Research review paperAdvances in in-situ product recovery (ISPR) in whole cell biotechnology during the last decade
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)
- et al.
Modeling of an integrated fermentation/membrane extraction process for the production of 2-phenylethanol and 2-phenylethylacetate
Enzym Microb Technol
(2011) - et al.
Continuous two stage acetone–butanol–ethanol fermentation with integrated solvent removal using Clostridium acetobutylicum B 5313
Bioresour Technol
(2012) - et al.
Extractive fermentation of l-(+)-lactic acid by Pediococcus pentosaceus using electrodeionization (EDI) technique
Biochem Eng J
(2011) - et al.
Extractive bioconversion to produce the Aedes albopictus akirin in an aqueous two-phase system supporting Pichia pastoris
Biochem Eng J
(2009) - et al.
In situ product recovery: submerged membranes vs. external loop membranes
J Membr Sci
(2012) - et al.
Optimal process/solvent design for ethanol extractive fermentation with cell recycling
Biochem Eng J
(2008) - et al.
Strategies for improved bioproduction of benzaldehyde by Pichia pastoris and the use of hytrel as tubing material for integrated product removal by in situ pervaporation
Biochem Eng J
(2014) - et al.
Manipulating the composition of absorbent polymers affects product and by-product concentration profiles in the biphasic biotransformation of indene to cis-1,2-indandiol
Biochem Eng J
(2013) - et al.
Metabolic engineering of Saccharomyces cerevisiae for production of ginsenosides
Metab Eng
(2013) - et al.
Modeling and simulation of butanol separation from aqueous solutions using pervaporation
J Membr Sci
(2006)
Bioproduction of butanol from biomass: from genes to bioreactors
Curr Opin Biotechnol
Challenges in biobutanol production: how to improve the efficiency?
Renew Sust Energ Rev
Application of electrodialysis to the production of organic acids: state-of-the-art and recent developments
J Membr Sci
Improvement of isopropanol production by metabolically engineered Escherichia coli using gas stripping
J Biosci Bioeng
Mathematical modelling approach for concentration and productivity enhancement of 1,3-propanediol using Clostridium diolis
Biochem Eng J
Separation of butanol from acetone–butanol–ethanol fermentation by a hybrid extraction–distillation process
Comput Chem Eng
Developments in biobutanol production: new insights
Appl Energy
An electrokinetic bioreactor: using direct electric current for enhanced lactic acid fermentation and product recovery
Tetrahedron
Integrated bioprocess for high-efficiency production of succinic acid in an expanded-bed adsorption system
Biochem Eng J
Determination of glucose and ethanol in bioethanol production by near infrared spectroscopy and chemometrics
Anal Chim Acta
Substrate and product inhibition kinetics in succinic acid production by Actinobacillus succinogenes
Biochem Eng J
Energy requirement during butanol production and in situ recovery by cyclic vacuum
Renew Energy
Enhanced biotransformation of l-phenylalanine to 2-phenylethanol using an in situ product adsorption technique
Process Biochem
Intensification of 2-phenylethanol production in fed-batch hybrid bioreactor: biotransformations and simulations
Chem Eng Process
Production of l-lactic acid by electrodialysis fermentation (EDF)
Process Biochem
Development of a continuous electrodialysis fermentation system for production of lactic acid by Lactobacillus rhamnosus
Process Biochem
Improvement of epothilone B production by in situ removal of ammonium using cation exchange resin in Sorangium cellulosum culture
Biochem Eng J
Reduction in butanol inhibition by perstraction: utilization of concentrated lactose/whey permeate by Clostridium acetobutylicum to enhance butanol fermentation economics
Food Bioprod Process
Integrated bioprocesses
Curr Opin Microbiol
Intensified crystallization in complex media: heuristics for crystallization of platform chemicals
Chem Eng Sci
Pervaporative recovery of ABE during continuous cultivation: enhancement of performance
Bioresour Technol
Synergistic inhibition effect of 2-phenylethanol and ethanol on bioproduction of natural 2-phenylethanol by Saccharomyces cerevisiae and process enhancement
J Biosci Bioeng
In-situ combination of fermentation and electrodialysis with bipolar membranes for the production of lactic acid: continuous operation
Bioresour Technol
Membrane separation process—pervaporation through zeolite membrane
Sep Purif Technol
Adsorptive bioconversion of ethylene glycol to glycolic acid by Gluconobacter oxydans DSM 2003
Biochem Eng J
Enhanced biotransformation of (R, S)-mandelonitrile to (R)-(−)-mandelic acid with in situ production removal by addition of resin
Biochem Eng J
Two-stage in situ gas stripping for enhanced butanol fermentation and energy-saving product recovery
Bioresour Technol
Chain elongation with reactor microbiomes: upgrading dilute ethanol to medium-chain carboxylates
Energy Environ Sci
High-flux isobutanol production using engineered Escherichia coli: a bioreactor study with in situ product removal
Appl Microbiol Biotechnol
Ethanol production in a bioreactor with an integrated membrane distillation module
Chem Pap
Electrodialytic phenomena and their applications in the dairy industry: a review
Crit Rev Food Sci Nutr
Simulation of a hybrid fermentation–separation process for production of butyric acid
Chem Pap
In-situ product removal as an approach to improve the fermentative production of clavulanic acid
In situ product removal using a crystallization loop in asymmetric reduction of 4-oxoisophorone by Saccharomyces cerevisiae
Biotechnol Bioeng
In situ product recovery (ISPR) by crystallization: basic principles, design, and potential applications in whole-cell biocatalysis
Appl Microbiol Biotechnol
Application of near-infrared spectroscopy for monitoring and control of cell culture and fermentation
Biotechnol Prog
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Both authors contributed equally to this work.