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... Therefore, it is a measure of the hydrogel's elasticity and thus its capacity to resist deformation, such as the stress occurring during facial movements. The higher the G ′ , the higher its elasticity and resistance to deformation, creating a more stable product following its injection [4,23,24]. Products with different G ′ are used to target different areas and tissue layers of the face ( Figure 1). Products with a low G ′ are used for superficial tissue layers such as the dermis and promote hydration and enhance the skin quality, whereas products with a low-medium G ′ are used for deeper layers such as the superficial and deep fat layers to correct fine lines and increase volume [25]. ...
... deformation, such as the stress occurring during facial movements. The higher the G′, the higher its elasticity and resistance to deformation, creating a more stable product following its injection [4,23,24]. Products with different G′ are used to target different areas and tissue layers of the face (Figure 1). Products with a low G′ are used for superficial tissue layers such as the dermis and promote hydration and enhance the skin quality, whereas products with a low-medium G′ are used for deeper layers such as the superficial and deep fat layers to correct fine lines and increase volume [25]. ...
... It measures whether a filler is more elastic (solid/gel behavior) or more viscous (liquid behavior). The lower the tan δ, the higher the elastic elements (G ′ ) of the hydrogel [23,24]. A lower tan δ indicates a higher elasticity and storage modulus (G ′ ) [23]. ...
Article
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Hyaluronic acid (HA)-based dermal fillers are among the most popular non-invasive facial aesthetic treatments. To ensure an effective and safe treatment experience, knowledge of their biophysical and rheological characteristics, such as: HA concentration, molecular weight (MW), G′, and the degree of cross-linking is essential. Products with a higher MW, G′, and degree of cross-linking are more suitable for promoting volume and lift. Dermal fillers with a lower MW, G′, and degree of cross-linking can produce a soft filling effect that regulates hydration and elasticity. This review discusses how these rheological characteristics can inform treatment choice and their effects on clinical outcomes. The Aliaxin® line of HA dermal fillers, which are tailored to different clinical applications due to their rheological characteristics, highlights that extensive knowledge of the product can provide very safe and effective procedures for patients, whilst respecting their natural facial aesthetics. This review discusses studies using Aliaxin® dermal fillers for volumizing and hydrating treatments and fillers that can be used for lip augmentation. Treatment with Aliaxin® was overall very effective, with no reported adverse events. A full facial treatment using tailored dermal fillers may be a future approach to achieve an effective and safe harmonized and natural aesthetic.
... According to previous studies that compared the swelling ratios of different HA fillers, those with lower cross-linking density and G' were capable of absorbing more water and expand, even though expansion wasn't a direct variable and was instead deduced from water absorption [36,37]. ...
... As is shown in figure 9, all fillers expanded after being injected into the pig skin. This helps reenforce that clinicians should be careful when planning how much filler to inject into patients' skin, and that an under-filling may be beneficial [37], since it's expected that the initial volume will increase for at least up until 24 hours after the injection. ...
... A stronger gel, with higher G', crosslinking degree and viscosity, is expected to better resist deformation and lift the tissues [17,19,39]. Fillers with higher HA concentration and ratio of crosslinked HA/uncrosslinked HA similarly allow for bigger expansion [37]. Since lifting capacity correlates to how much projection fillers can induce, it would be expected that a filler meant to be applied in deeper planes of the skin and restore bigger volumes (such as Volume) should expand more, and a filler meant to be applied more superficially and correct more delicate fold and wrinkles (such as Fine Lines) should expand less [39]. ...
Article
Hyaluronic acid’s water absorption and expansion capacities define a filler’s ability to lift the tissues. Therefore, studying these properties is essential to better understand filler’s clinical performance. The aim of this study was to evaluate and compare water absorption and expansion (bidimensional and three-dimensional) of five Fillmed fillers (Universal, Fine Lines, Volume, Lips and Lips Soft). Water absorption was measured through swelling ratio 24 hours post-hydration. For two-dimensional expansion, samples were analysed quantitatively and qualitatively, using calibrated photographs, before and two hours after hydration. Three-dimensional volume was evaluated before and immediately after injecting the fillers, and 30 minutes, 2 hours and 24 hours post-injection in ex vivo pig skin. The tissue was scanned with the 3Shape TRIOS scanner and resulting STL files were compared. Group comparisons were analyzed with the one-way ANOVA test, and a p-value ≤ 0,05 was established. Lips showed a statistically higher swelling ratio than other fillers (p < 0,05). Fine Lines had the lowest swelling ratio, even if only statistically significant when compared to Universal (p= 0,021). Fine Lines had a significantly higher initial bidimensional width than all fillers (p <0,05) except Lips Soft. 24 hours post-injection, Fine Lines had the highest three-dimensional volume, which was statistically higher than Volume’s (p= 0,049). All fillers absorbed water and expanded, with Fine Lines tending to have the highest three-dimensional expansion, despite its lowest viscosity and water absorption. Further studies with larger sample sizes are needed to investigate the influence of other properties over water absorption and expansion.
... As is shown in Fig. 9, all llers expanded after being injected into the pig skin. This helps reenforce that clinicians should be careful when planning how much ller to inject into patients' skin, and that an underlling may be bene cial [24], since it's expected that the initial volume will increase for at least up until 24 hours after the injection. ...
... A stronger gel, with higher G', cross-linking degree and viscosity, is expected to better resist deformation and lift the tissues [8, 13,18]. Fillers with higher HA concentration and ratio of crosslinked HA/uncrosslinked HA similarly allow for bigger expansion [24]. Since lifting capacity correlates to how much projection llers can induce, it would be expected that a ller meant to be applied in deeper planes of the skin and restore bigger volumes (such as Volume) should expand more, and a ller meant to be applied more super cially and correct more delicate fold and wrinkles (such as Fine Lines) should expand less [18]. ...
... We aren't able to con rm this based on our results, since it was the least cohesive ller (Fine Lines) that showed the biggest capacity to expand vertically. Some papers mention that higher water absorption translates to a higher potential for volume increase [18,24], but such association was not perceived in this study, as Fine Lines expanded the most, even though it absorbed the least amount of water. ...
Preprint
Full-text available
Hyaluronic acid’s water absorption and expansion capacities define a filler’s ability to lift the tissues. Therefore, studying these properties is essential to better understand filler’s clinical performance. The aim of this study was to evaluate and compare water absorption and expansion (bidimensional and three-dimensional) of five Fillmed fillers (Universal, Fine Lines, Volume, Lips and Lips Soft). Water absorption was measured through swelling ratio 24 hours post-hydration. For two-dimensional expansion, samples were analysed quantitatively and qualitatively, using calibrated photographs, before and two hours after hydration. Three-dimensional volume was evaluated before and immediately after injecting the fillers, and 30 minutes, 2 hours and 24 hours post-injection in ex vivo pig skin. The tissue was scanned with the 3Shape TRIOS scanner and resulting STL files were compared. Group comparisons were analyzed with the one-way ANOVA test, and a p-value ≤ 0,05 was established. Lips showed a statistically higher swelling ratio than other fillers (p < 0,05). Fine Lines had the lowest swelling ratio, even if only statistically significant when compared to Universal (p = 0,021). Fine Lines had a significantly higher initial bidimensional width than all fillers (p < 0,05) except Lips Soft. 24 hours post-injection, Fine Lines had the highest three-dimensional volume, which was statistically higher than Volume’s (p = 0,049). All fillers absorbed water and expanded, with Fine Lines tending to have the highest three-dimensional expansion, despite its lowest viscosity and water absorption. Further studies with larger sample sizes are needed to investigate the influence of other properties over water absorption and expansion.
... In the field of aesthetic medicine, hyaluronic (HA)-based dermal fillers are among the most used products for the non-invasive treatment of skin defects. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] Characterization studies of the commercial gels are intensifying since strongly aiding clinicians in the optimal use of available products also contributing to the establishment of the correlation between the biophysical parameters of a gel and the clinical outcome. ...
... To predict relative in vivo permanence of HA gels, many in vitro studies have been performed on HA filler stability to enzymatic action while stability to ROS has been poorly investigated up to now. 6,[10][11][12][13] The current trend in HA-filler use aims to a "naturallooking" full face remodeling thanks to the availability of diverse formulations designed for specific needs, including Aliaxin gels. ...
... In the attempt to provide a complete panel of the flow behavior and of the hydration capacity of the gels, key properties for clinical outcome, secondary rheological parameters and evidence of the diverse water-uptake ability of the formulations were presented (Figures 1 and 2). 6,[13][14][15][16][17][18][19][20][21][22] The water absorption capacity of a filler is related to its in vivo hydro-action. The results of the hydration test ( Figure 1) are highly indicative of the huge hydration capacity of the Aliaxin gels. ...
Article
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Introduction Hyaluronic Acid (HA) fillers are among the most used products in cosmetic medicine. Companies offer different formulations to allow full facial treatment and/or remodeling. Gels are being studied to establish the biophysical properties behind the specific clinical use and a correlation between the gel biophysical properties and their clinical performance. Clinicians' awareness is growing about the potential benefit deriving from such biophysical characterization. Aim The Aliaxin® line of HA dermal fillers is the object of this study. The study aimed to widen the biophysical characterization of these gels by investigating a variety of properties to better support their optimal use. Further, we aimed to provide some clinical findings to gain a deeper insight into the correlation between filler features and clinical outcome. Methods The four gels of the line were investigated, for the first time, for their cohesivity and stability to Reactive Oxygen Species (ROS). Additional secondary rheological parameters; evidence of relative water-uptake ability; and some clinical findings on product safety, palpability and duration of the aesthetic effect are provided. Results and conclusion The gels proved highly cohesive and sensitive to ROS action with stability declining with the decrease in the overall gel elasticity. The G* and complex viscosity values at clinically relevant frequencies and gel water-uptake ability are consistent with the relative clinical indication related to gel projection and hydration capacity. Clinical outcomes showed the safety of the products and a perception of palpability well correlating with the cohesive/viscosity properties of the gels. A similar duration of the aesthetic effect (up to 1 year) was observed despite the diverse in vitro gel stability. The results broaden our knowledge of these gels and may contribute to optimize their clinical use towards the improvement of patient safety and satisfaction. Initial clinical observation indicated that gel biophysical properties allow for a reliable prediction of gel palpability, while in vitro data on gel stability cannot be related to the duration of the observed skin improvement. The latter finding further corroborates the idea of a skin restoration process activated by the gels besides the physical volumetric action.
... HA is widely applied as natural, modified, or auto-crosslinked molecules, or crosslinked with other molecules in different biomedical fields, including orthopedics, ophthalmology, dentistry, tissue repair, and cosmetics. The success of the medical applications of HA has led to several commercial products, a number of which have been evaluated in previous studies [1][2][3][4]. ...
... Chromatographic analyses of samples were performed using size exclusion chromatography coupled with a triple detection array (SEC-TDA) equipment from Viscotek (Malvern Instruments, Cambridge, U.K.). A detailed description of the system and its analytical conditions are reported elsewhere [2,23]. Rheological measurements were carried out using a Physica MCR301 oscillatory rheometer (Anton Paar, Ostfildern-Scharnhausen, Germany) equipped with a DG26.7/T200/AL ...
... (double gap) and a Peltier temperature control. Flow curves (dynamic viscosity as a function of the shear rate) were recorded as reported elsewhere [2]. Measurements were carried out at 25 • C over a shear rate of 0.01 to 300 s −1 . ...
Article
Full-text available
The effectiveness of hyaluronic acid (HA), also called as hyaluronan, and its formulations on tissue regeneration and epidermal disease is well-documented. High-molecular-weight hyaluronan (HHA) is an efficient space filler that maintains hydration, serves as a substrate for proteoglycan assembly, and is involved in wound healing. Recently, an innovative hybrid cooperative complex (HCC) of high- and low-molecular-weight hyaluronan was developed that is effective in wound healing and bioremodeling. The HCC proposed here consisted of a new formulation and contained 1.6 ± 0.1 kDa HHA and 250 ± 7 kDa LHA (low molecular weight hyaluronic acid). We investigated the performance of this HCC in a novel in vitro HaCaT (immortalized human keratinocytes)/HDF (human dermal fibroblast) co-culture model to assess its ability to repair skin tissue lesions. Compared to linear HA samples, HCC reduced the biomarkers of inflammation (Transforming Growth Factor-β (TGF-β), Tumor Necrosis Factor receptor-α (TNF-α), interleukin-6 (IL-6), and interleukin-8 (IL-8)), and accelerated the healing process. These data were confirmed by the modulation of metalloproteases (MMPs) and elastin, and were compatible with a prospectively reduced risk of scar formation. We also examined the expression of defensin-2, an antimicrobial peptide, in the presence of hyaluronan, showing a higher expression in the HCC-treated samples and suggesting a potential increase in antibacterial and immunomodulatory functions. Based on these in vitro data, the presence of HCC in creams or dressings would be expected to enhance the resolution of inflammation and accelerate the skin wound healing process.
... For instance, highly deformable gels are generally suggested for superficial injections, while volume restoration is achieved by using more rigid products able to maintain their shape under the stress of facial movements. Biophysical features of the gels are in turn dependent on manufacturing parameters such as the biopolymer crosslinking extent, the final gel concentration, the amount of soluble polymer in the formulation etc. [14][15][16][17][18][19][20][21]. ...
... As the understanding of processes governing facial aging improves, HA gel Biophysical characterization Soluble fraction quantification and hydrodynamic characterization. The water-soluble fraction of the gels was quantified as reported elsewhere [18,21]. Briefly, the gels were diluted to 4 mg/mL in PBS (1.0mL final volume). ...
... Hydration capacity. The hydration extent of the fillers was determined as previously reported, with slight modifications [18,21]. Specifically, 0,1mL (equivalent to 0,1g) of each filler was incubated in PBS (1.0mL final volume) at 37˚C under stirring (1000rpm) for 16h. ...
Article
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Biophysical and biochemical data on hyaluronan (HA)-based dermal fillers strongly support their optimal use and design to meet specific requisites. Here, four commercially available (in Europe) HA “volumetric” fillers, among the most used in the clinical practice, have been characterized in vitro. Analyses revealed the highest amounts of water-soluble HA reported so far and provided hydrodynamic data for these soluble polymeric fractions. Volumetric gels exhibit a wide range of rigidity with most of them showing G’ values around 200-300Pa. They greatly differ in cohesivity. 1mL of gel hydrates up to 2.4–3.2mL. The products completely solubilize due to Bovine Testicular Hyaluronidase (BTH)’s action, thus predicting in vivo complete resorption. For the first time, filler degradation due to reactive oxygen species (ROS) was studied by rheological measurements and a rank in stability was established. Studies using Human Dermal Fibroblasts (HDF) indicated a positive biological response to the HA networks. Further, gel capacity to prompt collagen I, elastin and aquaporin3 synthesis was demonstrated, thus suggesting a positive effect on skin elasticity and hydration, besides the physical volumetric action. The findings are the first wide assessment of features for the volumetric class of HA-fillers and include first data on their resistance to degradation by ROS and biological effects on HDF. The study represents a valuable contribution to the understanding of HA-fillers, useful to optimize their use and manufacture.
... The SEC-TDA (Size Exclusion Chromatography-Triple Detector Array) equipment by Viscotek (Viscotek, Malvern, UK) was used to accomplish a complete hydrodynamic characterization of the sample. A detailed description of the system and its analytical conditions are reported by us elsewhere [14,15]. The sample was diluted about 80fold in water in order to have a column load for each analysis (injection volume × sample concentration × intrinsic viscosity) within the range 0.2-0.4 ...
... The Mark-Houwink-Sakurada (MHS) curves (log [η] vs log M w ) were also directly obtained [14]. HA concentration in Aminogam® was derived by the SEC-TDA analyzes and determined also by means of the carbazole test which is usually employed to quantify HA in marketed formulations [15][16][17]. ...
... Specifically, when comparing the same molecular weight values, the intrinsic viscosity of the polymer responsible for this second signal is lower. This indicates a conformation far more compact than the one that HA molecules of the same length are known to exhibit [15,24]. These signals are likely to be due to PVP, which is a component of the formulation as declared by the manufacturer. ...
Article
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Hyaluronic acid (HA) preparations are widely used in clinical practice and recent data suggest that commercially available HA-based compounds promote ulcer re-epithelialization and induce pain relief. However, the pathophysiological basis of these effects remains poorly understood. In the present study, we investigated the biophysical, biomolecular and functional properties of a HA preparation combined with a pool of collagen precursor synthetic aminoacids, namely l-proline, l-leucine, l-lysine and glycine (Aminogam®). Hydrodynamic characterization of Aminogam® by size exclusion chromatography-triple detector array (SEC-TDA) revealed an average molecular weight in the range of 700–1700 kDa. Rheological measurements of the 1700kDa Mw lot showed a pseoudoplastic behaviour with a zero-shear viscosity (η0) equal to 90 ± 9 Pa∙s at 25°C and 55 ± 6 Pa∙s at 37°C. Automated time-lapse videomicroscopy studies in a fibroblast-free system demonstrated that 1% (v/v) Aminogam® significantly reduced the healing time of wounded keratinocyte monolayers. In AKGOS assays, Aminogam® stimulated cellular locomotion (chemokinesis) and directional migration (chemotaxis) of keratinocytes. Analysis of microarray data suggested that keratinocytes had a functional neuroendocrine machinery, and this was confirmed by testing the secretion of six neuroactive molecules by ELISA, namely α-MSH, β-endorphins, melatonin, substance P, cortisol, and neurotensin. Interestingly, Aminogam® regulated the production of several neuropeptides, including β-endorphins. In conclusion, our data shed light on the epithelial-dependent mechanisms that underlie the efficacy of Aminogam®, particularly in reference to wound healing and nociception.
... In its natural state, hyaluronic acid (HA) exhibits poor biomechanical properties as a dermal fillers due to the poor viscoelasticity and the short half-life of HA when injected into normal skin [1][2][3][4][5][6][7][8][9][10][11]. To provide the ability to lift and fill wrinkles in the skin, chemical modification is required to improve its mechanical properties. ...
... To provide the ability to lift and fill wrinkles in the skin, chemical modification is required to improve its mechanical properties. Crosslinking is attempted to improve biomechanical properties while maintaining biocompatibility and biological activity [1][2][3][4][5][6][7][8][9][10][11]. HA dermal fillers are classified into two types, monophasic and biphasic [3][4][5][6][7][8]. ...
... A 3-dimensional network of HAHs is easily formed when crosslinks between the HA chains are introduced. A strong gel has a high elasticity, meaning that the response to deformation is mainly elastic [2][3][4]. ...
Article
Full-text available
Background Hyaluronic acid (HA) dermal biphasic fillers are synthesized for their efficacy in correcting aesthetic defects such as wrinkles, scars and facial contouring defects. The fillers consist of crosslinked HA microspheres suspended in a noncrosslinked HA. To extend the duration of HAs within the dermis and obtain the particle texturing feel, HAs are crosslinked to obtain the suitable mechanical properties. Results Hyaluronic acid (HA) dermal biphasic fillers are prepared by mixing the crosslinked HA microspheres and the noncrosslinked HAs. The elastic modulus of the fillers increased with raising the volume fraction of the microspheres. The mechanical properties and the particle texturing feel of the fillers made from crosslinked HA (1058 kDa) microspheres suspended in noncrosslinked HA (1368 kDa) are successfully achieved, which are adequate for the fillers. Conclusions Dermal biphasic HA fillers made from 1058 kDa exhibit suitable elastic moduli (211 to 420 Pa) and particle texturing feel (scale 7 ~ 9).
... The HA samples and commercial products were characterized using SEC-TDA (Size Exclusion Chromatography-Triple Detector Array) equipment by Viscotek (Lab Service Analytica, Italy). A detailed description of the system and its analytical conditions were reported elsewhere (La Gatta, Schiraldi, Papa, & De Rosa, 2011;La Gatta, De Rosa, Marzaioli, Busico, & Schiraldi, 2010). The ...
... The intrinsic viscosity and hydrodynamic radius coherently varied with molecular weight and were consistent with literature data (La Gatta et al., 2013;La Gatta, Papa, Schiraldi, & De Rosa, 2016). The MHS curves of the linear HA samples overlap with the ones of commercial formulations (data not shown) indicating, as discussed above, equivalent conformation and, therefore, the presence of linear, naturally occurring HA in commercial products (La Gatta et al., 2010;Harding et al., 1992;Hokputsa et al., 2003;La Gatta et al., 2011). Overall, results in Table 2 indicate that the HA samples used cover the range of molecular weights found on the market. ...
... Actually, as it is shown inFigure 1a, the MHS curves (log [] vs log Mw) of the commercial samples evidently overlap. This means that chains from the diverse samples having the same molecular weight, also exhibit the same intrinsic viscosity, and therefore, the same hydrodynamic volume, the same arrangement (conformation) in solution (LaGatta et al., 2010;Harding, Rowe, & Horton, 1992;Hokputsa, Jumel, Alexander, & Harding, 2003;La Gatta et al., 2011). Finally, hydrodynamic analyses corroborated the limited data reported about the ranges of polymer molecular weights and concentrations generally encountered in the products on the market(Guillaumie et al., 2010;McDonald et al., 2002;Johnson et al., 2006;Liu et al., 2014). ...
Article
Full-text available
Hyaluronan (HA) is frequently incorporated in eye drops to extend the pre-corneal residence time, due to its viscosifying and mucoadhesive properties. Hydrodynamic and rheological evaluations of commercial products are first accomplished revealing molecular weights varying from about 360 to about 1200kDa and viscosity values in the range 3.7-24.2 mPa s. The latter suggest that most products could be optimized towards resistance to drainage from the ocular surface. Then, a study aiming to maximize the viscosity and mucoadhesiveness of HA-based preparations is performed. The effect of polymer chain length and concentration is investigated. For the whole range of molecular weights encountered in commercial products, the concentration maximizing performance is identified. Such concentration varies from 0.3 (wt%) for a 1100kDa HA up to 1.0 (wt%) for a 250kDa HA, which is 3-fold higher than the highest concentration on the market. The viscosity and mucoadhesion profiles of optimized formulations are superior than commercial products, especially under conditions simulating in vivo blinking. Thus longer retention on the corneal epithelium can be predicted. An enhanced capacity to protect corneal porcine epithelial cells from dehydration is also demonstrated in vitro. Overall, the results predict formulations with improved efficacy.
... More recently, the evaluation of biophysical features of marketed products has proven effective in supporting clinicians' choices [10] and then scientific efforts toward dermal fillers biophysical and biochemical characterization and studies on the correlation of these data to the clinical outcomes have increased [2,3,[8][9][10][11][12][13][14][15]. These studies have found that different manufacturing procedures result in different HA crosslinking degree and hydrogel particle size. ...
... Such properties, together with gel concentration, are responsible for different rheological behavior, water uptake (swelling), and resistance to degradation, characteristics that affect clinical performance (e.g. injectability, spreadability after injection, appropriateness of application site, lift capacity, duration of the effect, etc.) [2,3,[8][9][10][11][12][13][14][15]. ...
... The aim of this work was to apply current expertise in dermal filler characterization to this line of HA fillers to highlight differences between each other and to other marketed products and to predict relative clinical performance. In particular, among already commercialized products, Restylane, the first FDA approved dermal filler and, therefore, the one with the longest clinical history and the most extensive characterization, was selected for comparison [11,23]. A more recent product belonging to the Juvederm line of HA-based dermal fillers was also selected considering that this brand products lead, as well as Restylane, the market in HA fillers. ...
Article
Full-text available
Chemico-physical and biological characterization of hyaluronan based dermal fillers is of key importance to differentiate between numerous available products and to optimize their use. These studies on fillers are nowadays perceived as a reliable approach to predict their performance in vivo. The object of this paper is a recent line of hyaluronic acid (HA) based dermal fillers, Aliaxin®, available in different formulations that claim a complete facial restoration. The aim of the study is to provide biophysical and biological data that may support the clinical indications and allow to predict performance possibly with respect to similar available products. Aliaxin® formulations were tested for their content in soluble HA, water up-take capacity, rheological behavior, stability to enzymatic degradation and for in vitro capacity to stimulate extracellular matrix components production. The formulations were found to contain a low amount of soluble HA and were equivalent to each other regarding insoluble hydrogel concentration. The different crosslinking degree declared by the producer was consistent with the trend in water uptake capacity, rigidity, viscosity. No significant differences in stability to enzymatic hydrolysis were found. In vitro experiments, using a full thickness skin model, showed an increase in collagen production in the dermoepidermal junction.
... Some of these measures are useful to describe specific characteristics. Apart from crosslinking, the mechanical and physical properties of the hydrogels are also dependent on the degree of modification [26]. The relationship between degree of modification and of crosslinking to mechanical properties as well as to biocompatibility is of great importance and, as such, there are several methods that are used to describe this in literature [23,27]. ...
... All manufacturers declare the HA concentration (mg/mL) of the HA fillers; this refers to the total HA present in the formulations without specifying the amount of the insoluble crosslinked HA and of the non-crosslinked HA soluble fraction of the biopolymer. The soluble fraction is usually added to optimize the viscosity and improve the product extrusion through a needle of proper dimension or may originate from the small fragments of HA generated during the crosslinking process or the sterilization step [26,33,60]. It is easily metabolized and supposedly does not have any influence on the filler's characteristics involved in performance and effectiveness (i.e., injectability, spreadability, lifting capacity, duration, etc.) [61]. ...
Article
Full-text available
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.
... 18,[22][23][24][25] In addition, it has been shown to propagate the in ammatory response through the induction of macrophages and chemokine response, thus contributing to the healing process. [23][24][25][26][27][28] The use of a highly puri ed hyaluronic acid injectable, has been shown to have an e ect in wound healing in in-vitro studies, promoting broblast and keratinocyte proliferation and migration. [25][26][27][28] We believe that this contributes to the synergistic e ect of the HA injectable and the non-ablative laser used in our presented protocol. ...
... [23][24][25][26][27][28] The use of a highly puri ed hyaluronic acid injectable, has been shown to have an e ect in wound healing in in-vitro studies, promoting broblast and keratinocyte proliferation and migration. [25][26][27][28] We believe that this contributes to the synergistic e ect of the HA injectable and the non-ablative laser used in our presented protocol. ...
Article
Background: Postacne facial scars are often associated with significant patient distress. Energy-based devices, including non-ablative lasers, are commonly used for the treatment of postacne scarring. There is relatively limited data regarding the combination of non-ablative lasers with hyaluronic acid injections for postacne scarring. Objective: We aimed to evaluate the efficacy of a non-ablative 1,540-nm erbium:glass laser combined with a hyaluronic acid injectable for the treatment of postacne scars. Methods: This was a retrospective analysis of 12 patients who underwent the full treatment protocol. A before and after blinded clinical evaluation was performed independently by two dermatologists and graded on a scale from 0 (indicating a worsening of scarring) to 4 (indicating a 76-100% improvement in scarring). Pain perception, adverse effects, and patient satisfaction were evaluated. Results: A mean correct blinded before and after evaluation by two dermatologists was 96 percent. Patients demonstrated mild to moderate improvement as assessed by a quartile scale of improvement (25-50%). Mild transient pain was reported by most patients. The satisfaction level of the patients was high (4 out of 5). Limitations: The limitations of our study include the small cohort, retrospective design, and lack of a histological correlation. Conclusion: Our results suggest that this combination treatment using 1,540-nm fractional erbium:glass laser and hyaluronic acid injections is both safe and effective for patients with postacne facial scars.
... 5,7 When it is injected into the skin, it naturally degrades via enzymatic hydrolysis, showing relatively poor structural integrity and an insufficient ability of lift the skin. 17,18 Owing to its fast degradation, its bioactive effects decrease significantly over time, which has a negative effect on cell proliferation to produce new matrix under skin defects. 3 Thus, there have been many efforts to increase its stability by chemical crosslinking to provide gel networks 19,20 or by incorporating other materials to fabricate composite systems. ...
... In vivo persistence, another key factor for ideal injectable fillers, is highly dependent on sensitivity to enzymatic degradation. 17 Thus, a comparative analysis of the degradation profiles of the HAc-HAp composite and pure HAc fillers was performed using animal tests. For the evaluation of volumetric maintenance, MRI techniques are an efficient method for measuring filler volume. ...
Article
Hyaluronic acid (HAc)–hydroxyapatite (HAp) composite hydrogels were developed to improve the biostability and bioactivity of HAc for dermal filler applications. Two kinds of HAc-HAp composite fillers were generated: HAcmicroHAp and HAc-nanoHAp composites. HAc-microHAp was fabricated by mixing HAp microspheres with HAc hydrogels, and HAc-nanoHAp was made by in situ precipitation of nano-sized HAp particles in HAc hydrogels. Emphasis was placed on the effect of HAp on the durability and bioactivity of the fillers. Compared with the pure HAc filler, all of the HAc-HAp composite fillers exhibited significant improvements in volumetric maintenance based on in vivo tests owing to their reduced water content and higher degree of biointegration between the filler and surrounding tissues. HAc-HAp composite fillers also showed noticeable enhancement in dermis recovery, promoting collagen and elastic fiber formation. Based on their long-lasting durability and bioactivity, HAc-HAp composite fillers have great potential for soft tissue augmentation with multifunctionality.
... Though laser has been considered a golden alternative for direct treatment of nasolabial fold, dermal filler injection for skin rejuvenation has also become an evolving and emerging method that boosts facial rejuvenation rapidly and immediately.26 Commercial trending fillers comprise in hyaluronic acid (HA) combined with carriers to enhance its stability against fast hydrolysis properties.27,28 However, those crosslinked HA fillers display a weak tensile strength compared to other filler, which is less supportive scaffold under the skin.29,30 ...
Article
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Background Injectable filler, a nonsurgical beauty method, has gained popularity in rejuvenating sagging skin. In this study, polydioxanone (PDO) was utilized as the main component of the ULTRACOL200 filler that helps stimulate collagenesis and provide skin radiant effects. The study aimed to evaluate and compare the effectiveness of ULTRACOL200 with other commercialized products in visually improving dermatological problems. Methods Herein, 31 participants aged between 20 and 59 years were enrolled in the study. 1 mL of the testing product, as well as the quantity for the compared groups was injected into each participants face side individually. Subsequently, skin texture and sunken volume of skin were measured using ANTERA 3D CS imaging technology at three periods: before the application, 4 weeks after the initial application, and 4 weeks after the 2nd application of ULTRACOL200. Results The final results of skin texture and wrinkle volume evaluation consistently demonstrated significant enhancement. Consequently, subjective questionnaires were provided to the participants to evaluate the efficacy of the testing product, illustrating satisfactory responses after the twice applications. Conclusion The investigation has contributed substantially to the comprehension of a PDO‐based filler (ULTRACOL200) for skin enhancement and provided profound insight for future clinical trials.
... 113,114 However, due to the enzymatic activity of hyaluronidase which degrades hyaluronic acid inside the body, chemical crosslinking of HA is essential. 115 Viscosity, sheer thinning and self-healing are important parameters which impart injectable properties to a hydrogel. 116 4.3.1 Click-chemistry-based injectable organo-hydrogels. ...
Article
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The field of injectable hydrogels has demonstrated a paramount headway in the myriad of biomedical applications and paved a path toward clinical advancements. The innate superiority of hydrogels emerging from organic constitution has exhibited dominance in overcoming the bottlenecks associated with inorganic-based hydrogels in the biological milieu. Inorganic hydrogels demonstrate various disadvantages, including limited biocompatibility, degradability, a cumbersome synthesis process, high cost, and ecotoxicity. The excellent biocompatibility, eco-friendliness, and manufacturing convenience of organo-hydrogels have demonstrated to be promising in therapizing biomedical complexities with low toxicity and augmented bioavailability. This report manifests the realization of biomimetic organo-hydrogels with the development of bioresponsive and self-healing injectable organo-hydrogels in the emerging pharmaceutical revolution. Furthermore, the influence of click chemistry in this regime as a backbone in the pharmaceutical conveyor belt has been suggested to scale up production. Moreover, we propose an avant-garde design stratagem of developing a hyaluronic acid (HA)-based injectable organo-hydrogel via click chemistry to be realized for its pharmaceutical edge. Ultimately, injectable organo-hydrogels that materialize from academia or industry are required to follow the standard set of rules established by global governing bodies, which has been delineated to comprehend their marketability. Thence, this perspective narrates the development of injectable organo-hydrogels via click chemistry as a prospective elixir to have in the arsenal of pharmaceuticals.
... Generally, chemical crosslinking agents are used to prepare implantable hydrogels based on HA, such as 1,4-butanediol diglycidyl ether (BDDE) and divinyl sulfone (DVS) to overcome HA's very short half-life in the body, which is several hours because of its rapid enzymatic breakdown by hyaluronidase. 95 Furthermore, despite the utilization of chemical cross-linkers, the longevity, and stability of these hydrogels are typically just 6 months in vivo, necessitating frequent implantation to maintain efficacy. 96 As a result, there is an unmet demand for the development of new implantable materials that are both safer and longer-lasting. ...
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Over the last two decades, the process of delivering therapeutic drugs to a patient with a controlled release profile has been a significant focus of drug delivery research. Scientists have given tremendous attention to ultrasound-responsive hydrogels for several decades. These smart nanosystems are more applicable than other stimuli-responsive drug delivery vehicles (ie UV-, pH- and thermal-, responsive materials) because they enable more efficient targeted treatment via relatively non-invasive means. Ultrasound (US) is capable of safely transporting energy through opaque and complex media with minimal loss of energy. It is capable of being localized to smaller regions and coupled to systems operating at various time scales. However, the properties enabling the US to propagate effectively in materials also make it very difficult to transform acoustic energy into other forms that may be used. Recent research from a variety of domains has attempted to deal with this issue, proving that ultrasonic effects can be used to control chemical and physical systems with remarkable specificity. By obviating the need for multiple intravenous injections, implantable US responsive hydrogel systems can enhance the quality of life for patients who undergo treatment with a varied dosage regimen. Ideally, the ease of self-dosing in these systems would lead to increased patient compliance with a particular therapy as well. However, excessive literature has been reported based on implanted US responsive hydrogel in various fields, but there is no comprehensive review article showing the strategies to control drug delivery profile. So, this review was aimed at discussing the current strategies for controlling and targeting drug delivery profiles using implantable hydrogel systems.
... They only included Caucasian women to avoid ethnicity bias.Dermal quality, quantitatively assessed with the help of the Antera 3D® imaging device, confirmed that the wrinkle appearance and texture improve consistently with PN-HPT® monotherapy in the right-side, PN-HPT®-treated NLFs after 6 weeks compared with saline placebo. However, tentative and no more than exploratory, those Antera 3D® observations confirmed the profile of rapid PN-HPT® benefits in monotherapy on the NLF structure the authors had already reported in acne scars.27 Regarding the value of the PN-HPT® priming concept preliminary to HA consolidation, outcomes are contradictory, possibly due to low numbers, although the overall outcomes seem to confirm the working hypothesis. ...
Article
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Introduction: The mandibular profile undergoes progressive wasting with aging, and the deepening of nasolabial folds (NLFs) has a leading role. Hyaluronic acid (HA) efficiently controls tissue hydration and permeability to small and large molecules. NLFs are an acknowledged HA target; at the same time, another class of agents, PN-HPT® (Polynucleotides Highly Purified Technology), enjoy growing acknowledgement in aesthetic medicine. This exploratory, prospective study probed the rationale of sequentially associating PN-HPT® as a first priming agent acting in the skin followed by HA dermal filler injections for correcting moderate to severe NLFs. Methods: Following strict inclusion and exclusion criteria, the authors screened Caucasian ambulatory women aged 40 to 65 with moderate to severe NLFs and randomly selected two NLFs for each enrolled woman. Due to the purely explorative nature of the study, the authors initially planned to enroll no more than ten women. According to a split-face design, the selected right-side NLFs received 4 mL of PN-HPT® intradermally in the initial priming phase ("NLF Rx group"); the selected left-side NLFs received 4 mL of saline (placebo) ("NLF Lx group"). After three and six weeks, all patients received 2 mL of subdermal cross-linked HA over both NLF areas (4 mL overall). The total study follow-up was six months after the first injection, with objective assessments, based on the qualitative and quantitative Antera 3D® and Vectra H2® skin imaging technologies, after six weeks and 3 and 6 months. Results: Because of the favorable early outcomes, the authors let enrollment progress between January and June 2020 up to a total of 20 women and 40 NLFs. All treated women completed the six-month follow-up without reporting side effects, even clinically minor. The Antera 3D® device demonstrated that wrinkles and skin texture significantly improved in the NLF Rx after six weeks (monotherapy phase) and 3 and 6 months (PN-HPT® priming + HA phase) compared to baseline. HA levels, measured with the quantitative Vectra H2® assessment technology in the right NLFs, were significantly higher than contralaterally at both 3 and 6 months. Conclusions: Although conceived only as an exploratory investigation, the study confirmed that PN-HPT® monotherapy might be a valuable and effective option to rapidly improve the skin dermis texture and quality in individuals with moderate to severe NLFs. Acting as a priming agent in the skin, PN-HPT® prolong the clinical efficacy of cross-linked HA. Well-designed trials in larger treatment groups will hopefully confirm these early promising results.
... As the concentration of hyaluronidases is tissue-specific, it is difficult to predict the real concentration in vivo. In this study, the concentration of hyaluronidases used was 50 units/mL, in line with most of the concentrations used in the literature [58,59] for the same assay (10-100 units/mL); the molecular weight of the samples under examination was also considered. The chosen concentration proved to be an excellent compromise to be able to observe the degradation profile of both HA and its cross-linked derivative over a sufficiently long period of 24 h. ...
Article
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Hyaluronic acid (HA), an excellent biomaterial with unique bio properties, is currently one of the most interesting polymers for many biomedical and cosmetic applications. However, several of its potential benefits are limited as it is rapidly degraded by hyaluronidase enzymes. To improve the half-life and consequently increase performance, native HA has been modified through cross-linking reactions with a natural and biocompatible amino acid, Ornithine, to overcome the potential toxicity commonly associated with traditional linkers. 2-chloro-dimethoxy-1,3,5-triazine/4-methylmorpholine (CDMT/NMM) was used as an activating agent. The new product (HA–Orn) was extensively characterized to confirm the chemical modification, and rheological analysis showed a gel-like profile. In vitro degradation experiments showed an improved resistance profile against enzymatic digestions. Furthermore, in vitro cytotoxicity studies were performed on lung cell lines (Calu-3 and H441), which showed no cytotoxicity.
... For all the samples, the analyses of the MHS curves suggested water-soluble HA chains conformation other than linear thus indicating a certain extent of chemical modification. This is in agreement with previous studies on similar products [15]. Rationally, the water-soluble HA fraction may derive from the crosslinking process leaving HA chains that, even if crosslinked/modified, are still soluble in an aqueous medium due to low(er) molecular weight. ...
Article
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Background: Skinboosters represent the latest category of hyaluronan (HA) hydrogels released for aesthetic purposes. Different from originally developed gels, they are intended for more superficial injections, claiming a skin rejuvenation effect through hydration and possibly prompting biochemical effects in place of the conventional volumetric action. Here, three commercial skinboosters were characterized to unravel the scientific basis for such indication and to compare their performances. Methods: Gels were evaluated for water-soluble/insoluble-HA composition, rheology, hydration, cohesivity, stability and effect, in vitro, on human dermal fibroblasts towards the production of extracellular matrix components. Results: Marked differences in the insoluble-hydrogel amount and in the hydrodynamic parameters for water-soluble-HA chains were evidenced among the gels. Hydration, rigidity and cohesivity also varied over a wide range. Sensitivity to hyaluronidases and Reactive Oxygen Species was demonstrated allowing a stability ranking. Slight differences were found in gels' ability to prompt elastin expression and in ColIV/ColI ratio. Conclusions: A wide panel of biophysical and biochemical parameters for skinboosters was provided, supporting clinicians in the conscious tuning of their use. Data revealed great variability in gels' behavior notwithstanding the same clinical indication and unexpected similarities to the volumetric formulations. Data may be useful to improve customization of gel design toward specific uses.
... In general, HA-based injectable hydrogels are prepared using chemical crosslinking agents such as 1,4-butanediol diglycidyl ether (BDDE) and divinyl sulfone (DVS) to overcome the very short half-life of HA, several hours in the body, due to its fast enzymatic degradation by hyaluronidase [23]. However, despite the use of chemical crosslinking agents, the stability and longevity of these hydrogels usually shows a persistence of only 6 months in vivo, and they require repeated injection to maintain their efficacy [24,25]. ...
Article
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The transfer of some innovative technologies from the laboratory to industrial scale is many times not taken into account in the design and development of some functional materials such as hydrogels to be applied in the biomedical field. There is a lack of knowledge in the scientific field where many aspects of scaling to an industrial process are ignored, and products cannot reach the market. Injectable hydrogels are a good example that we have used in our research to show the different steps needed to follow to get a product in the market based on them. From synthesis and process validation to characterization techniques used and assays performed to ensure the safety and efficacy of the product, following regulation, several well-defined protocols must be adopted. Therefore, this paper summarized all these aspects due to the lack of knowledge that exists about the industrialization of injectable products with the great importance that it entails, and it is intended to serve as a guide on this area to non-initiated scientists. More concretely, in this work, the characteristics and requirements for the development of injectable hydrogels from the laboratory to industrial scale is presented in terms of (i) synthesis techniques employed to obtain injectable hydrogels with tunable desired properties, (ii) the most common characterization techniques to characterize hydrogels, and (iii) the necessary safety and efficacy assays and protocols to industrialize and commercialize injectable hydrogels from the regulatory point of view. Finally, this review also mentioned and explained a real example of the development of a natural hyaluronic acid hydrogel that reached the market as an injectable product.
... For this reason, there is an increased demand for scientifically based comparisons, and a number of publications have been presented where hyaluronic acid (HA) fillers are compared according to their physicochemical properties. [1][2][3][4][5][6][7][8][9][10] In these papers, many different analytical techniques are used, one of the more popular being rheometry. Rheology denotes the science of studying the deformation of materials while rheometry is the science of how to measure the rheological properties. ...
Article
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Factors Affecting the Rheological Measurament of Hyaluronic Acid Filler
... 10 A three-dimensional network can be obtained, which is water insoluble and less sensitive to enzymatic degradation. 11 There are several chemical crosslinkers, which covalently bond the HA chains, for instance, glutaraldehyde, divinyl sulfone (DVS) 12 and butanediol-diglycidyl ether (BDDE) 10 act on the hydroxyl group, while carbodiimides react with the carboxyl group. It was observed that with increasing crosslinker concentration, the degree of crosslinking can be enhanced, 10 which increases the time of degradation and improves mechanical stability. ...
Article
Hyaluronic acid (HA) is an ideal initial material for preparing hydrogels, which may be used as scaffolds in soft tissue engineering based on their advantageous physical and biological properties. In the present study, two crosslinking agents: divinyl sulfone and butanediol diglycidyl ether were used to investigate their effect on the properties of HA hydrogels. As HA hydrogels alone do not promote cell adhesion on the scaffold, fibrin and serum from platelet-rich fibrin were combined with the scaffold, the aim was to create a material intended to be used as soft tissue implant that facilitates new tissue formation, and degrades over time. The chemical changes were characterized and cell attachment capacity of the protein containing gels was examined using human mesenchymal stem cells, viability was assessed using live-dead staining. FTIR measurements revealed that linking fibrin into the gel was more effective than linking SPRF. The scaffolds were found to be able to support cell adherence onto the hydrogels, and the best result was achieved when HA was crosslinked with divinyl sulfone and contained fibrin. The most promising derivative, 5 % DVS crosslinked fibrin containing hydrogel was injected subcutaneously into C57BL/6 mice for 12 weeks. The scaffold was proven to be biocompatible, remodeling, and vascularization occurred, while shape and integrity were maintained.
... Despite the availability of hyaluronidases, it has being discussed whether all HA fillers are sensitive to the activity of these enzymes; in fact, several studies have shown that the resistance to degradation depends on numerous factors, such as the concentration of HA, the type and degree of crosslinking, and the cohesive properties [23][24][25][26]. ...
Article
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During last years, hyaluronic acid- (HA-) based dermal fillers have grown rapidly and continuously, as reported by the American Society of Aesthetic Plastic Surgery (ASAPS). In fact, HA fillers are considered the gold standard technique for soft tissue augmentation, deep skin hydration, and facial recontouring, playing a key role as an alternative to plastic surgery. HA fillers are less invasive, more biocompatible, and safer and with a more natural and immediate result if compared to plastic surgery. Hence, the safety of HA-based dermal fillers plays a crucial role, mostly in terms of biocompatibility and adjustability in case of unpleasant results and side effects such as, tyndall effect, edema, or granulomas. Hyaluronidase is a naturally occurring enzyme, present in the human body, and can degrade HA fillers avoiding more severe complications. In this article, we analyzed the bioavailability of hyaluronidase degradation of five fillers of Neauvia® hydrogels line (MatexLab SA, Lugano, CH), composed of pure hyaluronic acid and based on PEGDE cross-linking (polyethylene glycol) technology that guarantees a higher biocompatibility and an optimal biointegration and rheological characteristics. The performed in vitro testing is based on the colorimetric determination of the N-acetyl-D-glucosamine (NAG) present in solution after incubation with hyaluronidase, determined at different time points in order to assess the kinetic of each product degradation (1h, 3h, 6h, 24h, 48h, 72h, 120h, and 168h). The aim of this study was to assess, in vitro, how the difference in HA content and PEGDE concentration of the analyzed fillers can influence the product biocompatibility, intended as product enzymatic clearance and duration in time. The results demonstrated that the method was reproducible and easy to perform and that all the analyzed fillers are naturally immediately available for hyaluronidase-mediated degradation.
... The rheologic and physicochemical properties of hyaluronic acid gels are determined by multiple factors, including the crosslinking reactions used, the hyaluronic acid substrate's molecular weight, the hyaluronic acid concentration, and the process used to fragment the bulk gel into an injectable form. [5][6][7][8] Crosslinking is the basis for the mechanical strength of the gel and improves product longevity. 9,10 Crosslinking can be accomplished through the introduction of chemical linkages between the hyaluronic acid chains or by stabilizing the naturally occurring entanglements that the hyaluronic acid chains form on their own. ...
Article
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Background: Injectable hyaluronic acid fillers are routinely used for correction of soft-tissue volume loss and facial rejuvenation. Product differentiation has primarily been based on the rheologic parameter known as elastic modulus (G'), although other physicochemical properties are being explored to characterize potential product performance. As clinical data regarding product performance are lacking, the practical experience of injectors provides a valuable bridge in the knowledge gap between product rheologic data and product use. Methods: Rheologic and physicochemical measurements (swelling factor and cohesion) were collected for 18 products. To observe the impact of G' and hyaluronic acid concentration on swelling factor and cohesion, proportional relationships were evaluated. Contributing authors were queried regarding their G'-based selection of products when considering skin quality, degree of correction, injection depth, and anatomical location. Results: Relationships were observable between G' and swelling factor and G' and cohesion only when limited to products manufactured by the same crosslinking technology and the same concentration. No relationship between isolated hyaluronic acid concentration and swelling factor or cohesion was apparent. Although rheological parameters and the assumptions of ex vivo data translating to in vivo performance are oftentimes not completely aligned, in the clinical experience of the authors, in general, higher G' products are better suited for thicker skin and deeper injection planes, whereas lower G' products are better for more superficial planes, although exceptions to these trends are also made based on technical experience. Conclusions: While rheologic and physicochemical characteristics can vary widely between products and the methods and measurements of these parameters are often difficult to correlate, G' represents a useful and consistent parameter for product differentiation. Understanding how to select products based on G' is valuable knowledge for customizing injection plans and contributes to an optimal aesthetic outcome.
... To further examine the mechanical properties of the PG-Leu-Leu-Col-El scaffold we examined the effect of elastic storage moduli (G ) and viscous loss moduli (G ) under isothermal conditions at 25°C at an angular frequency range of 0.1 r/s of 100 r/s at a constant stress of 0.2 Pa. In general, G is a measure of the capacity of a specific material to deter deformation when stress is applied, and higher G values are indicative of higher capability to resist deformation, which is important for tendon, bone and cartilage TE applications (La Gatta et al., 2011). Results obtained are shown in Figure 5. ...
Article
We have developed a new biomimetic scaffold for potential applications in tendon tissue engineering (TE). The scaffold template was synthesised by conjugating polygalacturonic acid with the dipeptide leucyl-leucine to mimic the leucine rich proteoglycans found in the extracellular matrix (ECM) of tenocytes. To the template, type I collagen and an elastin derived peptide were incorporated in order to form the final PG-Leu-Leu-Col-El scaffold. Results indicated the formation of gelatinous, fibrous scaffolds. DSC analysis showed phase changes that included crystallisation and thermal melting due to re-organisation of the scaffold components. Young’s modulus was determined to be 832 r 2 MPa. Rheology studies showed that the scaffold maintained a constant Gc / Gs ratio over a wide range of angular frequency. Cell studies with bone marrow derived mesenchymal stem cells (BMSC) indicated that the scaffolds promoted cell proliferation and formed three dimensional cell-scaffold matrices. This newly developed scaffold may open new opportunities for tissue engineering applications.
... To further examine the mechanical properties of the PG-Leu-Leu-Col-El scaffold we examined the effect of elastic storage moduli (G ) and viscous loss moduli (G ) under isothermal conditions at 25°C at an angular frequency range of 0.1 r/s of 100 r/s at a constant stress of 0.2 Pa. In general, G is a measure of the capacity of a specific material to deter deformation when stress is applied, and higher G values are indicative of higher capability to resist deformation, which is important for tendon, bone and cartilage TE applications (La Gatta et al., 2011). Results obtained are shown in Figure 5. ...
... In the last decade, HA has been considered, in aesthetic medicine, as an ideal substance to be used to augment the skin volume, being highly biocompatible, non-immunogenic and capable of binding water to a large extent [22]. In order to increase the biomechanical properties and the resistance to enzymatic break down of natural HA containing preparations, various methods have been developed for chemical modification or cross-linking of native HA into gels by covalent links, resulting in larger and most stable derivatives that retain HA biocompatibility and biodegradability in vivo [23] [24]. ...
Article
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Neauvia Intense is biocompatible, injectable hyaluronic acid (HA) filler PEG cross-linked for facial soft-tissue augmentation that provides volume to tissues. The aim of the present study is to evaluate the sensitivity of Neauvia Intense in hyaluronidase from bovine testes in a time-course analysis. The test is based on the colourimetric determination of the N-acetyl – D - glucosamine (NAG) released by the hyaluronidase in standardised conditions. The in vitro conditions involve the treatment of Neauvia Intense with a known concentration of the enzyme (6080U/ml). The NAG content was determined at different times to assess the kinetics of the degradation (1h, 3h, 6h, 24h, 48h, 72h, 120h, and 168h); the Ehrlich’s reagent was used for the colourimetric quantification, by the method described by Reissing and colleagues. The intensity of the violet colour developed after the chemical reaction was proportional to the NAG present in each sample. A microplate reader at 585 nm read the absorbance. The amount of NAG released by the product was proportional to the time of incubation with bovine hyaluronidase, reaching a plateau after 168 hours.
... For this reason, there is an increased demand for scientifically based comparisons, and a number of publications have been presented where hyaluronic acid (HA) fillers are compared according to their physicochemical properties. [1][2][3][4][5][6][7][8][9][10] In these papers, many different analytical techniques are used, one of the more popular being rheometry. Rheology denotes the science of studying the deformation of materials while rheometry is the science of how to measure the rheological properties. ...
Article
Background: With the number of available dermal fillers increasing, so is the demand for scientifically based comparisons, often with rheological properties in focus. Since analytical results are always influenced by instrument settings, consensus on settings is essential to make comparison of results from different investigators more useful. Objective: Preferred measurement settings for rheological analysis of hyaluronic acid (HA) fillers are suggested, and the reasoning behind the choices is presented by demonstrating the effect of different measurement settings on select commercial HA fillers. Materials and methods: Rheological properties of 8 HA fillers were measured in a frequency sweep from 10 to 0.01 Hz at 0.1% strain, using an Anton Paar MCR 301, a PP-25 measuring system with a gap of 1 mm at 25°C. A 30-min period was used for relaxation of the sample between loading and measuring. Results: The data presented here, together with previously published data, demonstrate differences in G' from 1.6 to 7.4 times for the same product. Conclusion: A large part of the differences were concluded to be due to differences in rheometry measurement settings. The confusion from the many parameters involved in rheometry can be avoided by simply using the elastic modulus (G') to differentiate products. J Drugs Dermatol. 2017;16(9):876-882. .
... In particular, a Size Exclusion Chromatography-Triple Detector Array (SEC-TDA) equipment (Viscotek, Lab Service Analytica S.R.L., Italy) was used. A detailed description of the SEC-TDA system and analysis conditions are reported elsewhere [21,22]. Sample molecular weight (M w , M n , M w /M n ), molecular size (hydrodynamic radius-Rh) and intrinsic viscosity ( [η]) distributions were derived. ...
Article
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Hyaluronic Acid (HA)-based dermal formulations have rapidly gained a large consensus in aesthetic medicine and dermatology. HA, highly expressed in the Extracellular Matrix (ECM), acts as an activator of biological cascades, stimulating cell migration and proliferation, and operating as a regulator of the skin immune surveillance, through specific interactions with its receptors. HA may be used in topical formulations, as dermal inducer, for wound healing. Moreover, intradermal HA formulations (injectable HA) provide an attractive tool to counteract skin aging (e.g., facial wrinkles, dryness, and loss of elasticity) and restore normal dermal functions, through simple and minimally invasive procedures. Biological activity of a commercially available hyaluronic acid, Profhilo®, based on NAHYCO™ technology, was compared to H-HA or L-HA alone. The formation of hybrid cooperative complexes was confirmed by the sudden drop in η0 values in the rheological measurements. Besides, hybrid cooperative complexes proved stable to hyaluronidase (BTH) digestion. Using in vitro assays, based on keratinocytes, fibroblasts cells and on the Phenion® Full Thickness Skin Model 3D, hybrid cooperative complexes were compared to H-HA, widely used in biorevitalization procedures, and to L-HA, recently proposed as the most active fraction modulating the inflammatory response. Quantitative real-time PCR analyses were accomplished for the transcript quantification of collagens and elastin. Finally immunofluorescence staining permitted to evaluate the complete biosynthesis of all the molecules investigated. An increase in the expression levels of type I and type III collagen in fibroblasts and type IV and VII collagen in keratinocytes were found with the hybrid cooperative complexes, compared to untreated cells (CTR) and to the H-HA and L-HA treatments. The increase in elastin expression found in both cellular model and in the Phenion® Full Thickness Skin Model 3D also at longer time (up to 7 days), supports the clinically observed improvement of skin elasticity. The biomarkers analyzed suggest an increase of tissue remodeling in the presence of Profhilo®, probably due to the long lasting release and the concurrent action of the two HA components.
... HA fragments were characterized by SEC-TDA (Size Exclusion Chromatography-Triple Detector Array) equipment by Viscotek (Lab Service Analytica, Italy). A detailed description of the system and its analytical conditions are reported elsewhere ( La Gatta, Papa, Schiraldi & De Rosa, 2011). ...
Article
Nowadays there is a great interest in investigating the effect of particular hyaluronan fragments in the biomedical field and in cosmeceutical applications. Literature has reported that very low molecular weight HA (Mw < 5 kDa) has an inflammatory effect, whilst HA ranging from 15-250 has shown controversial effects. This work aims to give better elucidation on the correlation between the different sized HA fragments and their biological functions. In this respect, a simple and effective degradation strategy is used to obtain several HA fragments. Also, an hydrodynamic and structural characterization was performed in order to obtain samples suitable to evaluate cellular response. In particular an in vitro scratch test in time lapse experiments was used to study the effect of HA fragments, ranging from 1800 to 6 kDa on wound dermal reparation based on human keratinocytes. All high and low Mw HA used in this study allowed for faster wound closure compared to the un-treated cells, except for 6 kDa that, on the contrary, prevented repair.
... So the storage modulus values of the new HA-based product Variofill ® (Adoderm GmbH, Langenfeld, Germany) were published in Iannitti et al. (2013), and the physical characteristics of the Stylage ® products were presented (Ramos-e-Silva et al. 2013). La Gatta et al. (2011) studied the influence of molecular-weight characteristics of some commercial fillers on their swelling, rheology and degradation. Hee et al. (2015) tried to compare data on the elasticity of some commercial fillers, their lift capacity, resistance to deformation and tissue integration. ...
Article
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Systematic rheological characterisation of several injection implants based on hyaluronic acid (Belotero®, Teosyal®, Glytone® and Juvéderm® brands) has been carried out. All these dermal fillers are viscoelastic media with the storage modulus exceeding the loss modulus. So at low deformations, they are gel-like materials, but at increasing shear stress, they can flow demonstrating typical non-Newtonian behaviour. In some cases, though not always, the yield stress is expressed rather clearly. The application of the technique of large amplitude oscillation shear (LAOS) allowed us to distinguish two groups of rheological behaviour characterised by shear thinning or strain overshoot. The Belotero® fillers belong to the first group. Similar strong changes in the storage and loss moduli as a function of frequency and fuzzy yielding are characteristic of these materials. The Teosyal® and Juvéderm® Voluma filler belong to the second group. Their typical rheological features are existence of the minimum for the frequency dependence of the loss modulus and clearly expressed the yield stress. The Glytone® and Juvéderm® Ultra fillers occupy the intermediate position. When the dermal fillers of the second group were diluted, they demonstrated effects similar to the phase separation. As a result of the rheological characterisation, some assumptions have been advanced regarding correlations between the objective rheological parameters of dermal fillers and conditions of their application.
Article
Dermal fillers are among the most versatile tools in esthetic medicine. A broad range of temporary, semipermanent, and permanent filler products is on the market. We performed a narrative review on spontaneous and induced degradation of dermal fillers in vitro and in vivo. Hyaluronic acid-based fillers are the most frequently used temporary fillers. The products differ in their hyaluronic acid content, cross-linking, and rheological parameters. Endogenous hyaluronidase and reactive oxygen species are responsible for the spontaneous degradation of these fillers. Hyaluronidase digests the filler material by cleavage of the β-1,4 glycosidic linkage between N-acetyl-glucosamine and d-glucuronic acid. The enzyme can be used for treatment of medical and cosmetic adverse events due to hyaluronic acid-based filler. Higher hyaluronidase content and higher degree of cross-linking are major factors contributing to filler persistence over time. Semipermanent fillers are poly-(d),l-lactic acid and calcium hydroxylapatite. These filler types are decomposed by hydrolysis and osteoclastic enzymes. They usually persist up to 2 years, in single patients even more than 5 years. Sodium thiosulfate can stimulate degradation of calcium hydroxylapatite, but it is slow acting and not effective in case of emergency. Permanent fillers may show some kind of modification in situ, but spontaneous or induced degradation has not been documented. Once implanted the permanent fillers remain lifelong. Intralesional laser treatment supports the removal of permanent filler material as an alternative to surgery. Besides biocompatibility and toxicity, filler materials should also be assessed for degradation to improve patient safety.
Article
Injectable fillers based on hyaluronic acid are now frequently used to correct tissue volume loss when facial rejuvenation is sought. The way in which these commercially available HA fillers are manufactured has direct implications for the properties of the gel and the clinical applications of these products. These properties can be described using the science of rheology, which describes the flow and deformation of matter, allowing researchers to understand how these fillers act under mechanical stress, either at the time of injection or after implantation of the gel. It is important to note that the mechanical forces exerted on each anatomical region of the face vary in intensity and frequency, causing the filler to deform in different ways. The aim of this study was to review the literature on the rheological properties of hyaluronic acid gels and to emphasize the importance of knowing these properties when selecting fillers, so that harmonizing professionals can achieve the desired results.
Chapter
Hydrogels are highly hydrated three dimensional networks with the ability to mimic the extracellular matrix of bodily tissues and have thus found application in a wide range of biomedical applications. Unique physiochemical properties such as biocompatibility, water permeability, stimuli responsiveness and self-healing characteristics make them especially useful for use as scaffolds and matrices drug delivery, tissue engineering/regeneration and sensing. Their weak and brittle nature, however, often limits their widespread application where improved mechanical strength is required. To resolve this problem, there has been a significant amount of research into the improvement of their mechanical properties. Among these efforts, versatile multicomponent hydrogels have received much attention as their physiochemical properties can be structurally engineered to provide a wide range of desired properties. These multicomponent formulations also allow for the combination of natural and synthetic polymers, which offers the scope to exploit the advantages of each component, with the synergistic effects resulting from mutual interactions. This book critically discusses the fundamental chemistry, synthesis, characterisation, physiochemical and biological properties of various types of multicomponent hydrogels. It reviews the different strategies employed in designing and synthesizing cutting-edge multicomponent hydrogels and their key applications in biomedical fields. The work is suitable for researchers working in the specific area of multicomponent hydrogels, and also more generally for those working in materials science, biomedical engineering, biomaterials science and tissue engineering.
Article
Introduction: Injectable hyaluronic acid (HA) fillers are commonly used to provide tissue augmentation and combat the effects of facial aging. Ovine and human recombinant formulations of the enzyme hyaluronidase (HAse) are used interchangeably; however, it is unknown if there exists a difference in their ability to degrade HA. Objective: To compare rates at which ovine and human recombinant forms of HAse degrade various HA fillers in vitro. Methods: Increasing amounts of either ovine or human recombinant HAse were added to fixed amounts of nine unique HA filler products. Degradation rates were then analyzed using a colorimetric method by measuring absorbance levels of degraded product. Results: Human recombinant HAse degraded more HA when compared with ovine HAse overall (p = 0.014, confidence interval [-0.015 to -0.0018]). Conclusions: Human recombinant HAse was found to be more effective on average in degrading HA fillers when compared with ovine HAse in vitro.
Article
Individualized strategies are becoming critical for full-face aesthetics, especially for rejuvenating the aging face. This study aimed to assess the clinical outcomes following the Yes-lifting and Pyramid-volumized approaches with hyaluronic acid (HA) fillers. The Yes-lifting and Pyramid-volumized approaches represent the author's clinical experience of facial contouring techniques. The Yes-lifting method focuses on lifting the full-face using sharp needles to inject an appropriate volume of HA at 9 different positions, while the Pyramid-volumized method mainly refills the soft tissue with HA through a blunt cannula at 8 areas. These techniques are chosen based on patients' needs. After Yes-lifting treatment, the patient had an appreciable change to the face, which included lateral structural changes of the full-face and the support of deep malar fat pads. The oblique view exhibits improved zygomatic arch, a nicer jaw angle and chin-elongation and a more defined jawline. For another patient treated with the Pyramid-volumized approach, the facial shape improved immediately after treatment, with improvements in the bitemporal, bizygomatic, binasolabial fold, diminished T-troughs and chin. With pyramid-volumizing strategy, the patient looked more confident due to lateral structural changes of the full-face and the support of deep malar fat pads. The oblique view exhibits improved zygomatic arch, a nicer jaw angle, highlighted lips and a more defined jawline. Based on our experiences using the Yes-lifting or Pyramid-volumized technique can effectively improve aesthetic outcomes and provide a platform for user-friendly algorithms to help clinicians perform the facial contouring techniques, particularly for the Asian population.
Article
Background: The number of soft-tissue filler injections performed in the United States is constantly increasing and reflects the high demand for enhanced facial and body attractiveness. The objective of the present study was to measure the viscoelastic properties of soft-tissue fillers when subjected to different testing frequencies. The range of tested frequencies represents clinically different facial areas with more [lips (high frequency)] or less [zygomatic arch (low frequency)] soft-tissue movement. Methods: A total of 35 randomly selected hyaluronic acid-based dermal filler products were tested in an independent laboratory for their values of G', G″, tan δ, and G* at angular frequencies between 0.1 and 100 radian/second. Results: The results of the objective analyses revealed that the viscoelastic properties of all tested products changed between 0.1 and 100 radian/second angular frequency. Changes in G' ranged from 48.5 to 3116 percent, representing an increase in their initial elastic modulus, whereas changes in G″ ranged from -53.3 percent (i.e., decrease in G″) to 7741 percent (i.e., increase in G″), indicating both an increase and a decrease in their fluidity, respectively. Conclusions: The increase in G' would indicate the transition from a "softer" to a "harder" filler, and the observed decrease in G″ would indicate an increase in the filler's "fluidity." Changes in the frequency of applied shear forces such as those occurring in the medial versus the lateral face will influence the aesthetic outcome of soft-tissue filler injections.
Article
With the breadth and variety of hyaluronic acid hydrogels available, it can be challenging to understand the evolving product characteristics and associated terminology. Similarly, different hyaluronic acid hydrogels can share the same indication, and yet consist of different rheological and physiochemical properties. In this paper, hyaluronic acid biophysical properties, such as molecular weights, stabilisation (crosslinking), modification and hyaluronic acid concentration, are explored in relation to findings from current literature. The significance for these specific properties is explored in relation to specific indications and anti-ageing benefits.
Article
Hyaluronic acid (HA) is widely used as a filler owing to its excellent biocompatibility and biodegradability. However, commercial HA-based filler products have some limitations and can cause side effects due to the presence of residual chemical crosslinking agents. In this study, tyramine (Tyr) was introduced into HA to impart photocrosslinking ability to HA, and a photocrosslinked hydrogel was formed using a less toxic vitamin B2 derivative as a photoinitiator. For injection, an injectable filler was prepared by converting the photocrosslinked hydrogel to a microgel form. The crosslinking of the tyramine-modified HA (HA-Tyr) hydrogel, which can be applied as a soft tissue filler, increased with an increase in the irradiation time, and the crosslinked hydrogel showed excellent mechanical strength, elastic recovery rate, and injectability. It also showed non-cytotoxicity and cell proliferation behavior in fibroblasts. Therefore, injectable HA hydrogels have great potential as an alternative to conventional commercial dermal fillers.
Chapter
The ordered assembly of multicellular structures mimicking native tissues has lately come into prominence for various applications of biomedicine. In this respect, three-dimensional bioprinting (3DP) of cells and other biologics through additive manufacturing techniques has brought the possibility to develop functional in vitro tissue models and perhaps creating de novo transplantable tissues or organs in time. Bioinks, which can be defined as the printable analogues of the extracellular matrix, represent the foremost component of 3DP. In this chapter, we attempt to elaborate the major classes of bioinks which are prevalently being evaluated for the 3DP of a wide range of tissue models.
Article
Hyaluronan (HA)-based hydrogels obtained by crosslinking the biopolymer via ether bonds are widely used in clinical practice. There is interest in improving the design of these gels to match specific properties. Here, the possibility to tune HA-hydrogel behavior by adjusting the molecular weight distribution of the biopolymer undergoing crosslinking was investigated. Three HA samples (500, 1100 and 1600 kDa) underwent reaction with 1,4-butandioldiglycidyl-ether(BDDE) under reported conditions and the crosslinked products were characterized for chemical modification extent, swelling, rheological behavior, cohesivity, sensitivity to enzymatic degradation and effect on Human Dermal Fibroblasts (HDF). HA hydrolysis, under the highly alkaline crosslinking conditions, was also studied for the first time. The main achievements are that 1) varying HA chain length affects hydrogel behavior less than expected, due to the de-polymerization occurring alongside crosslinking, that reduces the differences in sample size 2) when differences in chain length persist notwithstanding hydrolysis, lowering HA size is a means to prepare more concentrated formulations, expected to exhibit longer duration and better cohesivity in vivo, while retaining a certain rigidity, preserving biocompatibility and slightly influencing HDF behavior in relation to CollagenI production. The study shed light on aspects concerning BDDE-HA gel manufacturing and contributed to the improvement of their design.
Article
Purpose: The purpose of this in vitro study was to assess the potential benefits of eye drops based on hybrid cooperative complexes (HCCs) obtained from high and low molecular weight hyaluronic acid (HA). Methods: Rheological measurements were performed to adjust the HCC concentration toward optimal resistance to drainage from the ocular surface. The viscosity and mucoadhesion profiles of the optimized preparation were derived. Primary porcine corneal epithelial cells were used for biological studies. Cells were exposed to dehydration after being pretreated with the HCC solution, and protection from desiccation was evaluated using cell viability assays. Time-lapse experiments were carried out to evaluate the ability of the HCC preparation to promote corneal wound healing. The characterization studies were performed in comparison with a control HA solution representative of commercial HA-based products. Results: The HCC formulation is able to deliver twice the amount of biopolymer compared with conventional products while avoiding discomfort due to excessive viscosity. The viscosity and mucoadhesion profiles allowed the authors to predict the longer in vivo retention and, therefore, an improved HCC formulation bioavailability. The new preparation also proved superior in protecting porcine corneal epithelial cells from desiccation and in hastening corneal cell wound repair in vitro. Conclusions: The results suggest that the developed formulation may be a promising topical ophthalmic medical treatment.
Article
The use of injectable materials as a biofiller for soft tissue augmentation has been increasing worldwide. Levan is a biocompatible and inexpensive polysaccharide with a great potential in biomaterial applications, but it has not been extensively studied. In this study, we evaluated the potential of levan as a new material for dermal filler and prepared an injectable and physical levan-based hydrogel by combining levan with Pluronic and carboxymethyl cellulose (CMC). A sol state was prepared by mixing the polymers in a specific ratio at 4 °C for 2 days and hydrogel was formed by increasing temperature to 37 °C. Elastic modulus of the levan hydrogel was higher than that of hyaluronic acid (HA)-based hydrogel. SEM images of the levan hydrogel showed an interconnected porous structure, similar to HA hydrogel. Levan showed non-cytotoxicity, enhanced cell proliferation, and higher expression of collagen synthesis in human dermal fibroblast cells compared to HA. The injected levan hydrogel was biocompatible and stable over 2 weeks in vivo, longer than Pluronic F127 hydrogel or HA hydrogel. Also, the levan hydrogel showed a higher amount of collagen production than HA hydrogel in vivo. More importantly, the levan hydrogel showed the enhanced anti-wrinkle efficacy compared to HA hydrogel in a wrinkle model mouse. Thus, the levan hydrogel with injectability, biocompatibility, and anti-wrinkle effect has a high potential as an alternative to existing commercial dermal filler.
Article
Semi-biodegradable copolymer networks derived from two immiscible components, a hyaluronan derivative (methacrylated hyaluronan) and poly(ethyl acrylate), have been developed for soft tissue engineering applications. These copolymer networks combine the hydrogel-like properties of hyaluronan networks with the rubber-like behavior and low water uptake of the poly(ethyl acrylate) networks. In order to copolymerize hyaluronan and ethyl acrylate, a hyaluronan derivative containing vinyl groups was first obtained. In spite of the different nature of both polymers, the variation of the weight fraction of ethyl acrylate in the copolymerization yields copolymer networks with co-continuity of phases, and tunable swelling degree and mechanical properties. In addition, the MeHA chains are susceptible of being enzymatically degraded, and the resulting materials are mainly composed of a PEA framework with structural integrity. These copolymers networks are good candidates to assist the regeneration process of soft tissues when longer residence times are required.
Article
Optical techniques are increasingly employed for monitoring cell–matrix interactions in suitably prepared 3D scaffolds. The ability of designing and realizing synthetic extracellular matrix with well-controlled optical properties is a crucial need in this field. For this purpose a crosslinked hyaluronic acid (HA) scaffold is prepared. Fourier transform infrared and UV–vis spectroscopies enable to monitor the scaffold preparation process and to evidence scaffold high transparency and low fluorescence in the visible range. 3D optical characteristics of the HA scaffold are tested by two-photon microscopy (TPM) imaging of embedded fluorescent microbeads and alive keratinocytes labeled with vital PKH67 dye at different depths from the scaffold surface. Some useful indications about the potentiality of TPM measurements for the determination of attenuation coefficient of turbid media are also reported. Moreover, the use of the presented HA scaffold for preparing tissue phantoms for fluorescence imaging or diffuse imaging is proposed. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2017, 134, 45243.
Article
Physico-chemical and mechanical properties of hyaluronic acid/carbon nanotubes nanohybrids have been correlated with the proportion of inorganic nanophase and the preparation procedure. The mass fraction of -COOH functionalized carbon nanotubes was varied from 0 to 0.05. Hyaluronic acid was crosslinked with divinyl sulfone to improve its stability in aqueous media and allow its handling as a hydrogel. A series of samples was dried by lyophilization to obtain porous scaffolds whereas another was room-dried allowing the collapse of the hybrid structures. The porosity of the former, together with the tighter packing of hyaluronic acid chains, results in a lower water absorption and lower mechanical properties in the swollen state, because of the easier water diffusion. The presence of even a small amount of carbon nanotubes (mass fraction of 0.05) limits even more the swelling of the matrix, owing probably to hybrid interactions. These nanohybrids do not seem to degrade significantly during 14 days in water or enzymatic medium.
Article
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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 ratio was observed for the uncrosslinked HA having the largest molecular weight. The expansion capacity of HA rose with increasing the amount of pure HA and was inversely proportional to the crosslinking degree due to an increased number of coiled HA chain interactions. Elastic modulus (G') of monophasic fillers having different ratios of 1.0 w/v% BDDE crosslinked HAs to pure HA (1368 kDa) were within 152 and 325 Pa. 178 Pa was observed for the biphasic fillers consisting of 15% crosslinked HA (697 kDa) nanoparticles suspended in 85% of uncrosslinked HA (1368 kDa).
Article
A hyaluronic acid (HA) was cross-linked with 1, 4-butanediol diglycidyl ether to produce nine BDDE-HA hydrogels. The degradation rates of six hydrogels were evaluated by HPLC and UV-Visible spectroscopy. The percentage amount of N-acetyl glucosamine NAG obtained after one-day enzymatic digestion to the total amount obtained after complete digestion was an indicative of the degradation rate of each hydrogel. The results were calculated with 95% confidence interval and showed 62.6% ±12.3 w/w, precision value % R.S.D =7.95, average recovery = 81.0%, LOD = 6.4 μg/ml for HPLC and 63.3 ± 13.9 w/w, precision value % R.S.D = 8.83, average recovery = 83.1%, LOD = 5.4 μg/ml for UV method. The two methods showed also good linearity with correlation coefficients R2 of 0.998 and 0.9995 for HPLC and UV method respectively. For a comparison purpose, the other three hydrogels were rated using the conventional weight loss method which showed relatively higher degradation rates with an average of 73.4% ± 5.7 w/w, % R.S.D = 3.13. Statistical analysis revealed that there was no significant difference between HPLC and UV-Visible methods, however, these values differed significantly (p < 0.05) from the value obtained from the weight loss method.
Article
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Soft tissue augmentation with temporary dermal fillers is a continuously growing field, supported by the ongoing development and advances in technology and biocompatibility of the products marketed. The longer lasting, less immunogenic and thus more convenient hyaluronic acid (HA) fillers are encompassing by far the biggest share of the temporary dermal filler market. Since the approval of the first HA filler, Restylane, there are at least 10 HA fillers that have been approved by the FDA. Not all of the approved HA fillers are available on the market, and many more are coming. The Juvéderm product line (Allergan, Irvine, CA), consisting of Juvéderm Plus and Juvéderm Ultra Plus, was approved by the FDA in 2006. Juvéderm is a bacterium-derived nonanimal stabilized HA. Juvéderm Ultra and Ultra Plus are smooth, malleable gels with a homologous consistency that use a new technology called "Hylacross technology". They have a high concentration of cross-linked HAs, which accounts for its longevity. Juvéderm Ultra Plus is used for volumizing and correcting deeper folds, whereas Juvéderm Ultra is best for contouring and volumizing medium depth facial wrinkles and lip augmentation. Various studies have shown the superiority of the HA filler products compared with collagen fillers for duration, volume needed, and patient satisfaction. Restylane, Perlane, and Juvéderm are currently the most popular dermal fillers used in the United States.
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Several biomaterials are available for the purpose of soft tissue augmentation, but none of them has all the properties of the ideal filler material. The recent development of hyaluronic acid gels for dermal implantation give the physician new possibilities of effective treatment in this field. This study provides a clinical and histological evaluation of safety and efficacy of a cross-linked stabilized non-animal hyaluronic acid gel (Restylane, Q-Med, Uppsala, Sweden) to determine its characteristics, advantages, disadvantages, and side-effects. 158 patients were treated with facial intradermal implant of hyaluronic acid gel for augmentation therapy of wrinkles and folds, and for lip augmentation and/or recontouring. The results were evaluated in all patients by subjective judgement by the physician and the patient, and by photographic method at time 0 and after 1, 2, 4 and 8 months from the procedure. In addition, a smaller histological study was carried out in five volunteer patients for a term of 52 weeks to determine the interaction and duration of the material in human healthy skin. Clinically, both the physicians' and patients' evaluations revealed very satisfactory results, with a global 78.5% and 73.4% respectively of moderate or marked improvement after eight months, independent of the treated area. The photographic evaluation revealed even better results with a 80.4% of moderate or marked improvement after 8 months. The safety evaluation showed a 12.5% of postoperative immediate adverse events, that were localized and transient. There was no evidence of major systemic side effects. Histologically, the product was shown to be long-lasting and well tolerated as judged by histological techniques. Stabilized, non-animal, hyaluronic acid gel is well tolerated and effective in augmentation therapy of soft tissues of the face. This material presents several advantages in comparison to previously used injectable biomaterials and expands the arsenal of therapeutic tools in the field of soft tissue augmentation.
Article
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Hyaluronic acid (HA) derivatives have been developed to try to enhance rheological properties of this molecule to make it suitable for various medical applications. The main dermatological application of HA derivatives is the augmentation of soft tissues, via injection into the dermis. HA derivatives are indicated for the correction of cutaneous contour deficiencies of the skin, particularly in cases of ageing or degenerative lesions or to increase lips. Two HA derivatives have been evaluated: Hylaform Viscoelastic Gel (Hylan B), derived from rooster combs and subjected to cross-linking, and Restylane, produced through bacterial fermentation (streptococci) and stabilized, as declared by the producer. In both cases the purpose is to improve HA theological characteristics and slow down its degradation once it is in contact with biological structures. Distribution of particle dimensions, pH, protein concentration and rheological properties have been investigated in order to evaluate their reliability as fillers for soft tissue augmentation. The results of the analyses showed that there are differences between Restylane and Hylaform. Especially as far as rheological characteristics are concerned, the results outline different structures of the products: Hylaform behaves as a strong hydrogel, Restylane as a weak hydrogel; rheologically Hylaform is clearly superior to Restylane. Hylaform contains a definitely minor quantity (about a quarter) of cross-linked hyaluronic acid than Restylane. Furthermore, although not declared by the manufacturer, Restylane contains protein, resulting from bacterial fermentation or added to enable cross-linking reaction; the quantity of proteins contained by Restylane can be as much as four times the quantity contained by Hylaform, for the same volume (1 ml). It is evident that Hylaform offers higher safety margin than Restylane. Furthermore, wide literature and 20 years of clinical experience on hyaluronan derived from rooster combs confirm the reliability of this derivative while we did not find evidence regarding about the safety of HA obtained from streptococcus.
Article
background.: Several biomaterials are available for the purpose of soft tissue augmentation, but none of them has all the properties of the ideal filler material. The recent development of hyaluronic acid gels for dermal implantation give the physician new possibilities of effective treatment in this field. objective.: This study provides a clinical and histological evaluation of safety and efficacy of a cross‐linked stabilized non‐animal hyaluronic acid gel (Restylane, Q‐Med, Uppsala, Sweden) to determine its characteristics, advantages, disadvantages, and side‐effects. methods.: 158 patients were treated with facial intradermal implant of hyaluronic acid gel for augmentation therapy of wrinkles and folds, and for lip augmentation and/or recontouring. The results were evaluated in all patients by subjective judgement by the physician and the patient, and by photographic method at time 0 and after 1, 2, 4 and 8 months from the procedure. In addition, a smaller histological study was carried out in five volunteer patients for a term of 52 weeks to determine the interaction and duration of the material in human healthy skin. results.: Clinically, both the physicians' and patients' evaluations revealed very satisfactory results, with a global 78.5% and 73.4% respectively of moderate or marked improvement after eight months, independent of the treated area. The photographic evaluation revealed even better results with a 80.4% of moderate or marked improvement after 8 months. The safety evaluation showed a 12.5% of postoperative immediate adverse events, that were localized and transient. There was no evidence of major systemic side effects. Histologically, the product was shown to be long‐lasting and well tolerated as judged by histological techniques. conclusions.: Stabilized, non‐animal, hyaluronic acid gel is well tolerated and effective in augmentation therapy of soft tissues of the face. This material presents several advantages in comparison to previously used injectable biomaterials and expands the arsenal of therapeutic tools in the field of soft tissue augmentation.
Article
In order to develop an artifical vitreous, a large series of hydrogels have been previously produced by polymerization of 1-vinyl-2-pyrrolidinone, with or without crosslinking. Based on the assumption that a functional vitreous substitute should possess viscoelastic properties after its delivery, a number of selected gels were characterized rheologically by both oscillatory shear stress analysis and shear creep analysis, using a controlled stress rheometer in the cone/plate configuration. The experiments demonstrated a dramatic effect of injecting the gels through small-gauge needles, as many lost their viscoelasticity to become free-flowing fluids, probably because of the cleavage of chains and crosslinks. It was also found that the increase of comonomer content (2-hydroxyethyl methacrylate) and of crosslinking level generally had a strengthening effect. However, the effects of hydrophilic crosslinking agents (diallyl ether and divinyl glycol) were irregular. Eventually, only four hydrogels in this series showed viscoelastic characteristics after injection through a 30-gauge (0.13 mm diameter) needle, maintaining behaviour typical of crosslinked networks and warranting further assessment as potential vitreous substitutes.
Article
The interaction of solvents with cross‐linked network structures, such as occur in vulcanized rubber, is subjected to a statistical mechanical treatment based on the model and procedure presented in the preceding paper. The activity of the solvent is expressed as a function of its concentration in the swollen network, and of the degree of cross‐linking. The maximum degree of swelling of the network in contact with the pure solvent is related to the degree of cross‐linking. The heat of interaction of the solvent with the network can be calculated from the temperature coefficient of maximum swelling. The theory leads to the conclusion that the swelling capacity should be diminished by the application of an external stress. Furthermore, the modulus of elasticity should decrease inversely with the cube root of the swelling volume.
Article
In order to develop an artificial vitreous, a large series of hydrogels have been previously produced by polymerization of 1-vinyl-2-pyrrolidinone, with or without crosslinking. Based on the assumption that a functional vitreous substitute should possess viscoelastic properties after its delivery, a number of selected gels were characterized rheologically by both oscillatory shear stress analysis and shear creep analysis, using a controlled stress rheometer in the cone/plate configuration. The experiments demonstrated a dramatic effect of injecting the gels through small-gauge needles, as many lost their viscoelasticity to become free-flowing fluids, probably because of the cleavage of chains and crosslinks. It was also found that the increase of comonomer content (2-hydroxyethyl methacrylate) and of crosslinking level generally had a strengthening effect. However, the effects of hydrophilic crosslinking agents (diallyl ether and divinyl glycol) were irregular. Eventually, only four hydrogels in this series showed viscoelastic characteristics after injection through a 30-gauge (0·13mm diameter) needle, maintaining behaviour typical of crosslinked networks and warranting further assessment as potential vitreous substitutes. © 1998 SCI.
Article
To measure the swollen gel strength of hydrogels, single isolated samples with a certain shape, e.g. spherical or cylindrical, are often tested. However, the commercial superabsobent polymer (SAP) hydrogels are mostly sugar-like particles with irregular shapes. Therefore, the usual testing of the strength of the swollen state of the gels is impossible. In this paper, an experimental method is investigated for the measuring the swollen gel strength of SAPs. Firstly, we determined absorbency under load (AUL) of a typical SAP sample and then the mechanical strength of the swollen sample was measured by a rheological method. The characterization was conducted by a controlled strain rheometer at 25 °C. Dependency of the rheological properties of the sample on strain and frequency was investigated. To determine the linear viscoelastic (LVE) zone, dynamic storage modulus (G′) and loss modulus (G″), measurements were carried out at constant frequency and in a range of strains on the SAP sample. Furthermore, G′ was obtained at constant strain over a range of frequencies. The storage modulus of the swollen SAP gel (already absorbed saline under 0.3–0.9 psi) was measured to be above 1000 Pa at 25 °C.
Article
Hyaluronic acid (HA) is a natural macromolecule with importance in the pharmaceutical, medical and cosmetic industries. The knowledge of its hydrodynamic properties is fundamentally important for further study on its applications. The aim of our study was to investigate and provide hydrodynamic parameters for six different molar mass samples chemically produced by depolymerisation of a high molar mass ‘parent’ HA using five different hydroxyl free radical concentrations. The main tools employed for these studies were size exclusion chromatography/multi-angle laser light scattering (SEC/MALLS), sedimentation velocity in the analytical ultracentrifuge and intrinsic viscosity. The results indicated that values for intrinsic viscosity, molar mass and sedimentation coefficient decreased with increasing hydroxyl free radical starting concentration. The six samples investigated here also represent a homologous series of a polysaccharide thus conformational information could be obtained, and the results indicate that HA adopts a ‘stiffish’ coil conformation in solution. Where appropriate our results were compared with previously published data.
Article
Crosslinked hyaluronan gels are used in various applications where their stability is a prerequisite. The sensitivity of such gels to hyaluronidase can be determined as an index of stability by several approaches: chromatography, electrophoresis, and viscometry. We describe here a test based on the colorimetric determination of the N-acetyl-d-glucosamine released by hyaluronidase in standardized conditions. The sensitivities to bovine testicular hyaluronidase of 11 different gels used to fill skin wrinkles (Restylane; Perlane; Juvéderm 18, 24, 24HV, 30, and 30HV; Surgiderm 18, 24XP, 30, and 30XP) were compared.The method was reproducible, easy to perform, not time-consuming and allowed us to demonstrate that the sensitivity to testicular hyaluronidase was dependent on the degree of crosslinking of the gels and also on their monophasic/biphasic nature. Under our conditions, Surgiderm 30, 24XP and 30XP were the most resistant gels.We propose to retain the hyaluronidase test to predict the in situ stability of a crosslinked gel used to fill skin wrinkles.
Article
Size exclusion chromatography coupled with triple detection (online laser light scattering, refractometry, and viscosimetry) (SEC-TDA) was applied for the study of hyaluronan (HA) fragments produced during hydrolysis catalyzed by bovine testicular hyaluronidase (BTH). The main advantage this approach provides is the complete hydrodynamic characterization without requiring further experiments. HA was hydrolyzed using several BTH amounts and for increasing incubation times. Fragments were characterized in terms of weight and number average molecular weights (M(w) and M(n), respectively), polydispersity index (M(w)/M(n)), hydrodynamic radius (R(h)), and intrinsic viscosity ([eta]). The Mark-Houwink-Sakurada (MHS) curves (log[eta] versus logM(w)) were then derived directly. Fragments covering a whole range of M(w) (10-900kDa) and size (R(h)=4-81nm) and presenting a rather narrow distribution of molar masses (M(w)/M(n)=1.6-1.7) were produced. From the MHS curves, HA conformation resulted in a change from a random coil toward a rigid rod structure while decreasing the M(w). HA enzymatic hydrolysis in the presence of a BTH inhibitor was also monitored, revealing that inhibition profiles are affected by ionic strength. Finally, a comparison of the kinetic data derived from SEC-TDA with the data from rheological measurements suggested different strengths of the two methods in the determination of the depolymerization rate depending on the hydrolysis conditions.
Article
The physical and chemical properties that control the clinical persistence of temporary dermal fillers are not well understood. Discovering the relationship between the clinical performance and physical properties of temporary fillers may stimulate the design of future, high-performance fillers. Described here is the rheology of polysaccharide dermal fillers composed of cross-linked hyaluronic acid (XLHA) or un-cross-linked sodium carboxymethylcellulose (CMC) and polyethylene oxide (PEO). Using measured rheology data and published clinical study data, we have developed a predictive model for the persistence of polysaccharide-containing dermal fillers. The XLHA dermal fillers were obtained from commercial sources. The CMC/PEO dermal filler formulation was prepared in house. The rheologic properties of the polysaccharide fillers were measured and related to comparative clinical persistence data available from controlled clinical studies. The clinical persistence of the polysaccharide dermal fillers correlates linearly with the concentration of polymer in the formulation divided by the tan delta (G''/G'). The work described here has shown that a model relating the concentration of the polysaccharide and the tan delta of the formulation can predict the comparative clinical persistence of XLHA and CMC/PEO dermal fillers.
Article
The past 5 years in the United States have seen an explosion in the popularity of noninvasive aesthetic procedures. Not only have fillers and Botox turned out to be fantastically reliable and effective aesthetic tools, but also they have vastly expanded the accessibility of cosmetic procedures. Our cosmetic filler options are growing quickly as more and more fillers are coming before the U.S. Food and Drug Administration (FDA), seeking entry into the lucrative U.S. market. This article outlines the approval process that foreign fillers go through in their home countries and gives an idea of the fillers that are currently under consideration by the FDA. As our armamentarium of injectable fillers grows, it will be essential to know each product's strengths and weaknesses so that we can provide our patients with the best possible aesthetic results.
Article
Over the past decade, the popularity of nonsurgical cosmetic procedures has increased exponentially. Last year, according to the American Society of Aesthetic Plastic Surgery, more than 5 million procedures were performed using cosmetic injectables such as botulinum toxin and dermal filling agents. According to the society's recent statistics, more than 85% of all dermal filler procedures occurred with a hyaluronic acid derivative.These numbers are expected to rise in the future as there is currently no other class of filling agent that rivals the popularity of hyaluronic acid. The popularity of hyaluronic acid specifically stems from its effectiveness, ease of administration, and safety profile.
Article
For people requiring large volumes to shape facial contours, add volume to a sunken midface, or correct asymmetry, the options today are limited. Fat injections for adding volume, solid implants for cheeks and chin enhancement, face lift and injectable permanent or semi-permanent products are some of the alternatives used. With the trend towards less invasive and nonpermanent alternatives to plastic surgery, the use of injectable filler materials for facial rejuvenation and correction of soft-tissue defects is becoming increasingly popular. These materials provide volume expansion within the dermis, thereby smoothing out overlying facial wrinkles and enhancing facial contours. Ease of application, minimal procedural discomfort, and rapid patient recovery make injectable fillers well suited for outpatient use. Ideally, a filler material should be biocompatible, nontoxic, nonimmunogenic, and nonmigratory. Several biomaterials have been developed, such as bovine collagen, autologous and allogeneic human collagen, autologous fat, fibroblasts, and hyaluronic acid. However, although they are largely biocompatible, reabsorption and lack of sustained cosmetic effect are major drawbacks. Non-animal stabilized hyaluronic acid (NASHA) offers a longer-lasting aesthetic effect than bovine collagen or avian hyaluronic acid in facial soft-tissue augmentation, and a potentially lower risk of inflammatory reactions. Restylane SubQ is a new NASHA product indicated for deep subcutaneous or supraperiostal injection to replace volume loss in facial adipose tissues and create more defined facial contours.
Article
Injectable synthetic hyaluronic acid is biodegradable and biocompatible with human hyaluronic acid. Soft tissue augmentation with this product does not require prior skin testing and provides robust augmentation. Its ability to attract and maintain significant amounts of water accounts for the volume and duration of correction that persists until the stabilized gel is completely metabolized.
Article
Hyaluronic acid (HA) fillers are becoming the material of choice for use in cosmetic soft tissue and dermal correction. HA fillers appear to be similar, but their physical characteristics can be quite different. These differences have the potential to affect the ability of the physician to provide the patient with a natural and enduring result. The objective of this article is to discuss the key physical properties and methods used in characterizing dermal fillers. These methods were then used to analyze several well-known commercially available fillers. Analytical methods were employed to generate data on the properties of various fillers. The measured physical properties were concentration, gel-to-fluid ratio, HA gel concentration, degree of HA modification, percentage of cross-linking, swelling, modulus, and particle size. The results demonstrated that commercial fillers exhibit a wide variety of properties. Combining the objective factors that influence filler performance with clinical experience will provide the patient with the optimal product for achieving the best cosmetic result. A careful review of these gel characteristics is essential in determining filler selection, performance, and patient expectations.
Article
Hyaluronic acid (HA) fillers have been proposed as alternatives to other temporary skin fillers, such as bovine collagen, for treating facial skin lines and for providing lip augmentation. Several types of commercial HA fillers are now available in many countries. They include Restylane, which is produced by microbiologic engineering techniques, and Hylaform, which is HA extract derived from rooster combs. They have been approved for use in several countries, but not currently in the United States. There are no recommendations to perform pretreatment skin testing by the manufacturers. Our purpose is to describe and comment on our experiences with Hylaform and Restylane fillers. Observation of any side effects and skin testing results were documented. Between September 1996 and September 2000, 709 patients were treated with Hylaform and Restylane and were followed up clinically for at least 1 year. Three of these patients (0.42%) developed delayed skin reactions. Three other patients were referred for evaluation of their skin reactions from other practitioners. Five of these 6 patients agreed to skin testing of their forearms. In the 5 patients tested, challenge intradermal skin testing was positive in 4 patients; the reactions started approximately 8 weeks after injection. There was a slight incidence of delayed inflammatory skin reactions to two HA fillers. Both of these reactions occurred after the first and repeat injections. Challenge skin testing was positive in 4 of 5 tested patients.
Article
Nonanimal hyaluronic acid gel was recently developed for soft tissue augmentation and volume expansion and has been shown to offer several advantages in comparison to other augmentation materials. There are rare reports of adverse events believed to be secondary to trace amounts of proteins in the hyaluronic acid raw material. To determine the safety profile of nonanimal stabilized hyaluronic acid gel (Restylane, Perlane, Restylane Fine Lines, Q-Med AB, Uppsala, Sweden) for soft tissue augmentation using a retrospective review of all adverse events data from Europe, Canada, Australia, South American, and Asia from 1999 and 2000. Data from an estimated 144,000 patients treated in 1999 indicated the major reaction to injectable hyaluronic acid was localized hypersensitivity reactions, occurring in approximately 1 of every 1400 patients treated. In 1999 there was an adverse event reported for 1 of every 650 patients (0.15%) treated. These were temporary events that included redness, swelling, localized granulomatous reactions, bacterial infection, as well as acneiform and cystic lesions. For 2000 there was an estimated 262,000 patients treated with hyaluronic acid gel. The total number of adverse events was 144, corresponding to one adverse event for every 1800 patients (0.06%) treated. The major adverse event was again hypersensitivity, occurring in 1 of every 5000 patients treated. According to the reported worldwide adverse events data, hypersensitivity to nonanimal hyaluronic acid gel is the major adverse event and is most likely secondary to impurities of bacterial fermentation. According to data from 2000, the incidence of hypersensitivity appears to be declining after the introduction of a more purified hyaluronic acid raw material.
Article
Ideally, rationally designed tissue engineering scaffolds promote natural wound healing and regeneration. Therefore, we sought to synthesize a biomimetic hydrogel specifically designed to promote tissue repair and chose hyaluronic acid (HA; also called hyaluronan) as our initial material. Hyaluronic acid is a naturally occurring polymer associated with various cellular processes involved in wound healing, such as angiogenesis. Hyaluronic acid also presents unique advantages: it is easy to produce and modify, hydrophilic and nonadhesive, and naturally biodegradable. We prepared a range of glycidyl methacrylate-HA (GMHA) conjugates, which were subsequently photopolymerized to form crosslinked GMHA hydrogels. A range of hydrogel degradation rates was achieved as well as a corresponding, modest range of material properties (e.g., swelling, mesh size). Increased amounts of conjugated methacrylate groups corresponded with increased crosslink densities and decreased degradation rates and yet had an insignificant effect on human aortic endothelial cell cytocompatibility and proliferation. Rat subcutaneous implants of the GMHA hydrogels showed good biocompatibility, little inflammatory response, and similar levels of vascularization at the implant edge compared with those of fibrin positive controls. Therefore, these novel GMHA hydrogels are suitable for modification with adhesive peptide sequences (e.g., RGD) and use in a variety of wound-healing applications.
Article
A modification of Dische's carbazole reaction for uronic acid in the presence of borate is described. The advantages of the procedure are: 1.(1) There is an approximately twofold increase of sensitivity. The OD is a linear function of concentration between 4 and 40 μg/ml.2.(2) Maximum color develops immediately.3.(3) The color is stable for at least 16 hr.4.(4) There is greater reproducibility and reduction of interference by chloride ion and oxidants.It has been found possible to distinguish between heparin, heparin derivatives, and other polyuronides of connective tissue by comparing the effect of chlorides on the color yield in both procedures.
Article
Since 1996, hyaluronic acid (HA) has been launched onto the market in Europe. Since then, different companies proposed their HAs. Biomatrix (NJ, USA) proposes an animal-derived HA (from rooster comb). Q-Med AB (Uppsala, Sweden) and LEA-DERM (Paris, France) are the main companies to have a nonanimal HA. HA is produced by bacterial fermentation from a specific strain of streptococci. HA has no species specificity and theoretically has no risk of allergy. No skin testing is necessary before injecting because HA is a biodegradable agent. To be utilized as a filler agent for improving wrinkles, scars, or increasing volumes, HA must be stabilized to obtain a sufficient half-life. Process of stabilization varies, according to each manufacturer. This explains the differences in longevity and in viscosity of the different products. Several HAs are suitable to fine lines, to deep wrinkles/folds, or to increase volume. A new indication for "rejuvenation" is injection into the superficial dermis and epidermis. The HA (stabilized or not) is not used to fill in but rather to hydrate and finally to rejuvenate the skin. This procedure must be repeated at intervals of a few weeks or months. If HA is the safest filler agent in cosmetic indications today, some rare side effects may appear and must be known to inform patients. Most of these complications are not severe and will disappear when the product is degraded.
Article
Nonsurgical procedures have become very popular for the rejuvenation of the aging face. Trends now are for less invasive procedures as well as for more preventative intervention to slow the damage from ultraviolet light and environmental factors, as well as from intrinsic aging. The goal of these procedures is to eliminate or delay the need for corrective surgery. The regular use of sunscreens; retinoids and improved cosmeceuticals; injectable neurotoxins; soft-tissue augmentation products; and minimally invasive laser, light, and radiofrequency treatments are decreasing and delaying need for invasive procedures. Injectable fillers entered mainstream cosmetic medicine with the development of bovine collagen injections in the 1980s. The availability of improved fillers that are less allergenic and longer lasting has resulted in a renaissance in filler techniques. No single filler has proven to be more popular than the category of hyaluronic acids (HA). This article will review the use of the hyaluronic acid fillers that are currently approved for use by the Federal Drug Administration in the United States and describe the significant differences between them to assist the practicing cosmetic physician in choosing and using this category of dermal filler.
Article
Nowadays, patients are demanding not only enhancement to their dental (micro) esthetics, but also their overall facial (macro) esthetics. Soft tissue augmentation via dermal filling agents may be used to correct facial defects such as wrinkles caused by age, gravity, and trauma; thin lips; asymmetrical facial appearances; buccal fold depressions; and others. This article will review the pathogenesis of facial wrinkles, history, techniques, materials, complications, and clinical controversies regarding dermal fillers for soft tissue augmentation.
Article
The persistence of dermal fillers containing crosslinked hyaluronic acid (XLHA) correlates linearly to the concentration of polymer in solution. For dermal fillers composed of XLHA, a polymer concentration above approximately 25 mg/mL is not practical because it cannot be easily injected through a small-bore needle. Formulating dermal fillers from mixtures of carboxymethylcellulose (CMC) and polyethylene oxide (PEO) has several advantages over XLHA. We hypothesize that increasing the concentration of CMC/PEO will increase the persistence in the dermis. These polymers of CMC and PEO can be formulated at higher concentrations than XLHA to produce smooth, particulate-free gels resulting in easier, more controllable injection. Second, these gels are not required to be covalently crosslinked; CMC/PEO forms a stable gel-like structure in solution without crosslinking. Here we have prepared dermal fillers from CMC/PEO polymer blends at concentrations of 20 mg/mL (dermal filler 1), 29 mg/mL (dermal filler 2), 37 mg/mL (dermal filler 3), and 45 mg/mL (dermal filler 4) and measured their rheologic properties compared to commercial XLHA dermal fillers. The data here demonstrate that it is possible to duplicate the rheologic properties of commercial XLHA fillers using CMC/PEO at different polymer concentrations to formulate improved dermal fillers. All of the dermal filler formulations prepared can be easily injected through 30-gauge needles.
Article
Temporary dermal fillers composed of crosslinked hyaluronic acid (XLHA) are space filling gels that are readily available in the United States and Europe. Several families of dermal fillers based on XLHA are now available and here we compare the physical and rheological properties of these fillers to the clinical effectiveness. The XLHA fillers are prepared with different crosslinkers, using HA isolated from different sources, have different particle sizes, and differ substantially in rheological properties. For these fillers, the magnitude of the complex viscosity, |eta*|, varies by a factor of 20, the magnitude of the complex rigidity modulus, |G*|, and the magnitude of the complex compliance, |J*| vary by a factor of 10, the percent elasticity varies from 58% to 89.9%, and the tan delta varies from 0.11 to 0.70. The available clinical data cannot be correlated with either the oscillatory dynamic or steady flow rotational rheological properties of the various fillers. However, the clinical data appear to correlate strongly with the total concentration of XLHA in the products and to a lesser extent with percent elasticity. Hence, our data suggest the following correlation: dermal filler persistence = [polymer] x [% elasticity] and the clinical persistence of a dermal filler composed of XLHA is dominated by the mass and elasticity of the material implanted. This work predicts that the development of future XLHA dermal filler formulations should focus on increasing the polymer concentration and elasticity to improve the clinical persistence.
Article
Hyaluronan (HA) has various biological functions that are strongly dependent on its chain length. In some cases, as in inflammation and angiogenesis, long and short chain-size HA effects are antagonistic. HA hydrolysis catalyzed by hyaluronidase (HAase) is believed to be involved in the control of the balance between longer and shorter HA chains. Our studies of native HA hydrolysis catalyzed by bovine testicular HAase have suggested that the kinetic parameters depend on the chain size. We thus used HA fragments with a molar mass ranging from 8x10(2) g mol(-1) to 2.5x10(5) g mol(-1) and native HA to study the influence of the chain length of HA on the kinetics of its HAase-catalyzed hydrolysis. The initial hydrolysis rate strongly varied with HA chain length. According to the Km and Vm/Km values, the ability of HA chains to form an efficient enzyme-substrate complex is maximum for HA molar masses ranging from 3x10(3) to 2x10(4) g mol(-1). Shorter HA chains seem to be too short to form a stable complex and longer HA chains encounter difficulties in forming a complex, probably because of steric hindrance. The hydrolysis Vm values strongly suggest that as the chain length decreases the HAase increasingly catalyses transglycosylation rather than hydrolysis. Finally, two HA chain populations, corresponding to HA chain molar masses lower and higher than approximately 2x10(4) g mol(-1), are identified and related to the bi-exponential character of the model we have previously proposed to fit the experimental points of the kinetic curves.
Sedimentation analysis of polysaccharides. In: Analytical ultracentrifugation in biochemistry and polymer science. Cam-bridge
  • Harding
  • Rowe Aj Se
  • Horton
  • Jc
Harding SE, Rowe AJ, Horton JC. Sedimentation analysis of polysaccharides. In: Analytical ultracentrifugation in biochemistry and polymer science. Cam-bridge: Royal Society of Chemistry; 1992. p. 495e513.
Sedimentation analysis of polysaccharides
  • S E Harding
  • A J Rowe
  • J C Horton
Harding SE, Rowe AJ, Horton JC. Sedimentation analysis of polysaccharides. In: Analytical ultracentrifugation in biochemistry and polymer science. Cambridge: Royal Society of Chemistry; 1992. p. 495e513.