bioprocess; bioreactor; in silico model; regenerative medicine; tissue engineering
Abstract :
[en] The cell therapy market is a highly volatile one, due to the use of disruptive technologies, the current economic situation and the small size of the market. In such a market, companies as well as academic research institutes are in need of tools to advance their understanding and, at the same time, reduce their R&D costs, increase product quality and productivity, and reduce the time to market. An additional difficulty is the regulatory path that needs to be followed, which is challenging in the case of cell-based therapeutic products and should rely on the implementation of quality by design (QbD) principles. In silico modelling is a tool that allows the above-mentioned challenges to be addressed in the field of regenerative medicine. This review discusses such in silico models and focuses more specifically on the bioprocess. Three (clusters of) examples related to this subject are discussed. The first example comes from the pharmaceutical engineering field where QbD principles and their implementation through the use of in silico models are both a regulatory and economic necessity. The second example is related to the production of red blood cells. The described in silico model is mainly used to investigate the manufacturing process of the cell-therapeutic product, and pays special attention to the economic viability of the process. Finally, we describe the set-up of a model capturing essential events in the development of a tissue-engineered combination product in the context of bone tissue engineering. For each of the examples, a short introduction to some economic aspects is given, followed by a description of the in silico tool or tools that have been developed to allow the implementation of QbD principles and optimal design.
Disciplines :
Engineering, computing & technology: Multidisciplinary, general & others
Author, co-author :
Geris, Liesbet ; Université de Liège > Département d'aérospatiale et mécanique > Génie biomécanique
Guyot, Y.
Schrooten, J.
Papantoniou, I.
Language :
English
Title :
In silico regenerative medicine: how computational tools allow regulatory and financial challenges to be addressed in a volatile market.
Publication date :
2016
Journal title :
Interface Focus
ISSN :
2042-8898
eISSN :
2042-8901
Publisher :
The Royal Society, London, United Kingdom
Volume :
6
Issue :
2
Pages :
20150105
Peer reviewed :
Peer Reviewed verified by ORBi
European Projects :
FP7 - 279100 - BRIDGE - Biomimetic process design for tissue regeneration: from bench to bedside via in silico modelling
Mason C, Dunnill P. 2008 A brief definition of regenerative medicine. Regen. Med. 3, 1-5. (doi:10.2217/17460751.3.1.1)
Greenwood HL, Singer PA, Downey GP, Martin DK, Thorsteinsdóttir H, Daar AS. 2006 Regenerative medicine and the developing world. PLoS Med. 3, e381. (doi:10.1371/journal.pmed.0030381)
Brindley DA, Reeve BC, Sahlman WA, Bonfiglio GA, Davie NL, Culme-Seymour EJ, Mason C. 2011 The impact of market volatility on the cell therapy industry. Cell Stem Cell 9, 397-401. (doi:10.1016/j.stem.2011.10.010)
Food and Drug Administration. 2003 Guidance for industry: PAT—a framework for innovative pharmaceutical manufacturing and quality assurance. Rockville, MD: Food and Drug Administration.
Faratian D et al. 2009 Systems biology reveals new strategies for personalizing cancer medicine and confirms the role of PTEN in resistance to trastuzumab. Cancer Res. 69, 6713-6720. (doi:10.1158/0008-5472.CAN-09-0777)
Kovatchev BP, Breton M, Man CD, Cobelli C. 2009 In silico preclinical trials: a proof of concept in closedloop control of type 1 diabetes. J. Diabetes Sci. Technol. 3, 44-55.
Food and Drug Administration. 2014 Reporting of Computational Modeling Studies in Medical Device Submissions—Draft Guidance for Industry and Food and Drug Administration Staff only. Food and Drug Administration, Rockville, MD.
Geris L (ed.). 2013 Computational modeling in tissue engineering. Studies in Mechanobiology, Tissue Engineering and Biomaterials, vol. 10, p. 400. Berlin, Germany: Springer-Verlag.
Geris L. 2014 Regenerative orthopaedics: in vitro, in vivo…in silico. Int. Orthop. 38, 1771-1778. (doi:10.1007/s00264-014-2419-6)
Gernaey KV, Gani R. 2010 A model-based systems approach to pharmaceutical product-process design and analysis. Chem. Eng. Sci. 65, 5757-5769. (doi:10.1016/j.ces.2010.05.003)
Misener R, Fuentes-Garí M, Rende M, Velliou E, Panoskaltsis N, Pistikopoulos EN, Mantalaris A. 2014 Global superstructure optimisation of red blood cell production in a parallelised hollow fibre bioreactor. Comput. Chem. Eng. 71, 532-553. (doi:10.1016/j.compchemeng.2014.10.004)
Guyot Y, Luyten FP, Schrooten J, Papantoniou I, Geris L. 2015 A three-dimensional computational fluid dynamics model of shear stress distribution during neotissue growth in a perfusion bioreactor. Biotechnol. Bioeng. 112, 2591-2600. (doi:10.1002/bit.25672)
Reklaitis GV, Khinast J, Muzzio F. 2010 Pharmaceutical engineering science—new approaches to pharmaceutical development and manufacturing. Chem. Eng. Sci. 65, 5-7. (doi:10.1016/j.ces.2010.08.041)
Winkle HN. 2010 Quality by design (QbD) and process analytical technologies (PAT): current status and future direction. Grayslake, IL: IFPAC.
Avicenna Roadmap. In silico clinical trials: how computer simulation will transform the biomedical industry. See http://avicenna-isct.org/roadmap/.
Suresh P, Basu PK. 2008 Improving pharmaceutical product development and manufacturing: impact on cost of drug development and cost of goods sold of pharmaceuticals. J. Pharm. Innov. 3, 175-187. (doi:10.1007/s12247-008-9043-1)
Singh R, Gernaey KV, Gani R. 2010 An ontological knowledge-based system for the selection of process monitoring and analysis tools. Comput. Chem. Eng. 34, 1137-1154. (doi:10.1016/j.compchemeng.2010.04.011)
World Health Organization. 2004 Global Database on Blood Safety: report 2001-2002. Geneva, Switzerland: World Health Organization Press. See http://www.who.int/bloodsafety/GDBS_Report_2001-2002.pdf.
Whitaker BI, Henry RA. 2007 The 2007 nationwide blood collection and utilization survey report. Washington, DC: Department of Health and Human Services.
Timmins NE, Nielsen LK. 2009 Blood cell manufacture: current methods and future challenges. Trends Biotechnol. 27, 415-422. (doi:10.1016/j.tibtech.2009.03.008)
Whitaker BI, Henry RA. 2011 The 2011 nationwide blood collection and utilization survey report. Washington, DC: Department of Health and Human Services.
Giarratana MC, Kobari L, Lapillonne H, Chalmers D, Kiger L, Cynober T, Marden MC, Wajcman H, Douay L. 2005 Ex vivo generation of fully mature human red blood cells from hematopoietic stem cells. Nat. Biotechnol. 23, 69-74. (doi:10.1038/nbt1047)
Macedo HM. 2011 A novel 3D dual hollow fibre bioreactor for the production of human red blood cells. PhD thesis, Imperial College, London, UK.
Panoskaltsis N, Mantalaris A, Wu JHD. 2005 Engineering a mimicry of bone marrow tissue ex vivo. J. Biosci. Bioeng. 100, 28-35. (doi:10.1263/jbb.100.28)
Colijn C, Mackey MC. 2005 A mathematical model of hematopoiesis: I. Periodic chronic myelogenous leukemia. J. Theor. Biol. 237, 117-132. (doi:10.1016/j.jtbi.2005.03.033)
Ma CYJ, Panoskaltsis N, Kumar R, Xu XY, Mantalaris A. 2012 Simulation of ex vivo bone marrow culture: application to chronic myeloid leukaemia growth model. Biochem. Eng. J. 61, 66-77. (doi:10.1016/j.bej.2011.10.002)
Misener R, Floudas CA. 2013 ANTIGONE: Algorithms for coNTinuous/Integer Global Optimization of Nonlinear Equations. J. Glob. Optim. 59, 503-526. (doi:10.1007/s10898-014-0166-2)
Bock AK, Ibarreta D, Rodriguez-Cerezo E. 2003 Human tissue engineered products: today’s market and future prospects; synthesis report. Report EUR 21000 EN. Institute for Prospective Technological Studies and European Commission Directorate General Joint Research Centre, Seville, Spain.
Ahlmann E et al. 2002 Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients. J. Bone Joint Surg. Am. 84-A, 2123-2134.
Olson S, Hahn D. 2006 Surgical treatment of nonunions: a case for internal fixation. Injury 37, 681-690. (doi:10.1016/j.injury.2004.11.039)
Pederson WC, Person DW. 2007 Long bone reconstruction with vascularized bone grafts. Orthop. Clin. North Am. 38, 23-35. (doi:10.1016/j.ocl.2006.10.006)
Roberts SJ, Howard D, Buttery LD, Shakesheff KM. 2008 Clinical applications of musculoskeletal tissue engineering. Br. Med. Bull. 86, 7-22. (doi:10.1093/bmb/ldn016)
Dahabreh Z, Dimitriou R, Giannoudis PV. 2007 Health economics: a cost analysis of treatment of persistent fracture non-unions using bone morphogenetic protein-7. Injury 38, 371-377. (doi:10.1016/j.injury.2006.08.055)
Sprague S, Bhandari M. 2002 An economic evaluation of early versus delayed operative treatment in patients with closed tibial shaft fractures. Arch. Orthop. Trauma Surg. 122, 315-323.
Chung KC, Saddawi-Konefka D, Haase SC. 2009 A cost-utility analysis of amputation versus salvage for Gustilo type IIIB and IIIC open tibial fractures. Plast. Reconstr. Surg. 124, 1965-1973. (doi:10.1097/PRS.0b013e3181bcf156)
Lysaght MJ, Jaklenec A, Deweerd E. 2008 Great expectations: private sector activity in tissue engineering, regenerative medicine, and stem cell therapeutics. Tissue Eng. Part A 14, 305-315. (doi:10.1089/tea.2007.0267)
Alliance for Regenerative Medicine. 2010 Economic impacts of regenerative medicine: initial findings. Washington, DC: Alliance for Regenerative Medicine.
Roberts SJ, van Gastel N, Carmeliet G, Luyten FP. 2015 Uncovering the periosteum for skeletal regeneration: the stem cell that lies beneath. Bone 70, 10-18. (doi:10.1016/j.bone.2014.08.007)
Van Bael S, Chai YC, Truscello S, Moesen M, Kerckhofs G, Van Oosterwyck H, Kruth JP, Schrooten J. 2012 The effect of pore geometry on the in vitro biological behavior of human periosteum-derived cells seeded on selective laser-melted Ti6Al4 V bone scaffolds. Acta Biomater. 8, 2824-2834. (doi:10.1016/j.actbio.2012.04.001)
Sonnaert M, Papantoniou I, Bloemen V, Kerckhofs G, Luyten FP, Schrooten J. 2014 Human periostealderived cell expansion in a perfusion bioreactor system: proliferation, differentiation and extracellular matrix formation. J Tissue Eng. Regen. Med. (doi:10.1002/term.1951)
Bidan CM, Kommareddy KP, Rumpler M, Kollmannsberger P, Fratzl P, Dunlop JW. 2013 Geometry as a factor for tissue growth: towards shape optimization of tissue engineering scaffolds. Adv. Healthc. Mater. 2, 186-194. (doi:10.1002/adhm.201200159)
Guyot Y, Papantoniou I, Chai YC, Van Bael S, Schrooten J, Geris L. 2014 A computational model for cell/ECM growth on 3D surfaces using the level set method: a bone tissue engineering case study. Biomech. Model Mechanobiol. 13, 1361-1371. (doi:10.1007/s10237-014-0577-5)
De Boodt S, Truscello S, Ozcan SE, Leroy T, Van Oosterwyck H, Berckmans D, Schrooten J. 2010 Bimodular flow characterization in tissue engineering scaffolds using computational fluid dynamics and particle imaging velocimetry. Tissue Eng. Part C Methods 16, 1553-1564. (doi:10.1089/ten.tec.2010.0107)
Cruel M, Bensidhoum M, Nouguier-Lehon C, Dessombz O, Becquart P, Petite H. 2015 Numerical study of granular scaffold efficiency to convert fluid flow into mechanical stimulation in bone tissue engineering. Tissue Eng. Part C Methods 21, 863-871. (doi:10.1089/ten.TEC.2014.0648)
Lesman A, Blinder Y, Levenberg S. 2010 Modeling of flow-induced shear stress applied on 3D cellular scaffolds: implications for vascular tissue engineering. Biotechnol. Bioeng. 105, 645-654. (doi:10.1002/bit.22555)
Nava MM, Raimondi MT, Pietrabissa R. 2013 A multiphysics 3D model of tissue growth under interstitial perfusion in a tissue-engineering bioreactor. Biomech. Model Mechanobiol. 12, 1169-1179. (doi:10.1007/s10237-013-0473-4)
Hossain MS, Bergstrom DJ, Chen XB. 2015 Prediction of cell growth rate over scaffold strands inside a perfusion bioreactor. Biomech. Model Mechanobiol. 14, 333-344. (doi:10.1007/s10237-014-0606-4)
Guyot Y, Papantoniou I, Luyten F, Geris L. 2016 Coupling curvature-dependent and shear stress stimulated neotissue growth in dynamic bioreactor cultures: a 3D computational model of a complete scaffold. Biomech. Model Mechanobiol. (doi:10.1007/s10237-015-0753-2)
Chapman LAC, Shipley RJ, Whiteley JP, Ellis MJ, Byrne HM, Waters SL. 2014 Optimising cell aggregate expansion in a perfused hollow fibre bioreactor via mathematical modelling. PLoS ONE 9, e105813. (doi:10.1371/journal.pone.0105813)
