Abstract
Biomaterials have long been explored in regenerative medicine strategies for the repair or replacement of damaged organs and tissues, due to their biocompatibility, versatile physicochemical properties and tuneable mechanical cues capable of matching those of native tissues. However, poor adhesion under wet conditions (such as those found in tissues) has thus far limited their wider application. Indeed, despite its favourable physicochemical properties, facile gelation and biocompatibility, gellan gum (GG)-based hydrogels lack the tissue adhesiveness required for effective clinical use. Aiming at assessing whether substitution of GG by dopamine (DA) could be a suitable approach to overcome this problem, database searches were conducted on PubMed® and Embase® up to 2 March 2021, for studies using biomaterials covalently modified with a catechol-containing substituent conferring improved adhesion properties. In this regard, a total of 47 reports (out of 700 manuscripts, ~6.7%) were found to comply with the search/selection criteria, the majority of which (34/47, ~72%) were describing the modification of natural polymers, such as chitosan (11/47, ~23%) and hyaluronic acid (6/47, ~13%); conjugation of dopamine (as catechol “donor”) via carbodiimide coupling chemistry was also predominant. Importantly, modification with DA did not impact the biocompatibility and mechanical properties of the biomaterials and resulting hydrogels. Overall, there is ample evidence in the literature that the bioinspired substitution of polymers of natural and synthetic origin by DA or other catechol moieties greatly improves adhesion to biological tissues (and other inorganic surfaces).
Highlights
The concept of regenerative medicine has been around for many decades
Among the manuscripts selected for inclusion, a large majority corresponded to studies dated from 2014, 2019 and 2020 (32/47, ~68%; Figure 3b) using naturally sourced polymers (34/47, ~72%; Figure 3c), and predominantly the shellfish-derived polysaccharide chitosan, either per se (8/47) or blended with other polymers (3/47, for a total of 11/47, ~23% of total, ~32% of natural polymers; Figure 3d)
Several strategies can be employed to minimise these adverse effects, including the optimisation of biomaterial surfaces to decrease hydrophilicity/wettability and the fine-tuning of biomaterial viscosity to increase the formation of interlocking structures with tissues, which are less prone to be affected by water
Summary
The concept of regenerative medicine has been around for many decades. From the capacity of newts (i.e., small urodele amphibians) to repeatedly regenerate their limbs [1], to human organ and bone marrow transplantation procedures [2], there is abundant evidence in nature and clinical practice of the ability to regenerate dysfunctional or diseased organs and tissues. Unmodified GG is severely limited by (i) low aqueous solubility (requiring heating to around 90 ◦C for preparation of solutions at 1%), (ii) inconvenient thermo-reversible gelation above physiological temperature (40–42 ◦C), and (iii) limited adhesiveness to biological structures For this reason, GG has been modified to optimise its physicochemical and biological properties. The semi-synthetic methacrylated GG (GG-MA, Figure 1), obtainable by the reaction of GG with glycidyl methacrylate [7], displays enhanced water solubility (so that solutions at 1–2% can be prepared in water at room temperature) and is capable of crosslinking mediated by monovalent and divalent cations, as well as by ultraviolet light (due to the methacrylate substituent) Both ionic- and photo-crosslinked GG-MA hydrogels have been shown to be biocompatible [8], with improved in vivo performance reported for cartilage repair procedures [9]. Despite improvements in terms of the aqueous solubility and physicochemical properties of GG and its second-generation derivative GG-MA, the tissue adhesiveness of native and semi-synthetic GG hydrogels remains problematic, especially for applications that require integration of the hydrogels with surrounding structures, such as cartilage
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