Publications by authors named "Michael Shuler"

156 Publications

Retrospective analysis of trends in surgery volumes between 2016 and 2019 and impact of the insurance deductible: Cross-sectional study.

Ann Med Surg (Lond) 2021 Mar 23;63:102176. Epub 2021 Feb 23.

Athens Orthopedic Clinic, 1765 Old West Broad St Bldg. 2 Athens, GA, 30606, USA.

Background: Understanding trends in surgical volumes can help Ambulatory Surgery Centers (ASCs) prevent clinician burnout and provide adequate staffing while maintaining the quality of patient care throughout the year. Health insurance deductibles reset in January each year and may contribute to an annual rhythm where the levee of year-end deductibles is breached in the last few months of every year, resulting in a flood of cases and several accompanying challenges. This study aims to identify and analyze monthly and yearly surgical volume patterns in ASCs and explore a relationship with the deductible reset.

Methods: De-identified, aggregate visit data for 2016-2019 were obtained retrospectively from 14 ambulatory surgery centers within the same benchmarking consortium in the Southeast. The ASCs subspecialty types consisted of orthopedics, urology, otolaryngology, and multispecialty. Kaiser Family Foundation survey data from 2016 to 2019 was used to inform deductible trends. Augmented Dickey-Fuller tests, linear regressions, and two-sample T-tests were conducted to explore and establish patterns in surgical volume between 2016 and 2019.

Results: Overall, average orthopedic surgical volume increased 38.04% from January to December in 2016-2019 with an average difference of 64 cases (95% CI: 47-80), while that of all ASCs combined increased 19.24% within the same timeframe with an average difference of 37 cases (95% CI: 21-52). Average health insurance deductibles rose 12% from $1476 to $1655 within the same timeframe. Regression analysis showed a stronger association between year and volume for orthopedic ASCs (R (Claxton et al., 2019) [2] = 0.796) than for all ASCs combined (R (Claxton et al., 2019) [2] = 0.645). Regression analysis also showed a stronger association between month and volume for orthopedic ASCs (R (Claxton et al., 2019) [2] = 0.488-0.805) than for all ASCs combined (R (Claxton et al., 2019) [2] = 0.115-0.493).

Conclusion: This study is first to identify regular and predictable yearly and monthly increases in orthopedic ASCs surgical volume. The study also identifies yearly increases in surgical volume for all ASCs. The combination of increasing yearly demand for orthopedic surgery and growing association between month and volume leads to an unnecessary year-end rush. The study aims to inform future policy decisions as well as help ASCs better manage resources throughout the year.
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http://dx.doi.org/10.1016/j.amsu.2021.02.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937670PMC
March 2021

Pumpless, unidirectional microphysiological system for testing metabolism-dependent chemotherapeutic toxicity.

Biotechnol Prog 2021 Mar 16;37(2):e3105. Epub 2020 Dec 16.

Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York, USA.

Drug development is often hindered by the failure of preclinical models to accurately assess and predict the efficacy and safety of drug candidates. Body-on-a-chip (BOC) microfluidic devices, a subset of microphysiological systems (MPS), are being created to better predict human responses to drugs. Each BOC is designed with separate organ chambers interconnected with microfluidic channels mimicking blood recirculation. Here, we describe the design of the first pumpless, unidirectional, multiorgan system and apply this design concept for testing anticancer drug treatments. HCT-116 colon cancer spheroids, HepG2/C3A hepatocytes, and HL-60 promyeloblasts were embedded in collagen hydrogels and cultured within compartments representing "colon tumor", "liver," and "bone marrow" tissue, respectively. Operating on a pumpless platform, the microfluidic channel design provides unidirectional perfusion at physiologically realistic ratios to multiple channels simultaneously. The metabolism-dependent toxic effect of Tegafur, an oral prodrug of 5-fluorouracil, combined with uracil was examined in each cell type. Tegafur-uracil treatment induced substantial cell death in HCT-116 cells and this cytotoxic response was reduced for multicellular spheroids compared to single cells, likely due to diffusion-limited drug penetration. Additionally, off-target toxicity was detected by HL-60 cells, which demonstrate that such systems can provide useful information on dose-limiting side effects. Collectively, this microscale cell culture analog is a valuable physiologically-based pharmacokinetic drug screening platform that may be used to support cancer drug development.
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http://dx.doi.org/10.1002/btpr.3105DOI Listing
March 2021

A Tissue Engineering Approach to Metastatic Colon Cancer.

iScience 2020 Nov 20;23(11):101719. Epub 2020 Oct 20.

Department of Cancer Biology, Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Cleveland, OH 44195, USA.

Colon cancer remains the third most common cause of cancer in the US, and the third most common cause of cancer death. Worldwide, colon cancer is the second most common cause of cancer and cancer deaths. At least 25% of patients still present with metastatic disease, and at least 25-30% will develop metastatic colon cancer in the course of their disease. While chemotherapy and surgery remain the mainstay of treatment, understanding the fundamental cellular niche and mechanical properties that result in metastases would facilitate both prevention and cure. Advances in biomaterials, novel 3D primary human cells, modelling using microfluidics and the ability to alter the physical environment, now offers a unique opportunity to develop and test impactful treatment.
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http://dx.doi.org/10.1016/j.isci.2020.101719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653071PMC
November 2020

Organ-on-a-chip systems: translating concept into practice.

Authors:
Michael L Shuler

Lab Chip 2020 08;20(17):3072-3073

Department of Biomedical Engineering, Cornell University, 381 Kimball Hall, Ithaca, USA.

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http://dx.doi.org/10.1039/d0lc90083dDOI Listing
August 2020

Differential Monocyte Actuation in a Three-Organ Functional Innate Immune System-on-a-Chip.

Adv Sci (Weinh) 2020 Jul 2;7(13):2000323. Epub 2020 Jun 2.

Hesperos, Inc. 12501 Research Parkway, Suite 100 Orlando FL 32826 USA.

A functional, human, multiorgan, pumpless, immune system-on-a-chip featuring recirculating THP-1 immune cells with cardiomyocytes, skeletal muscle, and liver in separate compartments in a serum-free medium is developed. This in vitro platform can emulate both a targeted immune response to tissue-specific damage, and holistic proinflammatory immune response to proinflammatory compound exposure. The targeted response features fluorescently labeled THP-1 monocytes selectively infiltrating into an amiodarone-damaged cardiac module and changes in contractile force measurements without immune-activated damage to the other organ modules. In contrast to the targeted immune response, general proinflammatory treatment of immune human-on-a-chip systems with lipopolysaccharide (LPS) and interferon- (IFN-) causes nonselective damage to cells in all three-organ compartments. Biomarker analysis indicates upregulation of the proinflammation cytokines TNF-, IL-6, IL-10, MIP-1, MCP-1, and RANTES in response to LPS + IFN- treatment indicative of the M1 macrophage phenotype, whereas amiodarone treatment only leads to an increase in the restorative cytokine IL-6 which is a marker for the M2 phenotype. This system can be used as an alternative to humanized animal models to determine direct immunological effects of biological therapeutics including monoclonal antibodies, vaccines, and gene therapies, and the indirect effects caused by cytokine release from target tissues in response to a drug's pharmacokinetics (PK)/pharmacodynamics (PD) profile.
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http://dx.doi.org/10.1002/advs.202000323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341107PMC
July 2020

New approach methodologies (NAMs) for human-relevant biokinetics predictions. Meeting the paradigm shift in toxicology towards an animal-free chemical risk assessment

ALTEX 2020 8;37(4):607-622. Epub 2020 Jun 8.

RIVM - The National Institute for Public Health and the Environment, Bilthoven, The Netherlands.

For almost fifteen years, the availability and regulatory acceptance of new approach methodologies (NAMs) to assess the absorption, distribution, metabolism and excretion (ADME/biokinetics) in chemical risk evaluations are a bottleneck. To enhance the field, a team of 24 experts from science, industry, and regulatory bodies, including new generation toxicologists, met at the Lorentz Centre in Leiden, The Netherlands. A range of possibilities for the use of NAMs for biokinetics in risk evaluations were formulated (for example to define species differences and human variation or to perform quantitative in vitro-in vivo extrapolations). To increase the regulatory use and acceptance of NAMs for biokinetics for these ADME considerations within risk evaluations, the development of test guidelines (protocols) and of overarching guidance documents is considered a critical step. To this end, a need for an expert group on biokinetics within the Organisation of Economic Cooperation and Development (OECD) to supervise this process was formulated. The workshop discussions revealed that method development is still required, particularly to adequately capture transporter mediated processes as well as to obtain cell models that reflect the physiology and kinetic characteristics of relevant organs. Developments in the fields of stem cells, organoids and organ-on-a-chip models provide promising tools to meet these research needs in the future.
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http://dx.doi.org/10.14573/altex.2003242DOI Listing
June 2020

Piezoelectric BioMEMS Cantilever for Measurement of Muscle Contraction and for Actuation of Mechanosensitive Cells.

MRS Commun 2019 Dec 20;9(4):1186-1192. Epub 2019 Sep 20.

Hybrid Systems Laboratory, University of Central Florida, NanoScience Technology Center, 12424 Research Parkway, Suite 400, Orlando, FL 32826.

A piezoelectric biomedical microelectromechanical system (bioMEMS) cantilever device was designed and fabricated to act as either a sensing element for muscle tissue contraction or as an actuator to apply mechanical force to cells. The sensing ability of the piezoelectric cantilevers was shown by monitoring the electrical signal generated from the piezoelectric aluminum nitride in response to the contraction of iPSC-derived cardiomyocytes cultured on the piezoelectric cantilevers. Actuation was demonstrated by applying electrical pulses to the piezoelectric cantilever and observing bending via an optical detection method. This piezoelectric cantilever device was designed to be incorporated into body-on-a-chip systems.
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http://dx.doi.org/10.1557/mrc.2019.129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995331PMC
December 2019

Multiorgan microfluidic platform with breathable lung chamber for inhalation or intravenous drug screening and development.

Biotechnol Bioeng 2020 02 25;117(2):486-497. Epub 2019 Nov 25.

Department of Biomedical Engineering, Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York.

Efficient and economical delivery of pharmaceuticals to patients is critical for effective therapy. Here we describe a multiorgan (lung, liver, and breast cancer) microphysiological system ("Body-on-a-Chip") designed to mimic both inhalation therapy and/or intravenous therapy using curcumin as a model drug. This system is "pumpless" and self-contained using a rocker platform for fluid (blood surrogate) bidirectional recirculation. Our lung chamber is constructed to maintain an air-liquid interface and contained a "breathable" component that was designed to mimic breathing by simulating gas exchange, contraction and expansion of the "lung" using a reciprocating pump. Three cell lines were used: A549 for the lung, HepG2 C3A for the liver, and MDA MB231 for breast cancer. All cell lines were maintained with high viability (>85%) in the device for at least 48 hr. Curcumin is used to treat breast cancer and this allowed us to compare inhalation delivery versus intravenous delivery of the drug in terms of effectiveness and potentially toxicity. Inhalation therapy could be potentially applied at home by the patient while intravenous therapy would need to be applied in a clinical setting. Inhalation therapy would be more economical and allow more frequent dosing with a potentially lower level of drug. For 24 hr exposure to 2.5 and 25 µM curcumin in the flow device the effect on lung and liver viability was small to insignificant, while there was a significant decrease in viability of the breast cancer (to 69% at 2.5 µM and 51% at 25 µM). Intravenous delivery also selectively decreased breast cancer viability (to 88% at 2.5 µM and 79% at 25 µM) but was less effective than inhalation therapy. The response in the static device controls was significantly reduced from that with recirculation demonstrating the effect of flow. These results demonstrate for the first time the feasibility of constructing a multiorgan microphysiological system with recirculating flow that incorporates a "breathable" lung module that maintains an air-liquid interface.
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http://dx.doi.org/10.1002/bit.27188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952570PMC
February 2020

Application of chemical reaction engineering principles to 'body-on-a-chip' systems.

AIChE J 2018 Dec 12;64(12):4351-4360. Epub 2018 Oct 12.

Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, 14853, USA.

The combination of cell culture models with microscale technology has fostered emergence of cell-based microphysiological models, also known as organ-on-a-chip systems. Body-on-a-chip systems, which are multi-organ systems on a chip to mimic physiological relations, enable recapitulation of organ-organ interactions and potentially whole-body response to drugs, as well as serve as models of diseases. Chemical reaction engineering principles can be applied to understanding complex reactions inside the cell or human body, which can be treated as a multi-reactor system. These systems use physiologically-based pharmacokinetic (PBPK) models to guide the development of microscale systems of the body where organs or tissues are represented by living cells or tissues, and integrated into body-on-a-chip systems. Here, we provide a brief overview on the concept of chemical reaction engineering and how its principles can be applied to understanding and predicting the behavior of body-on-a-chip systems.
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http://dx.doi.org/10.1002/aic.16448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6688854PMC
December 2018

On the potential of in vitro organ-chip models to define temporal pharmacokinetic-pharmacodynamic relationships.

Sci Rep 2019 07 3;9(1):9619. Epub 2019 Jul 3.

Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca, Cambridge, UK.

Functional human-on-a-chip systems hold great promise to enable quantitative translation to in vivo outcomes. Here, we explored this concept using a pumpless heart only and heart:liver system to evaluate the temporal pharmacokinetic/pharmacodynamic (PKPD) relationship for terfenadine. There was a time dependent drug-induced increase in field potential duration in the cardiac compartment in response to terfenadine and that response was modulated using a metabolically competent liver module that converted terfenadine to fexofenadine. Using this data, a mathematical model was developed to predict the effect of terfenadine in preclinical species. Developing confidence that microphysiological models could have a transformative effect on drug discovery, we also tested a previously discovered proprietary AstraZeneca small molecule and correctly determined the cardiotoxic response to its metabolite in the heart:liver system. Overall our findings serve as a guiding principle to future investigations of temporal concentration response relationships in these innovative in vitro models, especially, if validated across multiple time frames, with additional pharmacological mechanisms and molecules representing a broad chemical diversity.
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http://dx.doi.org/10.1038/s41598-019-45656-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610665PMC
July 2019

Correction: UniChip enables long-term recirculating unidirectional perfusion with gravity-driven flow for microphysiological systems.

Lab Chip 2019 Aug 2;19(15):2619. Epub 2019 Jul 2.

Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853-7202, USA. and Robert Frederick Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY 14853, USA.

Correction for 'UniChip enables long-term recirculating unidirectional perfusion with gravity-driven flow for microphysiological systems' by Ying I. Wang and Michael L. Shuler, Lab Chip, 2018, 18, 2563-2574.
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http://dx.doi.org/10.1039/c9lc90073jDOI Listing
August 2019

Strategies for using mathematical modeling approaches to design and interpret multi-organ microphysiological systems (MPS).

APL Bioeng 2019 Jun 20;3(2):021501. Epub 2019 Jun 20.

Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York 14853, USA.

Recent advances in organ-on-a-chip technology have resulted in numerous examples of microscale systems that faithfully mimic the physiology and pathology of human organs and diseases. The next step in this field, which has already been partially demonstrated at a proof-of-concept level, would be integration of organ modules to construct multiorgan microphysiological systems (MPSs). In particular, there is interest in "body-on-a-chip" models, which recapitulate complex and dynamic interactions between different organs. Integration of multiple organ modules, while faithfully reflecting human physiology in a quantitative sense, will require careful consideration of factors such as relative organ sizes, blood flow rates, cell numbers, and ratios of cell types. The use of a mathematical modeling platform will be an essential element in designing multiorgan MPSs and interpretation of experimental results. Also, extrapolation to will require robust mathematical modeling techniques. So far, several scaling methods and pharmacokinetic and physiologically based pharmacokinetic models have been applied to multiorgan MPSs, with each method being suitable to a subset of different objectives. Here, we summarize current mathematical methodologies used for the design and interpretation of multiorgan MPSs and suggest important considerations and approaches to allow multiorgan MPSs to recapitulate human physiology and disease progression better, as well as help to translation of studies on response to drugs or chemicals.
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http://dx.doi.org/10.1063/1.5097675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586554PMC
June 2019

Multi-organ system for the evaluation of efficacy and off-target toxicity of anticancer therapeutics.

Sci Transl Med 2019 06;11(497)

Hesperos Inc., 3259 Progress Drive, Room 158, Orlando, FL 32826, USA.

A pumpless, reconfigurable, multi-organ-on-a-chip system containing recirculating serum-free medium can be used to predict preclinical on-target efficacy, metabolic conversion, and measurement of off-target toxicity of drugs using functional biological microelectromechanical systems. In the first configuration of the system, primary human hepatocytes were cultured with two cancer-derived human bone marrow cell lines for antileukemia drug analysis in which diclofenac and imatinib demonstrated a cytostatic effect on bone marrow cancer proliferation. Liver viability was not affected by imatinib; however, diclofenac reduced liver viability by 30%. The second configuration housed a multidrug-resistant vulva cancer line, a non-multidrug-resistant breast cancer line, primary hepatocytes, and induced pluripotent stem cell-derived cardiomyocytes. Tamoxifen reduced viability of the breast cancer cells only after metabolite generation but did not affect the vulva cancer cells except when coadministered with verapamil, a permeability glycoprotein inhibitor. Both tamoxifen alone and coadministration with verapamil produced off-target cardiac effects as indicated by a reduction of contractile force, beat frequency, and conduction velocity but did not affect viability. These systems demonstrate the utility of a human cell-based in vitro culture system to evaluate both on-target efficacy and off-target toxicity for parent drugs and their metabolites; these systems can augment and reduce the use of animals and increase the efficiency of drug evaluations in preclinical studies.
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http://dx.doi.org/10.1126/scitranslmed.aav1386DOI Listing
June 2019

Author Correction: A recellularized human colon model identifies cancer driver genes.

Nat Biotechnol 2019 Jul;37(7):820

Department of Biomedical Engineering, Cornell University, Ithaca, New York, USA.

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/s41587-019-0163-6DOI Listing
July 2019

A SIMPLE ASPECT RATIO DEPENDENT METHOD OF PATTERNING MICROWELLS FOR SELECTIVE CELL ATTACHMENT.

2018 Des Med Devices Conf (2018) 2018 Apr;2018

Department of Biomedical Engineering, Duke University Durham, NC, United States.

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http://dx.doi.org/10.1115/DMD2018-6811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6408146PMC
April 2018

Engineering a Bioartificial Human Colon Model Through Decellularization and Recellularization.

Methods Mol Biol 2019 ;1907:91-102

Department of Biomedical Engineering, Cornell University, Ithaca, NY, USA.

The tissue engineering method of decellularization and recellularization has been successfully used in a variety of regenerative medicine applications. The protocols used to de/recellularize various organs and tissues are largely different. Here we describe a method to effectively engineer a bioartificial colon by completely removing original cells from human intestinal tissues followed by repopulating the acellular tissue matrix with cell cultures. This method provides a novel approach for human intestinal regeneration and can be used to identify potential cancer driver genes.
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http://dx.doi.org/10.1007/978-1-4939-8967-6_7DOI Listing
July 2019

Recent Advances in Body-on-a-Chip Systems.

Anal Chem 2019 01 11;91(1):330-351. Epub 2018 Dec 11.

Nancy E. and Peter C. Meinig School of Biomedical Engineering , Cornell University , Ithaca , New York 14853 , United States.

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http://dx.doi.org/10.1021/acs.analchem.8b05293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6687466PMC
January 2019

Circulating MIR148A associates with sensitivity to adiponectin levels in human metabolic surgery for weight loss

Endocr Connect 2018 Sep 1;7(9):975-982. Epub 2018 Sep 1.

Objective: We sought to discover secreted biomarkers to monitor the recovery of physiological adiponectin levels with metabolic surgery, focusing on epigenetic changes that might predict adiponectin function.

Design: We conducted a prospective observational study of patients undergoing metabolic surgery by Roux-en-Y Gastric Bypass (RYGB) for weight loss in a single center (IRB GHS # 1207-27).

Methods: All patients (n = 33; 27 females; 6 males) signed informed consent. Metabolites, adiponectin and MIR148A were measured in fasting plasma. We followed MIQE for transcript profiles.

Results: Patients lost on average 47 ± 12% excess BMI (%EBMI) after 12 weeks. Adiponectin pre, post or delta (post minus pre) did not correlate with %EBMIL. A decrease in adiponectin following weight loss surgery was observed in a subset of patients, chi-square test of independence rejects the null hypotheses that the liver DNA methyltransferase 1 (DNMT1) and delta adiponectin are independent (chi-square statistics χ2 = 6.9205, P = 0.00852, n = 33), as well as MIR148A and delta adiponectin are independent (chi-square statistics χ2 = 9.6823, P = 0.00186, n = 33). The presence of plasma MIR148A allows identification of patients that appear to be adiponectin insensitive at baseline.

Conclusion: We combined the presence of plasma MIR148A, the concentration of total adiponectin and the expression of DNA methyltransferase 1 (DNMT1) in liver biopsy tissue to identify patients with non-physiological adiponectin. Weight loss and physical activity interventions complemented with the new method presented here could serve to monitor the physiological levels of adiponectin, thought to be important for long-term weight loss maintenance.
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http://dx.doi.org/10.1530/EC-18-0205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6176280PMC
September 2018

Advances in organ-, body-, and disease-on-a-chip systems.

Authors:
Michael L Shuler

Lab Chip 2018 12;19(1):9-10

Department of Biomedical Engineering, Cornell University, 381 Kimball Hall, Ithaca, USA.

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http://dx.doi.org/10.1039/c8lc90089bDOI Listing
December 2018

UniChip enables long-term recirculating unidirectional perfusion with gravity-driven flow for microphysiological systems.

Lab Chip 2018 08;18(17):2563-2574

Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853-7202, USA.

Microphysiological systems, also known as body-on-a-chips, are promising "human surrogates" that may be used to evaluate potential human response to drugs in preclinical drug development. Various microfluidics-based platforms have been proposed to interconnect different organ models and provide perfusion in mimicking the blood circulation. We have previously developed a pumpless platform that combines gravity-driven fluid flow and a rocking motion to create reciprocating flow between reservoirs for recirculation. Such platform allows design of self-contained and highly integrated systems that are relatively easy and cost-effective to construct and maintain. To integrate vasculature and other shear stress-sensitive tissues (e.g. lung and kidney) into pumpless body-on-a-chips, we propose "UniChip" fluid network design, which transforms reciprocating flow input into unidirectional perfusion in the channel(s) of interest by utilizing supporting channels and passive valves. The design enables unidirectional organ perfusion with recirculation on the pumpless platform and provides an effective backflow-proof mechanism. To demonstrate principles of UniChip design, we created a demonstration chip with a single straight channel as a simple example of the organ perfusion network. A BiChip providing bidirectional perfusion was used for comparison. Computational and experimental fluid dynamic characterization of the UniChip confirmed continuous unidirectional flow in the perfusion channel and the backflow-proof mechanism. Vascular endothelial cells cultured on UniChips for 5 d showed changes matching cell responses to unidirectional laminar flows. Those include cell elongation and alignment to the flow direction, continuous network of VE-cadherin at cell borders, realignment of F-actin and suppressed cell proliferation. Cells on BiChips manifested distinct responses that are close to responses to oscillatory flows, where cells remain a polygonal shape with intermittent VE-cadherin networks and few F-actin realignment. These results demonstrate that microfluidic devices of UniChip design provide recirculating unidirectional perfusion suitable for long-term culture of shear stress-sensitive tissues. This is the first time a gravity-drive flow system has achieved continuous unidirectional perfusion with recirculation. The inherent backflow-proof mechanism allows hassle-free long-term operation of body-on-a-chips. Overall, our UniChip design provides a reliable and cost-effective solution for the integration of vasculature and other shear stress-sensitive tissues into pumpless recirculating body-on-a-chips, which can expedite the development and widespread application of moderately high-throughput, high-content microphysiological systems.
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http://dx.doi.org/10.1039/c8lc00394gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6143176PMC
August 2018

A pumpless body-on-a-chip model using a primary culture of human intestinal cells and a 3D culture of liver cells.

Lab Chip 2018 07;18(14):2036-2046

Department of Biomedical Engineering, 115 Weill Hall, Cornell University, USA.

We describe an expanded modular gastrointestinal (GI) tract-liver system by co-culture of primary human intestinal epithelial cells (hIECs) and 3D liver mimic. The two organ body-on-chip design consisted of GI and liver tissue compartments that were connected by fluidic medium flow driven via gravity. The hIECs and HepG2 C3A liver cells in the co-culture system maintained high viability for at least 14 days in which hIECs differentiated into major cell types found in native human intestinal epithelium and the HepG2 C3A cells cultured on 3D polymer scaffold formed a liver micro-lobe like structure. Moreover, the hIECs formed a monolayer on polycarbonate membranes with a tight junction and authentic TEER values of approximately 250 Ω cm2 for the native gut. The hIEC permeability was compared to a conventional permeability model using Caco-2 cell response for drug absorption by measuring the uptake of propranolol, mannitol and caffeine. Metabolic rates (urea or albumin production) of the cells in the co-culture GI-liver system were comparable to those of HepG2 C3A cells in a single-organ fluidic culture system, while induced CYP activities were significantly increased in the co-culture GI tract-liver system compared to the single-organ fluidic culture system. These results demonstrated potential of the low-cost microphysiological GI-liver model for preclinical studies to predict human response.
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http://dx.doi.org/10.1039/c8lc00111aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6039263PMC
July 2018

Microfluidic-Based Cell-Embedded Microgels Using Nonfluorinated Oil as a Model for the Gastrointestinal Niche.

ACS Appl Mater Interfaces 2018 Mar 6;10(11):9235-9246. Epub 2018 Mar 6.

Microfluidic-based cell encapsulation has promising potential in therapeutic applications. It also provides a unique approach for studying cellular dynamics and interactions, though this concept has not yet been fully explored. No in vitro model currently exists that allows us to study the interaction between crypt cells and Peyer's patch immune cells because of the difficulty in recreating, with sufficient control, the two different microenvironments in the intestine in which these cell types belong. However, we demonstrate that a microfluidic technique is able to provide such precise control and that these cells can proliferate inside microgels. Current microfluidic-based cell microencapsulation techniques primarily use fluorinated oils. Herein, we study the feasibility and biocompatibility of different nonfluorinated oils for application in gastrointestinal cell encapsulation and further introduce a model for studying intercellular chemical interactions with this approach. Our results demonstrate that cell viability is more affected by the solidification and purification processes that occur after droplet formation rather than the oil type used for the carrier phase. Specifically, a shorter polymer cross-linking time and consequently lower cell exposure to the harsh environment (e.g., acidic pH) results in a high cell viability of over 90% within the protected microgels. Using nonfluorinated oils, we propose a model system demonstrating the interplay between crypt and Peyer's patch cells using this microfluidic approach to separately encapsulate the cells inside distinct alginate/gelatin microgels, which allow for intercellular chemical communication. We observed that the coculture of crypt cells alongside Peyer's patch immune cells improves the growth of healthy organoids inside these microgels, which contain both differentiated and undifferentiated cells over 21 days of coculture. These results indicate the possibility of using droplet-based microfluidics for culturing organoids to expand their applicability in clinical research.
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http://dx.doi.org/10.1021/acsami.7b16916DOI Listing
March 2018

Multiorgan Microphysiological Systems for Drug Development: Strategies, Advances, and Challenges.

Adv Healthc Mater 2018 01 4;7(2). Epub 2017 Dec 4.

Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, 14853, USA.

Traditional cell culture and animal models utilized for preclinical drug screening have led to high attrition rates of drug candidates in clinical trials due to their low predictive power for human response. Alternative models using human cells to build in vitro biomimetics of the human body with physiologically relevant organ-organ interactions hold great potential to act as "human surrogates" and provide more accurate prediction of drug effects in humans. This review is a comprehensive investigation into the development of tissue-engineered human cell-based microscale multiorgan models, or multiorgan microphysiological systems for drug testing. The evolution from traditional models to macro- and microscale multiorgan systems is discussed in regards to the rationale for recent global efforts in multiorgan microphysiological systems. Current advances in integrating cell culture and on-chip analytical technologies, as well as proof-of-concept applications for these multiorgan microsystems are discussed. Major challenges for the field, such as reproducibility and physiological relevance, are discussed with comparisons of the strengths and weaknesses of various systems to solve these challenges. Conclusions focus on the current development stage of multiorgan microphysiological systems and new trends in the field.
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http://dx.doi.org/10.1002/adhm.201701000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5805562PMC
January 2018

Self-contained, low-cost Body-on-a-Chip systems for drug development.

Exp Biol Med (Maywood) 2017 11 17;242(17):1701-1713. Epub 2017 Feb 17.

1 Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA.

Integrated multi-organ microphysiological systems are an evolving tool for preclinical evaluation of the potential toxicity and efficacy of drug candidates. Such systems, also known as Body-on-a-Chip devices, have a great potential to increase the successful conversion of drug candidates entering clinical trials into approved drugs. Systems, to be attractive for commercial adoption, need to be inexpensive, easy to operate, and give reproducible results. Further, the ability to measure functional responses, such as electrical activity, force generation, and barrier integrity of organ surrogates, enhances the ability to monitor response to drugs. The ability to operate a system for significant periods of time (up to 28 d) will provide potential to estimate chronic as well as acute responses of the human body. Here we review progress towards a self-contained low-cost microphysiological system with functional measurements of physiological responses. Impact statement Multi-organ microphysiological systems are promising devices to improve the drug development process. The development of a pumpless system represents the ability to build multi-organ systems that are of low cost, high reliability, and self-contained. These features, coupled with the ability to measure electrical and mechanical response in addition to chemical or metabolic changes, provides an attractive system for incorporation into the drug development process. This will be the most complete review of the pumpless platform with recirculation yet written.
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http://dx.doi.org/10.1177/1535370217694101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5786364PMC
November 2017

Organ-, body- and disease-on-a-chip systems.

Authors:
Michael L Shuler

Lab Chip 2017 07;17(14):2345-2346

Department of Biomedical Engineering, Cornell University, 300 Kimball Hall, Ithaca, USA.

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http://dx.doi.org/10.1039/c7lc90068fDOI Listing
July 2017

A simple cell transport device keeps culture alive and functional during shipping.

Biotechnol Prog 2017 Sep 21;33(5):1257-1266. Epub 2017 Jun 21.

Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, 14853.

Transporting living complex cellular constructs through the mail while retaining their full viability and functionality is challenging. During this process, cells often suffer from exposure to suboptimal life-sustaining conditions (e.g. temperature, pH), as well as damage due to shear stress. We have developed a transport device for shipping intact cell/tissue constructs from one facility to another that overcomes these obstacles. Our transport device maintained three different cell lines (Caco2, A549, and HepG2 C3A) individually on transwell membranes with high viability (above 97%) for 48 h under simulated shipping conditions without an incubator. The device was also tested by actual overnight shipping of blood brain barrier constructs consisting of human induced pluripotent brain microvascular endothelial cells and rat astrocytes on transwell membranes to a remote facility (approximately 1200 miles away). The blood brain barrier constructs arrived with high cell viability and were able to regain full barrier integrity after equilibrating in the incubator for 24 h; this was assessed by the presence of continuous tight junction networks and in vivo-like values for trans-endothelial electrical resistance (TEER). These results demonstrated that our cell transport device could be a useful tool for long-distance transport of membrane-bound cell cultures and functional tissue constructs. Studies that involve various cell and tissue constructs, such as the "Multi-Organ-on-Chip" devices (where multiple microscale tissue constructs are integrated on a single microfluidic device) and studies that involve microenvironments where multiple tissue interactions are of interest, would benefit from the ability to transport or receive these constructs. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1257-1266, 2017.
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http://dx.doi.org/10.1002/btpr.2512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5647209PMC
September 2017

Body-on-a-chip systems for animal-free toxicity testing.

Altern Lab Anim 2016 Oct;44(5):469-478

Department of Biomedical Engineering, Cornell University, Ithaca, NY, USA, and Hesperos Inc., Orlando, FL, USA.

Body-on-a-chip systems replicate the size relationships of organs, blood distribution and blood flow, in accordance with human physiology. When operated with tissues derived from human cell sources, these systems are capable of simulating human metabolism, including the conversion of a prodrug to its effective metabolite, as well as its subsequent therapeutic actions and toxic side-effects. The system also permits the measurement of human tissue electrical and mechanical reactions, which provide a measure of functional response. Since these devices can be operated with human tissue samples or with in vitro tissues derived from induced pluripotent stem cells (iPS), they can play a significant role in determining the success of new pharmaceuticals, without resorting to the use of animals. By providing a platform for testing in the context of human metabolism, as opposed to animal models, the systems have the potential to eliminate the use of animals in preclinical trials. This article will review progress made and work achieved as a direct result of the 2015 Lush Science Prize in support of animal-free testing.
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http://dx.doi.org/10.1177/026119291604400508DOI Listing
October 2016

Comparison of NIRS, serum biomarkers, and muscle damage in a porcine balloon compression model of acute compartment syndrome.

J Trauma Acute Care Surg 2016 11;81(5):876-881

From the Department of Small Animal Medicine and Surgery (S.C.B,. M.S.S., M.H), College of Veterinary Medicine, University of Georgia, Athens, Georgia; Department of Upper Extremity and Micro Surgery (M.S.S.), Athens Orthopedic Clinic, PA, Athens, Georgia; Department of Pathology, College of Veterinary Medicine (E.U.), University of Georgia, Athens, Georgia; Landstuhl Regional Medical Center (B.A.F.), Landstuhl, Germany.

Background: Near-infrared spectroscopy (NIRS) has been shown to aid in the diagnosis of extremity acute compartment syndrome (ACS), offering continuous real-time capability to monitor perfusion in extremities. Porcine models of ACS have been developed to attempt to aid in the understanding of the development of ACS and provide better methods of diagnosing ACS. The objective of the present study was to assess and correlate NIRS, tibial intracompartmental pressure (TICP), tibial intracompartmental perfusion pressure (TIPP), serum markers of inflammation and muscle injury in a balloon compression model of ACS.

Methods: Six swine were used. Balloon catheters were inflated below the cranial tibial muscle. Systolic, diastolic, and mean arterial pressures; compartmental pressures; and oximetry were measured before, during, and after balloon inflation/deflation. Cranial tibial muscle was collected for muscle damage scoring. Serum creatine kinase, myoglobin, tumor necrosis factor α, IL-1β, and IL-6 were measured. Data analysis included comparing differences in TICP, NIRS, and TIPP measurements as well as creatine kinase, myoglobin, tumor necrosis factor α, IL-1β, and IL-6 levels between time points. Pearson correlations were calculated for muscle degeneration and edema and NIRS.

Results: Increases in TICP and decreases in TIPP were found. Near-infrared spectroscopy detected significant changes in tissue oxygenation at all the same time points. Myoglobin significantly increased from 45.7 ± 13.0 ng/mL (baseline) to 219.5 ± 57.3-ng/mL (balloon deflation) and continued to increase over the duration of the study. Creatine kinase significantly increased 2 hours after balloon deflation. Cranial tibial muscle degeneration, necrosis, and edema scores were higher in the test than the control legs.

Conclusions: Near-infrared spectroscopy of the compartment provided a reliable, sensitive measure of both an increase and decrease in TICP and TIPP in this porcine balloon model of ACS. Creatine kinase and myoglobin significantly increased following balloon removal. Significant correlations between muscle degeneration, edema, hemorrhage, and NIRS were found.
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http://dx.doi.org/10.1097/TA.0000000000001225DOI Listing
November 2016

Microfluidic blood-brain barrier model provides in vivo-like barrier properties for drug permeability screening.

Biotechnol Bioeng 2017 01 21;114(1):184-194. Epub 2016 Jul 21.

Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, 381 Kimball Hall, Ithaca, New York, 14853-7202.

Efficient delivery of therapeutics across the neuroprotective blood-brain barrier (BBB) remains a formidable challenge for central nervous system drug development. High-fidelity in vitro models of the BBB could facilitate effective early screening of drug candidates targeting the brain. In this study, we developed a microfluidic BBB model that is capable of mimicking in vivo BBB characteristics for a prolonged period and allows for reliable in vitro drug permeability studies under recirculating perfusion. We derived brain microvascular endothelial cells (BMECs) from human induced pluripotent stem cells (hiPSCs) and cocultured them with rat primary astrocytes on the two sides of a porous membrane on a pumpless microfluidic platform for up to 10 days. The microfluidic system was designed based on the blood residence time in human brain tissues, allowing for medium recirculation at physiologically relevant perfusion rates with no pumps or external tubing, meanwhile minimizing wall shear stress to test whether shear stress is required for in vivo-like barrier properties in a microfluidic BBB model. This BBB-on-a-chip model achieved significant barrier integrity as evident by continuous tight junction formation and in vivo-like values of trans-endothelial electrical resistance (TEER). The TEER levels peaked above 4000 Ω · cm on day 3 on chip and were sustained above 2000 Ω · cm up to 10 days, which are the highest sustained TEER values reported in a microfluidic model. We evaluated the capacity of our microfluidic BBB model to be used for drug permeability studies using large molecules (FITC-dextrans) and model drugs (caffeine, cimetidine, and doxorubicin). Our analyses demonstrated that the permeability coefficients measured using our model were comparable to in vivo values. Our BBB-on-a-chip model closely mimics physiological BBB barrier functions and will be a valuable tool for screening of drug candidates. The residence time-based design of a microfluidic platform will enable integration with other organ modules to simulate multi-organ interactions on drug response. Biotechnol. Bioeng. 2017;114: 184-194. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/bit.26045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6650146PMC
January 2017

A recellularized human colon model identifies cancer driver genes.

Nat Biotechnol 2016 08 11;34(8):845-51. Epub 2016 Jul 11.

Department of Biomedical Engineering, Cornell University, Ithaca, New York, USA.

Refined cancer models are needed to bridge the gaps between cell line, animal and clinical research. Here we describe the engineering of an organotypic colon cancer model by recellularization of a native human matrix that contains cell-populated mucosa and an intact muscularis mucosa layer. This ex vivo system recapitulates the pathophysiological progression from APC-mutant neoplasia to submucosal invasive tumor. We used it to perform a Sleeping Beauty transposon mutagenesis screen to identify genes that cooperate with mutant APC in driving invasive neoplasia. We identified 38 candidate invasion-driver genes, 17 of which, including TCF7L2, TWIST2, MSH2, DCC, EPHB1 and EPHB2 have been previously implicated in colorectal cancer progression. Six invasion-driver genes that have not, to our knowledge, been previously described were validated in vitro using cell proliferation, migration and invasion assays and ex vivo using recellularized human colon. These results demonstrate the utility of our organoid model for studying cancer biology.
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http://dx.doi.org/10.1038/nbt.3586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4980997PMC
August 2016