Crucial Challenges in the Development of Green Extraction Technologies to Obtain Antioxidant Bioactive Compounds from Agro-industrial By–products

Exploitation of agro-industrial by-products represents an important source of bioactive compounds that can be used both directly as ingredients and for the production of functional ingredients. Among these compounds, polyphenols are capable of strengthening endogenous antioxidant defences in human tissues, preventing cardiovascular and neurodegenerative diseases. The present paper aims to evaluate and review various green extraction technologies for a cheap, fast, eco-friendly procedure to obtain these bioactive molecules. Several physicochemical approaches can be used with the aim of optimizing the use of energy, solvents, and pressure; among them are ultrasound-assisted extraction, subcritical and supercritical fluid extraction, extraction with neoteric solvents (ionic liquids, deep eutectic solvents, and natural deep eutectic solvents), microwave-assisted extraction, pressurized liquid extraction, pulsed electric field, multi-frequency multimode modulated technology, rapid solid liquid dynamic extraction, and enzyme-assisted extraction. The challenges and future work regarding the development of these green products for the commercial markets were comprehensively evaluated.


Introduction
The food industry is increasingly globalized, and its constant search for new goods, technologies, services, and cultural practices runs in parallel with several environmental concerns. In fact, it is thought that, due to industrial processing, 30-50 % of agricultural foodstuffs are discarded as agro-industrial by-products, and food by-products are responsible for an estimated 8 % of greenhouse gas emissions. 1,2 Continued growth in the agro-industrial sector has knock effects on the quantity of waste produced in both the retail and consumption of products: this has led international agencies and authorities to search for common strategies to manage the growth of agricultural food processing by-products. 3 On the other hand, agro-industrial by-products are key sources of potentially profitable bioactive compounds (BACs). 4,5 The pharmaceutical, cosmetics, and food industries have shown a great deal of interest in these compounds, especially in those with antioxidant activity. 6 Recovery and recycling are fundamental parts of the process of converting "waste to wealth", a typical approach of the circular economy: the most profitable and sustainable challenge might be the recovery of beneficial compounds and the contemporaneous reduction of the amount of waste generated.
Extraction of natural origin compounds from the agro-industrial by-products is a well-established procedure for several production chains, such as oils, juices, and wine. Techniques are being updated constantly to overcome problems of recovery yield and separation of target compounds from the agro-industrial waste. Over the past ten years, extraction processes have been developing in the search for green solvents and evolving green practices. 7 In fact, the idea of green chemistry has immense importance in manufacturing processes to diminish or remove generation and use of dangerous substances, as well as in helping to develop green approach. 8 The use of GRAS (generally recognized as safe) or Safer Choice Standard solvents should guarantee environmentally friendly processes. 7, 9 Thus, a crucial challenge in agro-industrial by-product exploitation is the development of sustainable and green extraction technologies (GETs). This review focuses on recent approaches utilized in agro-industrial by-product exploitation using mainly green techniques. The primary focus of this review is on the most used green extraction procedures and the development of some promising techniques. Furthermore, current research about specific agro-industrial by-products and bioactive compounds recovery with antioxidant activity are discussed, as well as the extraction technologies and conditions used.
General aspects and properties of green extraction techniques multi-frequency multimode modulated technology (MMMT), 83,84 enzyme-assisted extraction (EAE), [85][86][87][88] and ionic liquid extraction (ILE). 89,90 All studies regarding these green processes and their advantages and disadvantages are reported in Table 1. Generally, all these GETs display cheap, fast, and eco-friendly features, and the most common advantages are: reduced energy consumption, safe and renewable products, high quality extract, low environmental impact, selectivity, and better isolation. 91 With the purpose of diminishing the use of organic, toxic solvents, which have unfavourable effects on food by-products quality and safety, the interest in GETs has been significantly amplified. Modern extraction methods are aimed at optimizing the use of energy, solvents, and other physical properties like pressure, which could also be further improved through enzyme application. 92 GET focused on use of energy Regarding the energy used, among these technologies a well-known example would be UAE, also called sonication or ultrasonic extraction. This technology uses ultrasound waves (ca. 20 kHz to 100 MHz) that have an impact on molecules present in the solvent (liquid medium). The UAE can work in an incessant or pulsed (PUAE) way. 93 The UAE process creates a phenomenon of cavitation, in which fast changes of the pressure of the solvent molecules cause growth and collapse of the voids or air bubbles that create pores, thus accelerating the extraction process. Moreover, UAE can be applied in the food extraction industry, on both small and large scale. 14,94 Also, MMMT is a GET that uses UAE approach: in this method many synchronously exciting vibration modes are coupled with sub-harmonics and harmonics in liquid and solids containers. Furthermore, it is characterised by high intensity, uniform, and repeatable multimode vibrations. Hence, the cavitation process is improved, due to the lack of stationary and standing waves, that guarantees full agitation of the whole vibrating system. 84 Taking into account the importance of energy as a part of the extraction method, MAE is another green technology, based on microwave energy. This energy is delivered straight to materials via molecular interactions with the electromagnetic field (300 MHz to 300 GHz) through changes of electromagnetic energy into thermal energy, whilst the solid matrix, penetrated by the solvent via diffusion, dissolves upon reaching its concentration limits. 14,95 Furthermore, PEFs extraction is a method, which increases mass transfer during extraction by destroying structures of the membrane. Not only that, it is a non-thermal technique that reduces the degradation of the thermolabile compounds. The investigated material is placed between two electrodes, while the pulse amplitude varies from 100-300 V cm -1 to 20-80 kV cm -1 . The treatment is performed at room temperature or slightly higher. 79,94 GET focused on extraction solvent and pressure Uses of non-hazardous and harmless solvents, like water, ethanol, and CO 2 have been applied to the extraction of various agro-industrial by-products, especially combined with pressure control. Two well-known and widely used GETs, which depend entirely on pressure, are SbFE and SFE. The first one, can use liquid water (SWE) at temperatures exceeding its boiling point (100 ºC), but remains under its critical temperature (374 ºC), due to the pressure. The idea of SWE is based on changes in water properties, like pH, density, polarity/dielectric constant, viscosity, and surface tension, caused by the elevated processes of the temperature in the subcritical region. 96 The second uses supercritical fluid (ScF) as the extraction solvent, which is fluid that has characteristics of both gases and liquids above its specific critical pressure and temperature. This extraction method is characterized by changes in pressure and temperature that convert the gas into ScF. The SFE method is composed of the solubilisation process of the chemical compounds occurring in the solid matrix, and separation of these molecules in the ScF. Due to the effects of pressure reduction and an increment of temperature, this solvent converts to a solvent-free extract. 94,97,98 Another GET where pressure plays an important role, is PLE, also called high-pressure solvent extraction, enhanced or accelerated solvent extraction, and accelerated fluid extraction. This process guarantees high penetration of the solvent in the matrix because elevated pressures maintain the solvent in liquid form above its boiling point. 94 Additionally, RSLDE focuses on a negative gradient of pressures between the interior of the material (high pressure) and the exterior of the solid matrix (low pressure). The changes in the pressure have an impact on the solid matrix following an active deed, in which a small quantity of material is extracted at each pressure and depression cycle. Specifically, due to the gradient pressure removal, the solvent runs out of the matrix very fast, transporting with it substances that are not chemically attached to the main structure of the matrix. Furthermore, these compounds are extracted with the force effect, and consequently, are able to be extracted in solvents with different polarity. 10 Focusing our attention on the solvent used, neoteric solvents (NSs) are unconventional or structurally novel solvents. Generally, they are characterized by adjustable chemical and physical properties used for different applications. NSs such as DESs, ionic liquids (ILs), ILs with co-solvents, and CO 2 -expanded ILs, can potentially replace conventional solvents due to their biocompatibility, low toxicity and recyclability. 99 ILE uses ILs (salts with melting point below 100 °C) that are a relatively new class of compounds. They are characterized by simple cationic (organic)-anionic (organic and inorganic) structure, which provides unparalleled and unusual properties. 100 ILs are non-volatile, due to low vapour pressure. Furthermore, they are highly polar, mixable with water and specific organic solvents, as well as being characterized by good solubility of inorganic and organic materials. 101 Many ILs have opposite properties when compared with supercritical CO 2 , which is volatile, nonpolar, nonconducting, nonviscous, and unable to dissolve large, unsaturated compounds. 102,103 ILs can be divided into many subclasses, like IL-based surfactants (formed by the long alkyl chains with micellar properties when dissolved in water), room temperature ILs (melting point lower than room temperature), magnetic ILs (possess paramagnetic constituents in the anion or cation moiety), polymeric ILs (synthesized by IL monomers), and task-specific ILs. 102 Among all the NSs, DESs are gaining more attention with regards to the extraction of BACs from food processing by-products due to their high biodegradability when compared to the imidazolium-based ILs. In addition, DESs have great potential in developing extraction procedures that offer clean and highly energy-efficient processes. However, current study on the use of DESs for extraction purposes needs to better understand different aspects, like external factors (time, temperature, and solid:solvent ratio), solvent (pH, polarity, solubility and viscosity), and cytotoxicity to achieve eco-friendly processes. 102 DESs were developed to surmount the environmental problems caused by ILs. Despite similar properties to ILs, they are more stable and cost-competitive, and simpler to synthesize. 99 On the other hand, extraction with NaDESs is carried out by mixing two or more naturally occurring components (Brønsted Lowry acids and bases), which are able to interact between hydrogen bonds. Mixtures are composed of a hydrogen bond acceptor (HBA) with an electric charge and hydrogen bond donator (HBD). Furthermore, DESs can be divided into four main groups: Type I (organic salt and metal), Type II (organic salt and metal salt hydrate), Type III (organic acids and HBD), and Type IV (aluminium/zinc chloride and HBD). 102 In turn, NaDESs are classified into five groups based on their composition (HBA and HBD): amino-acid, ionic liquids, neutral-basic, neutral-acid and neutral. 102 The common components are choline chloride (ChCl), urea, organic acids (citric, lactic, and malic acid), and sugars (fructose, glucose, and sucrose). 57,63 Furthermore, it has been proven that the -energy efficient -easy to use -high extraction efficiency -safe and friendly working conditions -highly specific enzymes -an alternative method due to mild environmental conditions -small amount of undesired products -high bioactive yielding technology -high catalytic efficiency -efficacy of the natural products -no or small amounts use of harsh substances -no involvement of wasteful protection or deprotection stages -easy isolation and product recovery -process recyclability -removal of the needless components from cell walls

GET focused on enzymatic approach
Another GET in use over the last decade is EAE. The practice of enzymes, particularly in biocatalysis of agro-industrial waste, is used as a technique focused on the hydrolytic impact of enzymes on the cell wall and membrane of components, as well as on the macromolecules inside the cell, which enable the release of the natural products. [85][86][87][88] Enzymes are very efficient and peculiar, and the enzymes that play the key role in this extraction method are α-amylase, cellulase, pectinase, and tannase. 85,94 The process of enzymatic extraction of polyphenols requires optimal pH, temperature, and time. As an example, application in enzymatic-catalysis of cellulase, pectinase and tannase allowed for extraction of ellagic acid, hesperetin, and naringenin from citrus residues. 85 It was observed that extraction time had very important impact on the extraction yield. The last two compounds reached the highest values after 24 h (decreased slightly at 30 h), while ellagic acid was the highest after 5 h of incubation and decreased up to 90 %. Furthermore, other compounds (naringin and hesperidin) significantly increased. These changes were due to simultaneous extraction and biotransformation during the enzymatic reaction. Possibly, the pectinase and cellulase hydrolysed most of the compounds in the citrus waste wall cell, which led to liberation of glycosylated phenolic compounds to be acted upon by tannase. In this instance, the tannase formed aglycon phenolics (naringenin and hesperetin).
Enzyme manufacture is a significant field in biotechnology, with global sales around 5 billion dollars yearly, and a growth rate of the large number of patents. 85 EAE has attracted many researchers especially due to its advantages: (1) high catalytic efficiency and preservation of original efficacy of the natural products; (2) high bioactive yielding; and (3) improvement in the transparency of the system by elimination of avoidable components from the cell wall. 92 Moreover, EAE can be an alternative method due to mild environmental conditions, without great quantity of unwanted products. Despite its advantages, EAE is not always applicable at an industrial scale, because enzyme behaviour is strictly limited by environmental conditions. [85][86][87][88]92 Advantages and disadvantages of GET According to the data reported in Table 1, it is not possible to indicate the best GET in terms of cost-effectiveness. First of all, therefore, all necessary information regarding the investigated agro-in-dustrial by-product should be collected, with the aim of finding the most appropriate extraction technique. In this way, it will be possible both to maximize the extraction of the target bioactive molecules, and to recover other components that may have beneficial aspects. For the sake of the environment, emphasis must be placed on development connected to bioeconomy and circular economics. Concerning new designs of processes, researchers propose novel green solvents and the use of less extreme conditions of pressure and temperature. The ecological character and costs of the extraction are determined by the source of BACs, solvent, temperature, processing time, and the occurrence aided extraction modes, like microwave or ultrasound. 99 Gallego et al. 105 observed that SbFE and SFE technologies have a lot of potential for effective extraction of BACs from many different plant matrices. However, some improvements in different aspects (e.g., chemical composition, natural materials), have to be taken into consideration. Water is regarded as the cleanest solvent. Yet, corrosion issues still do not allow for its application at industrial scale. 99 In turn, CO 2 is GRAS, and it is considered as thermodynamically stable, non-flammable, non-mutagenic, non-carcinogenic, and non-toxic. 99 However, its fruitful application in SFE depends on the exhaustive understanding of SFE and experimental strategy methods. 99 Comparing SFE-CO 2 with UAE, the first better isolates essential oils and other lipophilic compounds, but is less effective for extraction of polar compounds (e.g., polyphenols). That is why co-solvents are often used to improve the recovery of polar and medium polar molecules. However, despite many advantages, SFE has some limiting aspects, like complex industrial equipment and high processing expenditures. 99 Upcoming developments aiming to obtain more efficient extraction, take account of integration of techniques within the same process. An example could be the use of a procedure of enzyme treatments coupled with PLE or SFE process. With this approach, a better recovery of BACs may be obtained; by connecting green technologies, BACs in a diverse, more active, chemical form than that initially present in the natural matrix can be obtained. Another possibility for the future development of GET may be connected to the use of new solvents. 102 Hence, to PLE could be applied ILs or DESs, 106 as well as ScFs. Nevertheless, the toxicity of ILs is controversial and the use of ScFs is expensive. Thus, NaDESs appear to be a more auspicious and greener choice due to their bio-compatibility and low toxicity. 99 Taking into account that the pharmaceutical, cosmetic, food, and biomaterials industries are interested in exploitation of target high added value BACs, especially those with antioxidant properties, development of more environmentally sustainable production systems should be sought. This is fundamental in order to increase process efficiency with or without minimal changes in the biological and nutritional properties of natural matrixes.
Green extraction practices for the recovery of antioxidant bioactive compounds from agro-industrial by-products It is well known that each year, worldwide, 5 billion tons of biomass residues from agrifood by-products cause the emission of 3.3 billion tonnes of CO 2 . 99 It is imperative to decrease the amount of this biomass, which can cause serious environmental problems. Nevertheless, these remains can be rich in various BACs in such a way that their utilisation might have a favourable impact on the environment and industry. 104 Over the last 10 years, the number of publications on the application of green extraction practices of agro-industrial by-products has dramatically increased ( Fig. 1). Natural BACs from agro-industrial by-product processing are characterized by a wide range of molecules with different functionalities and structures, such as polyphenols, sugars, dietary fibres, amino acids, tocopherols, phytosterols, carotenoids, and vitamins. 99,102,104 Polyphenols are among the most sought after BAC, and their extraction from agro-industrial waste has driven scientists to explore more lucra-tive, efficient, and sustainable extraction techniques, premised on a green extraction procedure. Polyphenols show interesting properties like cardioprotection, anti-inflammation, anticancer, and antimicrobial activity. 107 Antioxidant activity in particular has been shown to be a very recognisable feature of polyphenols. 108 The antioxidant activity is usually evaluated using different types of assays to carry out a comparative assessment of various methods. A lot of chemical and biological assays are used to investigate the antioxidant activity, but the most commonly applied for agro-industrial by-products are: DPPH • (radical scavenging activity assay), ABTS •+ (radical cation scavenging activity assay), ORAC (oxygen radical absorption capacity assay), H-ORAC (hydrophilic oxygen radical absorption capacity assay), CUPRAC (cupric reducing antioxidant capacity assay), FRAP (ferric reducing antioxidant power assay), LPO (lipidic peroxidation inhibition assay), PPO (polyphenol oxidase assay), TBARS (thiobarbituric acid reactive substances assay), β-carotene bleaching method, cellular antioxidant activity, and Rancimat test. [4][5][6]28,29,33,39,40,42,54,76,85 Also, evaluation of total polyphenolic content (TPC) by Folin-Ciocalteu method can be applied as an antioxidant assay due to its redox chemical mechanism. [4][5][6]14,67,86 Table 2 reports information regarding the different GET used for an extraction of BACs with antioxidant properties from agro-industrial by-products.

Ta b l e 2 -Green extraction techniques used for extraction of antioxidant bioactive compounds from agro-industrial by-products
Agro-industrial by-products extraction with GET based on the energy used UAE has been widely used for extraction of polyphenols from a variety of fruits, like grape, pomegranate, mango, bilberry, strawberry, jujube, armenian plum, orange, passion fruit, avocado, as well as vegetables, like onion, potato, artichoke, chicory, and red beet. Moreover, UAE has been used for the extraction of polyphenolic compounds from nuts (chestnut, walnut, and almond), as well as grains (flax, rye, and coffee), and other plant sources, like pine. Specifically, Bibi et al. 12 extracted new low-cost and eco-friendly phenolic compounds with the use of UAE from seeds of Prunus armeniaca, Prunus persica and Prunus domestica, while Geerkens et al. 18 performed the quantitative isolation of alk(en)ylresorcinols from mango peels and rye grains with the same GET. Regarding different berry by-products, Varo et al. 32 used UAE for extraction of anthocyanins and flavonols from bilberry juice by-products, while Villamil-Galindo et al. 33 isolated these compounds from strawberry by-products. In the latter's findings, extracts with acidified methanol in two steps yielded the highest polyphenol concentration (15.01 g kg -1 ), and the highest antioxidant capacity. Moreover, agrimoniin was the main polyphenol detected, and the extraction with acetone in two steps produced the highest yield (2.45 g kg -1 ). In terms of extraction, another important crop investigated with ultrasound techniques were grape by-products. Trasanidou et al. 27 using UAE and water/glycerol mixtures as the solvent, re- covered polyphenols and anthocyanins from red grape pomace (wine industry solid waste). Furthermore, Poveda et al. 24 extracted different winemaking wastes (grape seeds, pomace and stems) from Vitis vinifera L. cv. Tempranillo, and seeds from V. vinifera L. cv. Cabernet Sauvignon, not only using UAE but also applying ASE. As a result, they obtained extracts rich in hydroxycinnamic acid derivatives, flavonols, tannins, catechins, and anthocyanins. Poveda et al. 24 also observed strong correlations among antioxidant activity of extracts and phenolic composition (Pearson correlation: 0.879 and 0.778 for ABTS •+ and DPPH • , respectively). Finally, regarding fruits by-products, Berkani et al. 13 applied UAE to extract polyphenols from jujube seeds. A maximum TPC (2383.10 mg GAE/100 g) was obtained under sonication temperature and time (29.01 ºC and 15.94 min, respectively), ethanol concentration (50.16 %), and solvent:solid ratio (34.10:1 mL g -1 ).
Regarding vegetable by-products as a source of polyphenols, several authors used UAE to extract these bioactive molecules. The findings of Nutter et al. 22 were focused on obtaining BACs from beet leaves. Moreover, surface methodology was employed to optimize UAE conditions (16 min, 90 W, and solid:solvent ratio, 1:20), under which the yields were 14.9 mg g -1 , 949.1 μg g -1 , and 562.2 μg g -1 for polyphenols, betaxanthins, and betacyanins, respectively. Vauchel et al. 31 used UAE under different operating conditions for the extraction of polyphenols from chicory grounds, while Punzi et al. 25 applied water UAE to obtain polyphenols from different artichoke parts (TPC: 1446, 1343, 907, and 774 mg kg -1 fresh weight, for hearts, leaves, outer bracts, and stems, respectively). Finally, the goal of Trujillo-Mayol et al. 28 was to study the combination of UAE and MAE principal factors such as sonication time, temperature, and microwave power in a new extraction procedure (U-MAE) for the maximum recovery of TPC from avocado peel by engaging a response surface methodology. As a result of the combination of optimal parameters (15 min of sonication followed by 95.1 s of microwaving) it was possible to recover 166.3 mg GAE g -1 dry matter, which was 1.1, 1.3, and 1.2 times greater than maceration, UAE, and MAE, respectively. Similarly, the U-MAE was higher in TPC yield (281.4 mg GAE g -1 dry matter), and antioxidant activity (DPPH • , FRAP and LPO: 779.1, and 167.0 μg TEAC, and 70.03 %, respectively). Boggia et al. 14 have also evaluated UAE and MAE of the fresh by-products (endocarp and aril residues) obtained after pomegranate juice processing, using water as extraction solvent in both cases. Dahmoune et al. 17 used both these methods for the recovery of TPC from lemon peels. The maximum forecasted TPC recoveries under the optimized conditions for UAE and MAE were 15.08 and 15.74 mg GAE g -1 dry weight, re- spectively, which were close to the experimental values, indicating the success of response surface methodology, in optimizing the extraction conditions. 17 Moreover, regarding citrus by-products, Khan et al. 21 used ethanol in UAE, in order to obtain polyphenols (275.8 mg of GAE/100 g fresh weight), especially flavanones (70.3 and 205.2 mg of naringin and hesperidin/100 g fresh weight) from orange peel. Different nuts were investigated by UAE. Tabaraki and Rastgoo 26 evaluated water, methanol, ethanol, and acetone extracts of green walnut husk. The results showed that TPC varied from 6.28 to 7.23 mg GAE g -1 dry sample, while FRAP and DPPH • values varied from 0.33 to 0.46 mmol Fe 2+ g -1 of dry sample, and 33.98 to 56.31 % inhibition, respectively. Tungmunnithum et al. 29 applied UAE with water and ethanol on Moroccan almond coldpressed oil residues, and were able to extract protocatechuic acid, p-hydroxybenzoic acid, chlorogenic acid, and p-coumaric acid from three different native Beldi genotypes. Finally, Lameirão et al. 19 used industrial chestnut shells to obtained extracts rich in polyphenols (255.8-408.0 mg GAE g -1 dry weight). Furthermore, with the use of UAE under optimal conditions, this research group was able to detect high amounts of ellagic acid, caffeic acid derivative and epigallocatechin (40.4, 15.4, and 15.3 μg mg -1 dry weight, respectively).
Regarding grains, Corbin et al., 16 with the use of water, methanol, ethanol, or butanol, applied to UAE technique, extracted flaxseed for phenolic compounds, including a macromolecular complex accumulated in seedcoat composed of flavonol (herbacetin diglucoside), hydroxycinnamic acids (p-couramic, caffeic and ferulic acid glucosides), and lignan (secoisolariciresinol diglucoside). Furthermore, Zhang et al. 30 used ultrasound water processing in order to recover TPC (2.79, 2.12 and 0.66 mg GAE g -1 of dry sample from coffee silver skin, potato peel, and brewer's spent grain, respectively) in 30 min. Liazid et al. 20 evaluated various GET, among which were UAE, MAE, and PLE, to obtain polyphenolic extracts from two varieties of pine (Pinus maritima and Pinus d'Alpes) seeds. Finally yet importantly, Oliveira et al. 23 applied a sustainable recovery extraction (UAE with different solvents, and SFE with CO 2 ) for the valorisation of two juice by-products, the passion fruit seed and the seed cake residue from the seed oil production by cold pressing.
Some authors have investigated agro-industrial by-products using UAE that work via pulses (PUAE). For instance, Donno et al. 34 applied this technique to extract different BACs (cinnamic acids, flavonols, benzoic acids, catechins, tannins, organic acids, and vitamin C) from Castanea spp. bud-derivatives, and their total content was 160.42 mg/100 g fresh weight. Likewise, Turrini et al. 35 used this method to extract the same BACs from the bud waste, remaining after the production of Castanea sativa glyceric macerates. The same research group extracted pomegranate juice by-products by PUAE in order to obtain polyphenol fractions. 36 Furthermore, MMMT based on UAE approach was used by some authors to extract BACs from agro-industrial by-products. Marangi et al. 83 used this technology to extract polyphenols (including flavonoid, chlorogenic acid and gallic acid derivatives) from hardy kiwi leaves. Moreover, the investigated extract showed a high antioxidant activity (DPPH • : IC 50 = 270.17 μg mL -1 , and FRAP: 3219.55 μmol Fe 2+ g -1 freeze-dried plant material). In turn, Puga et al. 84 were able to isolate several BACs, like 3-, 4-and 5-caffeoylquinic acid, 3-and 5-feruloylquinic acid, dicaffeoylquinic acids, caffeoyltryptophan, and caffeoylferuloylquinic acid from coffee chaff.
MAE is another GET that bases its extraction process on energy, and that has interested many researchers. Among all studied plant matrixes, it was possible to find kiwi, pitaya, grape, sea buckthorn, mango, and English walnut wastes. Carbone et al. 67 were evaluating MAE on kiwi juice pomace. Moreover, they were investigating the influence of the temperature, time, solvent composition and solid:solvent ratio on TPC. Ferreres et al. 68 were investigating MAE extracts of white-fleshed red and yellow pitaya peels. Their aim was to find the best conditions for extraction of phytochemicals (phenolic acids, flavonoids, and betacyanins). The study of Kwiatkowski et al. 69 was focused on MAE from grape skins of different white and red cultivars at veraison and harvest, while Périno-Issartier et al. 72 extracted isorhamnetin-3-O-rutinoside, isorhamnetin-3-O-glucoside, quercetin-3-O-glucoside, isorhamnetin from sea buckthorn pomace. The study of Sanchez-Camargo et al. 71 was interesting in terms of different extraction strategies. They performed MAE on supercritical CO 2 pre-extracted mango peel as a valorisation strategy, and with the aim to extract polyphenols. The highest TPC (52.08 mg GAE g -1 dry weight) and antioxidant activity (DPPH • : 2.75 mmol trolox equivalent g -1 dry weight) were obtained in 90 s and at 800 W, and 50 g mL -1 . Finally, Rosa et al. 70 applied MAE to fresh, male, English walnut flowers and unripe walnut seeds to evaluate the TCP of the extracts, as well as the percentage of water-soluble polyphenols.
Agro-industrial by-products extraction with GET based on the solvent used Neoteric solvents (ILs, DESs, and NaDESs) have been widely applied to the extraction of polyphenols from cocoa beans, spent coffee grounds, jabuticaba, grape and olive pomace, grape and mandarin peels, fig leaves, and onion, tomato, and pear by-products. Regarding extraction with ILs, Lima et al. 90 performed the extraction of anthocyanins from grape pomace via solid/liquid extraction with aqueous solutions of the ILs (1-ethyl-3-methylimidazolium acetate) and sequential purification in aqueous two-phase systems with additional salts. With the use of response surface methodology, the optimum conditions of extraction were obtained resulting in an anthocyanins yield of up to 3.58 mg g -1 . On the other hand, Larriba et al. 89 used hydrophobic ILs to replace conventional volatile organic compounds as extraction solvents to recover tyrosol from olive mill wastewater. Furthermore, 15 different DESs extracts of spent coffee grounds were investigated by Fanali et al. 56  On the other hand, NaDESs have been reported for the extraction of jabuticaba pomace (seeds and peel containing remaining pulp), targeting a selective and sequential extraction of anthocyanin and pectin. 61 Widely produced by-products (pomace) of grape and olive were extracted by Panić et al. 66 and Chanioti and Tzia 62 with the use of NaDESs in order to obtain polyphenol (oleuropein, hydroxytyrsol, caffeic acid, vanillin, rutin, and luteolin) fractions. Furthermore, Manuela et al. 65 extracted cocoa beans to obtain polyphenol and flavan-3-ol fraction with the use of NaDESs, while Jokić et al. 58 performed extractions of mandarin peel, to extract hesperidin as target compound. The results of the last research group showed that the most efficient hesperidin extraction (112.14 mg g -1 of plant) was obtained with ChCl:acetamide (1:2), while the lowest hesperidin yield (1.44 mg g -1 of plant) was detected with the use of ChCl:citric acid (1:1) solvent. As a further matter, Lakka et al. 64 used NaDESs composed of l-lactic acid and glycine in different ratio to extract polyphenols from saffron processing waste. Finally, De los Ángeles Fernández et al. 63 investigated NaDESs extracts of onion, tomato, pear and olive by-products for the extraction of 14 dif-ferent polyphenols, namely, gallic acid, hydroxytyrosol, tyrosol, catechin, caffeic acid, rutin, coumaric acid, t-ferulic acid, oleuropein, cinnamic acid, quercetin, luteolin, naringenin, and apigenin.
PEFs, as a non-thermal technique, has shown to be valuable technique for the extraction of BACs by some authors. For instance, Parniakov et al. 79 used this method to extract polyphenols, proteins, and carbohydrates from papaya peel, while Redondo et al. 82 were able to extract several polyphenols (catechin, coumaric acid, chlorogenic acid, neochlorogenic acid, and quercetin) from thinned peach fruits. Luengo et al. 80 applied PEFs treatment to orange peels in order to obtain extract rich in polyphenols (naringin and hesperin), while Boussetta et al., 81 using PEFs, were able to valorise oilseed residues (flaxseed hulls) obtaining extracts with high level of polyphenols.

Agro-industrial by-products extraction with GET based on the solvent and pressure used
GETs that involve pressurized solvents (PLE, ESE and ASE) have been applied by several researchers to obtain BACs fractions from different plant by-products. As an example, Fernández-Ponce et al. 74 evaluated PLE and ESE extracts of mango leaves for polyphenols. Interestingly, ethanol improved the selectivity of the PLE process, so extracts present the highest TPC (414.9-854.7 mg g -1 dry extract), and the antioxidant activity of PLE and ESE extracts ranged between 3.55-5.64 μg DPPH • μg -1 . In turn, Ballesteros-Vivas et al. 73 investigated PLE of mango seed kernel for polar fraction (polyphenols), as well as for non-polar fraction (fatty acids and lipids). On the other hand, Pagano et al., 76 using hot water PLE, were able to extract from artichoke bract and leaf, flavone glycosides and caffeoylquinic acids (3-19 and 14-37 mg g -1 , respectively). Plaza et al., 77 with the same green approach extracted different polyphenols (5-caffeoylquinic acid, hyperoside, isoquercitrin, reinutrin, phloridzin, avicularin, quercitrin, and quercetin) from apple by-products. Oliveira et al., 75 with the use of PLE, were able to extract a range of polyphenols, like ellagic acid, and its pentoside and deoxyhexose, quercitrin, kaempferol pentoside, quercetin hexoside from Brazilian cherry seeds. Gallo et al. 78 used the cyclically pressurized extraction RSLDE to extract polyphenols from the peels and seeds of grapes.
Compressed fluids-based GET, including sub-(SbFE) and supercritical (SFE) fluid approaches, have been widely applied for the extraction of BACs from plant by-products. Regarding the subcritical approach, Guthrie et al. 51 used this technique for the recovery of phenolic antioxidants from green kiwi fruit peel. Under optimum conditions (160 ºC, 20 min, pH 2, and 2 % solid:solvent ratio), TPC and TFC were 51.2 mg GAE g -1 dry weight, and 22.5 mg CE g -1 dry weight, respectively. Gabaston et al. 50 and Yammine et al. 55 used SWE for extraction of BACs from grape by-products. The former were able to extract complex stilbenes from grapevine by-products (wood, cane, and root), 50 while the latter recovered different polyphenols (anthocyanins, tannins, monomeric and oligomeric flavan-3-ols) from red and white grape pomace. 55 Vegetable by-products appeared to be interesting for SWE extraction. Alvarez et al. 47  On the other hand, Bodoira et al. 48 evaluated the economic importance of oil by-products after the oil extraction processes, by investigating SbFE of peanut skin, sesame seed cake, and pistachio nut cake. They investigated the possibility of using non-polluting extraction technologies for making natural biopesticides from these nut and grain wastes. 48 Narita and Inouye 54 and Jokić et al. 53 focused their attention on grain and nut by-products, evaluating SWE extracts of coffee silverskin for polyphenol, 5-caffeoylquinic acid, caffeine, 5-hydroxymethylfurfural, sugar, and protein content. It was observed that the antioxidant activity increased with increments of the temperature. Thus, the highest antioxidant activity was observed with the extracts obtained at 270 ºC (2629 and 379 μmol TE g -1 of coffee silverskin extract, for H-ORAC and DPPH • , respectively). 54 Jokić et al. 53 extracted cocoa shell, to extract a variety of bioactive molecules, like polyphenols, sugars (mannose, glucose, xylose, arabinose, rhamnose, and fructose), as well as their degradation products such as formic acid, levulinic acid, lactic acid, 5-hydroxymethylfurfural, and furfural. Jokić et al. 53 were able to obtain different concentration of epicatechin, catechin, theobromine, caffeine, theophylline, chlorogenic acid and gallic acid, applying different extraction conditions. The TPC and scavenging activity with the use of DPPH • assay was 27.26-130.33 mg GAE g -1 extract, and 19.20-91.69 %, respectively. Fabian et al. 49 used SWE to extract phenolic acids (gallic acid, caffeic acid, p-coumaric acid, and ferulic acid) from rice bran, while Ahmadian-Kouchaksaraie et al. 46 investigated saffron petals SWE extracts for polyphenol and flavonoid content. They determined that optimum extraction conditions (159 °C, 54 min and water:solid ratio of 36 mL g -1 ) resulted in the best TPC (1616 mg/100 g), TFC (239 mg/100 g), FRAP value (5.1 mM), and DPPH • (86.05 %).
In addition, an SFE approach was shown to be a common GET. Castro-Vargas et al. 39 investigated recovery of phenolic antioxidants from papaya seeds, and the highest TPC (15.34-34.23 mg GAE g -1 ) was found in extracts obtained with CO 2 -EtOH and ethanol. In contrast, Marić et al. 41 applied SFE to separate oil from seeds. Consequently, raspberry seed oils were analysed in terms of fatty acids content, tocopherols, and functional quality indices, while the residues after extractions were investigated in terms of free and total ellagic acid. Cocoa bean by-products were shown to be rich in BACs. Similarly, Valadez-Carmona et al. 45 used SFE to extract phenolic compounds from cacao pod husk. The extract gained at the optimum conditions (60 °C, 13.7 % of ethanol, and 299 bar) presented TPC (12.97 mg GAE g -1 extract) and antioxidant activity (0.213 mmol TE g -1 extract). In turn, Mazzutti et al. 42 applied pressurized ethanol extraction as well as SFE on cocoa bean hull, aiming to extract polyphenols and volatile compounds.
Other agro-industrial by-products investigated by SFE are leaves. As an example, Pavić et al. 43 were able to recover carnosol (0.46-65.5 μg mg -1 ) and carnosoic acid (0.29-120.0 μg mg -1 ) from sage leaves. Borja-Martínez et al. 38 extracted polyphenols, chlorophylls, β-carotene, α-tocopherol, and phytosterols from broccoli leaves and stems, while Lafka et al. 40 evaluated polyphenol and antioxidant potential of olive oil mill wastes SFE extracts. Campone et al. 15 developed an innovative and green SFE method with ethanol/water as a co-solvent to quantitatively extract flavonoids from onion skin. In the same paper, UAE was used to obtain the chemical profile of secondary metabolites of exhaustive extract. Very important agro-industrial wastes extracted with the use of SFE are grape pomace, skins and seeds. Pérez et al. 44 focused their attention on red grape seeds, from which they were able to extract fatty acids, and a range of phenolic acids (gallic acid, caffeic acid, p-coumaric acid, ferulic acid, and ellagic acid). In contrast, Aresta et al. 37 studied SFE of winemaker by-products (pomace, skins, and seeds) for polyphenol, t-resveratrol, β-sitosterol, and vitamins (α-tocopherol and vitamin C) content. Skin was shown to be the richest in polyphenols (603 μg GAE g -1 dry matter), while similar antioxidant activity was observed in skin and pomace (ca. 0.12 mmol trolox/g dry matter).
Agro-industrial by-products extraction with GET based on enzymatic approach The final GET described in this study is EAE. Gómez-García et al. 86 applied EAE on grape residues in order to extract polyphenols (gallic acid, resorcinol, and o-coumaric acid). In their findings, a good correlation between polyphenols and antioxidant activity was obtained. Moreover, the highest antioxidant activities (86.8, 82.9 and 90 %) were registered at 12 h for Celluclast ® 1.5 L, Pectinex ® Ultra and Novoferm ® , respectively. Saad et al. 88 applied different combinations of carbohydrases and proteases to raspberry pomace and pomace presscake for the recovery of polyphenols (2.7 and 2.5 g per 100 g of dry sample, respectively), and lipophilic compounds. Madeira and Macedo 85 were to obtain polyphenols from Brazilian citrus (Citrus latifolia and Citrus sinensis L.) albedo and flavedo, with high bioactivity, using simultaneous extraction (cellulase and pectinase) and biotransformation (tannase) by enzymatic process. The highest hesperetin, naringenin and ellagic acid production in this study (conditions: 40 ºC, 200 rpm, 5.0 U mL -1 of cellulose, and 7.0 U mL -1 of tannase) were 120, 80, and 11,250 μg g -1 , respectively. Likewise, Puri et al. 87 investigated EAE of kinnow peel. The aim of this research group was to develop an enzymatic hydrolysis of naringin that would simplify the processing of kinnow peel waste.
Regarding the analysed literature for this review and other experimental findings, it is difficult to choose, among all presented GETs, the most acceptable technique. 109 Each of them has advantages. Furthermore, regarding the BACs, it is not possible to choose just one GET that will allow for the best extraction of active compounds in general. For instance, focusing on polyphenols, the scientific findings show evidently that the extraction efficiency is determined by the type of extracted phenolic compound, its position in plant as well as type of plant material, quality, and selectivity. Furthermore, some GETs are able to extract the intracellular molecules selectively without fragmenting the treated tissue. Therefore, in choosing an extraction process, the selectivity, productivity, source, and total yield have to be taken into consideration. Also from our experience, extracting different plant materials and their by-products with different extraction type and conditions, allow to extract preferentially specific compounds of interest. To sum up, before choosing the right extraction method for a given ingredient or product, the final goal has to be defined, and the characteristics of each available method have to be considered.
In a broader view, the game-changing approach to use agro-industrial by-products in biorefinery allows the production of many biobased products (bioenergy, biofuels and other valuable chemicals). Although biofuels are mainstay of biorefineries, production of improved biomolecules such as biopolymers, biopigments, and biosurfactants has been widely studied in the last years with the use of tra-ditional methods. New approaches including holistic extraction and purification technologies with the use of renewable materials and improved processes should follow to evaluation of the entire production chain. 110 Hence, reduction in the production costs benefits waste recycling, making the environment eco-friendly. Furthermore, agro-industrial by-products favourable application in various industries (e.g., chemical, pharmaceutical, and nutraceutical), drives scientists to develop novel green approaches to make the technology cost-effective, and generating more efficient and healthier products used as active compounds (pharmaceutics), food supplements (nutrition), and ingredients (food, home and personal care). 111,112 Comprehensive investigation of previous and current literature confirms effectiveness of GETs in biorefinery. 112 Moreover, regarding extraction at industrial scale, conventional technologies, due to their many disadvantages (e.g., time consuming extraction, scarce yield recovery, intensive heating and/or mixing, and toxicity), should be replaced with GET. It is well known that biorefineries play a key role in sustainable bio-based economy. They involve the sustainable processes of converting bio-materials into marketable products. Furthermore, in a biorefinery, the idea of green extraction processes for extraction of natural products is focused on effective energy use, reduction in processing steps and equipment size, as well as on enhanced heat and mass transfer. The scientific findings show that many extraction applications may make a big difference in biorefineries, by significantly decreasing the costs and therefore making the processes competitive. Nevertheless, it is necessary to highpoint the exact separation challenges faced in biorefineries and indicate the effect of separations on the total costs. 113 Numerous separation technology challenges in biorefeneries depend on high temperatures, existence of reactive mixtures, complex organic matrix that can contain inorganic compounds, polarity of components in the mixture, and very diluted water solutions. 113

Conclusions
Turning unmanaged agro-industrial by-products into valuable source of BACs is a viable solution for both eliminating food wastes and at the same time obtaining high added value products. Thus, nowadays, the agro-industrial sector is pushed to increase its overall efficiency by optimizing the life cycle of their processes and products. This can be reached by upgrading existing processes or discovering new uses for waste. In this context, GETs have proved to be reliable strategies for recovering different types of BACs, including polyphenols and other antioxidant compounds. Moreover, the reprocessing of agro-industrial by-products may create secondary streams to obtain, for instance, valid models to design semisynthetic derivatives and/or synthetic analogues with enhanced health properties. However, several challenging aspects of GETs to optimize rates of recovery and the degree of BACs purity are yet to be overcome. The possibility of GETs being scaled-up at industrial level will have to take into account the proper choice of separation techniques and conditions (e.g., solvent type, material costs, extraction times, etc.) after economic analyses. However, it is incontrovertible that the development of GET for obtaining BACs from agro-industrial by-products could improve economic viability by creating profits in upcoming sustainable manufacture system.