The Rheology and Physicochemical Characteristics of Hyaluronic Acid Fillers: Their Clinical Implications

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.     

Transcriptomic Analysis in Human 3D Skin Model Injected with Resorbable Hyaluronic Acid Fillers Reveals Foreign Body Response

Usage of injectable dermal fillers applied for aesthetic purposes has extensively increased over the years. As such, the number of related adverse reactions has increased, including patients showing severe complications such as product migration, topical swelling and inflammatory reactions of the skin. In order to understand the underlying molecular events of these adverse reactions we performed a genome-wide gene expression study on the multi-cell type human Phenion^® Full-Thickness Skin Model exposed to five experimental hyaluronic acid (HA) preparations with increasing cross-linking degree, four commercial fillers from Perfectha^®, and non-resorbable filler Bio-Alcamid^®. In addition, we evaluated whether cross-linking degree or particle size of the HA-based fillers could be associated with the occurrence of adverse effects. In all cases, exposure to different HA fillers resulted in a clearly elevated gene expression of cytokines and chemokines related to acute inflammation as part of the foreign body response. Furthermore, for one experimental filler genes of OXPHOS complexes I-V were significantly down-regulated (adjusted p-value < 0.05), resulting in mitochondrial dysfunction which can be linked to over-expression of pro-inflammatory cytokines TNFα and IL-1β and chemokine CCL2. Our hypothesis that cross-linking degree or particle size of the HA-based fillers is related to the biological responses induced by these fillers could only partially be confirmed for particle size. In conclusion, our innovative approach resulted in gene expression changes from a human 3D skin model exposed to dermal fillers that mechanistically substantiate aforementioned adverse reactions, and thereby adds to the weight of evidence that these fillers may induce inflammatory and fibrotic responses.     

High-Molecular-Weight Hyaluronic Acid Inhibits IL-1β-Induced Synovial Inflammation and Macrophage Polarization through the GRP78-NF-κB Signaling Pathway

Recent evidence has suggested that synovial inflammation and macrophage polarization were involved in the pathogenesis of osteoarthritis (OA). Additionally, high-molecular-weight hyaluronic acid (HMW-HA) was often used clinically to treat OA. GRP78, an endoplasmic reticulum (ER) stress chaperone, was suggested to contribute to the hyperplasia of synovial cells in OA. However, it was still unclear whether HMW-HA affected macrophage polarization through GRP78. Therefore, we aimed to identify the effect of HMW-HA in primary synovial cells and macrophage polarization and to investigate the role of GRP78 signaling. We used IL-1β to treat primary synoviocytes to mimic OA, and then treated them with HMW-HA. We also collected conditioned medium (CM) to culture THP-1 macrophages and examine the changes in the phenotype. IL-1β increased the expression of GRP78, NF-κB (p65 phosphorylation), IL-6, and PGE2 in primary synoviocytes, accompanied by an increased macrophage M1/M2 polarization. GRP78 knockdown significantly reversed the expression of IL-1β-induced GRP78-related downstream molecules and macrophage polarization. HMW-HA with GRP78 knockdown had additive effects in an IL-1β culture. Finally, the synovial fluid from OA patients revealed significantly decreased IL-6 and PGE2 levels after the HMW-HA treatment. Our study elucidated a new form of signal transduction for HMW-HA-mediated protection against synovial inflammation and macrophage polarization and highlighted the involvement of the GRP78-NF-κB signaling pathway.     

透明质酸在电-膜分离过程中的迁移规律

对电-膜分离技术用于透明质酸分离过程的可行性进行了初步研究. 着重研究了透明质酸在电场作用下的行为,并考察了料液中透明质酸浓度、溶液pH值、离子强度、电流强度等因素对迁移过程的影响. 结果表明,透明质酸透过膜的速度在一定范围内与料液的浓度和电流强度成正比,在pH 7~9范围内透明质酸的电迁移率基本保持恒定. 膜孔径对迁移速度没有明显影响,单位膜面积的产量也与电流密度成正比. 该方法能有效地将透明质酸与蛋白质分离.     

透明质酸的制备及其应用进展

综述了近年来透明质酸在制备和应用方面的研究现状,并预测了其发展趋势。     

透明质酸的性能及生产

叙述了生化药物透明质酸的化学结构、性质及两种不同的生产方法.     

透明质酸的产需情况及市场分析

介绍了透明质酸的性能、生产方法、用途和市场情况。透明质酸(HA)是近年来较为热点的生化产品之一,由于具有优良的保湿、润滑和生物相容性能,被应用于日化、医药、保健食品等领域。目前,全球透明质酸的年生产能力达到20t/a,2006年国内发酵法透明质酸的生产厂家达到8家,年生产能力约8t/a,大约40%的产品出口美国、日本等地。     

发酵法生产医药用透明质酸

山东临朐华元生物工程有限公司通过对菌株的筛选培育、发酵原料配方和工艺的改进、提纯工艺和设备的优化、制粉工艺和设备的改进、生产环境的改造,利用生物工程技术发酵法研制生产出医药用透明质酸,并形成1.5t/a的生产规模。产品应用于眼科手术、滴眼液、手术防粘连等方面,改变了国内医药用透明质酸依赖进口或动物器官提取法微量生产自用的局面,为国内以透明质酸为基质的制剂产品发展打下了基础。     

透明质酸的制备及应用研究进展

介绍了透明质酸的结构、理化性质,并对透明质酸的制备及其在医药、化妆品和食品领域中的应用进行了综述。     

己二酸二酰肼交联透明质酸薄膜的制备及性能研究

利用己二酸二酰肼(ADH)作为交联剂,对HA分子进行化学修饰,制备出HA-ADH凝胶薄膜。利用差示扫描量热仪(DSC)和红外光谱(FTIR)对交联产物HA-ADH的结构进行表征,证实了交联反应的发生。当HA与ADH质量比为1∶8时,薄膜的性能最好。通过对HA-ADH薄膜的皮肤刺激性试验进行考察,发现经交联后的HA-ADH薄膜具有良好的生物相容性。     

透明质酸氧化降解的研究进展

低分子量透明质酸(LMWHA)和透明质酸寡聚糖(o-HA)具有抗氧化、免疫调节、促进伤口愈合、促血管生成和抗肿瘤等生物活性,透明质酸(HA)可以氧化降解为LMWHA和o-HA.对HA的氧化降解进行了综述.     

Anomalous Viscosity Behavior in Aqueous Solutions of Hyaluronic Acid

Summary Effects of steady shear flows on intermolecular interactions in dilute and semidilute aqueous solutions of hyaluronic acid (HA) are reported. Pronounced shear thinning behavior is observed for solutions of HA at high shear rates, and no hysteresis effects are detected upon the subsequent return to low shear rates. With the aid of the asymmetric flow field-flow fractionation (AFFFF) technique, it is shown that mechanical degradation of the polymer does not take place in these shear viscosity experiments, even at high shear rates. The low shear rate viscosity of a semidilute HA solution decreases by approximately 40% when the temperature is increased from 10 °C to 45 °C. It is shown that when a dilute HA solution is exposed to a low fixed shear rate (0.001 s^-1), a marked viscosification occurs in the course of time and prominent intermolecular complexes are formed. It is argued that shear-induced alignment and stretching of polymer chains promote the evolution of hydrogen-bonded structures, where cooperative zipping of stretched chains generates a network. At a higher constant shear rate (0.1 s^-1), the viscosity decreases as time goes because of the alignment of the polymer chains, but the higher shear flow perturbation prevents the chains in dilute solutions from building up association complexes. The viscosity of an entangled HA solution is not changed in the considered time window at this shear rate, but the network structures breakdown at the highest shear rate (1000 s^-1), and then they are restored upon return to a low shear rate.     

Physicochemical Properties of Injectable Hyaluronic Acid: Skin Quality Boosters

In addition to clinical research on the efficacy and compatibility of injectable hyaluronic acid (HA) based fillers, ample in vitro research on the physicochemical properties of these materials is published. Different HA-based product ranges are also available as skin quality boosters (SQBs) to improve skin quality. The aim of this study is to investigate the physicochemical properties of specific HAs for improving skin quality, as, to the best of the authors' knowledge, no data is published on this topic to date. This paper may provide a better understanding of clinical performance and differentiation between these SQBs. Five HA injectable hydrogels (Belotero Revive, Juvederm Volite, Restylane Skinbooster Vital, Viscoderm Hydrobooster, and Profilho) from the SQB product ranges of different companies and manufacturing technologies are investigated for their extrusion force, swelling degree, rheological performance, and cohesivity. There are significant differences in extrusion force, swelling degree, rheological performance, and cohesivity between the assessed SQBs. HA concentration (mg mL⁻¹) exhibits statistically significant positive correlations with extrusion force, swelling degree, tan delta, and cohesivity. This study provides a physicochemical characterization of different SQBs and information to improve understanding of this type of product.     

功能性聚氨酯表面层层自组装透明质酸和胶原

以功能性聚氨酯(PUR)为基体,用1,3-二氨基丙烷对PUR进行处理,发生胺解反应使PUR表面接枝上氨基(—NH2),然后再利用静电作用在氨基化的PUR材料上自组装透明质酸(HA)和胶原(Col).采用表面水接触角仪测试PUR材料的亲水情况,采用茚三酮分析法定量测试PUR膜表面接枝—NH2的密度,采用石英微晶天平(QC...     

Effect of Hyaluronic Acid on the Self-Assembly of a Dipeptide-Based Supramolecular Gel

The combination of polymers and low molecular weight (LMW) compounds is a powerful approach to prepare new supramolecular materials. Here we prepare two-component hydrogels made by a well-known and biologically active polymer, hyaluronic acid ( HA ), and a dipeptide-based supramolecular gelator. We undertake a detailed study of materials with different compositions including macroscopic (hydrogel formation, rheology) and micro/nanoscopic characterization (electron microscopy, X-ray powder diffraction). We observe that the two components mutually benefit in the new materials: a minimum amount of HA helps to reduce the polymorphism of the LMW network leading to reproducible hydrogels with improved mechanical properties; the LMW component network holds HA without the need for an irreversible covalent crosslinking. These materials have a great potential for biomedical application as, for instance, extracellular matrix mimetics for cell growth. As a proof of concept, we have observed that this material is effective for cell growth in suspension and avoids cell sedimentation even in the presence of competing cell-adhesive surfaces. This may be of interest to advanced cell delivery techniques.     

Liposomes Loaded with Everolimus and Coated with Hyaluronic Acid: A Promising Approach for Lung Fibrosis

Chronic lung allograft dysfunction (CLAD) and interstitial lung disease associated with collagen tissue diseases (CTD-ILD) are two end-stage lung disorders in which different chronic triggers induce activation of myo-/fibroblasts (LFs). Everolimus, an mTOR inhibitor, can be adopted as a potential strategy for CLAD and CTD-ILD, however it exerts important side effects. This study aims to exploit nanomedicine to reduce everolimus side effects encapsulating it inside liposomes targeted against LFs, expressing a high rate of CD44. PEGylated liposomes were modified with high molecular weight hyaluronic acid and loaded with everolimus (PEG-LIP(ev)-HA400kDa). Liposomes were tested by in vitro experiments using LFs derived from broncholveolar lavage (BAL) of patients affected by CLAD and CTD-ILD, and on alveolar macrophages (AM) and lymphocytes isolated, respectively, from BAL and peripheral blood. PEG-LIP-HA400kDa demonstrated to be specific for LFs, but not for CD44-negative cells, and after loading everolimus, PEG-LIP(ev)-HA400kDa were able to arrest cell cycle arrest and to decrease phospho-mTOR level. PEG-LIP(ev)-HA400kDa showed anti-inflammatory effect on immune cells. This study opens the possibility to use everolimus in lung fibrotic diseases, demonstrating that our lipids-based vehicles can vehicle everolimus inside cells exerting the same drug molecular effect, not only in LFs, but also in immune cells.     

In Vitro Investigation of Self-Assembled Nanoparticles Based on Hyaluronic Acid-Deoxycholic Acid Conjugates for Controlled Release Doxorubicin: Effect of Degree of Substitution of Deoxycholic Acid

Self-assembled nanoparticles based on a hyaluronic acid-deoxycholic acid (HD) chemical conjugate with different degree of substitution (DS) of deoxycholic acid (DOCA) were prepared. The degree of substitution (DS) was determined by titration method. The nanoparticles were loaded with doxorubicin (DOX) as the model drug. The human cervical cancer (HeLa) cell line was utilized for in vitro studies and cell cytotoxicity of DOX incorporated in the HD nanoparticles was accessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. In addition, cellular uptake of fluorescently labeled nanoparticles was also investigated. An increase in the degree of deoxycholic acid substitution reduced the size of the nanoparticles and also enhanced their drug encapsulation efficiency (EE), which increased with the increase of DS. A higher degree of deoxycholic acid substitution also lead to a lower release rate and an initial burst release of doxorubicin from the nanoparticles. In summary, the degree of substitution allows the modulation of the particle size, drug encapsulation efficiency, drug release rate, and cell uptake efficiency of the nanoparticles. The herein developed hyaluronic acid-deoxycholic acid conjugates are a good candidate for drug delivery and could potentiate therapeutic formulations for doxorubicin–mediated cancer therapy.     

高产量、高分子量透明质酸发酵条件优化

研究了搅拌转速、初糖浓度及通气量对兽疫链球菌Streptococcus zooepidemicus WSH24发酵生产透明质酸的影响. 研究结果表明,搅拌转速对透明质酸产量及分子量影响很大,搅拌转速为200 r/min时透明质酸产量达到5.3 g/L,平均分子量达到1.88×106 Da,产率系数为0.13 g/g;初始葡萄糖浓度为65.8 g/L时有利于透明质酸的生产,产量达5.9 g/L,平均分子量达1.90×106 Da,产率系数为0.17 g/g;通气量对透明质酸的发酵也有较大影响,通气量为1.2 L/(min·L)时透明质酸的产量及分子量均高于0.5 L/(min·L)时的发酵结果.     

细菌纤维素/透明质酸复合材料的生物合成及表征

在培育细菌纤维素(BC)过程中添加不同分子量的两种透明质酸(HA),分别制备出不同的细菌纤维素复合物HA/BC(Mw=3,000)和HA/BC(Mw=300,000)。采用红外光谱、扫描电子显微镜、X射线衍射和热重分析对其结构和性能进行了表征。添加HA后提高了复合物的产量;FTIR结果表明了HA与BC之间存在交联;添加HA增大了BC的热稳定性,而对BC的结晶指数影响不大,且HA/BC(3,000)的性能始终优于HA/BC(300,000);HA(3,000)增大了BC的拉伸强度,而HA(300,000)反而减小了其拉伸强度。结果表明添加小分子量的HA可制备最大热失重温度较高的HA/BC复合物。     

Effects of a Catechol-Functionalized Hyaluronic Acid Patch Combined with Human Adipose-Derived Stem Cells in Diabetic Wound Healing

Introduction: Chronic inflammation and impaired neovascularization play critical roles in delayed wound healing in diabetic patients. To overcome the limitations of current diabetic wound (DBW) management interventions, we investigated the effects of a catechol-functionalized hyaluronic acid (HA-CA) patch combined with adipose-derived mesenchymal stem cells (ADSCs) in DBW mouse models. Methods: Diabetes in mice (C57BL/6, male) was induced by streptozotocin (50 mg/kg, >250 mg/dL). Mice were divided into four groups: control (DBW) group, ADSCs group, HA-CA group, and HA-CA + ADSCs group (n = 10 per group). Fluorescently labeled ADSCs (5 × 10⁵ cells/100 µL) were transplanted into healthy tissues at the wound boundary or deposited at the HA-CA patch at the wound site. The wound area was visually examined. Collagen content, granulation tissue thickness and vascularity, cell apoptosis, and re-epithelialization were assessed. Angiogenesis was evaluated by immunohistochemistry, quantitative real-time polymerase chain reaction, and Western blot. Results: DBW size was significantly smaller in the HA-CA + ADSCs group (8% ± 2%) compared with the control (16% ± 5%, p < 0.01) and ADSCs (24% ± 17%, p < 0.05) groups. In mice treated with HA-CA + ADSCs, the epidermis was regenerated, and skin thickness was restored. CD31 and von Willebrand factor-positive vessels were detected in mice treated with HA-CA + ADSCs. The mRNA and protein levels of VEGF, IGF-1, FGF-2, ANG-1, PIK, and AKT in the HA-CA + ADSCs group were the highest among all groups, although the Spred1 and ERK expression levels remained unchanged. Conclusions: The combination of HA-CA and ADSCs provided synergistic wound healing effects by maximizing paracrine signaling and angiogenesis via the PI3K/AKT pathway. Therefore, ADSC-loaded HA-CA might represent a novel strategy for the treatment of DBW.