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FRAME Alternatives Laboratory
Introduction

FRAME Alternatives Laboratory

The aim of the FRAME Alternatives Laboratory (FAL) is to produce human-based systems that are better and more relevant to humans than current animal models. FRAME makes an annual donation to support work carried out there.

When the FAL was established in 1991 at the University of Nottingham Medical School, research primarily concentrated on replacements for acute toxicology testing such as the notorious LD50 test and the Draize eye irritancy test in rabbits. Many of its findings are now accepted in mainstream research, contributing to a reduction in the number of animals used for toxicology testing.

Since Dr Andrew Bennett’s appointment as Director in 2006, the FAL now concentrates on using samples obtained – with full ethical approval and under licence from the Human Tissue Authority – from operations at Nottingham University Hospitals NHS Trust, to construct in vitro models of human cells and organs for biomedical research.

The FAL uses cells derived from human tissues to produce biologically relevant in vitro models of human organs, which behave and respond in the way they would in the body. Rather than growing cells as a single layer on plastic surfaces, the lab uses three-dimensional scaffolds and introduces flow into these systems to replicate the environment found in living humans. Current cell models include human liver, skeletal muscle, adipose tissue and skin.

The grant funding FRAME contributes to the FAL allowed the laboratory to be fully refurbished in 2007. The funding also enables the laboratory to update and maintain state-of-the-art equipment for growing human tissue, as well as provides support for PhD students, postdocs and undergraduate students from the University of Nottingham to develop research projects that focus on alternatives.

Project

FRAME funded research looks at establishing D.magna model to study ageing

FRAME-funded research to characterise the water flea Daphnia magna as an invertebrate model for ageing research has recently been published.

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Project

Human dietary study involving FAL is published

FAL staff have contributed to a study investigating the effect of limiting food intake to 8 hours of the day on metabolic health and weight loss.

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Project

FRAME develops in vitro model for study of chemotherapy-associated liver disease

The FRAME Alternatives Laboratory (FAL) has developed an in vitro model to study fatty liver disease associated with chemotherapy.

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Project

FRAME awards grant to University of Hull cancer research project

FRAME has awarded the Department of Biomedical Sciences at the University of Hull with a grant to support an undergraduate on a cancer research project.

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Project

FRAME Summer Studentship winners complete research projects

The two winners of FRAME’s Summer Studentship Programme 2019 have completed projects relating to the development of alternatives to animal use in research.

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Project

FRAME’s study with Arthritis Research UK Pain Centre to be published

A paper involving the FRAME Alternatives Laboratory has been accepted for publication in the journal Osteoarthritis and Cartilage. 

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Project

Animal free research sheds light on link between obesity and skeletal muscle loss

Researchers at the FRAME Alternatives Laboratory are part of a collaboration that aims to elucidate how obesity leads to accelerated muscle loss.

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Project

Developing an animal free liver toxicity test using 3D printing technology

Clair Brooks, PhD intern in the FRAME Alternatives Laboratory, explains her research into developing a liver toxicity test using 3D printing technology.

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Published Papers

This is a list of recently published research papers involving the FRAME Alternatives Laboratory which benefit from the annual FRAME grant.

Mixed Polymer and bioconjugate core/shell electrospun fibres for biphasic protein release. Adala I, Ramis J, Moussinga C.N, Janowski I, Amer M.H, Bennett, A.J, Alexander C and Rose F.R.A.J. May 2021 Journal of Materials Chemistry B 9(suppl 4) doi: 10.1039/D1TB00129A

Two weeks of early time-restricted feeding (eTRF) improves skeletal muscle insulin and anabolic sensitivity in healthy men   Jones R, Pabla P, Mallison J, Nixon A, Taylor T, Bennett A and Tsintzas K. American Journal of Clinical Nutrition 2020. Volume 112, Issue 4, October 2020, Pages 1015–1028, https://doi.org/10.1093/ajcn/nqaa192

Comparison of primary human hepatocytes and HepG2 cells as models to study the development of hepatic steatosis Proceedings of The Nutrition Society 78(OCE1) 2019 Hugget Z, Brameld J M., Bennett AJ, Salter A.M.

Molecular expression patterns in the synovium and their association with advanced symptomatic knee osteoarthritis.Wyatt LA, Nwosu LN, Wilson D, Hill R, Spendlove I, Bennett AJ, Scammell BE, Walsh DA. Osteoarthritis Cartilage. 2019 Apr;27(4):667-675. doi: 10.1016/j.joca.2018.12.012. Epub 2018 Dec 28.

Postoperative inflammation and insulin resistance in relation to body composition, adiposity and carbohydrate treatment: A randomised controlled study. Tewari N, Awad S, Duška F, Williams JP, Bennett A, Macdonald IA, Lobo DN.Clin Nutr. 2019 Feb;38(1):204-212. doi: 10.1016/j.clnu.2018.01.032. Epub 2018 Feb 15.

n-3 polyunsaturated N-acylethanolamines are CB2 cannabinoid receptor-preferring endocannabinoids. Alharthi N, Christensen P, Hourani W, Ortori C, Barrett DA, Bennett AJ, Chapman V, Alexander SPH. Biochim Biophys Acta Mol Cell Biol Lipids. 2018 Nov;1863(11):1433-1440. doi: 10.1016/j.bbalip.2018.08.003. Epub 2018 Aug 7.

Obese subcutaneous adipose tissue impairs human myogenesis, particularly in old skeletal muscle, via resistin-mediated activation of NFκB. O’Leary MF, Wallace GR, Davis ET, Murphy DP, Nicholson T, Bennett AJ, Tsintzas K, Jones SW. Sci Rep. 2018 Oct 18;8(1):15360. doi: 10.1038/s41598-018-33840-x.

IL-15 promotes human myogenesis and mitigates the detrimental effects of TNFα on myotube development.O’Leary MF, Wallace GR, Bennett AJ, Tsintzas K, Jones SW.Sci Rep. 2017 Oct 11;7(1):12997. doi: 10.1038/s41598-017-13479-w.

Effects of short-term energy restriction on liver lipid content and inflammatory status in severely obese adults: Results of a randomized controlled trial using 2 dietary approaches. Baldry EL, Aithal GP, Kaye P, Idris IR, Bennett A, Leeder PC, Macdonald IA.

Diabetes Obes Metab. 2017 Aug;19(8):1179-1183. doi: 10.1111/dom.12918. Epub 2017 Mar 31. Bioprinting Using Mechanically Robust Core-Shell Cell-Laden Hydrogel Strands Pritesh Mistry, Aied Ahmed Morgan, Alexander Bennett, Andrew Jing Yang Macromolecular Bioscience 2017 17(6):1600472 DOI10.1002/mabi.2016004720172.

Gene expression patterns in the synovium and their association with symptomatic knee osteoarthritis Wyatt, L.A, Mapp, P.I, Wilson, D., Hill, R., Scamell, B.E. Bennett, A.J. Walsh D.A.Osteoarthritis and Cartilage 2016 24(1):S28S29DOI:10.1016/j.joca.2016.01.078.

Effects of short term very low energy diets prior to bariatric surgery on liver histology and circulating biomarkers: Results of a Randomised Controlled Trial (RCT) Journal of Hepatology 2015  62(2):S716 DOI: 10.1016/S0168-8278(15)31187-9 Emma L Baldry, Guruprasad P Aithal, Philip Kay,e Iskandar Idris, Paul Leeder, Andrew Bennett, Ian Macdonald.

Effects of short-term energy restriction prior to bariatric surgery on liver fat, inflammation and systemic metabolic parameters. Diabetic Medicine 2015 32DOI: 10.1111/dme.2015.32.issue-S1 Emma L Baldry, Guruprasad P Aithal, Philip Kaye, Iskandar Idris, Paul Leeder, Andrew Bennett, Ian Macdonald.

Cannabidiol enhances microglial phagocytosis via transient receptor potential (TRP) channel activation.Hassan S, Eldeeb K, Millns PJ, Bennett AJ, Alexander SP, Kendall DA. Br J Pharmacol. 2014 May;171(9):2426-39. doi: 10.1111/bph.12615.

Abnormal T regulatory cells (Tregs: FOXP3+, CTLA-4+), myeloid-derived suppressor cells (MDSCs: monocytic, granulocytic) and polarised T helper cell profiles (Th1, Th2, Th17) in women with large and locally advanced breast cancers undergoing neoadjuvant chemotherapy (NAC) and surgery: failure of abolition of abnormal treg profile with treatment and correlation of treg levels with pathological response to NAC.Verma C, Eremin JM, Robins A, Bennett AJ, Cowley GP, El-Sheemy MA, Jibril JA, Eremin O. J Transl Med. 2013 Jan 15;11:16. doi: 10.1186/1479-5876-11-16.

The S349T mutation of SQSTM1 links Keap1/Nrf2 signalling to Paget’s disease of bone.Wright T, Rea SL, Goode A, Bennett AJ, Ratajczak T, Long JE, Searle MS, Goldring CE, Park BK, Copple IM, Layfield R. Bone. 2013 Feb;52(2):699-706. doi: 10.1016/j.bone.2012.10.023. Epub 2012 Oct 29.

Independent and combined effects of acute physiological hyperglycaemia and hyperinsulinaemia on metabolic gene expression in human skeletal muscle.Tsintzas K, Norton L, Chokkalingam K, Nizamani N, Cooper S, Stephens F, Billeter R, Bennett A. Clin Sci (Lond). 2013 Jun;124(11):675-84. doi: 10.1042/CS20120481.

Oleamide activates peroxisome proliferator-activated receptor gamma (PPARγ) in vitro.Dionisi M, Alexander SP, Bennett AJ.Lipids Health Dis. 2012 May 14;11:51. doi: 10.1186/1476-511X-11-51.

An in vitro model of chemotherapy-associated steatohepatitis: Induction of lipid accumulation in hepatocyte/non-parenchymal cell co-culture by 5-flourouracil and irinotecan Journal of the American College of Surgeons 2012  215(3):S26 DOI: 10.1016/j.jamcollsurg.2012.06.088 John S Hammond, Monika Owen, Elke Gottschalg, Nicola De Vivo, Guruprasad P Aithal Andrew Bennett, Dileep N Lobo.

Mechanistic randomised control trial of mesalazine in symptomatic diverticular disease 2012 Gut 61(Suppl 2):A51-A52 DOI: 10.1136/gutjnl-2012-302514a.119 Janette K Smith, David J Humes, Klara Garsad,  Ching Lam, Andrew Bennett, John Scholefield, Abed Zaitoun, Robin Spiller.

Translation of New Technologies in Biomedicines: Shaping the Road from Basic Research to Drug Development and Clinical Application-and Back Again April 2012 DOI: 10.1002/9783527632909.ch6 Pharmaceutical Biotechnology Michael Balls, Andrew Bennett, David Kendall.

Visceral hypersensitivity in symptomatic diverticular disease and the role of neuropeptides and low grade inflammation. Humes DJ, Simpson J, Smith J, Sutton P, Zaitoun A, Bush D, Bennett A, Scholefield JH, Spiller RC. Neurogastroenterol Motil. 2012 Apr;24(4):318-e163. doi: 10.1111/j.1365-2982.2011.01863.x. Epub 2012 Jan 25.

Impaired uptake of serotonin by platelets from patients with irritable bowel syndrome correlates with duodenal immune activation. Foley S, Garsed K, Singh G, Duroudier NP, Swan C, Hall IP, Zaitoun A, Bennett A, Marsden C, Holmes G, Walls A, Spiller RC. Gastroenterology. 2011 May;140(5):1434-43.e1. doi: 10.1053/j.gastro.2011.01.052. Epub 2011 Mar 23.

Skeletal muscle metabolic gene expression is not affected by dichloroacetate-mediated modulation of substrate utilisation. Tisdale PB, Seevaratnam N, Macdonald IA, Tsintzas K, Bennett AJ. Ann Nutr Metab. 2011;58(1):19-24. doi: 10.1159/000322971. Epub 2011 Feb 8. Erratum in: Ann Nutr Metab. 2011;58(1):41.

The Use of Human Tissues and Cells in Biomedical Research: The Unusual Suspects 2010 Alternatives to laboratory animals: ATLA 38 Suppl 1:5-9 Andrew Bennett.

Inter- and intra-laboratory study to determine the reproducibility of toxicogenomics datasetsScott DJ1Devonshire ASAdeleye YASchutte MERodrigues MRWilkes TMSacco MGGribaldo LFabbri MCoecke SWhelan MSkinner NBennett AWhite AFoy CAToxicology. 2011 Nov 28;290(1):50-8. doi: 10.1016/j.tox.2011.08.015. Epub 2011 Aug 19.

An interlaboratory study to evaluate the reproducibility of toxicogenomics datasets 2010 Toxicology Letters 196DOI: 10.1016/j.toxlet.2010.03.518 Laura Gribaldo, Daniel Scott, Alison Devonshire, Andrew Bennett.

Systems Biology in Alternatives: The Importance of Human-based Studies 2009 ATLA 37 Suppl 2:89-91 Andrew Bennett.

MOLECULAR MECHANISMS UNDERLYING THE EFFECT OF PIOGLITAZONE THERAPY IN NON-ALCOHOLIC STEATOHEPATITIS (NASH) 2009Journal of Hepatology 50 DOI: 10.1016/S0168-8278(09)60694-2 Abdul Rahim, Guruprasad P Aithal, Ian Macdonald, Andrew Bennett.

Increased Intraepithelial Lymphocytes and Mast Cells with Depressed Serotonin Transporter in Duodenal Biopsies and Platelets of Patients with IBS and Diarrhoea (IBS-D): Correlation with Bowel Frequency 2008 Gastroenterology 134(4) DOI: 10.1016/S0016-5085(08)60196-1 Stephen J. Foley Gulzar Singh Laurie Chi Kwong Lau Andrew F Walls Geoffrey K Holmes Andrew Bennett Charles Marsden Robin Spiller.

The effects of underfeeding on whole-body carbohydrate partitioning, thermogenesis and uncoupling protein 3 expression in human skeletal muscle. Seevaratnam N, Bennett AJ, Webber J, Macdonald IA. Diabetes Obes Metab. 2007 Sep;9(5):669-78.

Searching for the answer to irritable bowel syndrome in the colonic mucosa: SERTainty and unSERTainty.Spiller R, Bennett A. Gastroenterology. 2007 Jan;132(1):437-41.

Elevated serum alanine transaminase in patients with Type 1 or Type 2 diabetes December 2006QJM 99(12):871-6 DOI: 10.1093/qjmed/hcl116 J West, James Brousil, A Gazis, Lucina Jackson, Peter Mansell, Andrew Bennett, Guruprasad P Aithal.

Differential regulation of metabolic genes in skeletal muscle during starvation and refeeding in humans.Tsintzas K, Jewell K, Kamran M, Laithwaite D, Boonsong T, Littlewood J, Macdonald I, Bennett A. J Physiol. 2006 Aug 15;575(Pt 1):291-303. Epub 2006 Jun 8.

Other Publications

These research projects received FRAME funding via a grant or award.  

Constantinou A., Sullivan J. & Mirbahai L. (2019). Ageing differently: Sex-dependent ageing rates in Daphnia magna. Experimental Gerontology 121 (2019), pp 33 – 45

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