Elsevier

Biotechnology Advances

Volume 32, Issue 7, 15 November 2014, Pages 1245-1255
Biotechnology Advances

Research review paper
Advances in in-situ product recovery (ISPR) in whole cell biotechnology during the last decade

https://doi.org/10.1016/j.biotechadv.2014.07.003Get rights and content

Abstract

The review presents the state-of-the-art in the applications of in-situ product recovery (ISPR) in whole-cell biotechnology over the last 10 years. It summarizes various ISPR-integrated fermentation processes for the production of a wide spectrum of bio-based products. A critical assessment of the performance of various ISPR concepts with respect to the degree of product enrichment, improved productivity, reduced process flows and increased yields is provided. Requirements to allow a successful industrial implementation of ISPR are also discussed. Finally, supporting technologies such as online monitoring, mathematical modeling and use of recombinant microorganisms with ISPR are presented.

Introduction

A growing predilection towards utilization of sustainable resources and production protocols due to depleting petrochemical feedstocks and an ambition to reduce import of oil are the impetus for the implementation of biotechnological production processes. Nowadays modern genetic tools are available to the biotechnologist for metabolic pathway engineering enabling the production of biochemicals by utilizing previously inaccessible pathways, a decrease in byproduct formation and an increase in titer and yield (Smolke, 2009). Despite this progress, several bio-based processes are still plagued by limited product titers and volumetric productivities due to product inhibition. Other processes still suffer from side reactions decreasing the yield (total product produced to total substrate consumed) of the process. All this leads to substantial downstream processing costs, high waste water volumes, high fermentor costs and an increased substrate cost in the case of a decreased yield.

Therefore, it can be advantageous to invest in a recovery technology that allows the selective separation of the product during fermentation in order to: 1. enrich the product leading to a decrease in downstream processing costs; 2. improve the volumetric productivity by alleviation of product inhibition; 3. reduce the process flows (decrease amount of waste water per weight unit of product); and 4. improve the yield by removing the target product from the fermentation broth and rendering it unavailable for side reactions. These reasons are the rationale behind all in-situ product recovery (ISPR) technologies. These include various kinds of techniques whose application depends mainly on the nature of the product (Takors, 2004). It may also be noted that albeit ISPR is predominantly used to remove the target product from the production medium, it may also be used in certain cases to separate inhibitory by-products whose high concentrations affect the titer of the target compound e.g. a protein (Wong et al., 2009, Wong et al., 2010).

Section snippets

Scope of review

Stark and von Stockar (2003) extensively reviewed the literature on ISPR processes in whole cell biotechnology from 1983 to 2003. It is the aim of the present review to critically delineate the advances in whole-cell biotechnological applications of ISPR over the last 10 years from 2003 onwards. Several reviews focus on a particular ISPR technique such as pervaporation, aqueous-two phase system (ATPS), perstraction, and crystallization (Bazinet, 2005, Buque-Taboada et al., 2006, Carstensen et

Organization of review

Four major product categories have been included in this review i.e. alcohol/solvents (Table 1), organic acids (Table 2), flavors/fragrances and other products such as (recombinant) proteins and enzymes (Table 3). The review first gives an overview of the trends observed in ISPR applications over the last 10 years using various ISPR techniques. This is followed by a discussion of the advantages of ISPR. Finally, online monitoring, modeling and the use of metabolic engineering are discussed to

Trends in ISPR applications over the last 10 years

In the past 10 years, about 140 papers have been published which describe fermentations coupled with ISPR technology. The contribution of each product category in ISPR reports during 2003–2013 is shown in Fig. 1. About 32% of them addressed alcohol/solvent fermentations while organic acids and flavors/fragrances/other products constituted 21% and 46% respectively (not shown in Fig. 1). These findings are similar to the trends reported by Stark and von Stockar (2003) for the previous period of

Advantages of ISPR

The following section of review attempts to delineate the improvements made with respect to product enrichment, productivity, reduced process flows and yield in comparison with non-ISPR processes. The above mentioned advantages are interdependent. Thus an improvement in one parameter might lead to a decrease in another parameter and therefore all process streams and parameters need to be considered when integrating a fermentation with an ISPR technology.

Not all the published articles on coupled

Requirements

Stark and von Stockar (2003) considered the added complexity of a fermentation integrated with ISPR as a reason for the failure of many previous ISPR projects, along with the lack of highly selective separation techniques. Several requirements can be formulated for industrial implementation: 1. keep the technology as simple as possible to allow a straightforward upscaling; 2. demonstrate long term robustness and stability of the integrated test set-up; 3. demonstrate decreased energy

Online monitoring

Continuous operation using flash distillation is utilized by Gevo, but it was stated by Mariano et al. (2008) that it might be difficult to allow stable conditions in the flash tank due to fluctuations in substrate and product concentrations. Kansiz et al. (2005) investigated mid-infrared to monitor ABE fermentations while Liebmann et al. (2009) investigated near infrared spectroscopy for determination of glucose and ethanol in bioethanol production. Chemometric models need to be established

Concluding remarks and perspectives

Introduction of ISPR in a bioprocess makes sense only when the desired product is inhibitory or/and unstable. In these cases, ISPR will lead to enhancements in terms of overall product titer, productivity, and yield and to reduced process flows.

Almost all reports in the last decade involved laboratory scale investigation of ISPR-coupled processes (1–10 L). Flash distillation was introduced at production plant scale as ISPR technology for production of isobutanol. Production of bulk chemicals is

Abbreviations

    2  PE

    2-phenylethanol

    2,3-BD

    2,3 butanediol

    2  PAc

    2-phenylacetate

    3  HPA

    3-hydroxypropionaldehyde

    3  MC

    3-methylcatechol

    ABE

    Acetone–butanol–ethanol

    AKR

    Aedes albopictus akirin

    ATPS

    Aqueous two-phase system

    B

    Batch cultivation

    BZA

    Benzaldehyde

    DOIP

    6R-Dihydrooxoisophorone

    C

    Continuous cultivation

    ED

    External-direct

    EDI

    Electrodeionization

    EI

    External-indirect

    FB

    Fed-batch cultivation

    GFP

    Green fluorescent protein

    HFBII

    hydrophobin protein from Trichoderma reesei

    HPA

    3-hydroxypropionaldehyde

    IBE

    Isopropanol–butanol–ethanol

    ID

Acknowledgment

This work was funded by the 7th Framework Programme of the European Union (BioConSepT contract no. 289194).

References (102)

  • T.C. Ezeji et al.

    Bioproduction of butanol from biomass: from genes to bioreactors

    Curr Opin Biotechnol

    (2007)
  • V. García et al.

    Challenges in biobutanol production: how to improve the efficiency?

    Renew Sust Energ Rev

    (2011)
  • C. Huang et al.

    Application of electrodialysis to the production of organic acids: state-of-the-art and recent developments

    J Membr Sci

    (2007)
  • K. Inokuma et al.

    Improvement of isopropanol production by metabolically engineered Escherichia coli using gas stripping

    J Biosci Bioeng

    (2010)
  • G. Kaur et al.

    Mathematical modelling approach for concentration and productivity enhancement of 1,3-propanediol using Clostridium diolis

    Biochem Eng J

    (2012)
  • K. Kraemer et al.

    Separation of butanol from acetone–butanol–ethanol fermentation by a hybrid extraction–distillation process

    Comput Chem Eng

    (2011)
  • M. Kumar et al.

    Developments in biobutanol production: new insights

    Appl Energy

    (2011)
  • H. Li et al.

    An electrokinetic bioreactor: using direct electric current for enhanced lactic acid fermentation and product recovery

    Tetrahedron

    (2004)
  • Q. Li et al.

    Integrated bioprocess for high-efficiency production of succinic acid in an expanded-bed adsorption system

    Biochem Eng J

    (2011)
  • B. Liebmann et al.

    Determination of glucose and ethanol in bioethanol production by near infrared spectroscopy and chemometrics

    Anal Chim Acta

    (2009)
  • S.K.C. Lin et al.

    Substrate and product inhibition kinetics in succinic acid production by Actinobacillus succinogenes

    Biochem Eng J

    (2008)
  • A.P. Mariano et al.

    Energy requirement during butanol production and in situ recovery by cyclic vacuum

    Renew Energy

    (2012)
  • J. Mei et al.

    Enhanced biotransformation of l-phenylalanine to 2-phenylethanol using an in situ product adsorption technique

    Process Biochem

    (2009)
  • M. Mihal et al.

    Intensification of 2-phenylethanol production in fed-batch hybrid bioreactor: biotransformations and simulations

    Chem Eng Process

    (2012)
  • G. Min-tian et al.

    Production of l-lactic acid by electrodialysis fermentation (EDF)

    Process Biochem

    (2004)
  • G. Min-tian et al.

    Development of a continuous electrodialysis fermentation system for production of lactic acid by Lactobacillus rhamnosus

    Process Biochem

    (2005)
  • S.W. Park et al.

    Improvement of epothilone B production by in situ removal of ammonium using cation exchange resin in Sorangium cellulosum culture

    Biochem Eng J

    (2007)
  • N. Qureshi et al.

    Reduction in butanol inhibition by perstraction: utilization of concentrated lactose/whey permeate by Clostridium acetobutylicum to enhance butanol fermentation economics

    Food Bioprod Process

    (2005)
  • K. Schügerl et al.

    Integrated bioprocesses

    Curr Opin Microbiol

    (2005)
  • J. Urbanus et al.

    Intensified crystallization in complex media: heuristics for crystallization of platform chemicals

    Chem Eng Sci

    (2012)
  • W. Van Hecke et al.

    Pervaporative recovery of ABE during continuous cultivation: enhancement of performance

    Bioresour Technol

    (2013)
  • H. Wang et al.

    Synergistic inhibition effect of 2-phenylethanol and ethanol on bioproduction of natural 2-phenylethanol by Saccharomyces cerevisiae and process enhancement

    J Biosci Bioeng

    (2011)
  • X. Wang et al.

    In-situ combination of fermentation and electrodialysis with bipolar membranes for the production of lactic acid: continuous operation

    Bioresour Technol

    (2013)
  • S.L. Wee et al.

    Membrane separation process—pervaporation through zeolite membrane

    Sep Purif Technol

    (2008)
  • G. Wei et al.

    Adsorptive bioconversion of ethylene glycol to glycolic acid by Gluconobacter oxydans DSM 2003

    Biochem Eng J

    (2009)
  • Y.P. Xue et al.

    Enhanced biotransformation of (R, S)-mandelonitrile to (R)-(−)-mandelic acid with in situ production removal by addition of resin

    Biochem Eng J

    (2010)
  • C. Xue et al.

    Two-stage in situ gas stripping for enhanced butanol fermentation and energy-saving product recovery

    Bioresour Technol

    (2013)
  • M.T. Agler et al.

    Chain elongation with reactor microbiomes: upgrading dilute ethanol to medium-chain carboxylates

    Energy Environ Sci

    (2012)
  • Anton DR, Cirakovic J, Diner BA, Grady MC, Woerner FJ, inventors; Butamax™ Advanced Biofuels Llc, assignee. Extraction...
  • A. Baez et al.

    High-flux isobutanol production using engineered Escherichia coli: a bioreactor study with in situ product removal

    Appl Microbiol Biotechnol

    (2011)
  • M. Barancewicz et al.

    Ethanol production in a bioreactor with an integrated membrane distillation module

    Chem Pap

    (2012)
  • L. Bazinet

    Electrodialytic phenomena and their applications in the dairy industry: a review

    Crit Rev Food Sci Nutr

    (2005)
  • Bhadra R, Bhalla R, Kruckeberg AL, Nagarajan V, Patnaik R, Suh W, inventors; Butamax™ Advanced Biofuels Llc, assignee....
  • M. Blahušiak et al.

    Simulation of a hybrid fermentation–separation process for production of butyric acid

    Chem Pap

    (2010)
  • S. Brethauer

    In-situ product removal as an approach to improve the fermentative production of clavulanic acid

    (2007)
  • E.M. Buque-Taboada et al.

    In situ product removal using a crystallization loop in asymmetric reduction of 4-oxoisophorone by Saccharomyces cerevisiae

    Biotechnol Bioeng

    (2004)
  • E.M. Buque-Taboada et al.

    In situ product recovery (ISPR) by crystallization: basic principles, design, and potential applications in whole-cell biocatalysis

    Appl Microbiol Biotechnol

    (2006)
  • Burlew KH, Dicosimo R, Grady MC, inventors; Butamax™ Advanced Biofuels Llc, assignee. Extraction solvents derived from...
  • A.E. Cervera et al.

    Application of near-infrared spectroscopy for monitoring and control of cell culture and fermentation

    Biotechnol Prog

    (2009)
  • Coutts MW, inventor; Coutts MW, assignee. Process for the manufacture of beer, ale and the like. 1966 Feb...
  • Cited by (0)

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    Both authors contributed equally to this work.

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