In Vivo Sampling: A Promising Technique for Detecting and Profiling

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In Vivo Sampling: A Promising Technique for Detecting and Profiling Endogenous Substances in Living Systems Xiaoxue Kou, Guosheng Chen, Siming Huang, Yuxin Ye, Gangfeng Ouyang, Jay J. Gan, and Fang Zhu J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.8b06981 • Publication Date (Web): 06 Feb 2019 Downloaded from http://pubs.acs.org on February 6, 2019

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Journal of Agricultural and Food Chemistry

In Vivo Sampling: A Promising Technique for Detecting and Profiling Endogenous Substances in Living Systems

Xiaoxue Koua, Guosheng Chena, Siming Huangb, Yuxin Yea, Gangfeng Ouyanga, Jay Ganc, Fang Zhua*

aSchool

of Chemistry, Sun Yat-sen University, Guangzhou 510275, China

bDepartment

of Radiology, Sun Yat-sen Memorial Hospital Sun Yat-sen University,

Guangzhou 510120, Guangdong, China cDepartment

of Environmental Sciences, University of California, Riverside, CA

92521, United States *Corresponding

author: Tel.: +86-20-84110943; Fax: +86-20-84110845

E-mail address: [email protected] (F. Zhu)

1

ACS Paragon Plus Environment


1

Abstract Endogenous substances, naturally occurring in living organisms, are critical

2

components with physiological and biological functions. Discovery and quantitative

3

measurement of endogenous substances in living biotas is important for food analysis,

4

crop cultivation and quality assessment. Low- or non-invasive in vivo sampling

5

techniques offer the advantages of minimal perturbation to the investigated system

6

and potentially obtain more accurate feedback as compared to in vitro sampling. In

7

this perspective, we summarize the up-to-date progress in the development of

8

Microdialysis and Solid-phase microextraction as valuable tools for in vivo sampling

9

of endogenous substances in food and agriculture chemistry. We discuss their

10

feasibility for on-site and real-time in vivo monitoring and highlight the prospects in

11

searching for highly specific coatings, miniaturized sampling devices and instruments

12

which well meet the trend for high-efficient and high-through analysis.

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Key words In vivo sampling; Solid-phase microextraction; Microdialysis;

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Endogenous substances; Food analysis

2


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INTRODUCTION

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Endogenous substances are significant components with physiological and

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biological functions abound in living organisms. For example, the fresh agricultural

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products (e,g. vegetables, fish and livestock) provide a series of hormones that

19

regulate their own development and metabolism processes. Meanwhile, the

20

endogenous compounds, especially those associated with special aroma profiling, are

21

widely used as the markers for food safety assessments, metabolomics fingerprinting

22

and various other applications. Furthermore, in vivo tracing of endogenous substances

23

when plants under multiple environmental stresses may contribute to the discovery of

24

new metabolism pathways and thus provide ideas for the improvement about the

25

plants tolerance relevant to food production and environmental sustainability.1 In view

26

of these facts, a fast and accurate analytical approach for the detection of endogenous

27

substances is of great value in food and agriculture science.

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A suitable sampling technique is the foundation of a successful analytical method,

29

as it may greatly influence the temporal resolution and accuracy of the analytical

30

results. Traditionally, in vitro sampling techniques coupled with detection instruments

31

have been employed to analyze endogenous substances in agricultural products.2

32

However, in vitro methods are usually labor and time-consuming, and may also cause

33

stresses to the complex chemical network of organisms so as to produce artifacts. In

34

comparison, in vivo sampling has several advantages, such as being easy-to-handle

35

and non-invasive, and having the potential to streamline the entire pretreatment

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process. In addition, the non-destructive in vivo operation mode minimizes 3



37

perturbation towards a living organism, thus eliminating analytical artifacts associated

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with the perturbation. Moreover, the in vivo sampling mode also endows the capacity

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of continuous real-time monitoring, which reduces the inter-organism variation and

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results in improved observations.

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In this perspective, we briefly review in vivo sampling techniques for the detection

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of endogenous substances in fresh agricultural product. The state-of-art advances of

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two in vivo sampling techniques, namely, microdialysis (MD) and solid-phase

44

microextraction (SPME), are summarized. These are two typical in vivo sampling

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techniques sharing the characteristics of being minimally invasive to the organism,

46

and have been tested for real-time monitoring of endogenous substances owing to

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their good temporal resolution and easiness to operate. The other less-used in vivo

48

sampling techniques, such as implantable biosensors, biopsy, and sorptive tape

49

extraction, are not considered in the discussion.3-5 We then highlight promising future

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directions and perspectives in identifying coating materials, quantitative analysis,

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miniaturization and single-cell analysis, and potential in vivo sampling applications

52

for food analysis.

53 54

IN VIVO SAMPLING TECHNIQUES

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MICRODIALYSIS

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Microdialysis (MD) is an efficient sampling technique and has gained an important

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role for monitoring unbound concentrations of target substances at tissue sites. The

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most typical application of MD emerged from the brain chemistry experiments for 4


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measuring neurotransmitters in rats in the 1970s.6 Due to its inherent advantages of

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low-invasiveness and continuous sampling capability, this technique has evolved into

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a promising platform for investigating a wider range of target substances in living

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organisms over the recent decades. Its applications include the monitoring of both

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endogenous and exogenous compounds such as food bioactives, metabolites,

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biomarkers, and drugs.7-11

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In a typical MD setup, the system generally consists of a syringe-pump, a catheter

66

(also called probe), a perfusate reservoir and a micro-vial sample collector. During the

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in vivo sampling process, one probe or a series of probes are implanted into the soft

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tissue, e.g., body fluid, extracellular fluid and even cerebrospinal fluid, whereby

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arranged in a way like blood vessels. Probes of smaller diameters are more desirable

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because of reduced tissue disturbance. Based on the principle of dialysis, the MD

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sampling process allows target molecules to continuously diffuse from the region of

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interest across the semipermeable membrane located at the tip of the U-shaped probe,

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and finally collected in the micro-vial collector via a syringe-pump for the subsequent

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off-line analysis (Figure 1A). The membrane with specific molecular mass cut-off

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does not allow biomacromolecules (e.g., proteins, nucleotides) into the perfusate fluid,

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thus reducing the matrix effect. Notably, the design of perfusate fluid needs to mimic

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ionic strength of the surrounding milieu of sample in general, ensuring the diffusion

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process in the correct direction. The design facilitates sampling in a continuous

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manner and enables real-time monitoring.

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Due to the aforementioned merits of MD, it has been frequently employed in 5



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various important areas, including food and science technology field for endogenous

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compounds. For example, Liang et al. identified over 50 neuropeptides using in vivo

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MD in crab Cancer borealis, and obtained the correlation of neuropeptide dynamics

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with different behaviors, which was helpful for discovering potential metabolism

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candidates associated with the circadian rhythm in crab species, and provide a view

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for crab breeding.7 Understanding how different kinds of stresses effect on plants and

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the characteristics of plant bioactive substances is essential to our knowledge on a

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better cultivation of cash crops. The ascorbic acid content and antioxidant capacity

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from cladodes of prickly pear, a plant derived food consumption, was determined by

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in vivo MD technique. The method has been applied to investigate antioxidant ratio in

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the cladode under control and water-stressed condition.8 An in vivo dual-probe MD

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procedure for simultaneously sampling of endogenous metabolites from the kidney

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tissues and jugular vein of rats was also established. The configuration made

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contribution to the metabolic pathways of plant derived Chinese medicine G.

95

jasminoides for treating diabetes.9 With the assistance of in vivo MD technique, such a

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deep dive into the mechanisms of plant bioactive substances yields some surprising

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insights. Moreover, assisted with separation-based analytical systems, such as liquid

98

chromatography and capillary electrophoresis, the dialysate can be directly used

99

without centrifugation or protein precipitation, which provides real-time feedback of

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biological conditions and changes in living organisms. Kim et al.12 developed a

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sensitive method combining in vivo MD and liquid chromatography-tandem mass

102

spectrometry (LC-MS/MS), and demonstrated its use for simultaneously determining 6


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endogenous concentrations of dopamine, serotonin and their main metabolites,

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without any tedious pretreatment steps. The method eliminated potential target loss or

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degradation due to pretreatment, and enabled the discovery of trace neurotransmitters

106

and metabolites in rat brain.

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Microdialysis (MD) possesses several advantages for in vivo sampling of

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endogenous substances in biological fluids. In addition to its good compatibility and

109

easiness in implementation, there are two distinct strengths including high temporal

110

resolution and good spatial resolution. The MD sampling is capable of continuous

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sampling and monitoring for a prolonged time. Therefore, the concentration of

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endogenous substances in the biological fluid can be detected as frequently as

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possible and to capture transient changes. Compared to most invasive sampling

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techniques, MD is less labor intensive and less time consuming, which leads to

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refined temporal resolution. It is also feasible to implant multiple probes

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simultaneously in the same tissue or organ, allowing monitoring of endogenous

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substances in different micro-regions. Due to the miniature sizes of probes, MD has

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the potential for profiling the distribution of target with high spatial resolution.

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However, one continuous challenge for MD is the sampling of hydrophobic

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compounds. In perfusate, which comprises of polar physiological buffers,

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hydrophobic compounds tend to be sorbed onto the inner wall of probe tubing and

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dialysis membranes. This may result in a very low relative recovery, defined as the

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ratio of hydrophobic analytes between the concentration in the dialysate to that in the

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tissue fluid. Generally, decreasing the flow rate of the dialysate is one option for 7



125

improving relative recovery in MD applications. However, using low flow rates of the

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dialysate may not be able to achieve high temporal resolution. In consequence, it is

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often difficult to balance relative recovery and time-resolution of the measurement.

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Although the addition of affinity agents, such as C18 surface functionalized and

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antibody-coated particles, may prevent undesired binding between hydrophobic

130

analytes and tubing,13 the modification may also cause disturbance to the

131

surroundings.14 Furthermore, because the diameter of the MD probes is usually in the

132

millimeter range, it is inevitable to cause a minor trauma when implanting the MD

133

probes into living organisms, which may also trigger an inflammatory response,

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especially in long-term investigations. This may influence the collected data; long

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pre-equilibration under the representative physiological conditions may become

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necessary to obtain better calibration.7 In addition, limited by the flowing sampling

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pattern, MD is difficult to be applied for sampling in the solid or semi-solid biological

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tissues; it is also poorly suited for detecting volatile endogenous substances. Finally,

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the relatively high cost associated with the assembly, including syringe pumps and

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aseptic probes, may make MD not affordable in resource-constrained regions.

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SOLID PHASE MICROEXTRACTION

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Solid phase microextraction (SPME), invented by Arthur and Pawliszyn in 1990,

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is an advanced solvent-free sampling technique. It integrates sampling, isolation and

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sample preconcentration into one single step, and is highly compatible with analytical

146

instruments such as gas chromatography (GC) or high performance liquid 8


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chromatography (HPLC). Completely automatic sampling and analysis workflow has

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been introduced for the detection of environmental pollutants, pharmaceuticals,

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flavors and clinic biomarkers in gas, liquid and solid samples. In recent years, owing

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to its ultra-simplified workflow, miniaturized extraction assembly and non-invasive

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sampling feature, SPME is becoming a promising in vivo sampling technique that

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circumvents some of the barriers faced by the MD approach.15-17 Figure 2 shows a

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typical in vivo SPME sampling workflow.

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The SPME technique was first introduced as a complementary method to MD for in

155

vivo sampling by Pawliszyn.17 Compared with the traditional SPME, first, in vivo

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SPME fibers are externally immobilized with a small amount of desired sorbent as the

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extraction phase on a much thinner stainless steel wire, allowing implanting into

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biological tissues with minimal invasiveness. The extraction phase, or the so-called

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coating, is generally considered to significantly affect the performance of extraction.

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Recently, a growing number of highly selective extraction materials have been

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fabricated for in vivo SPME coating. For instance, molecularly imprinted polymers

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(MIPs) based in vivo SPME fibers have been applied for long-time glucose

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monitoring in live plants, giving a binding constant three orders of magnitude higher

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than simple non-imprinted phenylboronic acid based materials.18 DNA aptamer

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modified in vivo SPME fibers could specifically enrich low abundance proteins from

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human plasma. The introduction of DNA aptamers was demonstrated to dynamically

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enhance the selectivity toward target proteins.19

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Secondly, diverse SPME workflows are well-suited for novel investigations for in 9



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vivo analysis of a broad range of compounds. In the context of SPME, headspace

170

extraction mode (HS) is suitable for sampling volatile species and can effectively

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avoid the contamination to both coating and instruments caused by the attachment of

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macromolecules from complex matrixes. The major investigations for food

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commodities reported to date have focused on the determination of volatile organic

174

compounds (VOCs) by HS-SPME. In view of the demand for rapid quality control in

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food industry, Miks-Krajnik et al.20 identified and quantified VOCs from spoilage

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microorganisms during the tissue deterioration of fresh salmon fillets by

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SPME-GC-MS. Meanwhile, this investigation explained the possible associations

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between spoilage microorganisms and off-flavours. Besides, in vivo SPME has been

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positioned as a convenient tool for analysis of agrochemicals. The VOCs production

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from four endophytic strains were analyzed by in vivo HS-SPME. It has contributed to

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develop biological control methods which may potentially replace the excessive use

182

of synthetic pesticides (Figure 3A).21 In another application, during food fermentation

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such as cheese ripening, changes in VOCs profile from lactic acid bacteria

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metabolism were analyzed by SPME-GC-MS for the better understanding of aroma

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formation.22 However, HS sampling mode is incapable to guarantee a balanced

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coverage of analytes. It is quite limited for analytes with good solubility in the matrix

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and low vapor pressure values, with consequent scarce partition into the headspace

188

extraction fiber. In such cases, direct insert extraction mode (DI) can earn a more

189

comprehensive

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biocompatibility and antifouling function of DI-SPME coating should be considered

analyte

coverage.

For

in

vivo

sampling

10


applications,

the

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first, ensuring the material is nontoxic as well as no biofouling to the living system.

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To date, biocompatible materials like polydimethylsiloxane (PDMS), polyacrylonitrile

193

(PAN), polypyrrole (PPY) and polyethyleneglycol (PEG) have been used.

194

Additionally, those non-biocompatible coating can be further covered by a

195

biointerface layer such as polydopamine (PDA) that possess hydrophilic properties

196

and antifouling function to improve the biocompatible property for in vivo sampling.23

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Besides, unlike in vitro systems, facing the complexity matrixes in the area of in vivo

198

analysis, SPME is amenable to the various challenges. To ensure data quality from

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diverse living systems, appropriate calibration methods for in vivo SPME have been

200

proposed, including sampling-rate calibration and kinetic calibration with preloaded

201

standards.24

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The portable and miniaturized configuration, and the flexibility for hyphenation

203

with sensitive detection instruments, make in vivo SPME suitable for long-term

204

monitoring and repeated sampling of endogenous substances in solid biological

205

tissues, semi-solid tissues and biological fluids, while avoiding inflammatory

206

response.25 In addition, the inherent enrichment capacity of SPME may significantly

207

increase the sensitivity of the overall analytical method. Figure 3B is an example of in

208

vivo SPME sampling for monitoring of edible Malabar spinach and leaf of aloe.

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Initially, the micro-scale SPME fiber is cleaned to remove any potential contaminants.

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The pre-conditioned SPME fiber is carefully implanted into the living organism to

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extract the target analytes for a pre-determined time interval and then withdrawn.

212

Such a “lab on a fiber” approach not only simplifies the operation procedure, but also 11



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is unlikely to trigger artificial response. Subsequently, the enriched targets on the

214

SPME fiber are directly introduced into GC-MS, HPLC-MS/MS, and even ambient

215

mass spectrometry (AMS) for analysis. Figure 3C depicts the microscopic images of

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in vivo SPME sampling of an individual Daphnia magna and its embryo, followed by

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the experimental setup of MS analysis.26

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For in vivo sampling, in vivo SPME offers several advantages over MD. It confers a

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much broader range of sampling applications. The selection of diverse SPME coating

220

materials allows in vivo SPME can enable the balanced coverage of hydrophilic and

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hydrophobic analytes in solid tissues, semi-solid tissues and biological fluids than

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MD. In comparison, MD is difficult to be used for capturing hydrophobic compounds.

223

The workflow pattern of MD also limits its applicability in solid and semi-solid

224

biological tissues. In addition, in vivo SPME sampling facilitates sampling of labile or

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short-lived metabolites in biological systems. It was capable of sampling esters for

226

evaluating metabolic changes during the period of fruit ripening, and those

227

compounds also provided crucial information associated with fruit aroma, consumer

228

acceptance and varietal apple differentiation.27

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The use of in vivo SPME also imparts less matrix influence. In in vivo SPME

230

sampling, the engineered biocompatible coatings with small pore sizes effectively

231

prevent the conglutination of biomacromolecules onto the fiber surface, hence

232

minimizing matrix effect. Chen et al.23 established a rapid and sensitive method for

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the in vivo SPME sampling and determination of tetrodotoxin in living pufferfish and

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PDA was used as a promising sheathed surface modification to bring excellent 12


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anti-biofouling capability (Figure 3E). As toxins are a source of food contamination,

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such sensitive methods are essential for screening purposes.

237

Compared to MD, in vivo SPME sampling also provides much higher temporal and

238

spatial resolution. It has been shown that the in vivo SPME sampling procedure,

239

including separation, enrichment and extraction, can be completed within a few

240

minutes when the appropriate coating material is an option. For instance, an SPME

241

device containing commercial prototype RP-amide as biocompatible coatings was

242

applied as a convenient tool for in vivo sampling from circulating blood. The whole

243

sampling procedure was as short as 4 min.28 Compared to the millimeter-scale MD

244

probe, the micro-scale in vivo SPME fiber also offers higher spatial resolution.

245

Recently, an etched metal tip coated with a thin layer (approximately 5 μm) of

246

biocompatible nano-structured PPY was reported, and it could sample from various

247

biological matrices such as blood, urine, or even Allium cepa L single-cells (Figure

248

3D).29 Meanwhile, Deng et al. demonstrated a novel in vivo SPME method for

249

investigating microscale lipid species from small organisms and even a single HepG2

250

cell, and the mapping of lipid distribution in Daphnia magna was obtained owing to

251

the high spatial resolution.30 Apart from the aforementioned advantages, the portable

252

and miniaturized SPME configuration and “lab on a fiber” pattern make SPME an

253

appealing technique for repeated in vivo analysis, without complicated instruments.31

254

These features are especially advantageous for in situ or on-site in vivo analysis.

255 256

FUTURE PERSPECTIVES 13



257

It is generally assumed that MD and SPME are two dominant sampling techniques

258

for in vivo sampling of endogenous substances. In the past years, MD has been

259

regarded as a relatively mature sampling technique meeting the fundamental

260

requirements for in vivo monitoring. However, the pump-assisted workflow and the

261

invasive sampling mode restrict its practical applications. In comparison, SPME is a

262

green sampling technique that eliminates some of the barriers associated with MD. As

263

a new sampling technique, however, in vivo SPME still has room for improvements to

264

meet cutting-edge analytical challenges.

265

Food analysis demands a broad range of purposes including both targeted and

266

untargeted screening and determination for exogenous and endogenous substances.

267

Generally, the tunable in vivo sampling techniques, especially SPME, can afford high

268

selective extraction phases to the achievement of the best extraction condition for a

269

given set of targeted analytes, as well as appropriate extraction phases can enable the

270

highest amount of compounds toward a balanced coverage of analytes. SPME has

271

been positioned in various studies of food analysis, including food quality control,

272

aroma profiling, nutraceutical value assessment, and metabolomics detection. Though

273

most of them have focused on exogenous contaminant from food packing and

274

processing in the past decades, the abovementioned advantages of in vivo SPME,

275

especially for complex matrixes, endows the SPME huge potential for endogenous

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bioactive profiling in fresh agricultural products in vivo and in-situ, and receiving

277

more and more attention in current years.

278

An abundance of coating materials, such as porous carbon materials, metal-organic 14


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frameworks (MOFs), porous polymers, covalent-organic frameworks and metallic

280

oxides, have been successfully developed as SPME extraction phases. These sorbent

281

phases may be used to extract a wide range of substances. However, highly specific

282

SPME fibers that have not only high sensitivity but also the capacity to sustain

283

disturbance from the complex biological matrices, are rarely reported. MIPs is an

284

effective approach to fabricate the artificial memory cavities, and can be used to

285

develop SPME fibers with desirable selectivity. One of the challenges, however, is

286

that the presence of an equilibrium system in complex pre-polymerization usually

287

creates unwanted non-specific binding sites, leading to low imprinting efficiency.

288

Antibodies and aptamer modified coatings may open a new way for highly specific

289

extraction. It has been demonstrated that the introduction of DNA aptamer

290

dynamically enhances the selectivity toward target proteins. In most cases, the

291

captured targets within the SPME coatings need to be desorbed through harsh

292

conditions such as thermal or solvent desorption. Thus, when using the antibody- or

293

aptamer-assisted extraction, the stability of the extraction phase is an important issue

294

that must be carefully evaluated. Biomineralization, inorganic materials with

295

controlled structure produced by living organisms, may be a promising strategy to

296

provide sufficient stability in the future. MOFs are a type of extensively used

297

materials

298

biomineralization effect to protect these bioactive substances. The enzymes and

299

proteins embedded in MOFs showed higher activity compared to the free form in

300

solution, even when exposed to high temperature.32 Inspired by these studies, it is

to

encapsulate

proteins,

enzymes

and

15


DNA,

mimicking

the


301

reasonable to expect that the MOF-mimicked biomineralization may provide a viable

302

solution for designing highly specific antibody or aptamer-based SPME fibers.

303

Generally, the qualitative and quantitative analysis in MD and SPME approaches

304

relies on sensitive instruments, such as GC-MS and HPLC-MS/MS. The analysis is

305

usually done in the laboratory after sampling. Degradation or loss of the target

306

analytes may occur during sample transportation and storage, especially for unstable

307

endogenous substances. To solve this problem, coupling MD or SPME with portable

308

or miniaturized instruments that are capable of on-site operation may be another

309

important R&D direction. In fact, coupling SPME with portable GC-MS (PGC-MS)

310

for on-site contaminant detection at a construction impacted lake was reported,33 but

311

the feasibility of SPME-PGC-MS for on-site in vivo analysis needs to be further

312

explored. It is understandable that detection using GC-MS and HPLC-MS/MS could

313

offer good qualitative and quantitative information, but the GC or HPLC-assisted

314

separation procedure is usually time-consuming. Several new interfaces for directly

315

coupling SPME configuration with ambient mass spectrometry (SPME-AMS) have

316

been introduced, and the recent progress of this technology was summarized in a

317

review.34 However, the main challenge of the SPME-AMS method is the quantitative

318

accuracy. Because in most cases the distribution of the captured analytes is not

319

homogeneous, the ionization efficiency of inter-fiber and intra-fiber may be different,

320

resulting in poor repeatability of the analytical results. Therefore, how to improve the

321

accuracy and repeatability of the SPME-AMS method becomes an important research

322

question. 16


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Although the micro-scale SPME configuration is appealing for non-invasive

324

sampling in small regions, to the best of our knowledge, the application of in vivo

325

SPME so far has mainly focused on the visible biological organ, tissues or

326

individuals, such as fish muscle tissues, plant leave or fruits, fresh products, blood

327

vessels and animal organs. Extending in vivo SPME to the single-cell analysis merits

328

attention in the near future, because single-cell analytical techniques are essential for

329

understanding the microheterogeneity and functions of cells. We believe that “lab on a

330

fiber” will make in vivo SPME a valuable tool for single-cell analysis in the future.

331

In food analysis, it is hopefully that a rapid growth in the methods and applications

332

associated with food and agricultural chemistry will be motivated by the future

333

development of SPME technology. And the introduction of anti-fouling coatings and

334

portable instruments is foreseen to become promised for direct analysis of food

335

commodities. In analytical practice, the feature of integrated sample preparation steps

336

with on-site sampling greatly reduce the consumption of organic solvents and the total

337

cost. Furthermore, with the current availability, this technique can provide

338

information as a standard method for Regulatory Agencies when applied for rapid

339

screening of pesticides, toxins and other contamination in the quality assessment area.

340

Additionally, in view of the benefits of in vivo SPME aforementioned, there will be

341

new scenarios for metabolomics studies and other in vivo studies in food and

342

agricultural commodities.

343

Besides MD and SPME, wearable flexible chemical sensors for in vivo sampling

344

and non-invasive health monitoring have also come into people’s view. These new 17



345

generation sensors enable real-time and fast detection of biomarkers in dynamic status

346

at the molecular level.35 However, it is still at the early development stage, and the

347

key challenges for wearable flexible chemical sensors are the limited scope of

348

analytes, because in most cases they could only focus on a small number of major

349

metabolites and electrolytes. Additionally, the accuracy of quantitative analysis by

350

wearable flexible chemical sensors is not as precise as by approaches similar to in

351

vivo SPME. In the near future, we anticipate that in vivo sampling techniques will

352

better integrate advantages of MD, SPME and other emerging techniques, and their

353

applications will make significant contributions in high-through profiling of

354

endogenous compounds in food and agriculture chemistry.

355 356

AUTHOR INFORMATION

357

Corresponding Author

358

*Telephone: +86-20-84110943; Fax: +86-20-84110845

359

E-mail: [email protected] (F. Zhu)

360

Funding

361

This research was supported by projects of National Natural Science Foundation of

362

China (21225731, 21477166, 21527813, 21677182 and 21737006).

363

Notes

364

The authors declare no competing financial interest.

365 366

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2008, 59, 651-681.

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[2] Fibigr, J.; Satinsky, D.; Solich, P. Current trends in the analysis and quality control

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Samples

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Matrix-Compatible

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Figure captions

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Figure 1. (A) Setup of in vivo MD analysis. Reprinted with permission from ref 8.

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Copyright 2014 Elsevier (B) Analysis of potential therapeutic biomarkers in blood

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and kidney by dual-probe in vivo MD sampling. Reprinted with permission from ref 9.

487

Copyright 2017 Nature

488 489

Figure 2. In vivo SPME workflow. Reprinted with permission from ref 16. Copyright

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2015 Elsevier.

491 492

Figure 3. (A) In vivo antifungal effect of the VOCs' mixture on cherry tomatoes.

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Reprinted with permission from ref 22. Copyright 2018 Elsevier (B) In vivo SPME

494

sampling in edible Malabar spinach and leaf of aloe. Reprinted with permission from

495

ref 24. Copyright 2016 RSC (C) In vivo sampling schematic of one Daphnia magna

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and its egg cell, and the illustration of followed by the experimental setup of the

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subsequent MS analysis. Reprinted with permission from ref 26. Copyright 2015 ACS

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(D) 150 μm tip inserted into a single cell of Allium cepa and the chromatographic

499

peak of quercetin extracted by the fabricated mini-SPME fiber. Reprinted with

500

permission from ref 29. Copyright 2016 Wiley. (E) In vivo SPME sampling of

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tetrodotoxin in living pufferfish. Reprinted with permission from ref 23. Copyright

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2017 Elsevier.

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Figure 1.

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Figure 3.

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In Vivo Sampling: A Promising Technique for Detecting and Profiling

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