We designed bioinspired cross-linkers based on desmosine, the cross-linker in natural elastin, to prepare hydrogels with thiolated hyaluronic acid. These short, rigid cross-linkers are based on pyridinium salts (as in desmosine) and can connect two polymer backbones. Generally, the obtained semi-synthetic hydrogels are form-stable, can withstand repeated stress, have a large linear-elastic range, and show strain stiffening behavior typical for biopolymer networks. In addition, it is possible to introduce a positive charge to the core of the cross-linker without affecting the gelation efficiency, or consequently the network connectivity. However, the mechanical properties strongly depend on the charge of the cross-linker. The properties of the presented hydrogels can thus be tuned in a range important for engineering of soft tissues by controlling the cross-linking density and the charge of the cross-linker.
The aza-Michael reaction of amino-functionalized polymers with acrylate and acrylamide crosslinkers for the formation of hydrogels is investigated. It is studied how far the reaction conditions (pH value, chemical structures of the compounds involved) infl uence the crosslinking and degradation rate of the gels. When crosslinking the polymer poly(1-glycidylpiperazine), high pH values lead to fast crosslinking. Fast degradation of β -aminoester crosslinks is observed when acrylate crosslinkers are used due to a neighboring group effect. With acrylamide crosslinkers, hydrolytically stable gels are formed, in which the shear moduli and swelling ratio can be adjusted and in which the extracts show no toxic effect on primary human fi broblasts, making them a promising material for biotechnological applications. molecular structure that results in macroscopic properties like equilibrium degree of swelling (EDS), elastic moduli ( G ′ ), or degradation behavior. [ 2 ] In the fi eld of biomaterial science, hydrogels have found applications in a variety of A. Southan, [+] Dr.
The [1,1′‐biisoquinoline]‐4,4′‐diol (4a), which was obtained as hydrochloride 4a⋅2 HCl in two steps starting from the methoxymethyl (MOM)‐protected 1‐chloroisoquinoline 8 (Scheme 3), opens access to further O‐functionalized biisoquinoline derivatives. Compound 4a⋅2 HCl was esterified with 4‐(hexadecyloxy)benzoyl chloride (5b) to give the corresponding diester 3b (Scheme 4), which could not be obtained by Ni‐mediated homocoupling of 6b (Scheme 2). The ether derivative 2b was accessible in good yield by reaction of 4a⋅2 HCl with the respective alkyl bromide 9 under the conditions of Williamson etherification (Scheme 4). Slightly modified conditions were applied to the esterification of 4a⋅2 HCl with galloyl chlorides 10a–h as well as etherification of 4a⋅2 HCl with 6‐bromohexyl tris(alkyloxy)benzoates 11b,d–h and [(6‐bromohexyl)oxy]‐substituted pentakis(alkyloxy)triphenylenes 14a–c (Scheme 5). Despite the bulky substituents, the respective target 1,1′‐biisoquinolines 12, 13, and 15 were isolated in 14–86% yield (Table).
A small library of cross-linkers for hydrogels was synthesized. The cross-linkers consisted of 2,6-and 3,5-diacylpyridine or 2,4,6-triacylpyridine as the core unit, which were tethered via ethylene glycol, amino ethanol, and 1,n-diamine spacers to terminal acrylate or acrylamide moieties. Esterification and amide formation of the terminal acryl units were found to be dependent on the ratio of NH/O in the spacer, the constitution pattern of the pyridine ring, and the total number of acryl groups. Thus, esters generally gave higher yields than amides decreasing with increasing number of NH in the spacer and with increasing number of acryl units. In the case of 3,5-diacylpyridine derivatives, these trends were less prominent as compared to the 2,6-diacylpyridine series, indicating that steric hindrance and unfavorable hydrogen bonding interaction of the spacers might influence the observed reactivity differences. The 3,5-diacylpyridines were converted to the N-methylpyridinium salts and selected members of both neutral and cationic 3,5-diacylpyridinium derivatives were submitted to hydrogelations with synthetic polymer poly(1-glycidylpiperazine) via aza-Michael addition and thiolated natural hyaluronan via thio-Michael reaction, respectively. Rheological properties of the resulting hydrogels were studied, revealing that both spacer type as well as charge affected elastic moduli and degree of swelling.
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