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1,4-Butanediol diglycidyl ether (BDDE) crosslinked hyaluronic acid (HA) suspended in three different HAs (697, 1058, 1368 kDa) were prepared to investigate the effect of HA molecular weight on swelling property and elastic modulus of the hydrogels. The amount of the residual BDDE after final dialysis was less than 0.5 ppm. The highest swelling rati...
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Context 1
... different HAs are crosslinked with BDDE (0, 0.3, 0.5, 1.0 w/v%) to extend the duration because uncrosslinked HA is completely metabolized a few day after injection. 12 The epoxide groups in BDDE preferentially react with the alcohol in the HA backbone, forming an ether bond connections, as depicted in Figure 2. The presence of residual BDDE after dialysis was evaluated by using a GC, as shown in Figure 3. Since the BDDE, detected at 4.8 min in GC graph (Figure 3), is likely to be the mutagenic potential, the amount of unreacted residual BDDE is maintained at trace amounts of <2 ppm, which has been determined to be safe after a Food and Drug Administration (FDA). ...
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Hyaluronic acid (HA) or hyaluronan is a naturally occurring linear polysaccharide that is widely used to make hydrogels for biomedical applications. There are many different macromolecular structures that are possible for physical and chemical hydrogels; they include: the crosslinked or entangled networks of linear homopolymers, linear copolymers,...
Citations
... Its main functions are to draw water into the tissues, volumizing and giving structure to the skin by binding collagen and elastin fibres into a supportive matrix. [1][2][3][4] Additionally, HA intervenes in inflammation regulation, drug delivery, angiogenesis, cell migration and proliferation (caused by HA binding itself specifically to proteins that are responsible for these processes, whether they are in the extracellular matrix, on the cell surface, where they're called hyaladherins, or in the cellular cytosol), wound healing (based on its antioxidant properties and ability to eliminate free radicals), and cancer progression (based on its hydrodynamics and ability to interact with tumour cell surfaces and influence the porosity and malleability of extracellular and pericellular matrices, and also based on the fact that an increase in HA links to apoptosis, invasiveness, and drug resistance). [5][6][7][8][9][10][11][12] HA was first discovered in 1934 at Colombia University of New York by two American scientists, Karl Meyer and John Palmer, when they isolated it from bovine vitreous humor. ...
... Whether it is derived from animal or bacterial cultures, its structure is identical, consisting of repeating units of nonsulphated disaccharide, which include molecules of D-glucuronic acid and N-acetylglucosamine, linked by β-(1-4) and β-(1-3) glycosides. [1][2][3]11,13,18,19 In each monomer, the HA molecule contains a carboxylic acid and a primary alcohol, which are important for recognition by hyaladherins, and an amide, which improves the adhesive properties of the molecule. 12 Each disaccharide monomer has a molecular weight of around 400 Da, and the complete polymer can reach a total of 10 MDa. ...
... These cross-linking agents modify the HA by creating "bridges" (ether bonds) between its molecules, which increase the filler's biostability by transforming the filler from a viscous liquid into a gel and making it harder for the filler to be degraded by hyaluronidase and increasing resistance to oxidative stress. 2,3,14,[18][19][20][21]32 Cross-linking degree is reported by many as the most influential factor for rheological properties, particularly when it comes to gel stiffness. 31 However, even though they are rare, hypersensitivity reactions tend to happen because of the cross-linking process that is caused by the epoxide groups in the residual BDDE (a BDDE molecule that hasn't reacted with any other molecules). ...
Synopsis Hyaluronic acid’s (HA) main functions are absorbing water into the tissues and structuring the skin. It is mostly used in dermal fillers, treatments for certain diseases, and wound healing. This study intends to review current literature of HA’s rheology and its physicochemical properties as an injectable filler. Data were acquired from articles concerning HA-based biomaterials published within the last 25 years in PubMed and ScienceDirect. The MeSH terms “hyaluronic acid” and “dermal fillers,” were used either alone or combined with “rheology,” “physicochemical concepts,” “cross-linking reagents,” “viscoelastic substances,” “cohesivity,” and “cosmetic techniques.” Some articles not found during the initial search were chosen from the reference lists of previously selected publications. All articles that fit in the theme were considered valid regardless of study type. Available literature describes intrinsic properties of HA as a glycosaminoglycan. As an injectable filler, its rheology (viscoelasticity and cohesivity) and its physicochemical properties (cross-linking, hydrophilia, particle size, and HA concentration) define its clinical behavior by influencing its longevity, lifting capacity, resistance to external forces, and needle extrusion force. HA is promising as a dermal filler and healing agent. Understanding its properties is essential, as each patient benefits from different products. Future research should continue to explore these propertie
... An HA filler close to its equilibrium has already reached its hydration capacity and then has a low swelling factor; a filler far from its equilibrium has a higher swelling factor and hydration capacity. All crosslinked HA fillers absorb added solvent and swell, but they can swell only to a certain level as is determined by the polymer network thickness and by the grade of crosslinking [13,65,66]. The crosslink grade determines the capability of the polymer chains to remain bonded together, limiting the chains from outdistance, reducing water molecule penetration and binding. ...
Hyaluronic acid (HA) fillers have become the most popular material for facial volume augmentation and wrinkle correction. Several filler brands are currently on the market all around the world and their features are extremely variable; for this reason, most users are unaware of their differences. The study of filler rheology has become a wellspring of knowledge, differentiating HA fillers, although these properties are not described thoroughly by the manufacturers. The authors of this review describe the more useful rheological properties that can help clinicians understand filler characteristics and the likely correlation of these features with clinical outcomes.
... potentially leading to harmful adverse reactions.17 Main dermal filler products discussed in this review, all commonly used in the UK ...
Soft‐tissue augmentation has gained much popularity in recent years. Hyaluronic acid (HA) based dermal fillers; a non‐permanent injectable device, can restore volume loss, fill fine lines and wrinkles and add curves and contours. HA based dermal fillers entered the non‐surgical treatment market in the late 1990's, however there is a lack of data and literature comparing the range of products and detailing the complexities of these products and how it relates to tissue performance. Measuring the physico‐chemical properties of these dermal fillers provide key parameters to predict their performance after injection into the body. This article reviews the currently reported methods and parameters used to characterize dermal fillers. The review of these methods and data from the literature provides a useful guide to clinicians and injectors in selecting the optimal product suitable for the needs of each patient This article is protected by copyright. All rights reserved.
... The degree of swelling of a hydrogel can be calculated using gravimetry, the measured change in weight after liquid uptake. 7,10,13,15 A precision balance (Mettler AK160; Mettler Toledo) and a fixed-angle rotor centrifuge (EBA 20; Hettich Centrifuges) were used. ...
... Because water uptake is reduced by chemical modification of HA hydrogel, the higher the crosslinking, the lower the swelling degree. 10,15 There is one study reporting swelling factor for CPM ® technology (BEL B 16.9 ml/g), but a different study protocol with higher volumes was used; therefore, values cannot be compared directly. 9 Another study described the water uptake as a Three studies have reported comprehensive rheological values for BEL B allowing this gel to be characterized as a viscoelastic gel (tan delta <1, G′ > G′′). ...
Background
The clinical indications, applications, and effect of the injectable hyaluronic acid range skin quality boosters (SQBs) are different than those of filler products. Material properties are increasingly being discussed for differentiation and in connection with clinical effects and esthetic indications.
Aims
The aim of this study is to evaluate whether SQB products can be differentiated from filler products by their physicochemical material properties.
Material and methods
Physicochemical properties (extrusion force, swelling degree, rheology, and cohesivity) of two SQBs (BELR, JUVVE) were compared with those of fillers (BELB, JUVVT) using the same manufacturing technology.
Results
Cohesivity was almost equal for SQBs and fillers. Few statistically significant differences in physicochemical properties were found. Properties of SQBs differed from fillers mainly in their delta of rheological properties and extrusion force.
Conclusion
In this study, physicochemical differences between SQB and filler were determined and described, supporting the presence of two categories and their different clinical indications and applications.
... Application Reference HA 1 -collagen matrix cartilage tissue repair and neural regeneration [40,41] HA-gelatin hydrogels bone regeneration and chondrogenic differentiation [42][43][44][45] HA-CHI 2 composite cartilage TE [36,46,47] oxi-HA-resveratrol hydrogel cell carrier for chondrocytes [48,49] PGS-PCL-Me-HA heart valve TE [50] Alginate-HA myocardial TE [51] thiolated-HA hydrogels Adipose-substitutes TE [52][53][54] collagen-PEG-grafted-HA intradermal drug delivery [55] oxi-HA-gelatin microspheres drug delivery [56] HA-g-poly-(HEMA) lung TE [57] HA-ADH 3 -EDCI 4 drug delivery [58,59] HA-DVS 5 viscosupplement [60,61] HA-BDDE 6 viscosupplement [62][63][64] HA-PRP 7 regenerative medicine [65][66][67] ...
Hyaluronic acid (HA) is a natural polyelectrolyte abundant in mammalian connective tissues, such as cartilage and skin. Both endogenous and exogenous HA produced by fermentation have similar physicochemical, rheological, and biological properties, leading to medical and dermo-cosmetic products. Chemical modifications such as cross-linking or conjugation in target groups of the HA molecule improve its properties and in vivo stability, expanding its applications. Currently, HA-based scaffolds and matrices are of great interest in tissue engineering and regenerative medicine. However, the partial oxidation of the proximal hydroxyl groups in HA to electrophilic aldehydes mediated by periodate is still rarely investigated. The introduced aldehyde groups in the HA backbone allow spontaneous cross-linking with adipic dihydrazide (ADH), thermosensitivity, and noncytotoxicity to the hydrogels, which are advantageous for medical applications. This review provides an overview of the physicochemical properties of HA and its usual chemical modifications to better understand oxi-HA/ADH hydrogels, their functional properties modulated by the oxidation degree and ADH concentration, and the current clinical research. Finally, it discusses the development of biomaterials based on oxi-HA/ADH as a novel approach in tissue engineering and regenerative medicine.
... Porous scaffolds play a pivotal role in tissue engineering, making them suitable for cell ingrowth, 1-3 water or biological fluid retention capacity, 4 5 new tissue formation, and nutrient and oxygen transport. [6][7][8][9][10][11][12][13][14][15] Scaffolds with interconnected pore networks, 1-3 high surface area, 4 5 structural integrity, 6 and adequate biodegradation provide desirable conditions for the treatment of skin wounds. 7 Porous networks can contain large amounts of water or biological fluids, as well as facilitate cell and nutrient transport. ...
... The chemical properties of the g/P scaffold were examined by Fourier transform infrared spectroscopy (FT-IR, Spectrum Two, PerkinElmer, UK). 8 14-20 The morphologies of the g/P scaffolds were examined using a scanning electron microscope (SEM, S-3000H, Hitachi, Japan) and an optical microscope (SV-55, Sometech, Korea). [14][15][16][17][18][19][20] The compressive strength of the g/P scaffolds was examined using an Instron 5564 with a crosshead speed of 10 mm/min. 8 9 The specimen ( : 10 mm, t: 5 mm) was fabricated and the strength was determined at the point where the thickness of the specimen decreased by 50%. ...
... 3 The cytotoxicity of the g/P scaffolds as a function of the g/P ratio in the range of 10/0 to 7/3 determines whether a product or compound will have a toxic effect on living cells. [14][15][16][17][18][19][20] The test extracts with the scaffolds, regardless of the g/P ratio, showed no evidence of L-929 cell lysis or toxicity, as depicted in Figure 6. The g/P scaffolds containing a g/P ratio of 10/0, 9/1, 8/2, and 7/3 exhibited cell viabilities of 116%, 197%, 115%, and 124%, respectively, compared to the negative control as measured at a wavelength of 415 nm using a microplate absorbance spectrophotometer. ...
Gelatin/polyvinyl alcohol (PVA) (g/P) porous scaffolds with a glutaraldehyde/g ratio of 3 were synthesized by freeze/thaw and lyophilization to evaluate the effect of the g/P ratio (10/0 to 7/3) on the mechanical properties and cell growth behavior of the scaffolds. Fourier transform infrared spectroscopy results showed that the g/P scaffolds exhibited good crosslinking between gelatin and gelatin (imine), PVA and PVA (acetal group), and gelatin and PVA (imine). The pore size decreased gradually from 170 ± 63 m, to 140 ± 60 m, 129 ± 64 m, and 74 ± 23 m by varying the g/P ratio from 10/0, to 9/1, 8/2, and 7/3, respectively. As the g/P ratio was changed from 10/0 to 7/3, the compressive strength and swelling rate increased gradually from 150 ± 17 kPa to 290 ± 28 kPa and 1268 ± 11% to 1640 ± 35%, respectively. Among the scaffolds, 7/3 g/P scaffolds with tailored properties are suitable for wound healing.
... With aging, the total amount of HA decreases, contributing to the disorganization of collagen and elastin fibers and to reduced water binding with a consistent loss of moisture. Apparent dehydration, reduced turgidity and loss of elasticity are among the most common changes that characterize skin aging [3]. Over the last few years, increasing attention has been paid to appearance, increasing the demand for HA-based dermal fillers, which have become the material of choice in corrective medical practice. ...
... Dermal hyaluronic acid fillers are widely used in medical rejuvenation applications to restore lost volume and revitalize skin appearance [3]. Matex Lab S.p.A. focused its research toward an innovative and advanced SXT cross-linking technology based on the use of PEGDE as a cross-linker. ...
(1) Background: Injectable hyaluronic acid (HA) dermal fillers are used to restore volume, hydration and skin tone in aesthetic medicine. HA fillers differ from each other due to their cross-linking technologies, with the aim to increase mechanical and biological activities. One of the most recent and promising cross-linkers is polyethylene glycol diglycidyl ether (PEGDE), used by the company Matex Lab S.p.A., (Brindisi, Italy) to create the HA dermal filler PEGDE family. Over the last few years, several studies have been performed to investigate the biocompatibility and biodegradability of these formulations, but little information is available regarding their matrix structure, rheological and physicochemical properties related to their cross-linking technologies, the HA content or the degree of cross-linking. (2) Methods: Seven different injectable HA hydrogels were subjected to optical microscopic examination, cohesivity evaluation and rheological characterization in order to investigate their behavior. (3) Results: The analyzed cross-linked dermal fillers showed a fibrous “spiderweb-like” matrix structure, with each medical device presenting different and peculiar rheological features. Except for HA non cross-linked hydrogel 18 mg/mL, all showed an elastic and cohesive profile. (4) Conclusions: The comparative analysis with other literature works makes a preliminary characterization of these injectable medical devices possible.
... Hyaluronidase and free radical-mediated degradation is the natural elimination process of HA filler because of constant exposure to endogenous hyaluronidase and free radical Pharmaceutics 2021, 13, 133 9 of 12 oxidation [4,25]. The swelling of HA dermal filler is known to follow first-order kinetics in in vitro swelling tests, in accordance with the following equations [26][27][28][29][30]. ...
Dermal fillers are gel-type substances for nonsurgical medical-device use to achieve facial rejuvenation. Currently, the most widely used skin fillers are hyaluronic-acid-based dermal fillers. This study aimed to explain the change in the volume of injected dermal fillers by developing a mathematical kinetic model for various dermal fillers. The kinetics of the injected fillers were separated by a biphasic phenomenon. We attributed an increase in filler volume to the hydration of hyaluronic acid molecules and injection-site reaction and a decrease in volume to enzyme-mediated degradation. To explain these in vivo characteristics of dermal fillers, we proposed a two-compartment model, divided into a depot compartment (where the filler was injected) and a subcutaneous compartment (an observation compartment where the fillers swell and degrade), assuming that the swelling and degradation occurred in accordance with the swelling and degradation rate constants, respectively. The model was developed using five hyaluronic-acid-based dermal fillers and NONMEM. We determined that the rate-limiting step for the complete degradation of the dermal fillers in vivo was the swelling phase, as described by the swelling rate constant (Kswell). This study could enable scientists developing novel dermal fillers to predict the in vivo behavior of fillers.
... It is believed that as the MW increases, the resulting material after swelling will have a larger mesh size, resulting in a higher swelling ratio (Park et al., 2009). A previous study has reported that the HA 1,368 kDa film possessed a significantly higher swelling ratio than HA 1,058 and 697 kDa films (Lee et al., 2015). The swelling ratio of scaffolds reached their maximum about 60 min, and then the values were gradually decreased. ...
Interest is rapidly growing in the design and preparation of bioactive scaffolds, mimicking the biochemical composition and physical microstructure for tissue repair. In this study, a biomimetic biomaterial with nanofibrous architecture composed of silk fibroin and hyaluronic acid (HA) was prepared. Silk fibroin nanofiber was firstly assembled in water and then used as the nanostructural cue; after blending with hyaluronan (silk:HA = 10:1) and the process of freeze-drying, the resulting composite scaffolds exhibited a desirable 3D porous structure and specific nanofiber features. These scaffolds were very porous with the porosity up to 99%. The mean compressive modulus of silk-HA scaffolds with HA MW of 0.6, 1.6, and 2.6 × 10 ⁶ Da was about 28.3, 30.2, and 29.8 kPa, respectively, all these values were much higher than that of pure silk scaffold (27.5 kPa). This scaffold showed good biocompatibility with bone marrow mesenchymal stem cells, and it enhanced the cellular proliferation significantly when compared with the plain silk fibroin. Collectively, the silk-hyaluronan composite scaffold with a nanofibrous structure and good biocompatibility was successfully prepared, which deserved further exploration as a biomimetic platform for mesenchymal stem cell-based therapy for tissue repair.
... Reportedly, products with an excessive degree of crosslinking have been found to have increased reactivity and may also increase the risk of inflammation and granuloma formation [42]. Nonetheless, a balanced degree of crosslinking may be beneficial in reducing the material swelling of the filler [43]. ...
Soft-tissue fillers made of hyaluronic acid and combined with lidocaine have recently become a popular tool in aesthetic medicine. Several manufacturers have developed their own proprietary formulae with varying manufacturing tools, concentrations, crosslinked three-dimensional network structures, pore size distributions of the fibrous networks, as well as cohesivity levels and rheological properties, lending fillers and filler ranges their unique properties and degradability profiles. One such range of hyaluronic acid fillers manufactured using the novel eXcellent three-dimensional reticulation (XTR™) technology was evaluated in comparison with other HA fillers and filler ranges by an independent research laboratory. Fillers manufactured with the XTR™ technology were shown to have characteristic rheological, crosslinking and biophysical factors that support the suitability of this filler range for certain patient profiles.
