- expansion of emerging therapeutic applications on *in vitro* disease modelling and microtissue formation and maturation

- additional and wide clinical trials and harmonised regulatory frameworks

The toolbox of polysaccharides available and their inherent charac-
teristics establish a comprehensive range of opportunities for the syn-
ergistic development of innovative systems. We expect that these
examples may outline forthcoming directions in biomedicine and
biotechnology, which will expedite the clinical use of natural poly-
saccharide materials and prospect manufacturing and analysis
processes.

5.1. *Bioactive polysaccharides*

5.1.1. *Current challenges*

Polysaccharides have been ingredients in traditional medicines since antiquity. This includes remedies prepared as water extracts from plants and other organisms that have proven helpful for treating various ailments. However, the role of the bioactive polysaccharide components and how they could contribute to healing was not understood. The polysaccharides in such traditional medicines are mainly obtained from plants, animals, or fungi, whereas polysaccharides in modern medications can also be sourced from microorganisms. Currently, polysaccharides are incorporated as the bioactive component in drugs, nutraceuticals, cosmetics, and other products. The function of these polysaccharides includes anti-coagulant, anti-microbial, anti-viral, antioxidant, cholesterol-lowering, anti-lipidemic, haemostatic, and adjudvant activity as well as tumour suppression, regenerative and rejuvenating action, and immunomodulation. The biological action is mostly mediated by the binding to cell surface receptors, different types of cytokines, and plasma proteins, but polysaccharides also interact with other molecules such as lipids or radicals. The biological activity is either based on the mammalian origin (e.g., heparin) or, when obtained from other species, often modulated and further enhanced by chemical modification and conjugation to introduce receptor targeting moieties, specific binding domains to proteins with regulatory functions (e.g., cytokines), drugs, and other biomolecules. Polysaccharides and polysaccharide conjugates in general possess low toxicity and are compatible with living tissue under many circumstances due to their native structure, which is a significant advantage when considering clinical applications. Biodegradability and predictable metabolic fate also reduce the probability of unexpected adverse reactions. Furthermore, chemical derivatives with modified structures are now also important. An example of modern medicines developed from traditional remedies is Krestin, a β-glucan polysaccharide extract from the mushroom *Trametes (Coriolus) versicolor*. It is a T-cell proliferation stimulator approved as a prescription drug for cancer therapy in Japan in 1977 and is currently used as adjuvant therapy for cancer.

Another important example is heparin, an anionic sulfated glycos-
aminoglycan discovered as an anti-coagulant in the 20th century. It is
isolated from porcine and bovine internal organs and has been widely
used since the 1930s. It binds to anti-thrombin III and induces a
conformation change increasing greatly its affinity to active blood
coagulation factors, particularly factor Xa and thrombin. Heparin is used
to prevent thrombotic events and is included in the World Health Or-
ganization list of essential medicines (WHO, 2023). In general, the
polysaccharide sequence regarding (i) types of monosaccharide units,
(ii) pattern of glycosidic linkages, and (iii) the regioselective function-
alization with sulfate and carboxylic groups plays an important role for
the functional activity of glycosaminoglycans like chondroitin sulfate,
dermatan sulfate, heparane sulfate, and heparin (Köwitsch, Zhou, &
Groth, 2018). Analysing these sequences and their unique biological
structure-property-relationships poses major challenges to poly-
saccharide analytics and chemistry. As an example, the therapeutic ac-
tion of heparin is related to a pentasaccharide sequence that is

characterised by a specific sulfation pattern with presence of O-sulfo-
nates and carboxylates with a repetitive sequence of 2-O-sulfated idur-
onic acid linked to a 6-O-sulfated glucosamine (Mohamed & Coombe,
2017). It has also been found that 3-O-sulfation of glucosamine is
essential for the anti-Xa activity of the pentasaccharide (Nahain, Ignja-
tovic, Monagle, Tsanaktsidis, & Ferro, 2018).

Unfractionated heparin is associated with serious side effects such as bleeding, thrombocytopenia, and others, which is also related to the binding of unfractionated heparin to many other plasma proteins. In addition, it has a very short half-life of less than 1 h. Nowadays, depo-lymerised low molecular weight versions are preferred, and different synthetic and chemically modified oligosaccharides like Fondaparinux and Idraparinux have also been introduced as heparin analogues. Fon-daparinux represents a pentasaccharide, which is a methylglycoside analogue of the natural anti-thrombin III binding pentasaccharide sequence. The methylation reduces the non-specific binding to other plasma proteins. It has longer half-life than low molecular weight hep-arins and does not induce thrombopenia. Idraparinux is a hyper-methylated derivative of Fondaparinux with an extended half-life. Whereas daily administrations are required for fondaparinux, a weekly subcutaneous administration of Idraparinux is sufficient to maintain a therapeutic effect. A disadvantage of these heparin analogues is that protamine cannot be used to neutralize their anti-coagulant activity like in the case of heparin. Hence, Idrabiotaparinux as a biotinylated de-rivative of Idraparinux represents a safer drug since avidin can be administered as an antidote when bleeding complications occur.

Chitosan (poly-β-1-4 D-glucosamine) is a cationic polymer that has an anti-microbial effect and can be used to induce coagulation. These properties have been utilised in dressing, such as HemCon®, to stop bleedings and for wound treatment. Chitosan can also stimulate tissue regeneration and has been used in bone cement and tissue engineering scaffolds. Moreover, chitosan and its derivatives have been used to promote tight junction opening in drug delivery applications and as an adjuvant for vaccines.

Acarbose is a tetrameric pseudo-oligosaccharide that inhibits inte-
tinal alpha-glucosidase. It is an anti-diabetic drug used to reduce glucose
uptake and lower blood glucose levels. Sugammadex is a γ-cyclodextrin
(cyclooctaamylose) derivative introduced as a drug to reverse the effect
of the steroidal neuromuscular blockers rocuronium and vecuronium,
which are medications used as muscle relaxants in major surgery.
Sugammadex forms a 1:1 inclusion complex with these neuromuscular
blockers and is used in an emergency to reverse life-threatening respi-
ratory suppression and aid recovery following surgery. Other cyclo-
dextrin derivatives, such as hydroxypropyl β-cyclodextrin and sulfobutyl
β-cyclodextrin, have also been introduced as complexing excipients used
to stabilise, solubilise, and aid the dissolution of lipophilic drugs. These
cyclodextrin derivatives have been included in drug formulations
approved for oral, ocular, intramuscular, and intravenous applications.

Notwithstanding the long history of polysaccharide use in medicine and the recent introduction of synthetic and semi-synthetic oligosaccharide drugs, there are considerable challenges that need to be overcome to reach the true therapeutic potential for this class of molecules. Advances in our understanding of their role in inter- and intracellular communication, interaction with other biomolecules, and receptor binding are needed. This especially applies to their role in modulating immune responses. Improved knowledge could contribute to the development of therapeutic polysaccharides, including new vaccines and treatments for autoimmune diseases and cancer investigations to determine the structure-activity-relationship is a vital part of the discovery and development of synthetic and semi-synthetic drugs. Such studies are very challenging for complex polysaccharide conjugates and derivatives. Natural polysaccharides are a mixture of structural isomers with different molecular weights, side-chain distribution, and structure. Chemical modification leads to further increased structural variation between individual polymer chains. Chemical analysis can be very challenging to fully characterise and define all aspects of this structural
- expansion of emerging therapeutic applications on *in vitro* disease modelling and microtissue formation and maturation

- additional and wide clinical trials and harmonised regulatory frameworks

The toolbox of polysaccharides available and their inherent charac-
teristics establish a comprehensive range of opportunities for the syn-
ergistic development of innovative systems. We expect that these
examples may outline forthcoming directions in biomedicine and
biotechnology, which will expedite the clinical use of natural poly-
saccharide materials and prospect manufacturing and analysis
processes.

5.1. *Bioactive polysaccharides*

5.1.1. Current challenges

Polysaccharides have been ingredients in traditional medicines since antiquity. This includes remedies prepared as water extracts from plants and other organisms that have proven helpful for treating various ailments. However, the role of the bioactive polysaccharide components and how they could contribute to healing was not understood. The polysaccharides in such traditional medicines are mainly obtained from plants, animals, or fungi, whereas polysaccharides in modern medications can also be sourced from microorganisms. Currently, polysaccharides are incorporated as the bioactive component in drugs, nutraceuticals, cosmetics, and other products. The function of these polysaccharides includes anti-coagulant, anti-microbial, anti-viral, antioxidant, cholesterol-lowering, anti-lipidemic, haemostatic, and adjudvant activity as well as tumour suppression, regenerative and rejuvenating action, and immunomodulation. The biological action is mostly mediated by the binding to cell surface receptors, different types of cytokines, and plasma proteins, but polysaccharides also interact with other molecules such as lipids or radicals. The biological activity is either based on the mammalian origin (e.g., heparin) or, when obtained from other species, often modulated and further enhanced by chemical modification and conjugation to introduce receptor targeting moieties, specific binding domains to proteins with regulatory functions (e.g., cytokines), drugs, and other biomolecules. Polysaccharides and polysaccharide conjugates in general possess low toxicity and are compatible with living tissue under many circumstances due to their native structure, which is a significant advantage when considering clinical applications. Biodegradability and predictable metabolic fate also reduce the probability of unexpected adverse reactions. Furthermore, chemical derivatives with modified structures are now also important. An example of modern medicines developed from traditional remedies is Krestin, a β-glucan polysaccharide extract from the mushroom *Trametes (Coriolus) versicolor*. It is a T-cell proliferation stimulator approved as a prescription drug for cancer therapy in Japan in 1977 and is currently used as adjuvant therapy for cancer.

Another important example is heparin, an anionic sulfated glycos-
aminoglycan discovered as an anti-coagulant in the 20th century. It is
isolated from porcine and bovine internal organs and has been widely
used since the 1930s. It binds to anti-thrombin III and induces a
conformation change increasing greatly its affinity to active blood
coagulation factors, particularly factor Xa and thrombin. Heparin is used
to prevent thrombotic events and is included in the World Health Or-
ganization list of essential medicines (WHO, 2023). In general, the
polysaccharide sequence regarding (i) types of monosaccharide units,
(ii) pattern of glycosidic linkages, and (iii) the regioselective function-
alization with sulfate and carboxylic groups plays an important role for
the functional activity of glycosaminoglycans like chondroitin sulfate,
dermatan sulfate, heparane sulfate, and heparin (Köwitsch, Zhou, &
Groth, 2018). Analysing these sequences and their unique biological
structure-property-relationships poses major challenges to poly-
saccharide analytics and chemistry. As an example, the therapeutic ac-
tion of heparin is related to a pentasaccharide sequence that is

characterised by a specific sulfation pattern with presence of *O*-sulfo-
nates and carboxylates with a repetitive sequence of 2-*O*-sulfated idur-
onic acid linked to a 6-*O*-sulfated glucosamine (Mohamed & Coombe,
2017). It has also been found that 3-*O*-sulfation of glucosamine is
essential for the anti-Xa activity of the pentasaccharide (Nahain, Ignja-
tovic, Monagle, Tsanaktsidis, & Ferro, 2018).

Unfractionated heparin is associated with serious side effects such as bleeding, thrombocytopenia, and others, which is also related to the binding of unfractionated heparin to many other plasma proteins. In addition, it has a very short half-life of less than 1 h. Nowadays, depo-lymerised low molecular weight versions are preferred, and different synthetic and chemically modified oligosaccharides like Fondaparinux and Idraparinux have also been introduced as heparin analogues. Fon-daparinux represents a pentasaccharide, which is a methylglycoside analogue of the natural anti-thrombin III binding pentasaccharide sequence. The methylation reduces the non-specific binding to other plasma proteins. It has longer half-life than low molecular weight hep-arins and does not induce thrombopenia. Idraparinux is a hyper-methylated derivative of Fondaparinux with an extended half-life. Whereas daily administrations are required for fondaparinux, a weekly subcutaneous administration of Idraparinux is sufficient to maintain a therapeutic effect. A disadvantage of these heparin analogues is that protamine cannot be used to neutralize their anti-coagulant activity like in the case of heparin. Hence, Idrabiotaparinux as a biotinylated de-rivative of Idraparinux represents a safer drug since avidin can be administered as an antidote when bleeding complications occur.

Chitosan (poly-β-1-4 D-glucosamine) is a cationic polymer that has an anti-microbial effect and can be used to induce coagulation. These properties have been utilised in dressing, such as HemCon®, to stop bleedings and for wound treatment. Chitosan can also stimulate tissue regeneration and has been used in bone cement and tissue engineering scaffolds. Moreover, chitosan and its derivatives have been used to promote tight junction opening in drug delivery applications and as an adjuvant for vaccines.

Acarbose is a tetrameric pseudo-oligosaccharide that inhibits inte-
tinal alpha-glucosidase. It is an anti-diabetic drug used to reduce glucose
uptake and lower blood glucose levels. Sugammadex is a γ-cyclodextrin
(cyclooctaamylose) derivative introduced as a drug to reverse the effect
of the steroidal neuromuscular blockers rocuronium and vecuronium,
which are medications used as muscle relaxants in major surgery.
Sugammadex forms a 1:1 inclusion complex with these neuromuscular
blockers and is used in an emergency to reverse life-threatening respi-
ratory suppression and aid recovery following surgery. Other cyclo-
dextrin derivatives, such as hydroxypropyl β-cyclodextrin and sulfobutyl
β-cyclodextrin, have also been introduced as complexing excipients used
to stabilise, solubilise, and aid the dissolution of lipophilic drugs. These
cyclodextrin derivatives have been included in drug formulations
approved for oral, ocular, intramuscular, and intravenous applications.

Notwithstanding the long history of polysaccharide use in medicine and the recent introduction of synthetic and semi-synthetic oligosaccharide drugs, there are considerable challenges that need to be overcome to reach the true therapeutic potential for this class of molecules. Advances in our understanding of their role in inter- and intracellular communication, interaction with other biomolecules, and receptor binding are needed. This especially applies to their role in modulating immune responses. Improved knowledge could contribute to the development of therapeutic polysaccharides, including new vaccines and treatments for autoimmune diseases and cancer investigations to determine the structure-activity-relationship is a vital part of the discovery and development of synthetic and semi-synthetic drugs. Such studies are very challenging for complex polysaccharide conjugates and derivatives. Natural polysaccharides are a mixture of structural isomers with different molecular weights, side-chain distribution, and structure. Chemical modification leads to further increased structural variation between individual polymer chains. Chemical analysis can be very challenging to fully characterise and define all aspects of this structural
complexity. This is also a significant issue for manufacturing under *Good Manufacturing Practice* and standardisation of polysaccharides as therapeutic substances. Efficient delivery is also an issue. Polysaccharides are hydrophilic macromolecules that cannot be absorbed intact from the gastrointestinal tract or through the skin. Thus, systemic administration or the utilisation of advanced delivery systems, such as nanoparticles and liposomes, may be needed to reach drug targets in the body.

### 5.1.2. Expected achievements and developments in the next 20 years

Modified polysaccharides such as hydroxypropyl methyl cellulose, methyl cellulose, and carboxymethyl cellulose are widely used as excipients in oral and topical drugs as fillers, dissolution enhancers, thickeners, and coating materials. Hydroxypropyl methyl cellulose is also used for therapeutic action in artificial tear formulation. These derivatives are generally considered safe and lack toxicity also in subcutaneous and intravenous administration. Additionally, they are widely used in cosmetics, including skincare and haircare products. Thus, it is well established that polysaccharide derivatives can be safely used in medicine.

Polysaccharides are generally recognised as safe for human use. Many polysaccharides are hydrolysed by enzymatic action to form mono- or oligosaccharides identical to endogenous carbohydrates in the body. Therefore, the formation of toxic metabolites, which need to be considered for other non-biological drugs, is unlikely. Chemically modified polysaccharides are, in general, not absorbed after oral intake and will be excreted intact in faeces. Parenterally administered oligosaccharides, polysaccharides, and their derivatives are thought to be eliminated mainly by renal secretion.

Investigations to explore the therapeutic potential of natural polysaccharides will continue. These will especially focus on immunomodulatory substances for treating cancer, inflammation, and other diseases. The use of polysaccharides and polysaccharide-based material to stimulate tissue regeneration is a strong focus in biomaterial research and cosmetics. In this context, the clearance of polysaccharides from the human body must be discussed. Some polysaccharides like chitosan, dextran, and amylose are degraded enzymatically within the human body. Others like cellulose are more stable due to the lack of the corresponding degrading enzymes (e.g., cellulases) and have to either remain within the body or are cleared by other mechanisms such as oxidative degradation.

The development of biologically active chemically modified carbohydrates is only starting, with a few approved drugs in current use. Further advances in carbohydrate chemistry will allow more efficient synthesis and selective modification. Detailed structure characterisation will help to realise the full potential of synthetic and chemically modified oligo- and polysaccharides as active pharmaceutical ingredients.

Nanoparticles based on polysaccharides are promising for therapeutic application. The inherent biocompatibility and biodegradability of polysaccharides such as chitosan, hyaluronate, and alginate can thus be exploited to improve the delivery of drugs. In addition to serving as the core material for the polymeric matrix of the particles, these bio-polymers can be chemically modified to introduce receptor ligands to target specific cell types.

### 5.1.3. Required research activities

Studies in vitro and in vivo are necessary to better understand the role of polysaccharides in the communication between cells, cell adhesion, and guiding the protein binding. Further development of selective chemical and enzymatic modifications are needed to precisely tailor the structure of polysaccharide derivatives and conjugates with drugs, peptides, proteins, and other bioactive moieties. Investigations to improve the efficiency and precision of analytical techniques such as NMR and SEC-MALLS are needed. This should also include more advanced techniques such as cryo-electron microscopy and ToF secondary ion MS. Pharmacokinetic studies to determine absorption, distribution, metabolism, and excretion of modified polysaccharides.

Progress in these investigations should aid detailed studies into the structure-activity-relationship and optimise the therapeutic effect. The development of improved delivery systems and efficient manufacturing technologies will also be needed.

## 5.2. Cosmetics

### 5.2.1. Current challenges

Polysaccharides, monosaccharides (special sugars) and derivatives thereof (e.g., polyols, carbohydrate-based emulsifiers and surfactants) are largely used in cosmetics as functional and active ingredients. Functional polysaccharides usually control physicochemical properties of formulations acting as gelling agents, viscosity adjusters, thickeners, emulsifiers, conditioners, film formers, and suspension agents. Different ionic (anionic, cationic, amphoteric) polysaccharides (e.g., xanthan, polyglucan derivatives, chitosan or carboxymethyl chitosan, inulin, cellulose, and starch derivatives) and non-ionic polysaccharides (e.g., starch, guar gum, and cellulose ethers) are used in this context. Active polysaccharides give skin hydrating, anti-oxidant, and anti-bacterial properties to cosmetic formulations. These include a multitude of biopolymers, such as cellulose and starch derivatives, pectin, gum, mucilage, seaweed and botanical polysaccharides as well as microbial and animal polysaccharides (Kanlayavattanakul & Lourith, 2015). Application-related properties of polysaccharides involve performance, product sensory, and product stability of cosmetics (Alves et al., 2020).

Product performance concerns the intended function of the end-product, which may, among others, cover moisturising, providing skin protection and cleansing. There exist polysaccharide-based humectants that aid in retaining moisture in films. Other polysaccharides like carboxymethyl β-glucan provide additional health benefits: the polymer assists in protecting and repairing the skin. Its revitalising effects are exploited in anti-aging products, while its protective function can be applied in sunscreen. Hyaluronic acid is a polysaccharide with nourishing and rejuvenating properties that keeps the skin supple and elastic. To support removing grease, grime, and dirt, the emulsifying and dispersant aspects of polysaccharides are highly valued. Alternatively, these polymers may support the incorporation of poorly soluble ingredients into the formulation. Methyl cellulose and carboxymethyl cellulose can be exploited for this purpose. Besides skin products, polysaccharides even play an active role in hair products. Polyquaternium-10, a polymeric quaternary ammonium salt of hydroxyethyl cellulose provides shine, radiance and mends the split ends of hair. Cationic inulin or guar can also be used as conditioners in shampoo.

Product sensory feeling describes the experience when applying the products. It covers thickness, viscosity, and smear-ability, as well as more complex sensational concepts as satiny or smooth feeling, cooling or relaxing effects, creaminess, and smoothness. Carboxymethyl cellulose, guar, and xanthan gum provide thickness to formulations, even when present in small concentrations. Hydroxyethyl cellulose assists in evenly spreading the product; it further boosts the feeling of creaminess in foams and a smooth texture to creams. Hydroxypropyl starch phosphate addition in cosmetics grants smoothness and provides the end-product with a satiny, velvety note. Sodium alginate is a well-known thickener but further applies a soothing and softening effect to the skin. Cellulose microfibres can be used as thickeners and help to suspend particles (for example, encapsulated perfumes).

Another relevant aspect is the product stability. Within product stability, different functions are covered: from binders, emulsifiers, and dispersants to surfactants. Binders provide cohesion in solid cosmetic products. Methyl cellulose and pectins both display this property. Emulsifiers aid in dispersing oil in water, while stabilisers are added to prevent unmixing of the emulsion or to prevent particle settling in suspensions. Methyl cellulose is a good stabiliser for emulsion and foams. It also coats particles preventing their agglomeration. Other frequently exploited stabilisers include hydroxyethyl cellulose and
complexity. This is also a significant issue for manufacturing under *Good Manufacturing Practice* and standardisation of polysaccharides as therapeutic substances. Efficient delivery is also an issue. Polysaccharides are hydrophilic macromolecules that cannot be absorbed intact from the gastrointestinal tract or through the skin. Thus, systemic administration or the utilisation of advanced delivery systems, such as nanoparticles and liposomes, may be needed to reach drug targets in the body.

### 5.1.2. Expected achievements and developments in the next 20 years

Modified polysaccharides such as hydroxypropyl methyl cellulose, methyl cellulose, and carboxymethyl cellulose are widely used as excipients in oral and topical drugs as fillers, dissolution enhancers, thickeners, and coating materials. Hydroxypropyl methyl cellulose is also used for therapeutic action in artificial tear formulation. These derivatives are generally considered safe and lack toxicity also in subcutaneous and intravenous administration. Additionally, they are widely used in cosmetics, including skincare and haircare products. Thus, it is well established that polysaccharide derivatives can be safely used in medicine.

Polysaccharides are generally recognised as safe for human use. Many polysaccharides are hydrolysed by enzymatic action to form mono- or oligosaccharides identical to endogenous carbohydrates in the body. Therefore, the formation of toxic metabolites, which need to be considered for other non-biological drugs, is unlikely. Chemically modified polysaccharides are, in general, not absorbed after oral intake and will be excreted intact in faeces. Parenterally administered oligosaccharides, polysaccharides, and their derivatives are thought to be eliminated mainly by renal secretion.

Investigations to explore the therapeutic potential of natural polysaccharides will continue. These will especially focus on immunomodulatory substances for treating cancer, inflammation, and other diseases. The use of polysaccharides and polysaccharide-based material to stimulate tissue regeneration is a strong focus in biomaterial research and cosmetics. In this context, the clearance of polysaccharides from the human body must be discussed. Some polysaccharides like chitosan, dextran, and amylose are degraded enzymatically within the human body. Others like cellulose are more stable due to the lack of the corresponding degrading enzymes (e.g., cellulases) and have to either remain within the body or are cleared by other mechanisms such as oxidative degradation.

The development of biologically active chemically modified carbohydrates is only starting, with a few approved drugs in current use. Further advances in carbohydrate chemistry will allow more efficient synthesis and selective modification. Detailed structure characterisation will help to realise the full potential of synthetic and chemically modified oligo- and polysaccharides as active pharmaceutical ingredients.

Nanoparticles based on polysaccharides are promising for therapeutic application. The inherent biocompatibility and biodegradability of polysaccharides such as chitosan, hyaluronate, and alginate can thus be exploited to improve the delivery of drugs. In addition to serving as the core material for the polymeric matrix of the particles, these bio-polymers can be chemically modified to introduce receptor ligands to target specific cell types.

### 5.1.3. Required research activities

Studies *in vitro* and *in vivo* are necessary to better understand the role of polysaccharides in the communication between cells, cell adhesion, and guiding the protein binding. Further development of selective chemical and enzymatic modifications are needed to precisely tailor the structure of polysaccharide derivatives and conjugates with drugs, peptides, proteins, and other bioactive moieties. Investigations to improve the efficiency and precision of analytical techniques such as NMR and SEC-MALLS are needed. This should also include more advanced techniques such as cryo-electron microscopy and ToF secondary ion MS. Pharmacokinetic studies to determine absorption, distribution, metabolism, and excretion of modified polysaccharides.

Progress in these investigations should aid detailed studies into the structure-activity-relationship and optimise the therapeutic effect. The development of improved delivery systems and efficient manufacturing technologies will also be needed.

## 5.2. Cosmetics

### 5.2.1. Current challenges

Polysaccharides, monosaccharides (special sugars) and derivatives thereof (e.g., polyols, carbohydrate-based emulsifiers and surfactants) are largely used in cosmetics as functional and active ingredients. Functional polysaccharides usually control physicochemical properties of formulations acting as gelling agents, viscosity adjusters, thickeners, emulsifiers, conditioners, film formers, and suspension agents. Different ionic (anionic, cationic, amphoteric) polysaccharides (e.g., xanthan, polyglucan derivatives, chitosan or carboxymethyl chitosan, inulin, cellulose, and starch derivatives) and non-ionic polysaccharides (e.g., starch, guar gum, and cellulose ethers) are used in this context. Active polysaccharides give skin hydrating, anti-oxidant, and anti-bacterial properties to cosmetic formulations. These include a multitude of biopolymers, such as cellulose and starch derivatives, pectin, gum, mucilage, seaweed and botanical polysaccharides as well as microbial and animal polysaccharides (Kanlayavattanakul & Lourith, 2015). Application-related properties of polysaccharides involve performance, product sensory, and product stability of cosmetics (Alves et al., 2020).

Product performance concerns the intended function of the end-product, which may, among others, cover moisturising, providing skin protection and cleansing. There exist polysaccharide-based humectants that aid in retaining moisture in films. Other polysaccharides like carboxymethyl β-glucan provide additional health benefits: the polymer assists in protecting and repairing the skin. Its revitalising effects are exploited in anti-aging products, while its protective function can be applied in sunscreen. Hyaluronic acid is a polysaccharide with nourishing and rejuvenating properties that keeps the skin supple and elastic. To support removing grease, grime, and dirt, the emulsifying and dispersant aspects of polysaccharides are highly valued. Alternatively, these polymers may support the incorporation of poorly soluble ingredients into the formulation. Methyl cellulose and carboxymethyl cellulose can be exploited for this purpose. Besides skin products, polysaccharides even play an active role in hair products. Polyquaternium-10, a polymeric quaternary ammonium salt of hydroxyethyl cellulose provides shine, radiance and mends the split ends of hair. Cationic inulin or guar can also be used as conditioners in shampoo.

Product sensory feeling describes the experience when applying the products. It covers thickness, viscosity, and smear-ability, as well as more complex sensational concepts as satiny or smooth feeling, cooling or relaxing effects, creaminess, and smoothness. Carboxymethyl cellulose, guar, and xanthan gum provide thickness to formulations, even when present in small concentrations. Hydroxyethyl cellulose assists in evenly spreading the product; it further boosts the feeling of creaminess in foams and a smooth texture to creams. Hydroxypropyl starch phosphate addition in cosmetics grants smoothness and provides the end-product with a satiny, velvety note. Sodium alginate is a well-known thickener but further applies a soothing and softening effect to the skin. Cellulose microfibres can be used as thickeners and help to suspend particles (for example, encapsulated perfumes).

Another relevant aspect is the product stability. Within product stability, different functions are covered: from binders, emulsifiers, and dispersants to surfactants. Binders provide cohesion in solid cosmetic products. Methyl cellulose and pectins both display this property. Emulsifiers aid in dispersing oil in water, while stabilisers are added to prevent unmixing of the emulsion or to prevent particle settling in suspensions. Methyl cellulose is a good stabiliser for emulsion and foams. It also coats particles preventing their agglomeration. Other frequently exploited stabilisers include hydroxyethyl cellulose and
alginates.

The limited accessibility of many natural polysaccharides in large quantities and the numerous functionalisation techniques (that frequently demand the use of hazardous materials) have hampered their full potential in cosmetics. For these reasons, research expanded in three different directions to broaden the variety and availability of functional polysaccharides and materials. (I) Polysaccharide production in previously unexplored species is continuously being studied, which includes a characterisation of the properties of the biopolymers obtained by these new routes. Advancements in genetic engineering in bacteria and fungi have further widened the assortment of highly engineered polysaccharides. (II) The expansion of green chemistry principles in the context of chemical functionalisation of polysaccharides will proceed even further. The use of irritating or toxic components in the fabrication of multifunctional polysaccharide compounds will diminish in favour of greener and less toxic alternatives. Less unwanted side-products and energy consumption will be the outcome of the ever-increasing appearance of highly selective catalysts and the use of highly engineered enzymes. (III) The processing and shaping of polysaccharide-based materials in cosmetics will also see a shift towards using new technologies that are less harmful and less energy consuming.

### 5.2.2. Expected achievements and developments in the next 20 years

Polysaccharides have a promising future in cosmetics because of their multifunctional capabilities (abilities to combine both functional and active properties in one component, for example). Multifunctionalisation of polysaccharides can be achieved via chemical and enzymatic methods and via biotechnological routes for biofabrication of these biopolymers. Another relevant capability is the shape of polysaccharide materials such as capsules, particles, spheres, fibres, and films. The combination of multifunctionalities alongside shaping technology has a promising future to create highly engineered shapes suitable for unique product performance and sensory properties.

Future trends of polysaccharides in cosmetics involve a combination of cosmetic and pharmaceutical properties of polysaccharides, including new methods for encapsulation and stimuli-responsive delivery of active compounds and new formulation technologies for skin moisturisation and repair incorporating biological ingredients and nanotechnology. These trends target to enhance skin hydrating efficiency and protection, treat wrinkles, and provide anti-aging properties. Future business opportunities will be based on skin performance (helping with moisturisation/preventing de-moisturisation), skin sensory (the signal that you are doing something good to your skin), product sensory (the right thickness, viscosity, smear-ability of the product), product stability (including anti-bacterial activity) and opportunity for claims (e.g., attractive terms such as *naturally derived* and *nature provided ingredients*).

### 5.2.3. Required research activities

New technologies for sustainable production of polysaccharides, polysaccharide derivatives, and functional shapes need to be developed that include, among other things, the following aspects:

- extraction, purification, and biofabrication of polysaccharides with a focus on green chemistry principles and (bio)engineering, recycling and circularity of materials, as well as sustainable sourcing from marine and agricultural side streams

- functionalisation methods focussed on sustainable chemistry, highly engineered enzymes, solvent-free media, cell factories, and self-assembly

- design and fabrication of functional shapes with highly controlled properties (including size, shape, surface morphology, hierarchical structures, and colloidal features)

- removal of additives with potential harm to human health from the bioactive products (e.g., dysbiosis inducers and hormone-mimicking chemicals)

- fast and accurate high-throughput analytical characterisation techniques for comprehensive analyses of macromolecular properties of functional polysaccharides (preferably for multiple parameters at the same time)

- advanced methods that combine imaging and information on chemical composition (e.g., chemical microscopy)

- new methods for modelling and simulation of structure-property-relationships

## 5.3. Drug delivery and nanomedicine

### 5.3.1. Current challenges

Ever since humanity made the first attempts to fight diseases and life adverse cases, many remedies have been prepared by mixing natural components, including polysaccharides. The latter was occasionally the active components, but even more frequently, they were present as support - *excipients* - added intentionally or naturally occurring in the preparations. Over time and with the evolution of medicinal products towards more scientifically sound compositions, the role of polysaccharides evolved, and, especially in the last 150 years, polysaccharides have found rational use. In particular, the evolution of polysaccharide chemistry has allowed the creation of materials with increasingly tailored functions, aiming for the improvement of drug performances intended both for therapeutic efficacy and technological processability. It is well-known that polysaccharides and their derivatives play a decisive role in pharmaceutical formulations, carrying out multiple roles and functions. In the so-called conventional pharmaceutical preparations, biopolymers like cellulose, starch, and the various gums, to mention the most used polymer systems and their uncountable derivatives, act as fillers, aggregating or disaggregating agents, film-formers, rheological property modifiers, support materials, or adjuvants, to name the most important activities. In this sense, scientific and technological evolution has made it possible to find adequate solutions to pharmaceutical needs, working appropriately such as the characteristics of the primary structure, the molecular weight, and the backbone derivatisation with specific moieties (e.g., hydrophobic or ionisable) to confer new properties (e.g., solubility, gel-forming, rapid disaggregation, and film-forming).

Another pharmaceutical area in which polysaccharides play an important role and can find an interesting and profitable development in the coming years can be found in those systems collectively named *drug delivery systems*. These are formulations specifically designed to modulate the release of active ingredients, both in time (continuously, shot like, or modulated profiles) and in space (i.e., targeted body area such as organs, cells, and subcellular level of specific tissue) in order to maximise the effectiveness of the active pharmaceutical ingredient itself or to minimise side effects, generally associated to the specific toxic effect of conventional drug delivery. The so-called Paul Ehrlich's *magic bullet* concept is the approach underlying this pharmaceutical area, and nanomedicine adheres to this concept more closely than other delivery systems.

### 5.3.2. Expected achievements and developments in the next 20 years

There is no doubt that the technological level reached by now for the so-called *conventional formulations* is very high, and it can be considered mature. Moreover, the introduction of a new polysaccharide-based material, considering the complexity of the current regulations, would find its justification in a significant improvement in pharmaceutical performance. In this sense, a push forward in which polysaccharides could play a significant role replacing the fossil-based polymers currently used, or developing new formulations with advanced therapeutic or processing performances can be given taking into account their good compatibility in biological environment, beneficial physical properties (e.g., high T<sub>g</sub>), ease of derivatisation (e.g., possibility to induce pH-responsive properties), and the abundance of the starting material, low ecological impact in production, and inertia in carrying
alginates.

The limited accessibility of many natural polysaccharides in large quantities and the numerous functionalisation techniques (that frequently demand the use of hazardous materials) have hampered their full potential in cosmetics. For these reasons, research expanded in three different directions to broaden the variety and availability of functional polysaccharides and materials. (I) Polysaccharide production in previously unexplored species is continuously being studied, which includes a characterisation of the properties of the biopolymers obtained by these new routes. Advancements in genetic engineering in bacteria and fungi have further widened the assortment of highly engineered polysaccharides. (II) The expansion of green chemistry principles in the context of chemical functionalisation of polysaccharides will proceed even further. The use of irritating or toxic components in the fabrication of multifunctional polysaccharide compounds will diminish in favour of greener and less toxic alternatives. Less unwanted side-products and energy consumption will be the outcome of the ever-increasing appearance of highly selective catalysts and the use of highly engineered enzymes. (III) The processing and shaping of polysaccharide-based materials in cosmetics will also see a shift towards using new technologies that are less harmful and less energy consuming.

### 5.2.2. Expected achievements and developments in the next 20 years

Polysaccharides have a promising future in cosmetics because of their multifunctional capabilities (abilities to combine both functional and active properties in one component, for example). Multifunctionalisation of polysaccharides can be achieved via chemical and enzymatic methods and via biotechnological routes for biofabrication of these biopolymers. Another relevant capability is the shape of polysaccharide materials such as capsules, particles, spheres, fibres, and films. The combination of multifunctionalities alongside shaping technology has a promising future to create highly engineered shapes suitable for unique product performance and sensory properties.

Future trends of polysaccharides in cosmetics involve a combination of cosmetic and pharmaceutical properties of polysaccharides, including new methods for encapsulation and stimuli-responsive delivery of active compounds and new formulation technologies for skin moisturisation and repair incorporating biological ingredients and nanotechnology. These trends target to enhance skin hydrating efficiency and protection, treat wrinkles, and provide anti-aging properties. Future business opportunities will be based on skin performance (helping with moisturisation/preventing de-moisturisation), skin sensory (the signal that you are doing something good to your skin), product sensory (the right thickness, viscosity, smear-ability of the product), product stability (including anti-bacterial activity) and opportunity for claims (e.g., attractive terms such as *naturally derived* and *nature provided ingredients*).

### 5.2.3. Required research activities

New technologies for sustainable production of polysaccharides, polysaccharide derivatives, and functional shapes need to be developed that include, among other things, the following aspects:

- extraction, purification, and biofabrication of polysaccharides with a focus on green chemistry principles and (bio)engineering, recycling and circularity of materials, as well as sustainable sourcing from marine and agricultural side streams

- functionalisation methods focussed on sustainable chemistry, highly engineered enzymes, solvent-free media, cell factories, and self-assembly

- design and fabrication of functional shapes with highly controlled properties (including size, shape, surface morphology, hierarchical structures, and colloidal features)

- removal of additives with potential harm to human health from the bioactive products (e.g., dysbiosis inducers and hormone-mimicking chemicals)

- fast and accurate high-throughput analytical characterisation techniques for comprehensive analyses of macromolecular properties of functional polysaccharides (preferably for multiple parameters at the same time)

- advanced methods that combine imaging and information on chemical composition (e.g., chemical microscopy)

- new methods for modelling and simulation of structure-property-relationships

## 5.3. Drug delivery and nanomedicine

### 5.3.1. Current challenges

Ever since humanity made the first attempts to fight diseases and life adverse cases, many remedies have been prepared by mixing natural components, including polysaccharides. The latter was occasionally the active components, but even more frequently, they were present as support - *excipients* - added intentionally or naturally occurring in the preparations. Over time and with the evolution of medicinal products towards more scientifically sound compositions, the role of polysaccharides evolved, and, especially in the last 150 years, polysaccharides have found rational use. In particular, the evolution of polysaccharide chemistry has allowed the creation of materials with increasingly tailored functions, aiming for the improvement of drug performances intended both for therapeutic efficacy and technological processability. It is well-known that polysaccharides and their derivatives play a decisive role in pharmaceutical formulations, carrying out multiple roles and functions. In the so-called conventional pharmaceutical preparations, biopolymers like cellulose, starch, and the various gums, to mention the most used polymer systems and their uncountable derivatives, act as fillers, aggregating or disaggregating agents, film-formers, rheological property modifiers, support materials, or adjuvants, to name the most important activities. In this sense, scientific and technological evolution has made it possible to find adequate solutions to pharmaceutical needs, working appropriately such as the characteristics of the primary structure, the molecular weight, and the backbone derivatisation with specific moieties (e.g., hydrophobic or ionisable) to confer new properties (e.g., solubility, gel-forming, rapid disaggregation, and film-forming).

Another pharmaceutical area in which polysaccharides play an important role and can find an interesting and profitable development in the coming years can be found in those systems collectively named *drug delivery systems*. These are formulations specifically designed to modulate the release of active ingredients, both in time (continuously, shot like, or modulated profiles) and in space (i.e., targeted body area such as organs, cells, and subcellular level of specific tissue) in order to maximise the effectiveness of the active pharmaceutical ingredient itself or to minimise side effects, generally associated to the specific toxic effect of conventional drug delivery. The so-called Paul Ehrlich's *magic bullet* concept is the approach underlying this pharmaceutical area, and nanomedicine adheres to this concept more closely than other delivery systems.

### 5.3.2. Expected achievements and developments in the next 20 years

There is no doubt that the technological level reached by now for the so-called *conventional formulations* is very high, and it can be considered mature. Moreover, the introduction of a new polysaccharide-based material, considering the complexity of the current regulations, would find its justification in a significant improvement in pharmaceutical performance. In this sense, a push forward in which polysaccharides could play a significant role replacing the fossil-based polymers currently used, or developing new formulations with advanced therapeutic or processing performances can be given taking into account their good compatibility in biological environment, beneficial physical properties (e.g., high T<sub>g</sub>), ease of derivatisation (e.g., possibility to induce pH-responsive properties), and the abundance of the starting material, low ecological impact in production, and inertia in carrying
drugs (Laffleur & Keckeis, 2020; Pooresmaeil & Namazi, 2021; Tomás, Palmeira-de-Oliveira, Simões, Martinez-de-Oliveira, & Palmeira-de-Oliveira, 2020).

A lot of drug delivery systems based on polysaccharides have been developed over the last 30 years in various therapeutic fields from the ocular to the intestinal, for inflammation, anti-microbial activity, and tumour therapy (Cui, Zhang, & Liu, 2021; Delshadi, Bahrami, McClements, Moore, & Williams, 2021; Dubashynskaya, Poshina, Raik, Urtti, & Skorik, 2020; Khatun, Toth, & Stephenson, 2020; Layek & Mandal, 2020; Mašková et al., 2020; Tomás et al., 2020). However, research to explore new opportunities in this field is not sufficiently boosted; to do this, a propulsive thrust is needed. First, new polysaccharides or oligosaccharides of different origins should be sought to exploit innovative properties, both as biocompatible and as *smart materials* with new properties, such as gelling, stimuli-responsive, mucoadhesive, cell- or organ targeting. At the same time, new chemistries capable of obtaining derivatives with smart properties should be developed.

A green and biocompatible chemistry approach could be very interesting in order to combine both problems of reducing the impact on health and safeguarding the environment. For sure, the quantities of materials involved in the creation of drug delivery systems are not comparable to the amount of polymer material involved in the production of commodities, but, inevitably, companies developing new products are very sensitive to these problems, even just for the regulations. Moreover, ecofriendly and biocompatible chemistries, as well as production processes, are more appealing from an industrial point of view. Any system to be marketed depends on the budget of the realization costs (very high in the case of non-bio and non-eco systems) and of the revenues (related to the selling price of the drug, in turn, linked to the benefits obtainable in terms of therapeutic efficacy and any reimbursement by the national healthcare systems).

Throughout this story, nanomedicine must be considered as the most promising field. At present, polysaccharides are little used when compared to their vast potential. This is mostly due to the fact that fossil-based polymers are more easily manageable in terms of tailoring. For these reasons, both the culture of polysaccharide and the promotion of the study of their properties and their use must be improved, considering that, compared to fossil-based polymers, they generally show better biocompatibility. We must go in the direction of promoting new polysaccharides that support and replace the most studied and used polymers. Hyaluronic acid, for example, is undoubtedly the first-choice polymer for its properties. Other polysaccharides can open new possibilities in terms of the realization of new nanomedicines and improved therapeutic performances. As already mentioned in the introduction of the EPNOE Research Roadmap, the next decades will require carbon footprint reduction and improved sustainability in all sectors, including pharma activities. Innovations in pharma research and industry typically take 10 years or longer to reach application in patients, and therefore offering sustainable solutions at early stages of product development is an urgent requirement. Polysaccharides have many competitive advantages to improve sustainability in pharma by replacing persistent fossil-based polymers and actives with bioactive and biodegradable alternatives.

### 5.3.3. Required research activities

The research in the next few years can be divided into two different development lines. For the conventional formulations, the research should be finalised to develop polysaccharide derivatives in order to improve both the production of the conventional formulation, such as tablets, capsules, solutions, suspensions, films, creams and gels, and increasing the drug bioavailability and the specificity of the formulations, tailoring interaction with the human body, including mucoadhesion, drug permeation through the biological membranes, and responsiveness to physiological conditions. In this respect, the innovation should target new polysaccharide derivatives, obtained by different routes, for:

- continuous manufacturing processes for the preparation of the pharmaceutical dosage forms

- personalised medicine in terms of new materials for new processes, such as medicine on demand, realised ad hoc for a specific patient

- improvement of some conventional pharmaceutical dosage forms (e. g., as parenteral, drug depot, gels, and patches)

- improvement of the drug activity (e.g., anti-microbial or stimulating immune system response)

In terms of synthesis, the innovation for polysaccharides in drug delivery systems should target:

- new biocompatible and green chemistry, thus widening the possibility to modulate the physicochemical properties in acceptable processes from the industrial point of view

- new materials for new nano- and micro-particulate platforms

- new targeting agents for organs by a recognition system based on the physiological conditions

- new targeting agents for specific receptors expressed or overexpressed on cells

- new approaches for improving the bioavailability of incorporated drugs

- new suitable materials as transfecting agents in subcellular targeting

- intelligent carrier for drugs (systems responsive to physiological conditions related to specific diseases)

- carriers that are able to modify the fate of drugs, thus renewing the life of old drugs (e.g., enhancing the activity of anti-microbial drugs to fight the new emergency in anti-biotic resistance)

- theranostic applications

It is reasonable to approach the above-depicted program with a double-step comprehensive strategy. The first topics should be studied and developed in the first phase, as they need more fundamental research, whereas the other points can be approached soon after, once the basic science reaches significant results, allowing the researchers to target specific goals by using new efficient tools.

## 5.4. Biomedical devices

### 5.4.1. Current challenges

Biomedical devices comprise extracorporeal artificial organs, such as cardio-pulmonary bypasses and artificial lungs (extracorporeal membrane oxygenation) as well as devices used in haemodialysis and apheresis (for detoxification of blood). An integral part are the blood vessel endothelia that connect the vascular system of the patients with the artificial organs or special vascular access like an arterio-venous shunt. Implantable medical devices that support and replace organ functions comprise artificial heart valves, ventricular assist devices, cardiac pacemakers, stents, and artificial blood vessels. Furthermore, all kinds of intravenous and other catheters that are either in contact with blood or other tissues (e.g., urinary catheters) are more examples. On the other hand, there is a wide scale of hard and soft tissue implants that may be used temporarily to support the healing of tissues or to permanently re-establish or replace bone, joints, breast, and other soft tissue implants for medical and cosmetic reasons, but also materials for topical and other applications like sutures, wound dressings, periodontal membranes, tissue adhesives, haemostatic agents, and sensors. Finally, disposal materials, including syringes, packaging materials, medical gloves and masks as well as other protective equipment for patients and medical staff represent a significant part of biomedical devices (Bronzino & Peterson, 2015).

It must be underlined that polymeric materials play the most important role in the area of biomedical devices. A recent industrial review on the use of polymers states that the market for medical polymer products include medical fibres and resins (about 40 %), medical elastomers (about 15 %) and biodegradable medical plastics (Grand View
drugs (Laffleur & Keckeis, 2020; Pooresmaeil & Namazi, 2021; Tomás, Palmeira-de-Oliveira, Simões, Martinez-de-Oliveira, & Palmeira-de-Oliveira, 2020).

A lot of drug delivery systems based on polysaccharides have been
developed over the last 30 years in various therapeutic fields from the
ocular to the intestinal, for inflammation, anti-microbial activity, and
tumour therapy (Cui, Zhang, & Liu, 2021; Delshadi, Bahrami, McCle-
ments, Moore, & Williams, 2021; Dubashynskaya, Poshina, Raik, Urtti,
& Skorik, 2020; Khatun, Toth, & Stephenson, 2020; Layek & Mandal,
2020; Mašková et al., 2020; Tomás et al., 2020). However, research to
explore new opportunities in this field is not sufficiently boosted; to do
this, a propulsive thrust is needed. First, new polysaccharides or oligo-
saccharides of different origins should be sought to exploit innovative
properties, both as biocompatible and as *smart materials* with new
properties, such as gelling, stimuli-responsive, mucoadhesive, cell- or
organ targeting. At the same time, new chemistries capable of obtaining
derivatives with smart properties should be developed.

A green and biocompatible chemistry approach could be very
interesting in order to combine both problems of reducing the impact on
health and safeguarding the environment. For sure, the quantities of
materials involved in the creation of drug delivery systems are not
comparable to the amount of polymer material involved in the pro-
duction of commodities, but, inevitably, companies developing new
products are very sensitive to these problems, even just for the regula-
tions. Moreover, ecofriendly and biocompatible chemistries, as well as
production processes, are more appealing from an industrial point of
view. Any system to be marketed depends on the budget of the reali-
zation costs (very high in the case of non-bio and non-eco systems) and
of the revenues (related to the selling price of the drug, in turn, linked to
the benefits obtainable in terms of therapeutic efficacy and any reim-
bursement by the national healthcare systems).

Throughout this story, nanomedicine must be considered as the most
promising field. At present, polysaccharides are little used when
compared to their vast potential. This is mostly due to the fact that fossil-
based polymers are more easily manageable in terms of tailoring. For
these reasons, both the culture of polysaccharide and the promotion of
the study of their properties and their use must be improved, considering
that, compared to fossil-based polymers, they generally show better
biocompatibility. We must go in the direction of promoting new poly-
saccharides that support and replace the most studied and used poly-
mers. Hyaluronic acid, for example, is undoubtedly the first-choice
polymer for its properties. Other polysaccharides can open new possi-
bilities in terms of the realization of new nanomedicines and improved
therapeutic performances. As already mentioned in the introduction of
the EPNOE Research Roadmap, the next decades will require carbon
footprint reduction and improved sustainability in all sectors, including
pharma activities. Innovations in pharma research and industry typi-
cally take 10 years or longer to reach application in patients, and
therefore offering sustainable solutions at early stages of product
development is an urgent requirement. Polysaccharides have many
competitive advantages to improve sustainability in pharma by replac-
ing persistent fossil-based polymers and actives with bioactive and
biodegradable alternatives.

5.3.3. Required research activities

The research in the next few years can be divided into two different
development lines. For the conventional formulations, the research
should be finalised to develop polysaccharide derivatives in order to
improve both the production of the conventional formulation, such as
tablets, capsules, solutions, suspensions, films, creams and gels, and
increasing the drug bioavailability and the specificity of the formula-
tions, tailoring interaction with the human body, including mucoadhe-
sion, drug permeation through the biological membranes, and
responsiveness to physiological conditions. In this respect, the innova-
tion should target new polysaccharide derivatives, obtained by different
routes, for:

- continuous manufacturing processes for the preparation of the pharmaceutical dosage forms

- personalised medicine in terms of new materials for new processes, such as medicine on demand, realised ad hoc for a specific patient

- improvement of some conventional pharmaceutical dosage forms (e. g., as parenteral, drug depot, gels, and patches)

- improvement of the drug activity (e.g., anti-microbial or stimulating immune system response)

In terms of synthesis, the innovation for polysaccharides in drug
delivery systems should target:

- new biocompatible and green chemistry, thus widening the possibility to modulate the physicochemical properties in acceptable processes from the industrial point of view

- new materials for new nano- and micro-particulate platforms

- new targeting agents for organs by a recognition system based on the physiological conditions

- new targeting agents for specific receptors expressed or overex-pressed on cells

- new approaches for improving the bioavailability of incorporated drugs

- new suitable materials as transfecting agents in subcellular targeting

- intelligent carrier for drugs (systems responsive to physiological conditions related to specific diseases)

- carriers that are able to modify the fate of drugs, thus renewing the life of old drugs (e.g., enhancing the activity of anti-microbial drugs to fight the new emergency in anti-biotic resistance)

- theranostic applications

It is reasonable to approach the above-depicted program with a
double-step comprehensive strategy. The first topics should be studied
and developed in the first phase, as they need more fundamental
research, whereas the other points can be approached soon after, once
the basic science reaches significant results, allowing the researchers to
target specific goals by using new efficient tools.

5.4. *Biomedical devices*

5.4.1. Current challenges

Biomedical devices comprise extracorporeal artificial organs, such as
cardio-pulmonary bypasses and artificial lungs (extracorporeal mem-
brane oxygenation) as well as devices used in haemodialysis and
apheresis (for detoxification of blood). An integral part are the blood
vessel endothelia that connect the vascular system of the patients with
the artificial organs or special vascular access like an arterio-venous
shunt. Implantable medical devices that support and replace organ
functions comprise artificial heart valves, ventricular assist devices,
cardiac pacemakers, stents, and artificial blood vessels. Furthermore, all
kinds of intravenous and other catheters that are either in contact with
blood or other tissues (e.g., urinary catheters) are more examples. On the
other hand, there is a wide scale of hard and soft tissue implants that
may be used temporarily to support the healing of tissues or to perma-
nently re-establish or replace bone, joints, breast, and other soft tissue
implants for medical and cosmetic reasons, but also materials for topical
and other applications like sutures, wound dressings, periodontal
membranes, tissue adhesives, haemostatic agents, and sensors. Finally,
disposal materials, including syringes, packaging materials, medical
gloves and masks as well as other protective equipment for patients and
medical staff represent a significant part of biomedical devices (Bron-
zino & Peterson, 2015).

It must be underlined that polymeric materials play the most
important role in the area of biomedical devices. A recent industrial
review on the use of polymers states that the market for medical polymer
products include medical fibres and resins (about 40 %), medical elas-
tomers (about 15 %) and biodegradable medical plastics (Grand View
Research, 2021). Fibres and resins include synthetic polyvinyl chloride, polypropylene, polyethylene, polystyrene, and other thermoplastics. However, biodegradable polymers that are mostly represented by polyesters used as suture materials take only a very small share of the global medical polymers market, which is smaller than 5%. The number of products that are using polysaccharides-based materials is rather limited regarding the kind of biomedical devices but also the quantities used. Considering the problem that most synthetic polymers are non-degradable and represent a potential threat to our environment, it will be highly desirable to increase the share of polymers, including polysaccharides, that are degradable and feature a tailored durability within their target application.

It is predicted that the global medical polymers market will reach a value of USD 27.75 billion by the end of 2028, which is due to the growing demand for medical and pharmaceutical packaging materials, especially flexible packaging for medicines, blood bags, surgical gloves, and medical drapes. In addition, the increasing application of medical polymers in hip and joint replacement as well as spinal and cranial implants will have a significant impact on the market growth (Grand View Research, 2021). The growing market for the application of polymers also highlights the need to look for further applications of polysaccharides in the field of medical devices to reduce the consumption of synthetic fossil-based polymers with their negative impact on our environment.

Cellulose was one of the first polysaccharides used as a membrane in blood purification. First commercial devices during clinical establishment were based on cellulose, which had problems related to biocompatibility, e.g., complement activation, leading to the development of modified cellulose like cellulose triacetate and a dominance of dialyser based on synthetic polymers, e.g., polysulfones (Togo, Yamamoto, Imai, Akiyama, & Yamashita, 2018). Haemostatic materials like films and powders are required during surgical procedures or after injuries to stop bleeding. Additionally, oxidised cellulose, chitosan, and starch are used in commercial products due to their properties in activating blood platelets and coagulation processes (Chen et al., 2020). Another medical problem that shall be tackled using polysaccharides is the prevention of postoperative adhesions that can occur after surgical interventions, for example, in the visceral surgery, avoiding adhesion of peritoneum or connective tissue to the gut (Moris et al., 2017). Here, the hydrophilic properties of polysaccharides are desired to avoid the attachment of cells. For example, starch powder (microparticles) or membranes made of a combination of hyaluronan and carboxymethyl chitosan have been found to be useful (Li et al., 2008).

Heparin is not only used for anti-coagulation of blood by intramuscular injection in patients. It is also used in anti-coagulant coatings of different biomedical devices, like components of extracorporeal circulation devices, blood pumps like ventricular assist devices, vascular grafts, and stents to avoid clot formation on the surface of the devices. This also reduces the need for the prescription of systemic anti-coagulation to patients with possible undesired side effects (Biran & Pond, 2017). Moreover, an insufficiently addressed medical problem is the replacement of the vitreous body of the eye. Here, the first products based on hyaluronan (a major component of the vitreous humour) are making some progress (Li et al., 2008). Hyaluronan is also used to develop membranes that can be applied to support the repair of tympanic membranes (Martini, Morra, Aimonì, & Radice, 2000).

Overall, polysaccharides, depending on their source and chemistry, have a very broad spectrum of bioactivity that is interesting for tackling different medical problems, as highlighted above. On the other hand, processing of polysaccharides into the desired shapes like fibres, films and membranes is still challenging and may require different physical and chemical processes. Some polysaccharides like cellulose and chitin have very poor solubility and require partly harsh conditions to process them. The oldest textile technology using cellulose, the viscose process, goes back to 1925, which can be used to produce fibres, but also films and other shapes (Shearer, 1925). However, this requires the application

of harsh conditions, including treatment of wood pulp using sodium hydroxide forming alkali cellulose, followed then by mixing with carbon disulfide to form cellulose xanthate, which is spun into a coagulation bath containing sulfuric acid and salts. During this process, the cellulose xanthate is transformed back into cellulose (Cook, 1984). However, this process is not environmentally friendly and has a high-water consumption too (Bredereck & Hermanutz, 2005). Now, ionic liquids also allow the extrusion of cellulose fibres, which makes the process of fibre spinning easier and more environmentally friendly (Vocht et al., 2021). However, most polysaccharides are water-soluble (e.g., alginate, hyaluronan) and require physical or chemical shaping processes, like electrospinning, freeze-drying, and chemical cross-linking, to engineer them into the desired form (e.g., fibres, films, membranes, and hydrogels).

### 5.4.2. Expected achievements and developments in the next 20 years

Properties of polysaccharides that make them interesting for future application in biomedical devices are not only related to their abundance and low price of raw materials but also their hydrophilic nature that enables them to bind water, which can reduce undesired adsorption of proteins and other body components like blood cells. Other important factors are the presence of functional groups for chemical modifications, and the inherent bioactivity of certain polysaccharides. Particularly, the latter is one of the most interesting aspects to increase their application in the field of biomedical devices. Polysaccharides, especially sulphated ones, have the potential to inhibit coagulation of blood. Heparin, as representative of glycosaminoglycans, has been known for a long time as a polysaccharide with anti-coagulant properties due to its binding to anti-thrombin III and inhibition of activated coagulation factors like thrombin (Mueller & Scheidt, 1994; Wieringa, Søndergaard, & Ash, 2021). However, cellulose sulfates and other sulfated polysaccharides have been shown to inhibit the coagulation system and could replace heparin in several applications (Groth & Wagenknecht, 2001; Mes techkina & Shcherbukhin, 2010). Also, material combinations made of chitosan and pectin demonstrated excellent blood compatibility when used for making vascular patches (Bombaldi de Souza et al., 2019).

Polysaccharides also have an adsorptive capacity to remove uremic and other toxins, immune globulins, cytokines that play a role in end-stage renal diseases, autoimmune diseases, leukemia, sepsis, and others. Removal of uremic toxins by adsorption on lignin-binder or polysaccharides from algae are some reported examples (Sandeman et al., 2017). Moreover, the removal of proteins like low-density lipoprotein from the blood of patients in hyperlipidemia by heparin-mediated extracorporeal low-density lipoprotein precipitation apheresis using heparin has been reported as well as the use of particles made of dextran sulfate immobilized onto cellulose for binding of cytokines such as tumour necrosis factor that plays a role in sepsis on particles made of activated cellulose (Jaeger, 2003; Weber et al., 2005). However, the full potential of polysaccharides for biomedical applications has not yet been reached, which requires investments in research and development of new products.

### 5.4.3. Required research activities

Heparin is an efficient anti-coagulant but must be isolated from animal sources, particularly the mucosa of the small intestine of pigs. This is a time-consuming process resulting in high variability of activity and risks of contaminations that can represent a threat to patients (Liu, Zhang, & Linhardt, 2009). Therefore, for clinical application as systemic anti-coagulant, synthetic heparins might become dominating if the prices were lower than that of natural products. Attempts to establish a solid-phase synthesis of synthetic heparins have been undertaken by Seeberger et al. and chemoenzymatic synthesis of heparins has been reviewed recently (Seeberger & Werz, 2005; Wang, Liu, & Voglmeir, 2020). First synthetic heparins (pentasaccharide) with anti-Factor Xa activity preventing deep vein thrombosis are already on the market (Zhang, Zhang, Tan, Pan, & Zhang, 2019). It is expected that the use of synthetic or semisynthetic heparin analogues will increase during the
Research, 2021). Fibres and resins include synthetic polyvinyl chloride, polypropylene, polyethylene, polystyrene, and other thermoplastics. However, biodegradable polymers that are mostly represented by polyesters used as suture materials take only a very small share of the global medical polymers market, which is smaller than 5 %. The number of products that are using polysaccharides-based materials is rather limited regarding the kind of biomedical devices but also the quantities used. Considering the problem that most synthetic polymers are non-degradable and represent a potential threat to our environment, it will be highly desirable to increase the share of polymers, including polysaccharides, that are degradable and feature a tailored durability within their target application.

It is predicted that the global medical polymers market will reach a value of USD 27.75 billion by the end of 2028, which is due to the growing demand for medical and pharmaceutical packaging materials, especially flexible packaging for medicines, blood bags, surgical gloves, and medical drapes. In addition, the increasing application of medical polymers in hip and joint replacement as well as spinal and cranial implants will have a significant impact on the market growth (Grand View Research, 2021). The growing market for the application of polymers also highlights the need to look for further applications of polysaccharides in the field of medical devices to reduce the consumption of synthetic fossil-based polymers with their negative impact on our environment.

Cellulose was one of the first polysaccharides used as a membrane in blood purification. First commercial devices during clinical establishment were based on cellulose, which had problems related to biocompatibility, e.g., complement activation, leading to the development of modified cellulose like cellulose triacetate and a dominance of dialyser based on synthetic polymers, e.g., polysulfones (Togo, Yamamoto, Imai, Akiyama, & Yamashita, 2018). Haemostatic materials like films and powders are required during surgical procedures or after injuries to stop bleeding. Additionally, oxidised cellulose, chitosan, and starch are used in commercial products due to their properties in activating blood platelets and coagulation processes (Chen et al., 2020). Another medical problem that shall be tackled using polysaccharides is the prevention of postoperative adhesions that can occur after surgical interventions, for example, in the visceral surgery, avoiding adhesion of peritoneum or connective tissue to the gut (Moris et al., 2017). Here, the hydrophilic properties of polysaccharides are desired to avoid the attachment of cells. For example, starch powder (microparticles) or membranes made of a combination of hyaluronan and carboxymethyl chitosan have been found to be useful (Li et al., 2008).

Heparin is not only used for anti-coagulation of blood by intramuscular injection in patients. It is also used in anti-coagulant coatings of different biomedical devices, like components of extracorporeal circulation devices, blood pumps like ventricular assist devices, vascular grafts, and stents to avoid clot formation on the surface of the devices. This also reduces the need for the prescription of systemic anti-coagulation to patients with possible undesired side effects (Biran & Pond, 2017). Moreover, an insufficiently addressed medical problem is the replacement of the vitreous body of the eye. Here, the first products based on hyaluronan (a major component of the vitreous humour) are making some progress (Li et al., 2008). Hyaluronan is also used to develop membranes that can be applied to support the repair of tympanic membranes (Martini, Morra, Aimonì, & Radice, 2000).

Overall, polysaccharides, depending on their source and chemistry, have a very broad spectrum of bioactivity that is interesting for tackling different medical problems, as highlighted above. On the other hand, processing of polysaccharides into the desired shapes like fibres, films and membranes is still challenging and may require different physical and chemical processes. Some polysaccharides like cellulose and chitin have very poor solubility and require partly harsh conditions to process them. The oldest textile technology using cellulose, the viscose process, goes back to 1925, which can be used to produce fibres, but also films and other shapes (Shearer, 1925). However, this requires the application

of harsh conditions, including treatment of wood pulp using sodium hydroxide forming alkali cellulose, followed then by mixing with carbon disulfide to form cellulose xanthate, which is spun into a coagulation bath containing sulfuric acid and salts. During this process, the cellulose xanthate is transformed back into cellulose (Cook, 1984). However, this process is not environmentally friendly and has a high-water consumption too (Bredereck & Hermanutz, 2005). Now, ionic liquids also allow the extrusion of cellulose fibres, which makes the process of fibre spinning easier and more environmentally friendly (Vocht et al., 2021). However, most polysaccharides are water-soluble (e.g., alginate, hyaluronan) and require physical or chemical shaping processes, like electrospinning, freeze-drying, and chemical cross-linking, to engineer them into the desired form (e.g., fibres, films, membranes, and hydrogels).

### 5.4.2. Expected achievements and developments in the next 20 years

Properties of polysaccharides that make them interesting for future application in biomedical devices are not only related to their abundance and low price of raw materials but also their hydrophilic nature that enables them to bind water, which can reduce undesired adsorption of proteins and other body components like blood cells. Other important factors are the presence of functional groups for chemical modifications, and the inherent bioactivity of certain polysaccharides. Particularly, the latter is one of the most interesting aspects to increase their application in the field of biomedical devices. Polysaccharides, especially sulphated ones, have the potential to inhibit coagulation of blood. Heparin, as representative of glycosaminoglycans, has been known for a long time as a polysaccharide with anti-coagulant properties due to its binding to anti-thrombin III and inhibition of activated coagulation factors like thrombin (Mueller & Scheidt, 1994; Wieringa, Søndergaard, & Ash, 2021). However, cellulose sulfates and other sulfated polysaccharides have been shown to inhibit the coagulation system and could replace heparin in several applications (Groth & Wagenknecht, 2001; Mes techkina & Shcherbukhin, 2010). Also, material combinations made of chitosan and pectin demonstrated excellent blood compatibility when used for making vascular patches (Bombaldi de Souza et al., 2019).

Polysaccharides also have an adsorptive capacity to remove uremic and other toxins, immune globulins, cytokines that play a role in end-stage renal diseases, autoimmune diseases, leukemia, sepsis, and others. Removal of uremic toxins by adsorption on lignin-binder or polysaccharides from algae are some reported examples (Sandeman et al., 2017). Moreover, the removal of proteins like low-density lipoprotein from the blood of patients in hyperlipidemia by heparin-mediated extracorporeal low-density lipoprotein precipitation apheresis using heparin has been reported as well as the use of particles made of dextran sulfate immobilized onto cellulose for binding of cytokines such as tumour necrosis factor that plays a role in sepsis on particles made of activated cellulose (Jaeger, 2003; Weber et al., 2005). However, the full potential of polysaccharides for biomedical applications has not yet been reached, which requires investments in research and development of new products.

### 5.4.3. Required research activities

Heparin is an efficient anti-coagulant but must be isolated from animal sources, particularly the mucosa of the small intestine of pigs. This is a time-consuming process resulting in high variability of activity and risks of contaminations that can represent a threat to patients (Liu, Zhang, & Linhardt, 2009). Therefore, for clinical application as systemic anti-coagulant, synthetic heparins might become dominating if the prices were lower than that of natural products. Attempts to establish a solid-phase synthesis of synthetic heparins have been undertaken by Seeberger et al. and chemoenzymatic synthesis of heparins has been reviewed recently (Seeberger & Werz, 2005; Wang, Liu, & Voglmeir, 2020). First synthetic heparins (pentasaccharide) with anti-Factor Xa activity preventing deep vein thrombosis are already on the market (Zhang, Zhang, Tan, Pan, & Zhang, 2019). It is expected that the use of synthetic or semisynthetic heparin analogues will increase during the
next decade.

Anti-coagulant surface coatings of medical devices like extracorporeal devices, blood pumps, blood linings, catheters and cardiovascular stents that are currently based on heparin could benefit from the use of other polysaccharides that possess anti-coagulant effects (Martini et al., 2000). A reason for such replacement of heparin can be its relatively high cost and the lack of long-term stability regarding its anti-coagulant activity. Herein, the discussed anti-coagulant activity of different sulfated polysaccharides, like cellulose sulfates, has not been explored to a sufficient extent regarding anti-coagulant effects, the durability of coatings, and potential risks and side effects (Bombaldi de Souza et al., 2019; Sandeman et al., 2017). It is anticipated that anti-coagulant coatings for biomedical devices by semisynthetic heparin analogous polysaccharides will increase during the next decades.

Representatives of polysaccharides possess anti-inflammatory properties, which are known to be related to their ability to bind pro-inflammatory cytokines, to block binding of leukocytes to endothelial and other cells by inhibiting selectin-related cell-cell adhesion and to block pro-inflammatory signal transduction in monocytes/macrophages and other white blood cells (Köwitsch et al., 2018). Recent studies have also shown that coating material surfaces with glycosaminoglycans such as heparin and hyaluronan could be used to provide surfaces with anti-inflammatory properties that reduce activation of macrophages as a key player of innate immunity (Alkhoury et al., 2020; Zhou, Niepel, Saretia, & Groth, 2016). Also, different polysaccharides from plants possess anti-inflammatory effects, as recently reviewed, which may open new avenues for application (Hou, Chen, Yang, & Ji, 2020). Several polysaccharides possess anti-infective properties against bacteria, viruses, and fungi (Xie et al., 2016). Chitosan is a well-known example in this context, however, this area should be further developed (Abd El-Hack et al., 2020).

A further example of advanced research activities required for the use polysaccharides is their application as components of protective face masks to replace polypropylene that is dominating the materials for making fibres as major component of masks (O'Dowd et al., 2020). Chitosan or cationic chitosan derivatives have emerged as new materials for the production of fibres that can bind and destroy bacteria and viruses by electrostatic interaction (Abbas et al., 2021; Choi et al., 2021).

## 5.5. Tissue engineering and regenerative medicine

### 5.5.1. Current challenges

Multiscale constructs composed of polysaccharides combined with cells or bioactive factors have been extensively and successfully explored in preclinical studies as exogenous extracellular matrices for bone, cartilage, skin and cardiac tissue regeneration or integration. Nonetheless, only a small number of products employing a restricted number of polysaccharides, including alginate, hyaluronic acid, chitosan, and chondroitin sulfate, have reached the clinical realm, bearing in mind that quality, safety, efficacy, useability, and cost are hallmarks for their introduction in the market.<fnref n="4" />

Polysaccharide-based tissue engineering constructs may carry some of the risks associated with pharmaceuticals and medical devices but are likely to exhibit greater variability in composition, structural reproducibility, and performance since the structure of the biopolymers differs from in terms of the source, purification process, batch, and molecular weight. The complexity of the biological interface and immunogenicity, and the inadequate establishment of polysaccharide structure-property-function-relationships (both physical and biological) owing to chemical group modification can also pose regulatory and therapeutic translational challenges.

### 5.5.2. Expected achievements and developments in the next 20 years

The functional and structural diversity of polysaccharides prone to be processed into diverse architectures, conjointly with the abundance and renewable character of their sources (e.g., algae, plants, and microorganisms) will continue to fuel polysaccharide-based applications in tissue engineering owing to their specific chemical versatility, biodegradability, and biocompatibility (Azevedo, Mano, & Borges, 2021; Zhu et al., 2019). Such a concept can lead to the development of user-programmable biomaterials with a lower carbon footprint at the end of the product cycle and a valuable alternative to polymers derived from fossil sources.

The toolbox of polysaccharides available and their inherent characteristics can establish a comprehensive range of opportunities for synergistic fabrication through 3D/4D bioprinting and electrospraying technologies of innovative multifunctional hybrid systems (e.g., bioinks, cell-laden adaptable hydrogels, bioactive composites, films, or injectable capsules loaded with extracellular vesicles) with improved performance and spatiotemporally controlled design. In this sense, investigating cell-material interactions are noteworthy to promote the integration of biological, physicochemical, mechanical, and topographical cues into biomaterials in order to recapitulate tissue-scale organization, the pallet of dynamic features of human tissues, and vascularisation within the implant (when necessary).

### 5.5.3. Required research activities

Rational design of biomaterials at the molecular, macromolecular, and topological levels with tailored stimuli-responsive properties for controlled interactions with cells will be required to advance the field, as well as smart materials suitable for advanced processing while maintaining desired mechanical, physicochemical, and biological properties.

The development of new and simple advanced therapy medicinal products, systematic studies, and additional clinical trials urge us to try to find meaningful answers. Therefore, larger sample sizes, randomised control groups and long-term follow-up reports are important to empower such clinical studies and investigate rare adverse events. Rational and precise tissue engineering products and processes are evolving, although clinical translation and commercialisation are time-consuming and not always feasible. Hence, the debate should necessarily contemplate the manufacture, quality standards, and scale-up of implantable scaffolds from the research and development standpoint, their practicality, off-the-shelf use, cost-effectiveness, and business model, but also the preparation of harmonised wide regulatory frameworks to accelerate their introduction into the clinical practice in collaboration among academics, clinicians, companies, and regulatory authorities.

## 6. Polysaccharide Chemistry, Biology & Physics

In the next 20 years, a demand with high societal and political priority is the replacement of fossil-based products and synthetic polymers thereof in our daily life needs. In line with sustainability, protection of resources, and most importantly, care for the environment in all aspects, polysaccharides from renewable resources are most suited to fulfil this role. Novel techniques and methods in chemistry, biology, and physics will provide novel and innovative polysaccharide-based materials with defined properties on the molecular level that are specifically tailored for emerging applications. The challenges, necessary actions, and opportunities in these three major areas are manifold.

In Chemistry:

- transition of novel efficient synthesis approaches from academia into commercial products and large-scale production

- exploration of sophisticated organic synthesis concepts and homogeneous reaction media

<footnote n="4">⁴ https://clinicaltrials.gov.</footnote>
next decade.

Anti-coagulant surface coatings of medical devices like extracorpo-
real devices, blood pumps, blood linings, catheters and cardiovascular
stents that are currently based on heparin could benefit from the use of
other polysaccharides that possess anti-coagulant effects (Martini et al.,
2000). A reason for such replacement of heparin can be its relatively
high cost and the lack of long-term stability regarding its anti-coagulant
activity. Herein, the discussed anti-coagulant activity of different
sulfated polysaccharides, like cellulose sulfates, has not been explored to
a sufficient extent regarding anti-coagulant effects, the durability of
coatings, and potential risks and side effects (Bombaldi de Souza et al.,
2019; Sandeman et al., 2017). It is anticipated that anti-coagulant
coatings for biomedical devices by semisynthetic heparin analogous
polysaccharides will increase during the next decades.

Representatives of polysaccharides possess anti-inflammatory prop-
erties, which are known to be related to their ability to bind pro-
inflammatory cytokines, to block binding of leukocytes to endothelial
and other cells by inhibiting selectin-related cell-cell adhesion and to
block pro-inflammatory signal transduction in monocytes/macrophages
and other white blood cells (Köwitsch et al., 2018). Recent studies have
also shown that coating material surfaces with glycosaminoglycans such
as heparin and hyaluronan could be used to provide surfaces with anti-
inflammatory properties that reduce activation of macrophages as a key
player of innate immunity (Alkhoury et al., 2020; Zhou, Niepel, Saretia,
& Groth, 2016). Also, different polysaccharides from plants possess anti-
inflammatory effects, as recently reviewed, which may open new ave-
nues for application (Hou, Chen, Yang, & Ji, 2020). Several poly-
saccharides possess anti-infective properties against bacteria, viruses,
and fungi (Xie et al., 2016). Chitosan is a well-known example in this
context, however, this area should be further developed (Abd El-Hack
et al., 2020).

A further example of advanced research activities required for the use polysaccharides is their application as components of protective face masks to replace polypropylene that is dominating the materials for making fibres as major component of masks (O'Dowd et al., 2020). Chitosan or cationic chitosan derivatives have emerged as new materials for the production of fibres that can bind and destroy bacteria and viruses by electrostatic interaction (Abbas et al., 2021; Choi et al., 2021).

5.5. *Tissue engineering and regenerative medicine*

5.5.1. Current challenges

Multiscale constructs composed of polysaccharides combined with cells or bioactive factors have been extensively and successfully explored in preclinical studies as exogenous extracellular matrices for bone, cartilage, skin and cardiac tissue regeneration or integration. Nonetheless, only a small number of products employing a restricted number of polysaccharides, including alginate, hyaluronic acid, chitosan, and chondroitin sulfate, have reached the clinical realm, bearing in mind that quality, safety, efficacy, useability, and cost are hallmarks for their introduction in the market.<fnref n="4" />

Polysaccharide-based tissue engineering constructs may carry some
of the risks associated with pharmaceuticals and medical devices but are
likely to exhibit greater variability in composition, structural repro-
ducibility, and performance since the structure of the biopolymers dif-
fers from in terms of the source, purification process, batch, and
molecular weight. The complexity of the biological interface and
immunogenicity, and the inadequate establishment of polysaccharide
structure-property-function-relationships (both physical and biological)
owing to chemical group modification can also pose regulatory and
therapeutic translational challenges.

5.5.2. Expected achievements and developments in the next 20 years

The functional and structural diversity of polysaccharides prone to be processed into diverse architectures, conjointly with the abundance and renewable character of their sources (e.g., algae, plants, and microorganisms) will continue to fuel polysaccharide-based applications in tissue engineering owing to their specific chemical versatility, biodegradability, and biocompatibility (Azevedo, Mano, & Borges, 2021; Zhu et al., 2019). Such a concept can lead to the development of user-programmable biomaterials with a lower carbon footprint at the end of the product cycle and a valuable alternative to polymers derived from fossil sources.

The toolbox of polysaccharides available and their inherent charac-
teristics can establish a comprehensive range of opportunities for syn-
ergistic fabrication through 3D/4D bioprinting and electrospraying
technologies of innovative multifunctional hybrid systems (e.g., bioinks,
cell-laden adaptable hydrogels, bioactive composites, films, or inject-
able capsules loaded with extracellular vesicles) with improved perfor-
mance and spatiotemporally controlled design. In this sense,
investigating cell-material interactions are noteworthy to promote the
integration of biological, physicochemical, mechanical, and topo-
graphical cues into biomaterials in order to recapitulate tissue-scale
organization, the pallet of dynamic features of human tissues, and vas-
cularisation within the implant (when necessary).

5.5.3. Required research activities

Rational design of biomaterials at the molecular, macromolecular,
and topological levels with tailored stimuli-responsive properties for
controlled interactions with cells will be required to advance the field, as
well as smart materials suitable for advanced processing while main-
taining desired mechanical, physicochemical, and biological properties.

The development of new and simple advanced therapy medicinal
products, systematic studies, and additional clinical trials urge us to try
to find meaningful answers. Therefore, larger sample sizes, randomised
control groups and long-term follow-up reports are important to
empower such clinical studies and investigate rare adverse events.
Rational and precise tissue engineering products and processes are
evolving, although clinical translation and commercialisation are time-
consuming and not always feasible. Hence, the debate should neces-
sarily contemplate the manufacture, quality standards, and scale-up of
implantable scaffolds from the research and development standpoint,
their practicality, off-the-shelf use, cost-effectiveness, and business
model, but also the preparation of harmonised wide regulatory frame-
works to accelerate their introduction into the clinical practice in
collaboration among academics, clinicians, companies, and regulatory
authorities.

6. Polysaccharide Chemistry, Biology & Physics

In the next 20 years, a demand with high societal and political pri-
ority is the replacement of fossil-based products and synthetic polymers
thereof in our daily life needs. In line with sustainability, protection of
resources, and most importantly, care for the environment in all aspects,
polysaccharides from renewable resources are most suited to fulfil this
role. Novel techniques and methods in chemistry, biology, and physics
will provide novel and innovative polysaccharide-based materials with
defined properties on the molecular level that are specifically tailored
for emerging applications. The challenges, necessary actions, and op-
portunities in these three major areas are manifold.

In Chemistry:

- transition of novel efficient synthesis approaches from academia into commercial products and large-scale production

- exploration of sophisticated organic synthesis concepts and homo-
geneous reaction media

<footnote n="4">⁴ https://clinicaltrials.gov.</footnote>
- utilisation of novel types of polysaccharides, e.g., from marine sources, biotechnological processes, and waste material valorisation, as starting material for chemical synthesis

- adaptation of highly efficient and selective chemical and chemoenzymatical synthesis into polysaccharide research

- development of methods for the fabrication of novel types of semi-synthetic polysaccharide derivatives and well-defined all-poly-saccharide-co-polymers for advanced applications

- efficient control over the monosaccharide sequence and chemical functionalities therein

### In Biology:

- new efficient methods for fine-structure determination of polysaccharides on the molecular level and understanding of their relation to functional properties in vivo

- production of polysaccharide structures with defined molecular structure (in particular regarding the degree of polymerisation, polymer backbone, and branching pattern) using novel chemoenzymatic procedures harnessing a combination of in vivo and in vitro synthetic biology

- elucidation of polysaccharide biosynthetic pathways using multidisciplinary approaches

- development of methods for the in situ analysis of intact biological assemblies at a nanometer scale

- better understanding of the role of specific monosaccharide sequences of polysaccharides in biological systems and how they are controlled during biosynthesis

### In Physics:

- development of fundamental research to tune the chain dynamics and interactions of polymer chains in polysaccharides

- understanding the physical properties vs. the structural perfection/imperfection

- machine learning and AI for finding solutions based on new approaches and agreed protocols constructed in large data libraries

- development of multiscale simulations and models to design functionalities and properties of polysaccharides

The concerted research activities will be triggered by the identification of the needs of society and the environment. Targets and demands will be identified and tailored polysaccharide-based materials fabricated by the developed methods and techniques fulfilling the requirements will be applied.

## 6.1. Chemistry

### 6.1.1. Current challenges

A beneficial societal factor of polysaccharide research is the increasing public awareness of the need to replace fossil-based products with more sustainable alternatives coupled with an increasing acceptance of the higher costs usually associated with biobased products. Polysaccharide chemistry faces several challenges, which are quite different from medium-sized carbohydrate structures as well as conventional organic and polymer chemistry. Therefore, organic synthesis methods from low molecular carbohydrate structures cannot simply be transferred to polysaccharides. Chemical modification and characterization of polysaccharide materials and modified polysaccharides are still big challenges. Only a humble selection of the highly efficient synthesis methods known in modern organic and polymer chemistry is currently exploited in polysaccharide research partly due to the limitations in terms of suitable reaction media. Promising homogeneous synthesis approaches were studied in academia, but conversion into commercial routes is still lacking behind the potential. Moreover, chemical derivatisation (both in academia and industry) has mostly focussed on

cellulose and a few other polysaccharide, e.g., starch, chitosan, and dextran (Fan & Picchioni, 2020; Kostag, Gericke, Heinze, & El Seoud, 2019; Nicolle, Journot, & Gerber-Lemaire, 2021). Nevertheless, new sources of polysaccharides have been (re)discovered, and their value in the context of polysaccharide chemistry and material development has been recognised.

### 6.1.2. Expected achievements and developments in the next 20 years

In the next 20 years, it is expected and demanded that fossil-derived polymers in our daily life need to be replaced. Chemical modification of polysaccharides will provide novel and innovative materials with properties that are specifically tailored for applications in many areas, as described in this document.

The exploration of sophisticated organic synthesis concepts (e.g., modular synthesis, click chemistry, and green chemistry) and homogeneous reaction media (e.g., advances in ionic liquids, low-melting organic salts, and aqueous systems as polysaccharide solvents) as methods to chemically modify polysaccharides will expand, thus, providing access to yet unknown routes for the chemical derivatisation of polysaccharides. Recently emerged trends in this respect will definitively intensify in the upcoming decade (Geng, Shin, Xi, & Hawker, 2021; Morais et al., 2020; Sheldon, 2018; Zou et al., 2018). Another innovative aspect that will see a strong increase in research activities will be the utilisation of novel types of polysaccharides for chemical derivatisation that are available in large quantities yet currently neglected in polysaccharide chemistry, such as polysaccharides from marine sources. e.g., seaweed polysaccharides, biotechnological processes, e.g., fermentation, microalgae cultivation, and waste material valorisation, e.g., by-products from wood such as polyoses, crops, food processing (Chudasama, Sequeira, Moradiya, & Prasad, 2021; Reddy Shetty, Batchu, Buddana, Sambasiva Rao, & Penna, 2021). Thus, a significant impact can be expected by transferring the current knowledge from chemistry applied to cellulose and simple polysaccharides such as starch, chitosan, and dextran to other or even new types of polysaccharides starting materials.

An increasing number of polysaccharide derivatives and synthesis procedures will transition from academia into commercial products due to the general advances in the field of polysaccharide research (e.g., improved synthesis, novel highly desirable materials) as well as changing perspectives on sustainable biobased materials in general. Tackling the limitations of homogeneous synthesis at commercial scales (in particular solvent recycling) is going to be one of the major challenges in commercial polysaccharide chemistry. Access to homogeneous reaction conditions for polysaccharide chemistry will open avenues for other methods and techniques successfully applied in small molecule chemistry, such as, for example, flow chemistry, automated synthesis, and consequently large-scale production, especially for high and medium value-added applications. However, this is not restricted to the context of chemical derivatisation of polysaccharides, but it is also closely related to polysaccharide shaping (in particular fibre spinning) and fractionation of polysaccharides from biomass. Both of which will be major driving forces for the development of novel as well as the improvement of current polysaccharide solvent systems. Based on current trends, it can be stated that the pro & con assessment of heterogeneous vs. homogeneous polysaccharide chemistry will shift in the upcoming years in favour of the latter. Highly efficient chemical and chemo-enzymatic methods, including catalysis, for modification of polysaccharides will be adapted from organic chemistry and synthetic polymer chemistry into polysaccharide research for access to defined uniform structures in order to obtain biobased materials with well-defined physical, chemical, and biological properties for advanced applications and model compounds for structure-property-relationship studies (Smith et al., 2020). The development of novel types of semi-synthetic polysaccharide derivatives (e.g., polysaccharides modified with mono-/oligosaccharides or peptides, all-polysaccharide-co-polymers) will yield novel, highly engineered polysaccharide-based
- utilisation of novel types of polysaccharides, e.g., from marine sources, biotechnological processes, and waste material valorisation, as starting material for chemical synthesis

- adaptation of highly efficient and selective chemical and chemoenzymatical synthesis into polysaccharide research

- development of methods for the fabrication of novel types of semi-synthetic polysaccharide derivatives and well-defined all-poly-saccharide-co-polymers for advanced applications

- efficient control over the monosaccharide sequence and chemical functionalities therein

In Biology:

- new efficient methods for fine-structure determination of polysaccharides on the molecular level and understanding of their relation to functional properties in vivo

- production of polysaccharide structures with defined molecular structure (in particular regarding the degree of polymerisation, polymer backbone, and branching pattern) using novel chemoenzymatic procedures harnessing a combination of in vivo and in vitro synthetic biology

- elucidation of polysaccharide biosynthetic pathways using multidisciplinary approaches

- development of methods for the *in situ* analysis of intact biological assemblies at a nanometer scale

- better understanding of the role of specific monosaccharide sequences of polysaccharides in biological systems and how they are controlled during biosynthesis

In Physics:

- development of fundamental research to tune the chain dynamics and interactions of polymer chains in polysaccharides

- understanding the physical properties vs. the structural perfection/imperfection

- machine learning and AI for finding solutions based on new approaches and agreed protocols constructed in large data libraries

- development of multiscale simulations and models to design functionalities and properties of polysaccharides

The concerted research activities will be triggered by the identification of the needs of society and the environment. Targets and demands will be identified and tailored polysaccharide-based materials fabricated by the developed methods and techniques fulfilling the requirements will be applied.

## 6.1. Chemistry

### 6.1.1. Current challenges

A beneficial societal factor of polysaccharide research is the increasing public awareness of the need to replace fossil-based products with more sustainable alternatives coupled with an increasing acceptance of the higher costs usually associated with biobased products. Polysaccharide chemistry faces several challenges, which are quite different from medium-sized carbohydrate structures as well as conventional organic and polymer chemistry. Therefore, organic synthesis methods from low molecular carbohydrate structures cannot simply be transferred to polysaccharides. Chemical modification and characterization of polysaccharide materials and modified polysaccharides are still big challenges. Only a humble selection of the highly efficient synthesis methods known in modern organic and polymer chemistry is currently exploited in polysaccharide research partly due to the limitations in terms of suitable reaction media. Promising homogeneous synthesis approaches were studied in academia, but conversion into commercial routes is still lacking behind the potential. Moreover, chemical derivatisation (both in academia and industry) has mostly focussed on

cellulose and a few other polysaccharide, e.g., starch, chitosan, and dextran (Fan & Picchioni, 2020; Kostag, Gericke, Heinze, & El Seoud, 2019; Nicolle, Journot, & Gerber-Lemaire, 2021). Nevertheless, new sources of polysaccharides have been (re)discovered, and their value in the context of polysaccharide chemistry and material development has been recognised.

### 6.1.2. Expected achievements and developments in the next 20 years

In the next 20 years, it is expected and demanded that fossil-derived polymers in our daily life need to be replaced. Chemical modification of polysaccharides will provide novel and innovative materials with properties that are specifically tailored for applications in many areas, as described in this document.

The exploration of sophisticated organic synthesis concepts (e.g., modular synthesis, click chemistry, and green chemistry) and homogeneous reaction media (e.g., advances in ionic liquids, low-melting organic salts, and aqueous systems as polysaccharide solvents) as methods to chemically modify polysaccharides will expand, thus, providing access to yet unknown routes for the chemical derivatisation of polysaccharides. Recently emerged trends in this respect will definitively intensify in the upcoming decade (Geng, Shin, Xi, & Hawker, 2021; Morais et al., 2020; Sheldon, 2018; Zou et al., 2018). Another innovative aspect that will see a strong increase in research activities will be the utilisation of novel types of polysaccharides for chemical derivatisation that are available in large quantities yet currently neglected in polysaccharide chemistry, such as polysaccharides from marine sources. e.g., seaweed polysaccharides, biotechnological processes, e.g., fermentation, microalgae cultivation, and waste material valorisation, e.g., by-products from wood such as polyoses, crops, food processing (Chudasama, Sequeira, Moradiya, & Prasad, 2021; Reddy Shetty, Batchu, Buddana, Sambasiva Rao, & Penna, 2021). Thus, a significant impact can be expected by transferring the current knowledge from chemistry applied to cellulose and simple polysaccharides such as starch, chitosan, and dextran to other or even new types of polysaccharides starting materials.

An increasing number of polysaccharide derivatives and synthesis procedures will transition from academia into commercial products due to the general advances in the field of polysaccharide research (e.g., improved synthesis, novel highly desirable materials) as well as changing perspectives on sustainable biobased materials in general. Tackling the limitations of homogeneous synthesis at commercial scales (in particular solvent recycling) is going to be one of the major challenges in commercial polysaccharide chemistry. Access to homogeneous reaction conditions for polysaccharide chemistry will open avenues for other methods and techniques successfully applied in small molecule chemistry, such as, for example, flow chemistry, automated synthesis, and consequently large-scale production, especially for high and medium value-added applications. However, this is not restricted to the context of chemical derivatisation of polysaccharides, but it is also closely related to polysaccharide shaping (in particular fibre spinning) and fractionation of polysaccharides from biomass. Both of which will be major driving forces for the development of novel as well as the improvement of current polysaccharide solvent systems. Based on current trends, it can be stated that the pro & con assessment of heterogeneous vs. homogeneous polysaccharide chemistry will shift in the upcoming years in favour of the latter. Highly efficient chemical and chemo-enzymatic methods, including catalysis, for modification of polysaccharides will be adapted from organic chemistry and synthetic polymer chemistry into polysaccharide research for access to defined uniform structures in order to obtain biobased materials with well-defined physical, chemical, and biological properties for advanced applications and model compounds for structure-property-relationship studies (Smith et al., 2020). The development of novel types of semi-synthetic polysaccharide derivatives (e.g., polysaccharides modified with mono-/oligosaccharides or peptides, all-polysaccharide-co-polymers) will yield novel, highly engineered polysaccharide-based
materials with a huge application potential, especially in the health and personal care sector (Volokhova, Edgar, & Matson, 2020).

The development of polysaccharide-based materials cannot proceed without new methods and technologies to characterise and specify the new materials on a molecular, supramolecular, and macroscopic level. Therefore, known analytical methods will see constant improvements and novel ones will be developed or transferred to the field of polysaccharide research.

### 6.1.3. Required research activities

The transition of novel efficient synthesis approaches from academia into commercial products, and large-scale production is one of the most important issues that needs to be tackled in the near future. It is fuelled by the increasing public demand for biobased materials that are sustainable yet likewise affordable and highly functional. In order to successfully implement sustainability goals, interdisciplinary research efforts with significant industry contributions need to be promoted in order to approach this challenging task from different angles. Automated large-scale industrial production of defined and homogeneous polysaccharide materials with consistent quality is an indispensable requirement, which will be based on the aforementioned achievements.

Advanced characterisation of polysaccharides and polysaccharide-based materials is an integral part of academic and applied polysaccharide research, from biomass fractionation over chemical synthesis to routine quality control, from the elucidation of structure-property-relationships to the development of new biomaterials. Understanding the complex interaction of physical-, chemical-, and biological properties of polysaccharides along all hierarchical levels (from the molecular structure of the individual repeating units and polymer chains to their assembling along the nano-, micro-, and macro-scale) must become a key priority for the development of innovative new bio- as well as bio-based materials. This will require scientific and technological advances in different areas, including chemistry, analytics, and process engineering.

The development of task-specific biobased materials makes it necessary to synthesise ever more refined and homogeneous polysaccharide model compounds that are currently unavailable. Key chemical synthesis tools in this regard are protecting group and protecting group-free strategies for regioselective polysaccharide derivatisation, and catalysis as well as chemical/enzymatic synthesis of oligomers/polymers/block-co-polymers with highly defined substitution pattern along the chain starting from mono/disaccharide precursors. These sophisticated methods need to be employed and adapted to create tailored model compounds that are required to establish comprehensive structure-property-relationships in different areas and to elucidate highly complex open questions such as the interaction between bio-polymers (polysaccharides, lignin, proteins) in native biocomposites (e. g., wood, grasses, plant/animal cell walls). The answers to these open questions will contribute to creating new biocomposites with advanced and engineered functionality.

Purification methods need to be developed. Therefore, modern chromatographic techniques, such as different iterations of field flow fractionation that are currently only used for synthetic polymers, will require implementation for the separation and characterisation of mono-, oligo, and polysaccharides (both in routine methods and advanced academic research).

The constant improvement of analytical methods and tools and the influx of new concepts such as AI-based modelling, learning, and analysis must find their way into the field of polysaccharide research. Solid state and liquid state NMR spectroscopy are very important tools for analysing polysaccharides in their native state (e.g., in wood biomass), after processing (e.g., fibres, nano-assemblies), and after chemical modification (polysaccharide derivatives). However, advances in innovative biomaterial design leads to ever more complex questions and complex structures on a molecular level and the need for even shorter measurement times. Thus, it is necessary to fully implement the

technological evolution of NMR spectrometer (e.g., increasing magnetic field strength, novel mathematical models, development of pulse methods) and the recent introduction of advanced methods such as dynamic nuclear polarisation surface enhanced NMR spectroscopy in polysaccharide research.

## 6.2. Biology

### 6.2.1. Current challenges

Over the last decade, we have witnessed spectacular technological advances with ever more accurate and cheaper methods for sequencing genomes and metagenomes, for transcriptome analysis (e.g., using single-cell RNA seq), genome-wide analysis of epigenetic landmarks, proteomics, lipidomics, and metabolomics (Jamil et al., 2020). This is paralleled by extremely efficient and precise methods for genome editing using CRISPR-Cas9, which allow the introduction of almost any genetic change into genomes of almost any organism, including plants (Nasti & Voytas, 2021). Cell biology has been revolutionised with the improvement of the spatial resolution of light microscopy using super-resolution imaging and temporal resolution of observations using genetically encoded sensors and optogenetics, i.e., the use of light to manipulate cellular parameters (Goglia & Toettcher, 2019; Khater, Nabi, & Hamarneh, 2020; Kim, Ju, Lee, Chun, & Seong, 2021). Another rapidly evolving area is the application of soft matter physics in cell biology with the study of liquid-liquid phase separation and the formation of membrane-less organelles and their role in cellular metabolism and signalling (Shin & Brangwynne, 2017). These approaches will also be relevant for the understanding of *in vivo* properties of polysaccharides (Haas, Wightman, Peaucelle, & Höfte, 2021). Structural biology is also undergoing a revolution with the use of cryogenic electron microscopy to resolve structures of multiprotein complexes and of machine learning for highly accurate *ab-nihilo* 3D structure prediction, for instance, by using the Alphafold software (Jumper et al., 2021; Purushotham, Ho, & Zimmer, 2020). Finally, enzymology is being revolutionised with the development of microfluidics-based high-throughput enzyme kinetics assays (Markin et al., 2021). All this has led to an explosion of biological data, which can be mined with increasingly sophisticated bioinformatics tools combined with AI.

In contrast, the analysis of polysaccharide fine structures and their functional roles, despite considerable progress in glycomics and the study of glycan-related genetic diseases, is lagging behind that of other macromolecules in particular in plants and algae (Varki, 2017). This is in part due to the polydispersity as well as the complexity of polysaccharides and the heterogeneity in distribution patterns of side branches, but also to the difficulty of purifying intact polysaccharides and chemically synthesising them.

### 6.2.2. Expected achievements and developments in the next 20 years

Over the next 20 years, major advances are expected in the inventory of natural polysaccharide structures, our understanding of the fine structures on the molecular level of polysaccharides and their relation to functional properties *in vivo* and in the context of material applications. This will rely on new efficient methods for fine-structure determination of polysaccharides and our ability to produce polysaccharide structures of defined degree of polymerisation and branching pattern using novel chemo-enzymatic procedures harnessing a combination of *in vivo* and *in vitro* synthetic biology (Jamil et al., 2020).

We will have learned from studying natural assemblies how to align and pack polysaccharides to design fibres that mechanically outperform silk and nylon and show desired structural colours. We will have acquired the concepts and tools to predict the phase separation behaviour in mixtures of interacting polysaccharides and proteins and to exploit this to produce new materials or biologically active compounds (Sing & Perry, 2020). We will benefit from cost-effective and sustainable large-scale production systems of polysaccharides and fibres. These can be extracted as coproducts from selected food and feed crops, trees, or algae
materials with a huge application potential, especially in the health and personal care sector (Volokhova, Edgar, & Matson, 2020).

The development of polysaccharide-based materials cannot proceed without new methods and technologies to characterise and specify the new materials on a molecular, supramolecular, and macroscopic level. Therefore, known analytical methods will see constant improvements and novel ones will be developed or transferred to the field of polysaccharide research.

### 6.1.3. Required research activities

The transition of novel efficient synthesis approaches from academia into commercial products, and large-scale production is one of the most important issues that needs to be tackled in the near future. It is fuelled by the increasing public demand for biobased materials that are sustainable yet likewise affordable and highly functional. In order to successfully implement sustainability goals, interdisciplinary research efforts with significant industry contributions need to be promoted in order to approach this challenging task from different angles. Automated large-scale industrial production of defined and homogeneous polysaccharide materials with consistent quality is an indispensable requirement, which will be based on the aforementioned achievements.

Advanced characterisation of polysaccharides and polysaccharide-based materials is an integral part of academic and applied polysaccharide research, from biomass fractionation over chemical synthesis to routine quality control, from the elucidation of structure-property-relationships to the development of new biomaterials. Understanding the complex interaction of physical-, chemical-, and biological properties of polysaccharides along all hierarchical levels (from the molecular structure of the individual repeating units and polymer chains to their assembling along the nano-, micro-, and macro-scale) must become a key priority for the development of innovative new bio- as well as bio-based materials. This will require scientific and technological advances in different areas, including chemistry, analytics, and process engineering.

The development of task-specific biobased materials makes it necessary to synthesise ever more refined and homogeneous polysaccharide model compounds that are currently unavailable. Key chemical synthesis tools in this regard are protecting group and protecting group-free strategies for regioselective polysaccharide derivatisation, and catalysis as well as chemical/enzymatic synthesis of oligomers/polymers/block-co-polymers with highly defined substitution pattern along the chain starting from mono/disaccharide precursors. These sophisticated methods need to be employed and adapted to create tailored model compounds that are required to establish comprehensive structure-property-relationships in different areas and to elucidate highly complex open questions such as the interaction between bio-polymers (polysaccharides, lignin, proteins) in native biocomposites (e. g., wood, grasses, plant/animal cell walls). The answers to these open questions will contribute to creating new biocomposites with advanced and engineered functionality.

Purification methods need to be developed. Therefore, modern chromatographic techniques, such as different iterations of field flow fractionation that are currently only used for synthetic polymers, will require implementation for the separation and characterisation of mono-, oligo, and polysaccharides (both in routine methods and advanced academic research).

The constant improvement of analytical methods and tools and the influx of new concepts such as AI-based modelling, learning, and analysis must find their way into the field of polysaccharide research. Solid state and liquid state NMR spectroscopy are very important tools for analysing polysaccharides in their native state (e.g., in wood biomass), after processing (e.g., fibres, nano-assemblies), and after chemical modification (polysaccharide derivatives). However, advances in innovative biomaterial design leads to ever more complex questions and complex structures on a molecular level and the need for even shorter measurement times. Thus, it is necessary to fully implement the

technological evolution of NMR spectrometer (e.g., increasing magnetic field strength, novel mathematical models, development of pulse methods) and the recent introduction of advanced methods such as dynamic nuclear polarisation surface enhanced NMR spectroscopy in polysaccharide research.

## 6.2. Biology

### 6.2.1. Current challenges

Over the last decade, we have witnessed spectacular technological advances with ever more accurate and cheaper methods for sequencing genomes and metagenomes, for transcriptome analysis (e.g., using single-cell RNA seq), genome-wide analysis of epigenetic landmarks, proteomics, lipidomics, and metabolomics (Jamil et al., 2020). This is paralleled by extremely efficient and precise methods for genome editing using CRISPR-Cas9, which allow the introduction of almost any genetic change into genomes of almost any organism, including plants (Nasti & Voytas, 2021). Cell biology has been revolutionised with the improvement of the spatial resolution of light microscopy using super-resolution imaging and temporal resolution of observations using genetically encoded sensors and optogenetics, i.e., the use of light to manipulate cellular parameters (Goglia & Toettcher, 2019; Khater, Nabi, & Hamarneh, 2020; Kim, Ju, Lee, Chun, & Seong, 2021). Another rapidly evolving area is the application of soft matter physics in cell biology with the study of liquid-liquid phase separation and the formation of membrane-less organelles and their role in cellular metabolism and signalling (Shin & Brangwynne, 2017). These approaches will also be relevant for the understanding of *in vivo* properties of polysaccharides (Haas, Wightman, Peaucelle, & Höfte, 2021). Structural biology is also undergoing a revolution with the use of cryogenic electron microscopy to resolve structures of multiprotein complexes and of machine learning for highly accurate *ab-nihilo* 3D structure prediction, for instance, by using the Alphafold software (Jumper et al., 2021; Purushotham, Ho, & Zimmer, 2020). Finally, enzymology is being revolutionised with the development of microfluidics-based high-throughput enzyme kinetics assays (Markin et al., 2021). All this has led to an explosion of biological data, which can be mined with increasingly sophisticated bioinformatics tools combined with AI.

In contrast, the analysis of polysaccharide fine structures and their functional roles, despite considerable progress in glycomics and the study of glycan-related genetic diseases, is lagging behind that of other macromolecules in particular in plants and algae (Varki, 2017). This is in part due to the polydispersity as well as the complexity of polysaccharides and the heterogeneity in distribution patterns of side branches, but also to the difficulty of purifying intact polysaccharides and chemically synthesising them.

### 6.2.2. Expected achievements and developments in the next 20 years

Over the next 20 years, major advances are expected in the inventory of natural polysaccharide structures, our understanding of the fine structures on the molecular level of polysaccharides and their relation to functional properties *in vivo* and in the context of material applications. This will rely on new efficient methods for fine-structure determination of polysaccharides and our ability to produce polysaccharide structures of defined degree of polymerisation and branching pattern using novel chemo-enzymatic procedures harnessing a combination of *in vivo* and *in vitro* synthetic biology (Jamil et al., 2020).

We will have learned from studying natural assemblies how to align and pack polysaccharides to design fibres that mechanically outperform silk and nylon and show desired structural colours. We will have acquired the concepts and tools to predict the phase separation behaviour in mixtures of interacting polysaccharides and proteins and to exploit this to produce new materials or biologically active compounds (Sing & Perry, 2020). We will benefit from cost-effective and sustainable large-scale production systems of polysaccharides and fibres. These can be extracted as coproducts from selected food and feed crops, trees, or algae
or from dedicated feedstocks cultivated on marginal land to limit competition with food and feed production (Clifton-Brown et al., 2019).

### 6.2.3. Required research activities

New sensitive and efficient methods for the analysis of polysaccharide fine-structure, e.g., based on MS profiling, glycan arrays, and nanopore sequencing, as well as methods for the study of interactions of polysaccharides with other polysaccharides or ligands, need to be further developed. Methods need to be developed for the in situ analysis of the cell wall architecture at a nanometer scale based on super-resolution microscopy combined with anti-glycan nanoprobes and methods to measure micro-rheology and -mechanics of intact cell wall assemblies.

Collections of plants and algae adapted to a variety of environments need to be screened for new polysaccharide structures. Moreover, methods need to be further developed for the accelerated domestication of wild plants producing polysaccharides or fibres of interest or for the genetic selection or engineering of cultivated plants with improved yields or extractability of desired fibres or polysaccharides.

Polysaccharide biosynthetic pathways need to be elucidated using multidisciplinary approaches, including omics data mining, AI, molecular genetics, cell biology, and structural biology, combined with miniaturised analysis of polysaccharide structures and assemblies. The elucidated polysaccharide biosynthetic pathways need to be reproduced in heterologous systems or *in vitro* using synthetic biology and adapted for large-scale production. These studies will be carried out in model systems, but with improved tools for genome editing, this will be increasingly done on crop plants.

Carbohydrate active enzymes (glycosyl transferases, glycoside hydrolases, glycosynthases, carbohydrate phosphorylases, or other carbohydrate processing enzymes) in microorganisms and plants need to be identified and functions need to be assigned to enzymes through heterologous expression and enzymology. Databases need to be established as training sets with the goal of predicting enzymatic activity from a sequence. These enzymes need to be further improved through *in vitro* evolution by selecting for novel properties adapted to industrial processes. e.g., improved synthase vs. hydrolase activity, substrate preferences, catalytic activity, stability, and compatibility with solvents.

## 6.3. Physics

### 6.3.1. Current challenges

In the polymer physics perspective, polysaccharide chains behave differently from those of most of the classic bulk polymers, like polyolefins, polyesters, or nylons. The physical properties of classic polymers can be understood based on tight polymer coils, i.e., entropic springs where the stiffness is controlled by temperature, as well as on the entanglements of the coils. By contrast, polysaccharide chains are typically relatively rigid. They are worm-like based on the less flexible saccharide rings in the repeating units. The chain rigidity changes profoundly the behaviour, e.g., how the chains coil and entangle, which, in turn, changes the mechanical and flow properties. But equally importantly, the polymeric repeating units of polysaccharides contain a dense set of hydroxy groups leading to strong interchain physical interactions. However, the individual hydrogen bonds are weak, which makes it challenging to design, for example, sufficiently highly binding plasticising molecules to promote the processibility and rheology. However, the mutual arrangements of hydroxy groups along the polymer chains can allow synergism for complex binding motifs. Also, the hydroxy groups make the properties water sensitive. So, these aspects must be considered when trying to understand the physical properties of polysaccharides.

Polysaccharides have been used in numerous applications, such as in food, gels, paints, and in medical fields. A deeper understanding of the physical properties of polysaccharides is crucial for understanding and tailoring performance of materials derived from these biopolymers. The

specific semirigid polymer chain conformations have allowed new properties, such as strain-stiffening in hydrogel networks where the stiffness of the gel increases upon mechanical deformation. This is relevant, e.g., for tissue culture applications to mimic extracellular matrix environments where the biological fault tolerance is promoted by strain stiffening. Cellulose-based fibres have long been used in textiles. One problem involves challenges in identifying common and safe solvents. However, the recent findings in cellulose fibres suggest new and more benign solvent media based on ionic liquids for cellulose but also for polysaccharides in general. Therein, interactions between the solvent and polymer chain can be highly subtle to design and understand and can require careful modelling due to the complexity of the problem.

Various polysaccharides have already been considered as alternatives for fossil-based polymers. Therein the semirigid chains in a combination of the hydrogen bonds and water sensitivity posed challenges. Numerous approaches have been presented to plasticise the polymers to allow melt-processing, whereas the landmark findings are, however, still awaiting. As an alternative approach, polysaccharides have been used as additives within thermoplastic polymers in blends and (nano)composites, notably nanocelluloses within biodegradable matrices. Importantly, various forms of colloidal level nanocelluloses have recently been maturing to be technically and economically feasible to allow reinforcement in blends, spinning fibres, and allowing structural colours. As a remarkable state of the art, one can mention the Japanese *Nano Cellulose Vehicle* to demonstrate the technology readiness level.

### 6.3.2. Expected achievements and developments in the next 20 years

Polysaccharides and polysaccharide-based materials will have relevant applications in several specific functional applications. It is expected that deeper and fundamental understanding of their physical properties (e.g., solubility, rheological behaviour, optical/electrical/mechanical properties) will be gained. This will have a huge impact on the development of new processing strategies and biomaterial design. In the context of the energy storage and energy efficiency, one can foresee all-polysaccharide batteries and supercapacitors, also utilising lignin, as well as polysaccharide components in solar cells. This is suggested by the promising results on the complex physicochemical interaction between different types of polysaccharides as well as between polysaccharides and other biopolymers (e.g., proteins, lignin). Light-weight construction based on nanocellulose reinforcements is expected to gain application potential in specific technical applications. It exploits the versatility of nanocellulose compounds, ranging from reinforced nanocomposites and optical transparency to rigid and elastomeric composites. Comprehensive evaluation of polysaccharides in the context of polymer physics will benefit from the advances made in the field of synthetic macromolecules, resulting in novel biomaterial developments. As an example, polysaccharides will have growing relevance in tissue culture and medical sciences due to their biological compatibility but also due to their specific worm-like semirigid chain conformation. It is also expected that optical properties of native polysaccharides, chemically modified polysaccharide derivatives, and materials obtained therefrom can be mastered to allow, e.g., optical fibres and devices for sensing and biomedical applications. Novel insulation and flame-retardant materials will be developed that take advantage of fundamental studies on the thermal-, electrical-, and acoustic conductivity within polysaccharide-based foams and aerogels. The understanding of structural colours of cholesteric polysaccharide assemblies and nanocellulose liquid crystals is foreseen to mature for applications. We also foresee that disordered modified polysaccharide networks will allow to obtain sustainable white pigments that can replace hazardous metal oxide pigments in coatings and paints.

Dissolution of polysaccharides is indispensable for their processing (e.g., shaping, extraction from biomass, homogeneous chemistry). Significant advances are expected in understanding and predicting the solubility and insolubility of cellulose and other polysaccharides in aqueous and organic solvent media (Etale, Onyianta, Turner, &
or from dedicated feedstocks cultivated on marginal land to limit competition with food and feed production (Clifton-Brown et al., 2019).

### 6.2.3. Required research activities

New sensitive and efficient methods for the analysis of polysaccharide fine-structure, e.g., based on MS profiling, glycan arrays, and nanopore sequencing, as well as methods for the study of interactions of polysaccharides with other polysaccharides or ligands, need to be further developed. Methods need to be developed for the in situ analysis of the cell wall architecture at a nanometer scale based on super-resolution microscopy combined with anti-glycan nanoprobes and methods to measure micro-rheology and -mechanics of intact cell wall assemblies.

Collections of plants and algae adapted to a variety of environments need to be screened for new polysaccharide structures. Moreover, methods need to be further developed for the accelerated domestication of wild plants producing polysaccharides or fibres of interest or for the genetic selection or engineering of cultivated plants with improved yields or extractability of desired fibres or polysaccharides.

Polysaccharide biosynthetic pathways need to be elucidated using multidisciplinary approaches, including omics data mining, AI, molecular genetics, cell biology, and structural biology, combined with miniaturised analysis of polysaccharide structures and assemblies. The elucidated polysaccharide biosynthetic pathways need to be reproduced in heterologous systems or *in vitro* using synthetic biology and adapted for large-scale production. These studies will be carried out in model systems, but with improved tools for genome editing, this will be increasingly done on crop plants.

Carbohydrate active enzymes (glycosyl transferases, glycoside hydrolases, glycosynthases, carbohydrate phosphorylases, or other carbohydrate processing enzymes) in microorganisms and plants need to be identified and functions need to be assigned to enzymes through heterologous expression and enzymology. Databases need to be established as training sets with the goal of predicting enzymatic activity from a sequence. These enzymes need to be further improved through *in vitro* evolution by selecting for novel properties adapted to industrial processes. e.g., improved synthase vs. hydrolase activity, substrate preferences, catalytic activity, stability, and compatibility with solvents.

## 6.3. Physics

### 6.3.1. Current challenges

In the polymer physics perspective, polysaccharide chains behave differently from those of most of the classic bulk polymers, like polyolefins, polyesters, or nylons. The physical properties of classic polymers can be understood based on tight polymer coils, i.e., entropic springs where the stiffness is controlled by temperature, as well as on the entanglements of the coils. By contrast, polysaccharide chains are typically relatively rigid. They are worm-like based on the less flexible saccharide rings in the repeating units. The chain rigidity changes profoundly the behaviour, e.g., how the chains coil and entangle, which, in turn, changes the mechanical and flow properties. But equally importantly, the polymeric repeating units of polysaccharides contain a dense set of hydroxy groups leading to strong interchain physical interactions. However, the individual hydrogen bonds are weak, which makes it challenging to design, for example, sufficiently highly binding plasti-cising molecules to promote the processibility and rheology. However, the mutual arrangements of hydroxy groups along the polymer chains can allow synergism for complex binding motifs. Also, the hydroxy groups make the properties water sensitive. So, these aspects must be considered when trying to understand the physical properties of polysaccharides.

Polysaccharides have been used in numerous applications, such as in food, gels, paints, and in medical fields. A deeper understanding of the physical properties of polysaccharides is crucial for understanding and tailoring performance of materials derived from these biopolymers. The

specific semirigid polymer chain conformations have allowed new properties, such as strain-stiffening in hydrogel networks where the stiffness of the gel increases upon mechanical deformation. This is relevant, e.g., for tissue culture applications to mimic extracellular matrix environments where the biological fault tolerance is promoted by strain stiffening. Cellulose-based fibres have long been used in textiles. One problem involves challenges in identifying common and safe solvents. However, the recent findings in cellulose fibres suggest new and more benign solvent media based on ionic liquids for cellulose but also for polysaccharides in general. Therein, interactions between the solvent and polymer chain can be highly subtle to design and understand and can require careful modelling due to the complexity of the problem.

Various polysaccharides have already been considered as alternatives for fossil-based polymers. Therein the semirigid chains in a combination of the hydrogen bonds and water sensitivity posed challenges. Numerous approaches have been presented to plasticise the polymers to allow melt-processing, whereas the landmark findings are, however, still awaiting. As an alternative approach, polysaccharides have been used as additives within thermoplastic polymers in blends and (nano)composites, notably nanocelluloses within biodegradable matrices. Importantly, various forms of colloidal level nanocelluloses have recently been maturing to be technically and economically feasible to allow reinforcement in blends, spinning fibres, and allowing structural colours. As a remarkable state of the art, one can mention the Japanese *Nano Cellulose Vehicle* to demonstrate the technology readiness level.

### 6.3.2. Expected achievements and developments in the next 20 years

Polysaccharides and polysaccharide-based materials will have relevant applications in several specific functional applications. It is expected that deeper and fundamental understanding of their physical properties (e.g., solubility, rheological behaviour, optical/electrical/mechanical properties) will be gained. This will have a huge impact on the development of new processing strategies and biomaterial design. In the context of the energy storage and energy efficiency, one can foresee all-polysaccharide batteries and supercapacitors, also utilising lignin, as well as polysaccharide components in solar cells. This is suggested by the promising results on the complex physicochemical interaction between different types of polysaccharides as well as between polysaccharides and other biopolymers (e.g., proteins, lignin). Light-weight construction based on nanocellulose reinforcements is expected to gain application potential in specific technical applications. It exploits the versatility of nanocellulose compounds, ranging from reinforced nanocomposites and optical transparency to rigid and elastomeric composites. Comprehensive evaluation of polysaccharides in the context of polymer physics will benefit from the advances made in the field of synthetic macromolecules, resulting in novel biomaterial developments. As an example, polysaccharides will have growing relevance in tissue culture and medical sciences due to their biological compatibility but also due to their specific worm-like semirigid chain conformation. It is also expected that optical properties of native polysaccharides, chemically modified polysaccharide derivatives, and materials obtained therefrom can be mastered to allow, e.g., optical fibres and devices for sensing and biomedical applications. Novel insulation and flame-retardant materials will be developed that take advantage of fundamental studies on the thermal-, electrical-, and acoustic conductivity within polysaccharide-based foams and aerogels. The understanding of structural colours of cholesteric polysaccharide assemblies and nanocellulose liquid crystals is foreseen to mature for applications. We also foresee that disordered modified polysaccharide networks will allow to obtain sustainable white pigments that can replace hazardous metal oxide pigments in coatings and paints.

Dissolution of polysaccharides is indispensable for their processing (e.g., shaping, extraction from biomass, homogeneous chemistry). Significant advances are expected in understanding and predicting the solubility and insolubility of cellulose and other polysaccharides in aqueous and organic solvent media (Etale, Onyianta, Turner, &
Eichhorn, 2023; Mark, Xinzhong, Changlu, & Lianzhong, 2017; Norgren et al., 2023). Ultimately, this will enable the development of tailored polysaccharide solvents for different purposes.

### 6.3.3. Required research activities

Comprehensive physicochemical and theoretical studies are needed to fully understand the thermodynamic and kinetic principles of the dissolution of polysaccharides in aqueous and non-aqueous solvents. Finding answers to fundamental questions such as “Why are polysaccharides like cellulose insoluble in water and common organic solvents?”, “What is the influence of hydrophilicity, hydrophobicity, crystallinity, hydrogen bonding, entropic effects, and other parameters on the dissolution process?”, and “How can we exploit this knowledge to develop task-specific solvents for different polysaccharides and different applications?” will be crucial for advancing polysaccharide research in the next decades. Studying the interaction of polysaccharide-based materials with water is also important in this context, e.g., to reduce their sensitivity to moisture. Being a complex physical problem that involves an interplay of many parameters, it is expected that machine learning and AI could allow tools to find solutions. This requires major new approaches and agreed protocols to construct large data libraries.

Another major aim is that polysaccharide-based materials could growingly replace bulk polymers in applications presently dominated by fossil-based polymers, such as polyolefins, polyesters, and nylon, by exploiting waste streams in a circular economy. To this end, major developments are needed in several fields. To facilitate seamless market entry for bulk applications, polysaccharides should allow melt processing with the existing devices in the polymer industry with as small as possible modifications, such as extruders and injection moulding devices. This requires thermoplasticity based on tailorable rheology as a function of temperature. Even if considerable progress therein has already been recently made, fundamental research is needed to understand and tune the chain dynamics and interactions of polysaccharides and polysaccharide derivatives as the polymer chains are typically relatively rigid, also involving a multitude of hydrogen bonding interactions. The typical avenues are chemical side chain modifications or identification of suitable plasticisers. The latter approach is, in principle, highly attractive as, in this case, the biobased polymers require no modification. Developing truly versatile plasticisers will require fundamental understanding of their molecular interaction with polysaccharides, their diffusion properties in extended polysaccharides matrices (in order to prevent leakage), as well as the tailored control over chain dynamics and excessive polymer aggregation (in order to tune the thermoplastic properties). Such approaches are also critical to achieve toughness in mechanical deformations, i.e., to suppress catastrophic failures in technical applications. Also, the physical basis of promoted ductility of worm-like chains needs to be refined.

The polymer physics of semirigid polymers in general and polysaccharides in particular need to be further developed to understand their structural and rheological properties. This also requires multiscale simulations and models to design functionalities and properties and how to balance the strong intramolecular interactions with sufficiently repulsive groups allowed by plasticisers or grafted groups. From the physics perspective, a specific need is to develop rational routes for polysaccharide self-assemblies for controlled and useful nanostructures. In classical polymers, the self-assemblies are typically achieved using various architectures of block copolymers, where living polymerisation strategies have been developed over the recent decades. They allow narrow molecular weight distributions and copolymerisation of different polymer blocks in different architectures. Totally different physical, chemical, and biological strategies must be developed for polysaccharides. The first challenge is to achieve narrow polydispersity, which may be challenging to obtain simply from the naturally obtained polysaccharides by chopping. The block-like polysaccharide structures may have to be constructed by end-to-end linkages of low molecular weight precursors or polymers. This requires mastery of topochemical

end group reactions. Synthetic biological concepts need to be developed for well-defined polysaccharides and their block copolymer-like self-assemblies.

Research is needed to construct polysaccharides with novel functions such as optical/barrier/separation properties, electrical conductivity or insulation, and flame retardancy. This will require new ways to modify refractive indices, incorporate ionically or electronically conducting moieties, either chemically or supramolecularly. Moreover, it needs to be studied how advanced functions and physical properties are controlled by a defined (nano)structure over different length scales and hierarchies. Therein, it is expected that exploiting plant-based structures such as wood could serve as templates. Hints for this approach have already been shown, e.g., bullet-proof compacted wood as well as highly conducting polysaccharide-based electrolytes.

A very complex and important aspect that needs to be understood is the correlation between physical properties and the structural perfection/imperfection of polysaccharide-based materials. As an example, highly controlled nanocelluloses can be obtained based on subtle processes and well-defined sources. However, economical aspects may suggest using less expensive processes and less-controlled source material, notably waste streams. The ultimate question relates to understanding the relations between structural perfection and achievable properties.

The research activities in the development of new methods and techniques for polysaccharide chemistry, biology, and physics will be triggered by the identification of the needs of society and environment. Targets and demands will be identified, and together with tailored polysaccharide materials, will be accessible by application of the methods and approaches developed in fundamental research.

## 7. Skills and education systems needed towards 2040 goals

To date, professionals in biopolymers and polysaccharides are educated within degree programs in engineering and science subjects that equip the students with skills in physics, chemistry, biology, processes, technologies, and product solutions. The prospect for the next 20 years is that these professionals will, in addition, need to master framework skills that include knowledge of material circularity, life cycle, and socio-economic impact analyses. The framework topics of sustainability, circularity, and economics will become integral in the degree programs.

By 2040, the education of professionals in biopolymers and polysaccharides will become more connected in Europe. This will be facilitated by a virtual education platform that unites academia, industry, and the general public and by an iterative system to assess and validate key competencies and skill gaps for current and future needs. An educational system that provides professionals to Europe that are skilled in science and engineering as well as in framework skills will be in place. Digital education, mobility and inclusive and connected higher education will be the critical tools to reach the high-quality education landscape within science and engineering areas, such as biopolymers and polysaccharides.

### 7.1. Current challenges

The topics of biopolymers and polysaccharides are interdigitated in education in degrees in Materials Science & Engineering, Food & Nutrition, and Biomedical, Chemistry, Biology & Physics (Fig. 6). Master of Science degrees in biorefinery, food, and pulp and paper encompass polysaccharide topics, while degrees in chemistry and physics include the molecular and phenomenological principles applicable to the field of polysaccharides. Currently, there is no degree program dedicated specifically to biopolymers or polysaccharides in Europe. Institutions qualified by the European University Charter offer various modules dealing with biopolymers and polysaccharides. Examples of module themes taught at master level in English are:
Eichhorn, 2023; Mark, Xinzhong, Changlu, & Lianzhong, 2017; Norgren et al., 2023). Ultimately, this will enable the development of tailored polysaccharide solvents for different purposes.

### 6.3.3. Required research activities

Comprehensive physicochemical and theoretical studies are needed to fully understand the thermodynamic and kinetic principles of the dissolution of polysaccharides in aqueous and non-aqueous solvents. Finding answers to fundamental questions such as “Why are polysaccharides like cellulose insoluble in water and common organic solvents?”, “What is the influence of hydrophilicity, hydrophobicity, crystallinity, hydrogen bonding, entropic effects, and other parameters on the dissolution process?”, and “How can we exploit this knowledge to develop task-specific solvents for different polysaccharides and different applications?” will be crucial for advancing polysaccharide research in the next decades. Studying the interaction of polysaccharide-based materials with water is also important in this context, e.g., to reduce their sensitivity to moisture. Being a complex physical problem that involves an interplay of many parameters, it is expected that machine learning and AI could allow tools to find solutions. This requires major new approaches and agreed protocols to construct large data libraries.

Another major aim is that polysaccharide-based materials could growingly replace bulk polymers in applications presently dominated by fossil-based polymers, such as polyolefins, polyesters, and nylon, by exploiting waste streams in a circular economy. To this end, major developments are needed in several fields. To facilitate seamless market entry for bulk applications, polysaccharides should allow melt processing with the existing devices in the polymer industry with as small as possible modifications, such as extruders and injection moulding devices. This requires thermoplasticity based on tailorable rheology as a function of temperature. Even if considerable progress therein has already been recently made, fundamental research is needed to understand and tune the chain dynamics and interactions of polysaccharides and polysaccharide derivatives as the polymer chains are typically relatively rigid, also involving a multitude of hydrogen bonding interactions. The typical avenues are chemical side chain modifications or identification of suitable plasticisers. The latter approach is, in principle, highly attractive as, in this case, the biobased polymers require no modification. Developing truly versatile plasticisers will require fundamental understanding of their molecular interaction with polysaccharides, their diffusion properties in extended polysaccharides matrices (in order to prevent leakage), as well as the tailored control over chain dynamics and excessive polymer aggregation (in order to tune the thermoplastic properties). Such approaches are also critical to achieve toughness in mechanical deformations, i.e., to suppress catastrophic failures in technical applications. Also, the physical basis of promoted ductility of worm-like chains needs to be refined.

The polymer physics of semirigid polymers in general and polysaccharides in particular need to be further developed to understand their structural and rheological properties. This also requires multiscale simulations and models to design functionalities and properties and how to balance the strong intramolecular interactions with sufficiently repulsive groups allowed by plasticisers or grafted groups. From the physics perspective, a specific need is to develop rational routes for polysaccharide self-assemblies for controlled and useful nanostructures. In classical polymers, the self-assemblies are typically achieved using various architectures of block copolymers, where living polymerisation strategies have been developed over the recent decades. They allow narrow molecular weight distributions and copolymerisation of different polymer blocks in different architectures. Totally different physical, chemical, and biological strategies must be developed for polysaccharides. The first challenge is to achieve narrow polydispersity, which may be challenging to obtain simply from the naturally obtained polysaccharides by chopping. The block-like polysaccharide structures may have to be constructed by end-to-end linkages of low molecular weight precursors or polymers. This requires mastery of topochemical

end group reactions. Synthetic biological concepts need to be developed for well-defined polysaccharides and their block copolymer-like self-assemblies.

Research is needed to construct polysaccharides with novel functions such as optical/barrier/separation properties, electrical conductivity or insulation, and flame retardancy. This will require new ways to modify refractive indices, incorporate ionically or electronically conducting moieties, either chemically or supramolecularly. Moreover, it needs to be studied how advanced functions and physical properties are controlled by a defined (nano)structure over different length scales and hierarchies. Therein, it is expected that exploiting plant-based structures such as wood could serve as templates. Hints for this approach have already been shown, e.g., bullet-proof compacted wood as well as highly conducting polysaccharide-based electrolytes.

A very complex and important aspect that needs to be understood is the correlation between physical properties and the structural perfection/imperfection of polysaccharide-based materials. As an example, highly controlled nanocelluloses can be obtained based on subtle processes and well-defined sources. However, economical aspects may suggest using less expensive processes and less-controlled source material, notably waste streams. The ultimate question relates to understanding the relations between structural perfection and achievable properties.

The research activities in the development of new methods and techniques for polysaccharide chemistry, biology, and physics will be triggered by the identification of the needs of society and environment. Targets and demands will be identified, and together with tailored polysaccharide materials, will be accessible by application of the methods and approaches developed in fundamental research.

## 7. Skills and education systems needed towards 2040 goals

To date, professionals in biopolymers and polysaccharides are educated within degree programs in engineering and science subjects that equip the students with skills in physics, chemistry, biology, processes, technologies, and product solutions. The prospect for the next 20 years is that these professionals will, in addition, need to master framework skills that include knowledge of material circularity, life cycle, and socio-economic impact analyses. The framework topics of sustainability, circularity, and economics will become integral in the degree programs.

By 2040, the education of professionals in biopolymers and polysaccharides will become more connected in Europe. This will be facilitated by a virtual education platform that unites academia, industry, and the general public and by an iterative system to assess and validate key competencies and skill gaps for current and future needs. An educational system that provides professionals to Europe that are skilled in science and engineering as well as in framework skills will be in place. Digital education, mobility and inclusive and connected higher education will be the critical tools to reach the high-quality education landscape within science and engineering areas, such as biopolymers and polysaccharides.

### 7.1. Current challenges

The topics of biopolymers and polysaccharides are interdigitated in education in degrees in Materials Science & Engineering, Food & Nutrition, and Biomedical, Chemistry, Biology & Physics (Fig. 6). Master of Science degrees in biorefinery, food, and pulp and paper encompass polysaccharide topics, while degrees in chemistry and physics include the molecular and phenomenological principles applicable to the field of polysaccharides. Currently, there is no degree program dedicated specifically to biopolymers or polysaccharides in Europe. Institutions qualified by the European University Charter offer various modules dealing with biopolymers and polysaccharides. Examples of module themes taught at master level in English are:
<figure><img src="image_9.png" /><figcaption>**Fig. 6.** Schematic overview of the different education programs required for enabling skills needed for future biopolymer and polysaccharide research and engineering in Europe.</figcaption></figure>

- carbohydrate chemistry

- polysaccharide chemistry

- biomass chemistry and technology

- biorefinery

- bioorganic chemistry

- cellulose, wood, and paper technology

- analytical and characterisation techniques for carbon-based materials covering molecular, nano-structured up to macroscopic material level

- biochemistry and biological basics

- spectrum and utilisation of renewable materials

- environmental and ecological basics

- sustainability development goals and circular economy

- waste and emission management

The current degrees and courses in bachelor, master, and doctoral education address the various engineering and science subjects that equip the students with skills in physics, chemistry, biology, processes, technologies, and product solutions (Fig. 6). Education in what we call herein *framework skills*, which include knowledge of material circularity, life cycle, and socio-economic impact analyses, are not systematically embedded in educational programs.

## 7.2. The vision 2040

In 2040, material use will be shifted towards intentional consumption due to increasing awareness and knowledge of material life cycles and material socio-economic impact. This shift will be largely facilitated by national and European education efforts in science and engineering topics within sustainable and renewable materials, such as polysaccharides. The quality of science and engineering related education will rise, and the education programs will become more connected within Europe. Incorporating the education of framework skills that comprise numerical skills of material circularity, life cycle, and socio-economic impact analyses will contribute to transform the skill set of European graduates. Current critical tools to reach the high-quality

education scenery within science and engineering areas, such as bio-polymers and polysaccharides, are the EC's European Education Area activities on developing *digital education, life-long learning*, and *inclusive and connected higher education*.<fnref n="5" /> These promote key competencies such as (i) literacy, (ii) multilingualism, (iii) numerical, scientific, and engineering skills, (iv) digital and technology-based competencies, (v) interpersonal skills, (vi) the ability to adopt new competencies, (vii) active citizenship, (viii) entrepreneurship, and (ix) cultural awareness and expression.

Within the materials and products related bachelor, master, and doctoral education in biopolymers and polysaccharides, the benchmark is knowhow on making materials with targeted quality that matched with the purpose of use and its life cycle. This is facilitated by equipping the professionals with the skills in quantifying the societal, economic and environmental impact of materials and of constructing a sustainable production chain. These are continuous items in the curricula in all degree programs within biopolymers and polysaccharides. The technical competencies of students at bachelor and master levels have risen benefit of progress in the digitalisation of education. In science and engineering education, the use of digital teaching tools such as virtual laboratories that combine simulation, analysis, and calculations of societal, economic, and environmental impact, has been central in the skills development of the professionals. New tools in all degree programs have emerged that make use of digital tools for experimental design and predictive simulations to minimise training for the trial-and-error type of problem-solving.

The students in science and engineering fields are enrolled to home universities. However, the ECs initiative for inclusive and connected higher education has facilitated an education horizon that is not limited to the home universities.<fnref n="5" /> The connectedness of European education scenery is further made possible by topic networks, such as EPNOE, in the field of biopolymers and polysaccharides that bring together students from European countries and universities to work within a specific context but approach it from diverse application areas and socio-economic backgrounds. The topic networks have been transitional also for the education of postgraduates and professionals in working life.

<footnote n="5">⁵ European Education Area, Focus Topics, Digital Education, Digital action plan (2021–2027), https://education.ec.europa.eu/focus-topics/digital/education-action-plan; European Education Area, Focus Topics, Improving Quality, Council Recommendation on Key Competences for Lifelong Learning; https://education.ec.europa.eu/focus-topics/improving-quality-equity/key-competences-lifelong-learning; European Education Area, Education Levels, Inclusive and connected higher education, https://education.ec.europa.eu/education-levels/higher-education/inclusion-and-connectivity.</footnote>
<figure><img src="image_9.png" /><figcaption>**Fig. 6.** Schematic overview of the different education programs required for enabling skills needed for future biopolymer and polysaccharide research and engineering in Europe.</figcaption></figure>

- carbohydrate chemistry

- polysaccharide chemistry

- biomass chemistry and technology

- biorefinery

- bioorganic chemistry

- cellulose, wood, and paper technology

- analytical and characterisation techniques for carbon-based materials covering molecular, nano-structured up to macroscopic material level

- biochemistry and biological basics

- spectrum and utilisation of renewable materials

- environmental and ecological basics

- sustainability development goals and circular economy

- waste and emission management

The current degrees and courses in bachelor, master, and doctoral education address the various engineering and science subjects that equip the students with skills in physics, chemistry, biology, processes, technologies, and product solutions (Fig. 6). Education in what we call herein *framework skills*, which include knowledge of material circularity, life cycle, and socio-economic impact analyses, are not systematically embedded in educational programs.

## 7.2. The vision 2040

In 2040, material use will be shifted towards intentional consumption due to increasing awareness and knowledge of material life cycles and material socio-economic impact. This shift will be largely facilitated by national and European education efforts in science and engineering topics within sustainable and renewable materials, such as polysaccharides. The quality of science and engineering related education will rise, and the education programs will become more connected within Europe. Incorporating the education of framework skills that comprise numerical skills of material circularity, life cycle, and socio-economic impact analyses will contribute to transform the skill set of European graduates. Current critical tools to reach the high-quality

education scenery within science and engineering areas, such as bio-polymers and polysaccharides, are the EC's European Education Area activities on developing *digital education, life-long learning*, and *inclusive and connected higher education*.<fnref n="5" /> These promote key competencies such as (i) literacy, (ii) multilingualism, (iii) numerical, scientific, and engineering skills, (iv) digital and technology-based competencies, (v) interpersonal skills, (vi) the ability to adopt new competencies, (vii) active citizenship, (viii) entrepreneurship, and (ix) cultural awareness and expression.

Within the materials and products related bachelor, master, and doctoral education in biopolymers and polysaccharides, the benchmark is knowhow on making materials with targeted quality that matched with the purpose of use and its life cycle. This is facilitated by equipping the professionals with the skills in quantifying the societal, economic and environmental impact of materials and of constructing a sustainable production chain. These are continuous items in the curricula in all degree programs within biopolymers and polysaccharides. The technical competencies of students at bachelor and master levels have risen benefit of progress in the digitalisation of education. In science and engineering education, the use of digital teaching tools such as virtual laboratories that combine simulation, analysis, and calculations of societal, economic, and environmental impact, has been central in the skills development of the professionals. New tools in all degree programs have emerged that make use of digital tools for experimental design and predictive simulations to minimise training for the trial-and-error type of problem-solving.

The students in science and engineering fields are enrolled to home universities. However, the ECs initiative for inclusive and connected higher education has facilitated an education horizon that is not limited to the home universities.<fnref n="5" /> The connectedness of European education scenery is further made possible by topic networks, such as EPNOE, in the field of biopolymers and polysaccharides that bring together students from European countries and universities to work within a specific context but approach it from diverse application areas and socio-economic backgrounds. The topic networks have been transitional also for the education of postgraduates and professionals in working life.

<footnote n="5">⁵ European Education Area, Focus Topics, Digital Education, Digital action plan (2021–2027), https://education.ec.europa.eu/focus-topics/digital/education-action-plan; European Education Area, Focus Topics, Improving Quality, Council Recommendation on Key Competences for Lifelong Learning; https://education.ec.europa.eu/focus-topics/improving-quality-equity/key-competences-lifelong-learning; European Education Area, Education Levels, Inclusive and connected higher education, https://education.ec.europa.eu/education-levels/higher-education/inclusion-and-connectivity.</footnote>
Educating professionals and maintaining the skills of graduates working in the industry is used to circle back their competence to education (Fig. 6) and make it possible to iteratively identify skill gaps for the current and future needs of Europe. In the context of biopolymers and polysaccharides, an ambitious goal needs to be achieved by 2040: “A fully implemented educational system that provides professionals to Europe that are skilled in science and engineering as well as framework skills.”

### 7.3. Tools for enabling the vision

It is essential to combine the EC's education initiatives (e.g., digital education, key competencies, and inclusive and connected education in Europe) with the aims and opportunities of topic specific scientific and engineering focussed networks (such as EPNOE in the fields of bio-polymers and polysaccharides). Only then can the vision of a European education that is connected, inclusive, and of high quality become reality. Vital tools to (a) facilitate connectedness, high quality, and inclusiveness as well as (b) promote education in biopolymers and polysaccharides at the different professional stages are:

- mobility and training programs (e.g., ERASMUS+, Horizon Europe, Marie Skłodowska-Curie Actions, COST – European Cooperation in Science and Technology, CEEPUS – Central European Exchange Programme for University Studies)

- activities that strengthen cooperation between the different levels of educational institutions, research institutions, and companies

- employment of virtual tools that promote inclusiveness and accessibility of education

- virtual education platform that unites academia, industry, and the general public

- iterative systems to assess and validate key competencies and skill gaps for current and future needs

## 8. Summary & conclusion

Polysaccharides are abundantly available polymeric materials of today and tomorrow. Future sustainable materials based on polysaccharides will emerge for numerous targeted applications in engineering, materials science, food and nutrition and biomedical fields. In the context of a more sustainable planet and a more efficient circular economy, polysaccharides are very well-positioned to transition from fossil-based to sustainable biobased materials with equal or improved performances. The next generations of polysaccharides will find inspiration in nature in the attempt to mimic both form and function. The use of functional composites from sustainable and renewable resources will be pivotal in our future industrial practices. Polysaccharides can be used both as a continuous or a dispersed phase. The current increased digitalisation and continuous development around internet-of-things must be combined with sustainability. Polysaccharides will be strategic components for energy storage and harvesting, replacing fossil-based products for a wide range of industrial applications. Processing of polysaccharides must be economical and environmentally competitive. Although polysaccharides might appear as an inexhaustible resource, it is important to identify and study the available feedstock in relation to the techno-economical perspective for each specific product and application to enable a sustainable production. Interdisciplinarity combined with the sustainable and circular economy should be a general approach to advance.

Polysaccharides play a pivotal role in human nutrition and food structure design. Starches, being the major source of nutritional carbohydrates, were and remain to this date the prime focus of the research effort. However, the last two decades saw a growing interest in complex oligo- and polysaccharides and their assemblies that are not digestible by human enzymes. These types of carbohydrate materials are classified using the umbrella term *dietary fibre*. Importantly, dietary fibre influence

macronutrient digestibility and impact systemic, whole-body metabolism through a chain of events that begin with delaying gastric emptying and proceed to colonic fermentation of dietary fibre by the gut microbiome. Within the strategic horizon of the next two decades, a more detailed understanding of the structural characteristics and structure-function-relationships of dietary fibre will afford the development of targeted dietary fibre with programmable interactions, rheological properties (gelling, viscosifying), physiological response (fermentability, immune modulations), as well as techno-functional properties to benefit public health and sustainable food processing and manufacturing. This progress in understanding will require highly advanced analytical techniques based on chemical microscopy, NMR, and MS, for example.

The inherent biological and pharmacological activities, biocompatibility, biodegradability, distinctive physical and chemical properties of polysaccharide, and the versatility of their derivatives, have been extensively exploited to create biomaterials and medicinal products applied to clinical practice, under clinical trials or *in vivo* experiments. The scientific and biotechnological interest devoted to polysaccharides in biomedicine conflates five principal topics of research: (i) bioactive polysaccharides, (ii) cosmetics, (iii) drug delivery and nanomedicine, (iv) medical devices, and (v) tissue engineering and regenerative medicine. Within the strategic horizon of the next two decades, innovative clinical applications, processability, performance improvement, market introduction, and future perspectives of next-generation polysaccharide biomaterials will emerge, such as the development of new targeting agents and smart carriers for drugs, medical devices with anti-inflammatory, anti-infective, and anti-coagulant activities and expansion of emerging therapeutic applications on *in vitro* disease modelling, and microtissue formation and maturation. The toolbox of polysaccharides available and their inherent characteristics establish a comprehensive range of opportunities for the synergistic development of innovative systems. We expect these examples may outline future directions in biomedicine and biotechnology, which will expedite the clinical use of natural polysaccharide materials and prospect manufacturing and analysis processes.

Novel techniques and methods in chemistry, biology, and physics will provide innovative polysaccharide-based materials with defined properties on the molecular level that are specifically tailored for emerging applications. In the next 20 years, a demand with high priority for society as well as politics is the replacement of fossil-based products and synthetic polymers derived therefrom in our daily life needs. In line with sustainability, protection of resources, and most importantly, care for the environment in all aspects, polysaccharides from renewable resources are most suited to fulfil this role. A few examples of necessary actions and opportunities in these three major areas are described below. In chemistry, we envision the adaptation of highly efficient chemical and chemo-enzymatical synthesis into polysaccharide research and the development of methods for the fabrication of novel types of semi-synthetic polysaccharide derivatives, well-defined all-poly-saccharide-co-polymers, and combined co-polymers of polysaccharides with other biopolymers such as polypeptides for advanced applications. In biology, we foresee the production of polysaccharide assemblies of defined molecular structure (in particular regarding the degree of polymerisation, polymer backbone, and branching pattern) using novel chemo-enzymatic procedures harnessing a combination of *in vivo* and *in vitro* synthetic biology, elucidation of polysaccharide biosynthetic pathways using multidisciplinary approaches and the development of methods for the *in situ* analysis of intact biological assemblies at a nanometer scale. In physics, we envisage the development of fundamental research to tune the chain dynamics and interactions of polymer chains in polysaccharides and machine learning and AI for finding solutions based on new approaches and agreed protocols constructed in large data libraries. The concerted research activities will be triggered by the identification of the needs of society and environment - targets and demands will be identified, and tailored polysaccharide-based
Educating professionals and maintaining the skills of graduates working in the industry is used to circle back their competence to education (Fig. 6) and make it possible to iteratively identify skill gaps for the current and future needs of Europe. In the context of biopolymers and polysaccharides, an ambitious goal needs to be achieved by 2040: “A fully implemented educational system that provides professionals to Europe that are skilled in science and engineering as well as framework skills.”

### 7.3. Tools for enabling the vision

It is essential to combine the EC's education initiatives (e.g., digital education, key competencies, and inclusive and connected education in Europe) with the aims and opportunities of topic specific scientific and engineering focussed networks (such as EPNOE in the fields of bio-polymers and polysaccharides). Only then can the vision of a European education that is connected, inclusive, and of high quality become reality. Vital tools to (a) facilitate connectedness, high quality, and inclusiveness as well as (b) promote education in biopolymers and polysaccharides at the different professional stages are:

- mobility and training programs (e.g., ERASMUS+, Horizon Europe, Marie Skłodowska-Curie Actions, COST – European Cooperation in Science and Technology, CEEPUS – Central European Exchange Programme for University Studies)

- activities that strengthen cooperation between the different levels of educational institutions, research institutions, and companies

- employment of virtual tools that promote inclusiveness and accessibility of education

- virtual education platform that unites academia, industry, and the general public

- iterative systems to assess and validate key competencies and skill gaps for current and future needs

## 8. Summary & conclusion

Polysaccharides are abundantly available polymeric materials of today and tomorrow. Future sustainable materials based on polysaccharides will emerge for numerous targeted applications in engineering, materials science, food and nutrition and biomedical fields. In the context of a more sustainable planet and a more efficient circular economy, polysaccharides are very well-positioned to transition from fossil-based to sustainable biobased materials with equal or improved performances. The next generations of polysaccharides will find inspiration in nature in the attempt to mimic both form and function. The use of functional composites from sustainable and renewable resources will be pivotal in our future industrial practices. Polysaccharides can be used both as a continuous or a dispersed phase. The current increased digitalisation and continuous development around internet-of-things must be combined with sustainability. Polysaccharides will be strategic components for energy storage and harvesting, replacing fossil-based products for a wide range of industrial applications. Processing of polysaccharides must be economical and environmentally competitive. Although polysaccharides might appear as an inexhaustible resource, it is important to identify and study the available feedstock in relation to the techno-economical perspective for each specific product and application to enable a sustainable production. Interdisciplinarity combined with the sustainable and circular economy should be a general approach to advance.

Polysaccharides play a pivotal role in human nutrition and food structure design. Starches, being the major source of nutritional carbohydrates, were and remain to this date the prime focus of the research effort. However, the last two decades saw a growing interest in complex oligo- and polysaccharides and their assemblies that are not digestible by human enzymes. These types of carbohydrate materials are classified using the umbrella term *dietary fibre*. Importantly, dietary fibre influence

macronutrient digestibility and impact systemic, whole-body metabolism through a chain of events that begin with delaying gastric emptying and proceed to colonic fermentation of dietary fibre by the gut microbiome. Within the strategic horizon of the next two decades, a more detailed understanding of the structural characteristics and structure-function-relationships of dietary fibre will afford the development of targeted dietary fibre with programmable interactions, rheological properties (gelling, viscosifying), physiological response (fermentability, immune modulations), as well as techno-functional properties to benefit public health and sustainable food processing and manufacturing. This progress in understanding will require highly advanced analytical techniques based on chemical microscopy, NMR, and MS, for example.

The inherent biological and pharmacological activities, biocompatibility, biodegradability, distinctive physical and chemical properties of polysaccharide, and the versatility of their derivatives, have been extensively exploited to create biomaterials and medicinal products applied to clinical practice, under clinical trials or *in vivo* experiments. The scientific and biotechnological interest devoted to polysaccharides in biomedicine conflates five principal topics of research: (i) bioactive polysaccharides, (ii) cosmetics, (iii) drug delivery and nanomedicine, (iv) medical devices, and (v) tissue engineering and regenerative medicine. Within the strategic horizon of the next two decades, innovative clinical applications, processability, performance improvement, market introduction, and future perspectives of next-generation polysaccharide biomaterials will emerge, such as the development of new targeting agents and smart carriers for drugs, medical devices with anti-inflammatory, anti-infective, and anti-coagulant activities and expansion of emerging therapeutic applications on *in vitro* disease modelling, and microtissue formation and maturation. The toolbox of polysaccharides available and their inherent characteristics establish a comprehensive range of opportunities for the synergistic development of innovative systems. We expect these examples may outline future directions in biomedicine and biotechnology, which will expedite the clinical use of natural polysaccharide materials and prospect manufacturing and analysis processes.

Novel techniques and methods in chemistry, biology, and physics will provide innovative polysaccharide-based materials with defined properties on the molecular level that are specifically tailored for emerging applications. In the next 20 years, a demand with high priority for society as well as politics is the replacement of fossil-based products and synthetic polymers derived therefrom in our daily life needs. In line with sustainability, protection of resources, and most importantly, care for the environment in all aspects, polysaccharides from renewable resources are most suited to fulfil this role. A few examples of necessary actions and opportunities in these three major areas are described below. In chemistry, we envision the adaptation of highly efficient chemical and chemo-enzymatical synthesis into polysaccharide research and the development of methods for the fabrication of novel types of semi-synthetic polysaccharide derivatives, well-defined all-poly-saccharide-co-polymers, and combined co-polymers of polysaccharides with other biopolymers such as polypeptides for advanced applications. In biology, we foresee the production of polysaccharide assemblies of defined molecular structure (in particular regarding the degree of polymerisation, polymer backbone, and branching pattern) using novel chemo-enzymatic procedures harnessing a combination of *in vivo* and *in vitro* synthetic biology, elucidation of polysaccharide biosynthetic pathways using multidisciplinary approaches and the development of methods for the *in situ* analysis of intact biological assemblies at a nanometer scale. In physics, we envisage the development of fundamental research to tune the chain dynamics and interactions of polymer chains in polysaccharides and machine learning and AI for finding solutions based on new approaches and agreed protocols constructed in large data libraries. The concerted research activities will be triggered by the identification of the needs of society and environment - targets and demands will be identified, and tailored polysaccharide-based