1932

Abstract

High-throughput (HT) techniques built upon laboratory automation technology and coupled to statistical experimental design and parallel experimentation have enabled the acceleration of chemical process development across multiple industries. HT technologies are often applied to interrogate wide, often multidimensional experimental spaces to inform the design and optimization of any number of unit operations that chemical engineers use in process development. In this review, we outline the evolution of HT technology and provide a comprehensive overview of how HT automation is used throughout different industries, with a particular focus on chemical and pharmaceutical process development. In addition, we highlight the common strategies of how HT automation is incorporated into routine development activities to maximize its impact in various academic and industrial settings.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-chembioeng-060816-101411
2017-06-07
2024-06-16
Loading full text...

Full text loading...

/deliver/fulltext/chembioeng/8/1/annurev-chembioeng-060816-101411.html?itemId=/content/journals/10.1146/annurev-chembioeng-060816-101411&mimeType=html&fmt=ahah

Literature Cited

  1. Koch MV, VandenBussche KM, Chrisman RW. 1.  2007. Micro Instrumentation for High Throughput Experimentation and Process Intensification—A Tool for PAT Hoboken, NJ: Wiley [Google Scholar]
  2. Landers P. 2.  2004. Drug industry's big push into technology falls short: Testing machines were built to streamline research—but may be stifling it. Wall Street JournalFeb. 24 [Google Scholar]
  3. Macarron R, Banks MN, Bojanic D, Burns DJ, Cirovic DA. 3.  et al. 2011. Impact of high-throughput screening in biomedical research. Nat. Rev. Drug Discov. 10:188–95 [Google Scholar]
  4. Liu M, Chen K, Christian D, Fatima T, Pissarnitski N. 4.  et al. 2012. High-throughput purification platform in support of drug discovery. ACS Comb. Sci. 14:51–59 [Google Scholar]
  5. Jandeleit B, Schaefer D, Powers T, Turner H, Weinberg W. 5.  1999. Combinatorial materials science and catalysis. Angew. Chem. Int. Ed. 38:2494–532 [Google Scholar]
  6. Wang J, Yoo Y, Gao C, Takeuchi I, Sun X. 6.  et al. 1998. Identification of a blue photoluminescent composite material from a combinatorial library. Science 279:1712–14 [Google Scholar]
  7. Potyrailo R, Rajan K, Stoewe K, Takeuchi I, Chisholm B, Lam H. 7.  2011. Combinatorial and high-throughput screening of materials libraries: review of state of the art. ACS Comb. Sci. 13:579–633 [Google Scholar]
  8. Service R. 8.  1998. Winning combinations. MIT Technology ReviewMay 1 [Google Scholar]
  9. Nadin A, Hattotuwagama C, Churcher I. 9.  2012. Lead-oriented synthesis: a new opportunity for synthetic chemistry. Angew. Chem. Int. Ed. 51:1114–22 [Google Scholar]
  10. McWilliams JC, Sidler DR, Sun Y, Mathre DJ. 10.  2005. Applying statistical design of experiments and automation to the rapid optimization of metal-catalyzed processes in process development. J. Assoc. Lab. Autom. 10:394–407 [Google Scholar]
  11. Sheridan M. 11.  2001. Symyx, Merck to develop polymorph “Discovery Tools” system. ICIS NewsJune 26 [Google Scholar]
  12. McMullen JP, Jensen KF. 12.  2010. Integrated microreactors for reaction automation: new approaches to reaction development. Annu. Rev. Anal. Chem. 3:19–42 [Google Scholar]
  13. Guerrero-Sanchez C, Paulus RM, Fijten MWM, de la Mar MJ, Hoogenboom R, Schubert US. 13.  2006. High-throughput experimentation in synthetic polymer chemistry: from RAFT and anionic polymerizations to process development. Appl. Surf. Sci. 252:2555–61 [Google Scholar]
  14. Houben C, Lapkin AA. 14.  2015. Automatic discovery and optimization of chemical processes. Curr. Opin. Chem. Eng. 9:1–7 [Google Scholar]
  15. Potyrailo RA, Morris WG, Wroczynski RJ, McCloskey PJ. 15.  2004. Resonant multisensor system for high-throughput determinations of solvent/polymer interactions. J. Comb. Chem. 6:869–73 [Google Scholar]
  16. Thurow K, Weinmann H. 16.  2005. Automation highlights from literature. J. Assoc. Lab. Autom. 10:77–81 [Google Scholar]
  17. Meier MAR, Hoogenboom R, Schubert US. 17.  2004. Combinatorial methods, automated synthesis and high-throughput screening in polymer research: The evolution continues. Macromol. Rapid Commun. 25:21–33 [Google Scholar]
  18. Gruter G-JM, Graham A, McKay B, Gilardoni F. 18.  2003. R&D intensification in polymer catalyst and product development by using high-throughput experimentation and simulation. Macromol. Rapid Commun. 24:73–80 [Google Scholar]
  19. Dietrich JA, McKee AE, Keasling JD. 19.  2010. High-throughput metabolic engineering: advances in small-molecule screening and selection. Annu. Rev. Biochem. 79:563–90 [Google Scholar]
  20. Chubukov V, Mukhopadhyay A, Petzold CJ, Keasling JD, Martín HG. 20.  2016. Synthetic and systems biology for microbial production of commodity chemicals. npj Syst. Biol. Appl. 2:16009 [Google Scholar]
  21. Radzun KA, Wolf J, Jakob G, Zhang E, Stephens E. 21.  et al. 2015. Automated nutrient screening system enables high-throughput optimisation of microalgae production conditions. Biotechnol. Biofuels 8:1–17 [Google Scholar]
  22. Chundawat SPS, Balan V, Dale BE. 22.  2008. High-throughput microplate technique for enzymatic hydrolysis of lignocellulosic biomass. Biotechnol. Bioeng. 99:1281–94 [Google Scholar]
  23. Berlin A, Maximenko V, Bura R, Kang K-Y, Gilkes N, Saddler J. 23.  2006. A rapid microassay to evaluate enzymatic hydrolysis of lignocellulosic substrates. Biotechnol. Bioeng. 93:880–86 [Google Scholar]
  24. Goddard J-P, Reymond J-L. 24.  2004. Enzyme assays for high-throughput screening. Curr. Opin. Biotechnol. 15:314–22 [Google Scholar]
  25. Helbert W, Chanzy H, Husum TL, Schülein M, Ernst S. 25.  2003. Fluorescent cellulose microfibrils as substrate for the detection of cellulase activity. Biomacromolecules 4:481–87 [Google Scholar]
  26. Jenkins S. 26.  2011. Fermentation process development. Chemical EngineeringJan. 1 [Google Scholar]
  27. Parker TD 3rd, Wright DS, Rossi DT. 27.  1996. Design and evaluation of an automated solid-phase extraction method development system for use with biological fluids. Anal. Chem. 68:2437–41 [Google Scholar]
  28. Cork D, Sugawara T. 28.  2002. Laboratory Automation in the Chemical Industries New York: CRC Press [Google Scholar]
  29. Hüser J, Lohrmann E, Kalthof B, Burkhardt N, Brüggemeier U, Bechem M. 29.  2006. High-throughput screening for targeted lead discovery. High-Throughput Screening in Drug Discovery, Vol. 35 J Hüser 15–36 Hoboken, NJ: Wiley [Google Scholar]
  30. Diagne AB, Li S, Perkowski GA, Mrksich M, Thomson RJ. 30.  2015. SAMDI mass spectrometry-enabled high-throughput optimization of a traceless Petasis reaction. ACS Comb. Sci. 17:658–62 [Google Scholar]
  31. McNally A, Prier CK, MacMillan DWC. 31.  2011. Discovery of an α-amino C–H arylation reaction using the strategy of accelerated serendipity. Science 334:1114–17 [Google Scholar]
  32. Monfette S, Blacquiere JM, Fogg DE. 32.  2011. The future, faster: roles for high-throughput experimentation in accelerating discovery in organometallic chemistry and catalysis. Organometallics 30:36–42 [Google Scholar]
  33. Reetz MT, Kühling KM, Deege A, Hinrichs H, Belder D. 33.  2000. Super-high-throughput screening of enantioselective catalysts by using capillary array electrophoresis. Angew. Chem. Int. Ed. 39:3891–93 [Google Scholar]
  34. Reizman BJ, Jensen KF. 34.  2015. Simultaneous solvent screening and reaction optimization in microliter slugs. Chem. Commun. 51:13290–93 [Google Scholar]
  35. Robbins DW, Hartwig JF. 35.  2011. A simple, multidimensional approach to high-throughput discovery of catalytic reactions. Science 333:1423–27 [Google Scholar]
  36. Trapp O, Weber SK, Bauch S, Hofstadt W. 36.  2007. High-throughput screening of catalysts by combining reaction and analysis. Angew. Chem. Int. Ed. 46:7307–10 [Google Scholar]
  37. Shevlin M, Friedfeld MR, Sheng H, Pierson NA, Hoyt JM. 37.  et al. 2016. Nickel-catalyzed asymmetric alkene hydrogenation of α,β-unsaturated esters: high-throughput experimentation-enabled reaction discovery, optimization, and mechanistic elucidation. J. Am. Chem. Soc. 138:3562–69 [Google Scholar]
  38. Bellomo A, Celebi-Olcum N, Bu X, Rivera N, Ruck RT. 38.  et al. 2012. Rapid catalyst identification for the synthesis of the pyrimidinone core of HIV integrase inhibitors. Angew. Chem. Int. Ed. 51:6912–15 [Google Scholar]
  39. Murray PM, Tyler SNG, Moseley JD. 39.  2013. Beyond the numbers: charting chemical reaction space. Org. Process Res. Dev. 17:40–46 [Google Scholar]
  40. Davies IW, Welch CJ. 40.  2009. Looking forward in pharmaceutical process chemistry. Science 325:701–4 [Google Scholar]
  41. Morissette SL, Almarsson Ö, Peterson ML, Remenar JF, Read MJ. 41.  et al. 2004. High-throughput crystallization: polymorphs, salts, co-crystals and solvates of pharmaceutical solids. Adv. Drug Deliv. Rev. 56:275–300 [Google Scholar]
  42. McKenzie P, Kiang S, Tom J, Rubin AE, Futran M. 42.  2006. Can pharmaceutical process development become high tech?. AIChE J 52:3990–94 [Google Scholar]
  43. Rubin AE, Tummala S, Both DA, Wang C, Delaney EJ. 43.  2006. Emerging technologies supporting chemical process R&D and their increasing impact on productivity in the pharmaceutical industry. Chem. Rev. 106:2794–810 [Google Scholar]
  44. Alsenz J, Kansy M. 44.  2007. High throughput solubility measurement in drug discovery and development. Adv. Drug Deliv. Rev. 59:546–67 [Google Scholar]
  45. Black S, Dang L, Liu C, Wei H. 45.  2013. On the measurement of solubility. Org. Process Res. Dev. 17:486–92 [Google Scholar]
  46. Reus MA, van der Heijden AEDM, ter Horst JH. 46.  2015. Solubility determination from clear points upon solvent addition. Org. Process Res. Dev. 19:1004–11 [Google Scholar]
  47. Tong T. 47.  2007. Practical aspects of solubility determination. Solvent Systems and Their Selection in Pharmaceutics and Biopharmaceutics P Augustijns, ME Brewster 137–49 New York: Springer [Google Scholar]
  48. Ashcroft CP, Dunn PJ, Hayler JD, Wells AS. 48.  2015. Survey of solvent usage in papers published in organic process research & development 1997–2012. Org. Process Res. Dev. 19:740–47 [Google Scholar]
  49. Prat D, Pardigon O, Flemming H-W, Letestu S, Ducandas V. 49.  et al. 2013. Sanofi's solvent selection guide: a step toward more sustainable processes. Org. Process Res. Dev. 17:1517–25 [Google Scholar]
  50. Cohen B, Mahoney M, Remy B, Qiu J, Sfouggatakis C. 50.  et al. 2014. Development of a robust API crystallization in a multi-component solvent mixture: using high-throughput automation as enabling technology to develop comprehensive solubility maps Presented at AIChE Annual Meeting, Nov. 17–19 Atlanta, GA: [Google Scholar]
  51. Schmink J, Bellomo A, Berritt S. 51.  2013. Scientist-led high-throughput experimentation (HTE) and its utility in academia and industry. Aldrichimica Acta 46:71–80 [Google Scholar]
  52. Preshlock SM, Ghaffari B, Maligres PE, Krska SW, Maleczka RE, Smith MR. 52.  2013. High-throughput optimization of Ir-catalyzed C–H borylation: a tutorial for practical applications. J. Am. Chem. Soc. 135:7572–82 [Google Scholar]
  53. Cooper TWJ, Campbell IB, Macdonald SJF. 53.  2010. Factors determining the selection of organic reactions by medicinal chemists and the use of these reactions in arrays (small focused libraries). Angew. Chem. Int. Ed. 49:8082–91 [Google Scholar]
  54. Buitrago Santanilla A, Regalado EL, Pereira T, Shevlin M, Bateman K. 54.  et al. 2015. Nanomole-scale high-throughput chemistry for the synthesis of complex molecules. Science 347:49–53 [Google Scholar]
  55. Wei CS, Davies GHM, Soltani O, Albrecht J, Gao Q. 55.  et al. 2013. The impact of palladium(II) reduction pathways on the structure and activity of palladium(0) catalysts. Angew. Chem. Int. Ed. 52:5822–26 [Google Scholar]
  56. Leahy DK, Fan Y, Desai LV, Chan C, Zhu J. 56.  et al. 2012. Efficient and scalable enantioselective synthesis of a CGRP antagonist. Org. Lett. 14:4938–41 [Google Scholar]
  57. DiRocco DA, Dykstra K, Krska S, Vachal P, Conway DV, Tudge M. 57.  2014. Late-stage functionalization of biologically active heterocycles through photoredox catalysis. Angew. Chem. Int. Ed. 53:4802–6 [Google Scholar]
  58. Chen K, Risatti C, Bultman M, Soumeillant M, Simpson J. 58.  et al. 2014. Synthesis of the 6-azaindole containing HIV-1 attachment inhibitor pro-drug, BMS-663068. J. Org. Chem. 79:8757–67 [Google Scholar]
  59. Eastgate MD, Bultman MS, Chen K, Fanfair DD, Fox RJ. 59.  et al. 2016. Methods for the preparation of HIV attachment inhibitor piperazine prodrug compound US Patent No. 20150038712 A1 [Google Scholar]
  60. Collins KD, Gensch T, Glorius F. 60.  2014. Contemporary screening approaches to reaction discovery and development. Nat. Chem. 6:859–71 [Google Scholar]
  61. Moreira R, Havranek M, Sames D. 61.  2001. New fluorogenic probes for oxygen and carbene transfer: a sensitive assay for single bead-supported catalysts. J. Am. Chem. Soc. 123:3927–31 [Google Scholar]
  62. Hopkinson MN, Gómez-Suárez A, Teders M, Sahoo B, Glorius F. 62.  2016. Accelerated discovery in photocatalysis using a mechanism-based screening method. Angew. Chem. Int. Ed. 55:4361–66 [Google Scholar]
  63. Denmark SE, Butler CR. 63.  2008. Vinylation of aromatic halides using inexpensive organosilicon reagents. Illustration of design of experiment protocols. J. Am. Chem. Soc. 130:3690–704 [Google Scholar]
  64. Rosso VW, Pazdan JL, Venit JJ. 64.  2001. Rapid optimization of the hydrolysis of N′-trifluoroacetyl-S-tert-leucine-N-methylamide using high-throughput chemical development techniques. Org. Process Res. Dev 5:294–98 [Google Scholar]
  65. Domagalaski NR, Mack BC, Tabora JE. 65.  2015. Analysis of design of experiments with dynamic responses. Org. Process Res. Dev. 19:1667–82 [Google Scholar]
  66. Burt JL, Braem AD, Ramirez A, Mudryk B, Rossano L, Tummala S. 66.  2011. Model-guided design space development for a drug substance manufacturing process. J. Pharm. Innov. 6:181–92 [Google Scholar]
  67. Hallow DM, Mudryk BM, Braem AD, Tabora JE, Lyngberg OK. 67.  et al. 2010. An example of utilizing mechanistic and empirical modeling in quality by design. J. Pharm. Innov. 5:193–203 [Google Scholar]
  68. Königsberger K, Chen G-P, Wu RR, Girgis MJ, Prasad K. 68.  et al. 2003. A practical synthesis of 6-[2-(2,5-dimethoxyphenyl)ethyl]-4-ethylquinazoline and the art of removing palladium from the products of Pd-catalyzed reactions. Org. Process Res. Dev. 7:733–42 [Google Scholar]
  69. Welch CJ, Albaneze-Walker J, Leonard WR, Biba M, DaSilva J. 69.  et al. 2005. Adsorbent screening for metal impurity removal in pharmaceutical process research. Org. Process Res. Dev. 9:198–205 [Google Scholar]
  70. Flahive EJ, Ewanicki BL, Sach NW, O'Neill-Slawecki SA, Stankovic NS. 70.  et al. 2008. Development of an effective palladium removal process for VEGF oncology candidate AG13736 and a simple, efficient screening technique for scavenger reagent identification. Org. Process Res. Dev. 12:637–45 [Google Scholar]
  71. Flahive E, Ewanicki B, Yu S, Higginson PD, Sach NW, Morao I. 71.  2007. A high-throughput methodology for screening solution-based chelating agents for efficient palladium removal. QSAR Comb. Sci. 26:679–85 [Google Scholar]
  72. Lewen N, Soumeillant M, Qiu J, Selekman J, Wood S, Zhu K. 72.  2015. Use of a field-portable XRF instrument to facilitate metal catalyst scavenger screening. Org. Process Res. Dev. 19:2039–44 [Google Scholar]
  73. Selekman JA, Tran K, Xu Z, Dummeldinger M, Kiau S. 73.  et al. 2016. High throughput extractions: a new paradigm for workup optimization in pharmaceutical process development. Org. Process Res. Dev. 20:1728–37 [Google Scholar]
  74. Tung H-H, Paul EL, Midler M, McCauley JA. 74.  2008. Crystallization of Organic Compounds: An Industrial Perspective Hoboken, NJ: Wiley [Google Scholar]
  75. Stahly GP. 75.  2007. Diversity in single- and multiple-component crystals. The search for and prevalence of polymorphs and cocrystals. Cryst. Growth Des. 7:1007–26 [Google Scholar]
  76. Bauer J, Spanton S, Henry R, Quick J, Dziki W. 76.  et al. 2001. Ritonavir: an extraordinary example of conformational polymorphism. Pharm. Res. 18:859–66 [Google Scholar]
  77. Morissette SL, Soukasene S, Levinson D, Cima MJ, Almarsson Ö. 77.  2003. Elucidation of crystal form diversity of the HIV protease inhibitor ritonavir by high-throughput crystallization. PNAS 100:2180–84 [Google Scholar]
  78. Pfund LY, Matzger AJ. 78.  2014. Towards exhaustive and automated high-throughput screening for crystalline polymorphs. ACS Comb. Sci. 16:309–13 [Google Scholar]
  79. Aaltonen J, Allesø M, Mirza S, Koradia V, Gordon KC, Rantanen J. 79.  2009. Solid form screening—a review. Eur. J. Pharm. Biopharm. 71:23–37 [Google Scholar]
  80. Daniel S, Hsieh JH, Daniel R, Qi G, Alicia NG. 80.  et al. 2012. Determination of the relative stability of a multipolymorph system via a novel pure component free energy calculation. Cryst. Growth Des. 12:5481–90 [Google Scholar]
  81. Selekman JA, Roberts D, Rosso V, Qiu J, Nolfo J. 81.  et al. 2016. Development of a highly automated workflow for investigating polymorphism and assessing risk of forming undesired crystal forms within a crystallization design space. Org. Process Res. Dev. 20:70–75 [Google Scholar]
  82. Lee AY, Erdemir D, Myerson AS. 82.  2011. Crystal polymorphism in chemical process development. Annu. Rev. Chem. Biomol. Eng. 2:259–80 [Google Scholar]
  83. Bareither R, Pollard D. 83.  2011. A review of advanced small-scale parallel bioreactor technology for accelerated process development: current state and future need. Biotechnol. Prog. 27:2–14 [Google Scholar]
  84. Pollard J, McDonald P, Hesslein A. 84.  2016. Lessons learned in building high-throughput process development capabilities. Eng. Life Sci. 16:93–98 [Google Scholar]
  85. Jones S, Ransohoff T, Castillo F, Riske F, Levine H. 85.  2015. High-throughput process development approaches for biopharmaceuticals. American Pharmaceutical ReviewMarch 27 [Google Scholar]
  86. Russo AP, Benoit B, Wood C, Jan D, Ozturk SS. 86.  2012. Multi-parameter process optimization using the SimCell™ system. Proceedings of the 21st Annual Meeting of the European Society for Animal Cell Technology (ESACT), Dublin, Ireland, June 7–10, 2009 N Jenkins, N Barron, P Alves 515–18 Dordrecht, Neth.: Springer [Google Scholar]
  87. Rameez S, Mostafa SS, Miller C, Shukla AA. 87.  2014. High-throughput miniaturized bioreactors for cell culture process development: reproducibility, scalability, and control. Biotechnol. Prog. 30:718–27 [Google Scholar]
  88. Hsu W-T, Aulakh RPS, Traul DL, Yuk IH. 88.  2012. Advanced microscale bioreactor system: a representative scale-down model for bench-top bioreactors. Cytotechnology 64:667–78 [Google Scholar]
  89. Rathore AS, Bhambure R. 89.  2014. High-throughput process development: I. Process chromatography. Protein Downstream Processing: Design, Development and Application of High and Low-Resolution Methods EN Labrou 29–37 Totowa, NJ: Humana [Google Scholar]
  90. Bhambure R, Kumar K, Rathore AS. 90.  2011. High-throughput process development for biopharmaceutical drug substances. Trends Biotechnol 29:127–35 [Google Scholar]
  91. Wiendahl M, Schulze Wierling P, Nielsen J, Fomsgaard Christensen D, Krarup J. 91.  et al. 2008. High throughput screening for the design and optimization of chromatographic processes—miniaturization, automation and parallelization of breakthrough and elution studies. Chem. Eng. Technol. 31:893–903 [Google Scholar]
  92. Bhambure R, Rathore AS. 92.  2013. Chromatography process development in the quality by design paradigm I: establishing a high-throughput process development platform as a tool for estimating “characterization space” for an ion exchange chromatography step. Biotechnol. Prog. 29:403–14 [Google Scholar]
  93. Barker G, Calzada J, Ouyang Z, Domagalski N, Herzer S, Rieble S. 93.  2016. A systematic approach to improve data quality in high-throughput batch adsorption experiments. Eng. Life Sci. 16:124–32 [Google Scholar]
  94. Bergander T, Nilsson-Välimaa K, Öberg K, Lacki KM. 94.  2008. High-throughput process development: determination of dynamic binding capacity using microtiter filter plates filled with chromatography resin. Biotechnol. Prog. 24:632–39 [Google Scholar]
  95. Kelley BD, Switzer M, Bastek P, Kramarczyk JF, Molnar K. 95.  et al. 2008. High-throughput screening of chromatographic separations: IV. Ion-exchange. Biotechnol. Bioeng. 100:950–63 [Google Scholar]
  96. Kramarczyk JF, Kelley BD, Coffman JL. 96.  2008. High-throughput screening of chromatographic separations: II. Hydrophobic interaction. Biotechnol. Bioeng. 100:707–20 [Google Scholar]
  97. Chollangi S, Jaffe NE, Cai H, Bell A, Patel K. 97.  et al. 2014. Accelerating purification process development of an early phase MAb with high-throughput automation. BioProcess International March 1 [Google Scholar]
  98. Nfor BK, Noverraz M, Chilamkurthi S, Verhaert PDEM, van der Wielen LAM, Ottens M. 98.  2010. High-throughput isotherm determination and thermodynamic modeling of protein adsorption on mixed mode adsorbents. J. Chromatogr. A 1217:6829–50 [Google Scholar]
  99. Rathore AS, Muthukumar S. 99.  2014. High-throughput process development: II. Membrane chromatography. Protein Downstream Processing: Design, Development and Application of High and Low-Resolution Methods EN Labrou 39–44 Totowa, NJ: Humana [Google Scholar]
  100. Chandler M, Zydney A. 100.  2004. High throughput screening for membrane process development. J. Membr. Sci. 237:181–88 [Google Scholar]
  101. Rege K, Pepsin M, Falcon B, Steele L, Heng M. 101.  2006. High-throughput process development for recombinant protein purification. Biotechnol. Bioeng. 93:618–30 [Google Scholar]
  102. Muthukumar S, Rathore AS. 102.  2013. High throughput process development (HTPD) platform for membrane chromatography. J. Membr. Sci. 442:245–53 [Google Scholar]
/content/journals/10.1146/annurev-chembioeng-060816-101411
Loading
/content/journals/10.1146/annurev-chembioeng-060816-101411
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error