Biochemical Engineering Journal 176 (2021) 108193

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Biochemical Engineering Journal

journal homepage: www.elsevier.com/locate/bej

Environmental bio-oxidation of toxic furan by the co-recycling of waste

fermented broth and rest cells
Genlai Du a, b, c, Xia Hua a, b, c, Bin Xu d, Huan Wang d, Xin Zhou a, b, c, Yong Xu a, b, c, *
a
Key Laboratory of Forestry Genetics & Biotechnology (Nanjing Forestry University), Ministry of Education, Nanjing 210037, People’s Republic of China
b
Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources, College of Chemical Engineering, Nanjing Forestry University, Nanjing 210037,
People’s Republic of China
c
Jiangsu Province Key Laboratory of Green Biomass-based Fuels and Chemicals, Nanjing 210037, People’s Republic of China
d
ECO Zhuoxin Energy-saving Technology (Shanghai) Company Limited, Shanghai 200000, People’s Republic of China

A R T I C L E I N F O A B S T R A C T

Keywords: Furoic acid (FA) is used widely as raw material for bio-based resin, food, pharmaceutical and perfume products.
Furfural The biocatalysis of Gluconobacter oxydans is on the spotlight of furfural oxidation to FA because of high selec­
Furoic acid tivity, safety and environmental friendliness. However, like most bacterial fermentations, we have to treat a lot of
Gluconobacter oxydans
waste fermented broth, especially containing toxic furans. An integrated bioprocess was developed to achieve the
Whole-cell catalysis
co-recycling of cells and waste broth during FA bioproduction. We found sorbitol performed a critical role during
Co-recycling
Techno-economic analysis the co-recycling bioprocess and the cost of yeast extract was substituted entirely by cheaper corn extract. Here,
FA bioproduction efficiency kept six rounds with the productivity of 10.3 g/L/h and 98% yield. The integrated
bioprocess provides a novel idea for biotechnology developments not only on bioconversion of toxic furans but
also on industrial fermentation, especially for the troublesome problems around the recycling of waste fermented
broth.

1. Introduction
In the last few decades, the biomass-based furan chemicals had
attracted significant interest as a substitutable candidate for traditional
fossil materials, including furfural, 5-hydroxymethylfurfural (HMF),
furoic acid (FA), 2,5-furandicarboxylic acid (FDCA) and so on [1–7].
These furans were widely used for alternatives to petroleum fuels, syn­
thesis of plastics, fine chemicals and pharmaceutical industries, which
significantly improved the economic benefits of biomass. For example,
FA and its derivatives is widely used as a raw material in resin, plastic,
food, pharmaceutical and perfume industries by hydrogenation, decar­
boxylation, and esterification processes [8–13]. Another important
furan chemical of FDCA, is applied to synthesize polyalkylenefuranate
(PAF) and instead petroleum-derived polyethylene terephthalate (PET)
with a great biomass-based plastic market [14–18]. Currently, a new
synthetic route of FDCA from FA material has been developed and FA
was converted into FDCA with 89% yield by the combined with Cs2CO3
and CO2 [19,20].The commercial production of FA is, therefore, an
interesting topic to the value-added conversion of furfural.
Currently, the raw material for FA industrial production is furfural, a
furan compound that can only be obtained from biomass and the pri­
mary technology of FA industrial production depends on chemical
routes with metal catalysts, Cannizzaro reaction, electrochemical
oxidation, etc [21–24]. Generally, these catalysts belong to metals of
PbPt/C [25,26], Ag2O/CuO [27] and AuPd/Mg(OH)2 [28–30], which
involves the catalyst synthesis cost and the recycling difficulty. Mean­
while, a promising approach is currently in the spotlight and booming by
using whole-cell catalysis (WCC) and oxidation with aerobic bacteria,
with significant advantages of high selectivity, mild reactions and safe
operation [31–33]. In 1964, Kakinuma and Yamatodani reported the
isolation of biodegradable microorganisms capable of degrading and
metabolizing furan compounds [34]. Lately, Zhou et al. obtained 40 g/L
FA end-product at 98% yield from furfural [35]. This presents a prom­
ising potential for green industrial production of FA from biomass-based
furfural. However, as common biotoxins, furans certainly cause dam­
ages to cellular molecules, organelles, metabolism, growth and cell re­
productions [36–41]. Even low titer of furans have serious negative
effects on humans. For example, furfural is a toxic compound with.
1 mg/L in the reservoir and 0.05 mg/m3 in the air, while the median
lethal dose (LD50) of furfural to rats is 126 mg/kg [42–44]. This

* Correspondence to: College of Chemical Engineering, Nanjing Forestry University, No. 159 Longpan Road, Nanjing 210037, People’s Republic of China.
E-mail address: xuyong@njfu.edu.cn (Y. Xu).

https://doi.org/10.1016/j.bej.2021.108193
Received 29 June 2021; Received in revised form 4 August 2021; Accepted 15 August 2021
Available online 13 September 2021
1369-703X/© 2021 Elsevier B.V. All rights reserved.
G. Du et al.
disadvantage combined with the treatment of waste fermented broth
containing furans raises a big challenge for commercial production of FA
[45–47]. Currently, the limitation of most microbial industrial produc­
tion is the treatment of waste broth containing nutrients, especially
involved toxic substances. The critical issue to the fermentation industry
is such large volumes of fermented broth containing toxic furans and
nutrients cause tremendous environmental pressure and wastewater
treatment costs, which usually leads to the commercial failure of
biotechnology [48,49].
Based on our group works on WCC and furan bioconversion [35,50],
we propose an integrated biotechnology to improve the environmental
benefits of FA bioproduction. To resolve the above critical issues of fu­
rans toxicity and the treatment of waste fermented broth, we designed
and performed a combined co-recycling of cells and waste fermented
broth, combined with in-situ electrodialysis separation and the addition
of the fermenting co-factor.
2. Materials and methods
2.1. Microorganism and chemicals
Gluconobacter oxydans NL71 was maintained at 4 ℃ on sorbitol
culture medium containing 50 g/L sorbitol, 15 g/L agar, and 5 g/L yeast
extract. Cells were grown in 50 ml medium containing 100 g/L sorbitol
and 10 g/L yeast extract and cultivated at 30 ℃ and 220 rpm for 24 h.
All chemicals were purchased from Sigma-Aldrich Co., LTD.
2.2. The whole-cell catalysis
The whole-cell catalysis (WCC) was implemented in a 3 L bioreactor
with 1 L medium containing 15 g/L yeast extract, 0.5 g/L MgSO4, 1 g/L
KH2PO4, 2 g/L K2HPO4, 5 g/L(NH4)2SO4 and 10 g/L furfural. The
turbidity of the cell culture was measured at a wavelength of 600 nm by
ultraviolet spectrophotometry, and the cells with OD600 = 10 concen­
tration (the cell dry weight was about 6.8 g/L) were centrifuged and
inoculated into the medium. The medium was stirred at 500 rpm, 30 ℃
and 0.05–0.5 vvm aeration at a gas-pressure of 0.03–0.05 MPa. The pH
was stabilized within 5.5–6.0. After centrifugation at 6000 g for 5 min,
the cell was collected for the next batch.
2.3. Electrodialysis separation
Kejia Polymer Materials Technology Co LTD produced the bipolar
membrane electrodialysis in China. It consisted of a membrane stack of
15 films each with an area of 9 cm × 21 cm and had an electrode plate.
The output voltage of the power supply was set at 50 V. Electrodialysis
operation was completed when the conductivity value remained under
700–800 uS/cm [32,50].
2.4. Total protein determination
The protein level was quantified by the total protein quantitative test
box purchased from Nanjing Jiancheng Bioengineering Research Insti­
tute. The protein reduced the Cu2+ to Cu+ in alkaline condition, then
Cu+ and bicinchoninic acid (BCA) reagent formed a purple complex,
with a maximum absorption peak at 562 nm. The concentration of the
protein was calculated by the absorbance measurement, which was
proportional to its concentration [51].
2.5. Analytical methods
Furfural and FA were determined quantitatively using an Agilent
1200 HPLC equipped with an RI detector and an Aminex HPX-87H
column (Bio-Rad) with 5 mM H2SO4 at 0.6 ml/min for 55 min as the
mobile phase [38,50]. The formula used for the calculation are as fol­
lows: FA yield from furfural (%) = (FA/Furfural) * 0.857 * 100%; FA =
2
Biochemical Engineering Journal 176 (2021) 108193
Fig. 1. Fed-batch of WCC module of furfural bioconversion to FA.
FANa * 0.836. The values 0.857, 0.836 are conversion factors.
3. Results and discussion
3.1. Fed-batch WCC for the furfural bioconversion to FA
G. oxydans is now booming to drive a series of whole-cell catalysis
(WCC) and biooxidation by using an oxygen molecule as the end elec­
tron acceptor. Here, the oxygen transfer rate (ORT) is a principal factor
to the biooxidation production in organic acids productions [52]. Hua
et al. proposed a design of sealed-oxygen supply biotechnology named
SOS system to resolve the oxygen transferring rate barrier and foaming
problem [53]. Additionally, Zhou et al. showed that a high titer of
furfural has a severe inhibitory effect on G. oxydans [35]. Therefore, we
used a fed-batch operation in the SOS to reduce biotoxicity that resulted
in a final titer of 10 g/L furfural loading.
As is shown in Fig. 1, within 48 h, 40.5 g/L FA was obtained with
98.5% yield and the average productivity of 0.84 g/L/h. Notably, FA has
accumulated 20.3 g in 2 h with the productivity of 10.3 g/L/h, and then
the productivity showed a downward trend and finally remained low
about 0.25 g/L/h, which provided the basis for the following cell recy­
cling. We would ascribe it to the negative feedback effect of end-product
inhibition that usually makes WCC productivity inefficient. Hence, to
solve the problem of product inhibition, there is a precondition to
improve the economic competitiveness of furfural bioconversion to FA.
3.2. The solo-recycling of cells
The fed-batch of WCC module shows that G. oxydans, as hard-to-
culture bacterial cells, presents a typical product inhibition negative
feedback effect in the process of FA bioproduction. Therefore, we
overcame the feedback inhibition by cell solo-recycling every 2 h, and
the result was shown in Fig. 2a. The cells were reused for six rounds to
obtain a total of 114.8 g FA with a yield of 98%. However, after two
batches of cell solo-recycling, FA accumulation in each batch began to
decrease and at the end of the sixth batch of bioconversion, the accu­
mulation of FA was 16.8 g, only 78.5% of that in the first batch. Contrary
to expectations, with the increase of cell solo-recycling batches, the
bioconversion capacity of cells showed a downward trend, which was
not feasible in the industry. We hypothesize that the decrease in the
bioconversion capacity of the cells could not be wholly avoided by
taking this operation module alone for the toxicity of furfural and FA,
especially furfural, to the cells.
The incomplete oxidation ability of G. oxydans to furfural is derived
from the dehydrogenase family located on the periplasmic of bacteria
G. Du et al.
Fig. 2. (a) The cell sole-recycling module of furfural bioconversion to FA (b) The cell sole-recycling module of FA bioconversion with co-factor.
Fig. 3. The module of the combined co-recycling of waste fermented broth
and cells.
and furfural will not participate in the internal metabolic of the cells, so
we supplied the metabolizable sorbitol as an auxiliary carbon source
which we call co-factor in this paper, providing power and energy for the
oxidation and metabolism of cells. Therefore, every 10 g/L furfural was
fed-batch with 2 g/L sorbitol, the result is shown in Fig. 2b. The pro­
ductivity of FA was above 10 g/L/h and the total FA is 124.1 g with
98.1% yield which demonstrated an excellent solo-recycling
performance.
The results suggested the bioconversion capacity of cells stable and
maintained the productivity at 10 g/L/h by cell solo-recycling and fed-
batch with co-factor. However, like most biological fermentation in­
dustries, the cell solo-recycling brings a large amount of waste fer­
mented broth. Therefore, we must reduce water consumption and the
output of waste fermented broth in the FA bioproduction.
3.3. The combined co-recycling of cells and waste fermented broth
An effective strategy to manage water usage is to recycle the waste
fermented broth. To avoid the effects of negative feedback inhibition, FA
must be separated from the broth before the co-recycling of the waste
fermented broth and cells. Meanwhile, in the bioconversion of FA, the
accumulation of FA changed the pH of the broth, so we have adjusted the
pH of the broth with 20% NaOH solution to keep the bioconversion
capacity optimal. Therefore, the FANa broth after the bioconversion
required further acidification and separation of FA.
In the current chemical method for FA production, the reaction
environment is usually alkaline in order to move the reaction balance
toward the product. The chemical method to produce FA is mostly used
to add sulfuric acid into the prepared FANa solution and then washed
and dried to obtain high purity FA. In previous studies, we found that
3
Biochemical Engineering Journal 176 (2021) 108193
bipolar membrane electrodialysis can effectively achieve the separation
and concentration of FA and the yield of FA is above 98%, and finally
high-purity FA crystal was obtained (S1). Bipolar membrane electrodi­
alysis is used to ionize and convert ions into corresponding acid and
alkali under the action of an external electric field [54,55]. This ensures
that sorbose cannot pass through the electrodialysis membrane and will
therefore not affect the separation of FA. Meanwhile, this avoided the
negative effects of hyperosmotic pressure environment formed by high
sodium sulfate residue after use of sulfuric acid acidification in the
co-recycling of waste fermented broth and cells.
As is shown in Fig. 3, the cells were separated from the broth every
2 h, and then the fermented broth treated with bipolar membrane
electrodialysis was recycled as medium for next batch. The accumula­
tion of FA within 12 h was 109.2 g/L which was 13% decrease compared
to the cell solo-recycling model. At the end of the sixth batch, the
accumulation of FA dropped to 15.5 g, which was 75% of the accumu­
lation of FA in the first batch. It is foreseeable that with the increase of
co-recycling batches, the productivity and accumulation of FA will
decrease more significantly.
The results show that cells and waste fermented broth cannot achieve
effective co-recycling, which puts great pressure on wastewater treat­
ment and economic input on fresh medium for FA industrial-scale pro­
duction. Therefore, we must break this obstacle that the production of
FA declines in the co-recycling of waste fermented broth and cells
module.
3.4. The co-recycling of waste fermented broth during whole-cell catalysis
The combined co-recycling of cells and waste fermented broth shows
that cells and spent fermented broth cannot achieve effective co-
recycling directly, which puts great pressure on wastewater treatment
and economic input on fresh medium for FA industrial-scale production.
Therefore, further exploration of the factors affecting the bioconversion
capacity of cells in the module of co-recycling of spent fermented broth
and bacterial cells is a key step to establish the green production of FA in
industry.
According to Figs. 2b and 3, excellent bioconversion capacity can be
kept in the module of cell sole-recycling but it showed a downward trend
in the co-recycling of waste fermented broth and cells. Different from the
fresh medium, the waste fermented broth underwent multiple co-
recycling, which may lead to the loss of nutrients in the fermented
broth. The organic nitrogen source can be effectively utilized by cells to
synthesize somatic substances and nitrogen-containing metabolites to
maintain the normal metabolism and catalytic activity of the cell. Yeast
extract, a commonly used nutrients source, was used in the FA biocon­
version process. It provides enough protein to keep the bioconversion
capacity of the cells optimal. Hua et al. found yeast extracts plays a key
role in maintaining cell bioconversion capacity as nitrogen sources [56].
Therefore, we conducted quantitative tests on the total protein content
G. Du et al. Biochemical Engineering Journal 176 (2021) 108193

Table 1
The protein level of broth in the recycling of waste fermented broth.
Batch 1 2 3 4 5 6

Total protein (g/L) 2.43 ± 0.16 2.04 ± 0.09 1.67 ± 0.13 1.27 ± 0.06 0.91 ± 0.07 0.59 ± 0.11

as a nitrogen source in the process. Besides, we have carried out ex­

periments on the recycling of waste proliferation medium and the
replacement of yeast extract by corn extract during cell culture, and
have obtained satisfactory experimental results, but we have not intro­
duced them in this study.
The combined co-recycling of waste fermented broth and cells can
improve the cell utilization rate while avoiding the generation of a large
amount of waste fermented broth, which significantly reduces the water
consumption and cost input during bioproduction. Moreover, the high-
cost yeast extract was substituted entirely by the cheaper corn extract in
the combined co-recycling process. Therefore, supplying co-factor and
replenishing the lost nutrients to the broth to achieve the combined co-
recycling of the waste fermented broth and cells is green and feasible
biotechnology for FA production.

4. Comparison of various bioprocess-module integrations based

Fig. 4. The module of co-recycling with waste fermented broth and cells with
on techno-economic analysis (TEA)
replenishing 3 g/L yeast extract.

As shown in Table 3, the comparison of four bioprocess-module in­

in the broth to monitor the yeast extracts content. tegrations for the bioconversion of FA was systematically analyzed.
According to Fig. 3 and Table 1, the total protein content of each Compared with WCC module, the production of FA and cell utilization in
batch was reduced by 16%, and the cumulative of FA was reduced by other module are significantly better than that of WCC. However, the use
10%, that is, the content of total protein in fermented broth gradually of fresh fermentation medium during the cell sole-recycling module
decreased with the increase of co-recycling of the batch, which was increased the cost during fermentation and generated a large amount of
consistent with the declining trend of FA accumulation. If the loss of waste fermented broth. Furthermore, the co-recycling of broth and cells
protein leads to the decline of bioconversion capacity, the replenishment can accumulate an almost equal amount of FA, saving five times water
of the lost nitrogen source in the co-recycling process can effectively consumption and 66.6% input of yeast extract. Moreover, we success­
maintain the capacity of the cells bioconversion to FA. Therefore, we fully achieved substituting yeast extract with corn extract at much lower
replenished it with 3 g/L yeast extract in the waste fermented broth industrial prices than yeast extract. This greatly enhances the economic
before each batch of co-recycling of fermented broth and cells were relevance of microbial bioconversions for the production of FA.
performed.
As is shown in Fig. 4, six batches of co-recycling with waste fer­
mented broth and cells with replenishing 3 g/L yeast extract within
12 h. The final accumulated FA was 121.8 g with 98.4% yield and
average productivity of 10.2 g/L/h and the accumulation was similar to
the accumulation in the cell sole-recycling module. The accumulation of
sorbose in the broth was 14.53 g/L with 58% yield which was because
part of sorbitol was involved in the internal metabolism of cells.
Compared with the first batch, the accumulation of FA in the sixth batch
was still 92%, which shows excellent co-recycling performance
compared without the replenishment of yeast extract.
Based on the protein content required for the combined co-recycling
process, we further used cheaper corn extract as a substitute for yeast
extract. The comparison of the total protein concentration of different
titers of yeast extract and corn extract is shown in Table 2. It can be seen
that the protein content of the corn extract of the same titer was 60% of
the yeast extract. Therefore, the initial titer of corn extract was 25 g/L
and in the process of combined co-recycling of waste fermented broth
and cells with replenishing 5 g/L corn extract and the results were
shown in Fig. 5. After six batches in 12 h, 119.3 g of FA was accumulated
with 98.3% yield with average productivity of 9.9 g/L/h which was Fig. 5. The co-recycling module of substituting yeast extract with corn extract.
almost the same compared to its production when yeast extract was used

Table 2
Comparison of the total protein content of different titer of yeast extract and corn extract.
Titer (g/L) 0 3 5 15 25 35

Yeast extract 0 ± 0.04 0.45 ± 0.03 0.78 ± 0.03 2.43 ± 0.08 4.05 ± 0.05 5.66 ± 0.02
Corn extract 0 ± 0.02 0.27 ± 0.02 0.48 ± 0.06 1.47 ± 0.04 2.47 ± 0.03 3.46 ± 0.07

4
G. Du et al. Biochemical Engineering Journal 176 (2021) 108193

Table 3
The comparison of four bioprocess-module integrations within 12 h, “－”means it is infeasible, “＋”means it is feasible.
Bioprocess-module Furfural (g) Water (L) Yeast extract (g) Corn extract (g) Waste water (L) Cell recycling FA (g)

WCC 32.5 ± 2.3 1 ± 0.06 15 ± 0.64 0 1 ± 0.06 － 37.4 ± 1.4

Cell sole-recycling 108.4 ± 3.4 6 ± 0.1 90 ± 1.02 0 6 ± 0.1 ＋ 124.1 ± 2.1
Co-recycling of broth and cells 106.1 ± 2.7 1 ± 0.05 30 ± 0.54 0 1 ± 0.05 ＋ 121.8 ± 2.7
Bioconversion with corn extract 104.0 ± 3.1 1 ± 0.07 0 50 ± 1.04 1 ± 0.07 ＋ 119.3 ± 3.5

5. Conclusion
The limitation of water consumption and the problem of hard-to-
culture cells in bioproduction hinders the industrial development of
biologicals. This disadvantage is combined with the bioconversion of
furans means that a large amount of waste fermented broth containing
biotoxic compounds needs to be treated. By timely supply of co-factor
and replenishment of nutrients in the fermented broth, can effectively
keep the bioconversion capacity of the cells and allows the co-recycling
of waste fermented broth and cells. Thus, a co-recycling technological
approach was presented for improvement of the environmental and
economic benefits of FA bioproduction at the industrial scale.
CRediT authorship contribution statement
GLD and YX designed the project, and GLD performed experiments,
data analysis, and prepared the manuscript. XH, XZ and HW helped to
revise the manuscript. YX and BX supervised the project and revised the
manuscript. All authors read and approve the final manuscript.
Declaration of Competing Interest
There are no conflicts to declare.
Data Availability
The datasets used and analyzed during this article are availability
from the corresponding author on reasonable requests.
Acknowledgements
The research was supported by the National Natural Science Foun­
dation of China (31370573). Also, the authors gratefully acknowledge
financial support from ‘Forestry Engineering First-class Discipline Con­
struction Project of Nanjing Forestry University’, and ECO Zhuoxin
Energy-saving Technology (Shanghai) Company Limited.
Consent for publication
Not applicable.
Ethics approval and consent to participate
Not applicable.
Appendix A. Supporting information
Supplementary data associated with this article can be found in the
online version at doi:10.1016/j.bej.2021.108193.
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