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7 Carbohydrate-Specific Monoclonal Antibody Therapeutics
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8
Carbohydrates inTissue Engineering
Laura Russo
1
Università degli Studi di Milano-Bicocca, Department of Biotechnology and Biosciences, Piazza della Scienza 2,
Milan, 20126, Italy
2
National University of Ireland Galway, CÚRAM SFI Research Centre for Medical Devices, Galway,
1,2
and Francesco Nicotra
1
8.1 Introduction
Carbohydrates cover both the cellular and acellular components of organs and tissues. Their role as signaling molecules is well established today[1]. The diversity
and dynamism of the sodefined “glycosignature” on cell surfaces and the extracellular matrix (ECM) partner proteins are still intriguing and not yet fully understood.
In the fields of tissue engineering and medical devices, carbohydrates play a fundamental role in both structural and signaling properties. The first applications in
fact took advantage of the structural properties of numerous polysaccharides, prone
to generate hydrogels[2, 3]. Hyaluronic acid (HA), for example, has been widely
employed for regenerative purposes because of its capacity to generate a wide range
of hydrogel formulations. Besides this structural role, carbohydrates can be exploited
in the development of medical devices for their unique property to participate in
recognition events of physiological and pathological relevance. In this context, it is
also important to take into account that glycans are differently expressed in humans
in various pathophysiological states and across different species[4], with a consequent problem in terms of antigenicity when a medical device is made of animal
derived materials[5, 6]. Here in this chapter, we will review the glycoengineered
solution for both medical devices and tissue engineering applications, taking into
consideration not only the advantages but also the dark side that limits their translation in clinics and the challenges for their further development.
223
Carbohydrate-Based Therapeutics, First Edition. Edited by Roberto Adamo and Luigi Lay.
© 2024 WILEY-VCH GmbH. Published 2024 by WILEY-VCH GmbH.

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224
8.2 Biomaterials and Medical Devices: Natural and
Synthetic Strategies
In the last decades, the advancement in medical device and biomaterials research
gave rise to different strategies to substitute or replace tissues and organs damaged
by pathologies or trauma[7]. Several different biomaterials are available on the market for this purpose, and great efforts are still in place to overcome the current limitations to safely apply them in clinics.
The traditional classification of biomaterials employed as tissue substitutes
includes natural polymers, synthetic polymers, hybrid materials, and naturally
derived organs and tissues[8–10]. Polysaccharides are relevant components of an
ideal biomaterial for their structural properties[11–14]. However, it is important to
pay attention to the fact that smaller glycans can act as xenoantigens [15, 16], in
particular those exposed in animalderived prosthesis and medical devices. As often
in biomedical research, the current design of biocompatible materials replacing tissue structure and functions takes inspiration from Nature. Polysaccharides are present in natural ECMs as glycosaminoglycans (GAGs) and proteoglycans (PGs),
whereas N and Oglycosylation cover cell surface and act as a signature to interact
with proteinbased components of the ECM [3, 17, 18]. In this large plethora of
actors, glycans cover a multitude of roles fundamental to finely regulating tissue
morphogenesis and homeostasis. Depending on the features of the organ or tissue
that must be repaired or substituted, the origin of the damage (pathological or traumatic), its morphological features and functionalities, different classes of biomaterials can be exploited. The current approach to repair tissue damage includes both
total substitution[19] or the induction of tissue regenerationexploiting bioresponsive biomaterials able to stimulate the repair of the damaged tissue[20]. The traditional substitution approach requires the use of permanent prosthesis, whereas in
regenerative approaches, biodegradable biomaterials able to induce regeneration
invivo or exvivo are used. In the following paragraph, we will overview the role of
glycans in both approaches, presenting and discussing the devices already used in
clinical applications and the strategies studied for future developments.
8.2.1 Carbohydrates asBuilding Blocks forMedical
Device Formulation
Natural polysaccharides are largely employed in the formulation or coating of medical devices[2]. Those of human origin, even if in principle biocompatible, present
significant limitations related to availability and scaleup. Production by recombinant methodologies can be a solution, like in the case of HA[21]. A practical alternative consists of their isolation from vegetal or animal sources in which they are
abundant, provided that they are biocompatible and functional. The unique way to
obtain employable batches of sulfated polysaccharides, for example, is the extraction of them from animal source[22].

8.2 Biomaterials and Medical Devices: Natural and Synthetic Strategies
Heparan sulfate
8.2.1.1 Human Polysaccharides: Glycosaminoglycans (GAGs) and
Proteoglycans (PGs)
Polysaccharides like HA, heparan sulfate (HS), heparin, and chondroitin sulfate
(CS) (see Figure8.1) are naturally expressed in all human tissues and organs and
contribute to the physical properties and physiological function of the tissues of
reference[23]. They have been used in the formulation of bioactive medical devices
to perform their natural functions (structural and functional), properly affected by
functionalization and crosslinking that modulate the bioactivity and degradation
rate[24].
Since 1934, HA has been the most employed polysaccharide for the development
of medical devices, tissue engineering strategies, and cosmetic formulations[25].
Differentially crosslinked HA has been developed to produce dried matrix or injectable hydrogels, depending on the final application of interest[25]. The main fields
of application of HA include neurosurgery, orthopedy, and woundhealing treatment of the skin affected by trauma or pathologies[26]. Several examples of commercially available HAbased materials are currently employed in clinical practices.
The use of HAbased biomaterials for tissue regeneration takes inspiration from its
natural functions; the use in wound healing[4–6], for example, is inspired by the
massive presence of HA in the normal epidermis, where it plays a fundamental role
in the maintenance of tissue mechanical properties and hydration, as far as in cell
migration and proliferation. Remarkably, HAbased materials are also effective in
extreme disruptive conditions like chronic damage[27]. The fast invivo degradation
of HA is still one of the major limitations for its efficacious application in medical
devices, therefore requiring stabilization strategies. To stabilize HA and finely tune
the structural properties without affecting the biological properties[28], different
225
O
O
O
O
O
HO
OR
–
R1 = H or SO
3
Chondroitin sulphate
O
HO
OR
O O
R= H or SO
O
3
–
3
O
HO
OH
O
O
O
O
OH
HO
NH
OR
O
2
O
NHR
n
R= H or SO
O
1
n
–
3
OH
O
HO
O
S
O
O
O
R1 = SO
O
OH
Hyaluronic acid
O
–
OOC
O
O
R
2
–
or Ac; R2 = H or SO
3
Heparin
O
O
HO
R1HN
Figure8.1 Examples of polysaccharides expressed in human tissues.
OR
OR
1
O
NH
O
–
R3 = H or SO
3
O
HO
R1 = Ac or SO
O
O
2
O
O
NHR
n
–
3
O
S
O
O
1
n
–
3
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