel design and a proof-of-concept validation of a mobile skin bioprinting system that provides rapid on-site management of extensive wounds. Integrated imaging technology facilitated the precise delivery of either autologous or allogeneic dermal fibroblasts and epidermal keratinocytes directly into an injured area, replicating the layered skin structure. Excisional wounds bioprinted with layered autologous dermal fibroblasts and epidermal keratinocytes in a hydrogel carrier showed rapid wound closure, reduced contraction and accelerated re-epithelialization. These regenerated tissues had a dermal structure and composition similar to healthy skin, with extensive collagen deposition arranged in large, organized fibers, extensive mature vascular formation and proliferating keratinocytes.
- In vitro patient-derived 3D mesothelioma tumor organoids facilitate patient-centric therapeutic screeningMazzocchi, Andrea R.; Rajan, Shiny A. P.; Votanopoulos, Konstantinos I.; Hall, Adam R.; Skardal, Aleksander (Springer Nature, 2018-02-13)Variability in patient response to anti-cancer drugs is currently addressed by relating genetic mutations to chemotherapy through precision medicine. However, practical benefits of precision medicine to therapy design are less clear. Even after identification of mutations, oncologists are often left with several drug options, and for some patients there is no definitive treatment solution. There is a need for model systems to help predict personalized responses to chemotherapeutics. We have microengineered 3D tumor organoids directly from fresh tumor biopsies to provide patient-specific models with which treatment optimization can be performed before initiation of therapy. We demonstrate the initial implementation of this platform using tumor biospecimens surgically removed from two mesothelioma patients. First, we show the ability to biofabricate and maintain viable 3D tumor constructs within a tumor-on-a-chip microfluidic device. Second, we demonstrate that results of on-chip chemotherapy screening mimic those observed in subjects themselves. Finally, we demonstrate mutation-specific drug testing by considering the results of precision medicine genetic screening and confirming the effectiveness of the non-standard compound 3-deazaneplanocin A for an identified mutation. This patient-derived tumor organoid strategy is adaptable to a wide variety of cancers and may provide a framework with which to improve efforts in precision medicine oncology.
- Label-free analysis of physiological hyaluronan size distribution with a solid-state nanopore sensorRivas, Felipe; Zahid, Osama K.; Reesink, Heidi L.; Peal, Bridgette T.; Nixon, Alan J.; DeAngelis, Paul L.; Skardal, Aleksander; Rahbar, Elaheh; Hall, Adam R. (Springer Nature, 2018-03-12)Hyaluronan (or hyaluronic acid, HA) is a ubiquitous molecule that plays critical roles in numerous physiological functions in vivo, including tissue hydration, inflammation, and joint lubrication. Both the abundance and size distribution of HA in biological fluids are recognized as robust indicators of various pathologies and disease progressions. However, such analyses remain challenging because conventional methods are not sufficiently sensitive, have limited dynamic range, and/or are only semi-quantitative. Here we demonstrate label-free detection and molecular weight discrimination of HA with a solid-state nanopore sensor. We first employ synthetic HA polymers to validate the measurement approach and then use the platform to determine the size distribution of as little as 10 ng of HA extracted directly from synovial fluid in an equine model of osteoarthritis. Our results establish a quantitative method for assessment of a significant molecular biomarker that bridges a gap in the current state of the art.
- Multi-tissue interactions in an integrated three-tissue organ-on-a-chip platformSkardal, Aleksander; Murphy, Sean V.; Devarasetty, Mahesh; Mead, Ivy; Kang, Hyun-Wook; Seol, Young-Joon; Zhang, Yu Shrike; Shin, Su-Ryon; Zhao, Liang; Aleman, Julio; Hall, Adam R.; Shupe, Thomas D.; Kleensang, Andre; Dokmeci, Mehmet R.; Lee, Sang Jin; Jackson, John D.; Yoo, James J.; Hartung, Thomas; Khademhosseini, Ali; Soker, Shay; Bishop, Colin E.; Atala, Anthony (Springer Nature, 2017-08-18)Many drugs have progressed through preclinical and clinical trials and have been available - for years in some cases -before being recalled by the FDA for unanticipated toxicity in humans. One reason for such poor translation from drug candidate to successful use is a lack of model systems that accurately recapitulate normal tissue function of human organs and their response to drug compounds. Moreover, tissues in the body do not exist in isolation, but reside in a highly integrated and dynamically interactive environment, in which actions in one tissue can affect other downstream tissues. Few engineered model systems, including the growing variety of organoid and organ-on-a-chip platforms, have so far reflected the interactive nature of the human body. To address this challenge, we have developed an assortment of bioengineered tissue organoids and tissue constructs that are integrated in a closed circulatory perfusion system, facilitating inter-organ responses. We describe a three-tissue organ-on-a-chip system, comprised of liver, heart, and lung, and highlight examples of inter-organ responses to drug administration. We observe drug responses that depend on inter-tissue interaction, illustrating the value of multiple tissue integration for in vitro study of both the efficacy of and side effects associated with candidate drugs.