Influence of the Macro- and/or Microstructure of Cross-Linked Hyaluronic Acid Hydrogels on the Release of Two Model Drugs

Abstract

Injectable hyaluronic acid (HA) hydrogels, crosslinked with 1,4-butanediol diglycidyl ether (BDDE), are widely used in aesthetic medicine. Due to their high clinical tolerance, HA hydrogels are thought to be applicable as injectable drug delivery systems. Here, HA matrix structures of BDDE-crosslinked HA hydrogels were analysed, and the effects of the structures on the release of two model drugs were assessed. Seven crosslinked HA hydrogels were observed by optical microscopy and cryo scanning electron microscopy (cryo-SEM). We observed three specific matrix macrostructures under optical microscopy: two had a "spider web"-like structure, three had a particulate structure, and two had an intermediate structure. These differences were less evident under cryo-SEM, where all hydrogels exhibited fibrous microstructures of different homogeneity levels, with pore sizes between 0.5 and 18 μm. Three cross-linked HA hydrogels with different macrostructures were loaded with bovine serum albumin (BSA) and lidocaine to assess their capacities to release drug over 4 days. No differences in drug release were observed between gels, and BSA was released for up to 4 days, which was four times longer than lidocaine. Thus, BDDEcrosslinked HA hydrogels could be applied as an injectable drug delivery system, particularly for the delivery of high-molecular-weight molecules.

Effectiveness evaluation of two volumizing hyaluronic acid dermal fillers in a controlled, randomized, double-blind, split-face clinical study

“…However, this is not the only parameter to consider. Research has demonstrated that manufacturing technologies have an impact on matrix structure 21 , 22 as well as gel rheological properties. 23 , 24 CPM-26 is manufactured with CPM technology, which creates a product with variable cross-linking densities within the gel, where denser areas ensure a volumizing effect and less dense areas ensure a lower extrusion force, high cohesivity and tissue integration of the matrix.…”

Key rheological properties of hyaluronic acid fillers: from tissue integration to product degradation

“…With the rising interest in the HA treatments and the increasing number of available HA fillers on the worldwide market, there is a strong demand from the medical community to better understand the science behind these products in order to optimize aesthetic outcomes and safety. Available HA fillers are designed with different manufacturing technologies [3,4] , different HA concentrations [5] , different crosslinked three-dimensional network structures [6] , different pore size distributions of the fibrous HA networks [6] , and different cohesivity levels [7] and rheological properties [8,9] . Among the proprietary manufacturing technologies, which all allow obtaining specific rheological properties, we can mention the VYCROSS™ (Allergan Inc., Irvine, CA, USA), the NASHA™ (Galderma Pharma S.A., Lausanne, Switzerland) and the CPM™ (Merz Pharmaceuticals GmbH, Frankfurt am Main, Germany) technologies.…”

Toward Physicochemical and Rheological Characterization of Different Injectable Hyaluronic Acid Dermal Fillers Cross-Linked with Polyethylene Glycol Diglycidyl Ether

“…Several studies on the matrix structure were previously performed using currently available cross-linked HA gels. Mondon and colleagues [ 10 ] demonstrated the possibility of highlighting three HA matrix structures, namely a “spiderweb”-like structure, a particulate structure and an intermediate structure. These differences were detected by optical microscopy, whereas they were less evident with the use of cryoscanning electron microscopy (cryo-SEM) [ 9 ].…”

“…This behavior shows that non-cross-linked hyaluronic acid has higher solubility than cross-linked fillers, resulting in lower cohesivity and a greater spread ability, as demonstrated by our studies ( Figure 5 and Figure 6 ). All the analyzed cross-linked hydrogels present a fibrous/porous network with different levels of homogeneity; on the basis of the description provided by Mondon [ 10 ], this spiderweb organization is a feature closely related to the category of monophasic gels. The correct classification is useful for clinicians to create a natural-looking correction based on the properties of each filler.…”

“…Concerning HA-based fillers, chemical cross-linking is a process that is able to confer a 3D structure to the linear chain of HA through the formation of covalent bonds between HA and a cross-linker agent, improving the biophysical properties while, at the same time, maintaining the biocompatibility and biological activity [ 9 ]. Many molecules and polymers are the subject of interest for this purpose; their quality as HA chemical modifiers is determined by the study of two parameters, namely the degree of substitution (DS) and the degree of cross-linking (DC) [ 10 ]. The most commonly employed cross-linkers are 1,4-butanediol diglycidyl ether (BDDE), 1,8-diepoxyoctane (DEO), divinyl sulfone (DVS) and polyethylene glycol diglycidyl ether (PEGDE) [ 4 , 11 ].…”