Molecular Weight Hyaluronan Research Articles

Hyaluronan size and concentration: Effect on key biophysical and biochemical features

The effect of hyaluronan (HA) molecular weight (MW) and concentration (c) on key features of HA-formulations was systematically studied, in vitro, exploring the widest range/number of MW/c to date. Nine pharmaceutical-grade HA-samples (60–2500 kDa) were hydrodynamically characterized using Size-Exclusion-Chromatography-Triple-Detector-Array (SEC-TDA) also providing conformational data.HAs aqueous solutions (thirteen concentrations in the range 0.1–32 g/L) were tested for dynamic viscosity (η). η dependence on MW/c was analyzed providing mathematical correlations not only for the specific-zero-shear-viscosity, but also for the critical-shear-rate and the shear-thinning-extent. Besides confirming the dilute- and semi-dilute- c-regimes for the HAs, a third concentrated regime was evidenced for the 220–2500 kDa samples. Data on how MW affects the dependence of viscosity parameters on c and vice-versa were provided.The 60–90 kDa HAs proved stable to thermal sterilization and enzymatically catalyzed hydrolysis, while the 220–2500 kDa samples depolymerized to an extent depending, beyond concentration, on MW.HA size did not significantly affect fibroblasts behavior: under the conditions here tested, the HAs similarly sustained human-dermal-fibroblasts growth and wound-healing also showing comparable effect on collagen-I, elastin and hyaluronan-synthase-1 expression. Overall, results valuably contribute to the understanding of the HA MW/c impact on the rheological, stability and biochemical features of the final formulations also providing mathematical correlations allowing for their optimization towards specific performance.

Enzyme variants in biosynthesis and biological assessment of different molecular weight hyaluronan

In the present study, low- and high-molecular-weight hyaluronic acids (LMW-HA and HMW-HA) were synthesized in vitro by truncated Streptococcus equisimilis hyaluronan synthases (SeHAS). The enzyme kinetic parameters were determined for each enzyme variant. The MW, structure, dispersity, and biological activity of polymers were determined by electrophoresis, FTIR spectroscopy, carbazole, cell proliferation, and cell migration assay, respectively. The specific activities were calculated as 7.5, 6.8, 4.9, and 2.8 µgHA µgenzyme−1 min−1 for SeHAS, HAS123, HAS23, and HASIntra, respectively. The results revealed SeHAS produced a polydisperse HMW-HA (268 kDa), while HAS123 and HAS23 produced a polydisperse LMW-HA (< 30 kDa). Interestingly, HASIntra produced a low-disperse LMW-HA. Kinetics studies revealed the truncated variants displayed increased Km values for two substrates when compared to the wild-type enzyme. Biological assessments indicated all LMW-HAs showed a dose-dependent proliferation activity on endothelial cells (ECs), whereas HMW-HAs exhibited an inhibitory effect. Also, LMW-HAs had the highest cell migration effect at 10 µg/mL, while at 200 µg/mL, both LMW- and HMW-HAs postponed the healing recovery rate. The study elucidated that the transmembrane domains (TMDs) of SeHAS affect the enzyme kinetics, HA-titer, HA-size, and HA-dispersity. These findings open new insight into the rational engineering of SeHAS to produce size-defined HA.Graphical abstract

Study on the aggregation nature of sodium cocoyl glycinate and sodium hyaluronate mixture in aqueous and NaCl solutions

AbstractThe mixed system of sodium cocoyl glycinate and sodium hyaluronate (HA) with different mass concentrations and relative molecular weights was investigated by the surface tension method. All the curves of surface tension versus logarithm of concentration (γ‐lgc curves) of sodium cocoyl glycinate‐HA mixed system displayed the properties of double platform. The critical micelle concentration (cmc) of sodium cocoyl glycinate was 1.690 g/L at 25°C. The two inflection points of the γ‐lgc curves corresponding to the cocoyl glycine‐HA mixed system were cac (the critical aggregation concentration) and cmce (the extended cmc of sodium cocoyl glycinate), and cac &lt; cmce &lt; cmc. With the change of the mass concentration and relative molecular weight of HA, the cac values were almost constant. However, cmce increased with the increase of the mass concentration of HA at the same HA molecular weight. For the HA of molecular weight of 800 and 260000 Da, the mass concentration of HA increased from 0.05 to 0.4 g/L, and the cmce value increased from 1.199 to 1.390 g/L and 1.102 to 1.330 g/L, respectively. When the mass concentration of HA remained the same, the change in the relative molecular weight of HA had little effect on the cmce value. For the mixed system of sodium cocoyl glycine −0.1 g/L HA, when the concentration of NaCl was 2 g/L, the salt enhancement effect was dominant. When the concentration of NaCl was 4 to 8 g/L, the salt weakening effect was dominant. It is indicated that HA can improve the chemical properties of sodium cocoyl glycinate at a certain concentration, thus improving the cleaning, foaming, and foam stability of sodium cocoyl glycinate.

Decoupling stiffness and toughness of self-healing hydrogels for complex tissue regeneration via 3D bioprinting

Although polysaccharides are attractive biocompatible materials compared with synthetic polymers, most polysaccharide-based hydrogels exhibit suboptimal mechanical properties. In this study, we fabricated a hyaluronate (HA)-based self-healing hydrogel with enhanced toughness that can be used as a 3D bioink for complex tissue regeneration. We hypothesized that the incorporation of oxidation, aimed at minimizing the reduction in the molecular weight of HA, along with the introduction of a double network to the hydrogel, could facilitate the construction of 3D structures with decoupled stiffness and toughness. Various physicochemical properties of hydrogels comprising oxidized and hydrazide-modified HAs for potential use as bioinks were assessed. Bilayered constructs containing primary chondrocytes and osteoblasts were designed and fabricated using 3D printing to mimic the growth plate structure. Transplantation of the 3D-printed construct into a mouse model revealed the controlled differentiation stages of chondrocytes. This strategy for tailoring 3D scaffolds and addressing the limitations of polysaccharide-based hydrogels may hold promise for applications in the biomedical field, including the regeneration of complex tissues and organs.

Matrix‐Bound Hyaluronan Molecular Weight as a Regulator of Dendritic Cell Immune Potency (Adv. Healthcare Mater. 8/2024)

Matrix‐Bound Hyaluronan Molecular Weight as a Regulator of Dendritic Cell Immune Potency (Adv. Healthcare Mater. 8/2024)

The Role of Hyaluronan/Receptor for Hyaluronan-Mediated Motility Interactions in the Modulation of Macrophage Polarization and Cartilage Repair

Hyaluronan (HA), a negatively charged linear glycosaminoglycan, is a key macromolecular component of the articular cartilage extracellular matrix. The differential effects of HA are determined by a spatially/temporally regulated display of HA receptors, such as CD44 and Receptor for Hyaluronan Mediated Motility (RHAMM). HA signaling through CD44 with RHAMM has been shown to stimulate inflammation and fibrotic processes. This study shows an increased expression of RHAMM in pro-inflammatory macrophages. Interfering with HA/RHAMM interactions using a 15mer RHAMM-mimetic, HA binding peptide (P15-1) together with high molecular weight (HMW)HA reduced the expression and release of inflammatory markers and increased the expression of anti-inflammatory markers in pro-inflammatory macrophages. Interfering with HA/RHAMM interactions in vivo during the regeneration of a full thickness cartilage defect after microfracture surgery in rabbits using three intra-articular injections of P15-1 together with HMWHA reduced the number of pro-inflammatory macrophages and increased the number of anti-inflammatory macrophages in the injured knee joint and greatly improved the repair of the cartilage defect compared to intra-articular injections of HMWHA alone. These findings suggest that HA/RHAMM interactions play a key role in cartilage repair/regeneration via stimulating inflammatory and fibrotic events, including increasing the ratio of pro-inflammatory to anti-inflammatory macrophages. Interfering with these interactions reduced inflammation and greatly improved cartilage repair.

Design of synthetic peptide-based fluorescence probes for turn-on detection of hyaluronan

Herein, we designed and examined a series of fluorescent peptide-based probes for turn-on detection of hyaluronan (HA), a member of the glycosaminoglycan family. We utilized two kinds of synthetic HA-binding peptides as the binding unit for HA, and each peptide was coupled with three kinds of environment-sensitive fluorophores as the signaling unit. From the examination of the peptides, fluorophores, and the position and number of fluorophore modification, we found that X7 peptide (RYPISRPRKR) labelled with an aggregation-induced emission (AIE) fluorogen, tetraphenylethene (TPE), at the N-terminal (named TPE-X7) did function as a light-up probe for HA. The response of TPE-X7 was highly selective to higher molecular weight HA in comparison with lower ones, having the possible potential for the analysis of HA size. TPE-X7 was also applicable to the quantification of HA in synovial fluids.Graphical abstract

Matrix-Bound Hyaluronan Molecular Weight as a Regulator of Dendritic Cell Immune Potency.

Hyaluronic acid (HA) is a glycosaminoglycan in the extracellular matrix with immunoregulatory properties depending on its molecular weight (MW). However, the impact of matrix-bound HA on dendritic cells (DCs) remains unclear due to varying distribution of HA MW under different physiological conditions. To investigate DCs in defined biosystems, 3D collagen matrices modified with HA of specific MW with similar microstructure and HA levels are used. It is found that HA MW influences cytokine binding to matrix, suggesting modulation of cytokine availability by the different HA MWs. These studies on DC immune potency reveal that low MW HA (8-15kDa) enhances immature DC differentiation and antigen uptake, while medium (MMW-HA; 500-750kDa) and high MW HA (HMW-HA; 1250-1500kDa) increase cytokine secretion in mature DCs. The effect on DC phenotype and cytokine secretion by different MWs of HA is independent of CD44. However, blocking the CD44 receptor reveals its potential role in regulating acute inflammation through increased secretion of CCL2, CXCL8, and IL-6. Additionally, MMW- and HMW-HA matrices reduce migratory capacity of DCs, dependent on CD44. Overall, these findings provide insights into MW-dependent effects of matrix-bound HA on DCs, opening avenues for the design of DC-modulating materials to enhance DC-based therapy.

Disabled-2: a protein up-regulated by high molecular weight hyaluronan has both tumor promoting and tumor suppressor roles in ovarian cancer

Although the pro-tumorigenic functions of hyaluronan (HA) are well documented there is limited information on the effects and targets of different molecular weight HA. Here, we investigated the effects of 27 kDa, 183 kDa and 1000 kDa HA on ES-2 ovarian cancer cells overexpressing the stem cell associated protein, Notch3. 1000 kDA HA promoted spheroid formation in ES-2 cells mixed with ES-2 overexpressing Notch3 (1:3). We report disabled-2 (DAB2) as a novel protein regulated by 1000 kDa HA and further investigated its role in ovarian cancer. DAB2 was downregulated in ovarian cancer compared to normal tissues but increased in metastatic ovarian tumors compared to primary tumors. High DAB2 expression was associated with poor patient outcome and positively correlated with HA synthesis enzyme HAS2, HA receptor CD44 and EMT and macrophage markers. Stromal DAB2 immunostaining was significantly increased in matched ovarian cancer tissues at relapse compared to diagnosis and associated with reduced survival. The proportion of DAB2 positive macrophages was significantly increased in metastatic ovarian cancer tissues compared to primary cancers. However, DAB2 overexpression significantly reduced invasion by both A2780 and OVCAR3 cells in vivo. Our research identifies a novel relationship between HA signalling, Notch3 and DAB2. We highlight a complex relationship of both pro-tumorigenic and tumor suppressive functions of DAB2 in ovarian cancer. Our findings highlight that DAB2 has a direct tumor suppressive role on ovarian cancer cells. The pro-tumorigenic role of DAB2 may be mediated by tumour associated macrophages and requires further investigation.

Influence of Sodium hyaluronate molecular weight on critical quality attributes and filterability of solutions

Influence of Sodium hyaluronate molecular weight on critical quality attributes and filterability of solutions

Development of Therapeutic Agent for Osteoarthritis via Inhibition of KIAA1199 Activity: Effect of Ipriflavone In Vivo.

This study aimed to clarify the effects of ipriflavone, which effectively reduces KIAA1199 activity, on osteoarthritis (OA) development and progression in an in vivo OA mouse model. The OA model mice were divided into the ipriflavone (200 mg/kg/day) group and the control group. OA onset and progression were evaluated with the Mankin score, and KIAA1199 expression and hyaluronan (HA) accumulation were analyzed by immunostaining. The molecular weight of HA in the cartilage tissue and serum HA concentration were analyzed by chromatography and competitive HA enzyme-linked immunoassay. The effects of ipriflavone on the bovine cartilage explant culture under the influence of IL-1β were also investigated. In the ipriflavone group, Safranin-O stainability was well-preserved, resulting in significant reduction of the Mankin score (p = 0.027). KIAA1199 staining positivity decreased and HA stainability was preserved in the ipriflavone group. The serum HA concentration decreased, and the molecular weight of HA in the cartilage tissue increased in the ipriflavone group. The results of the cartilage explant culture indicated that ipriflavone could reduce GAG losses and increase the molecular weight of HA. Thus, ipriflavone may have an inhibitory effect on OA development/progression. Ipriflavone could be a therapeutic drug for OA by targeting KIAA1199 activity.

Restoring Adipose Tissue Homeostasis in Response to Aging: Initial Clinical Experience with Profhilo Structura®.

The aim of the case series was to determine the efficacy of a new medical device developed for adipose tissue restoration in the face. The medical device used the patented NAHYCO® Hybrid Technology to deliver 45 mg of high- (1400 ± 200 kDa) and 45 mg of low- (100 ± 20 kDa) molecular-weight hyaluronan, in 2 mL. Patients and methods: Twenty-two volunteers, aged 36-60 years. Two mL of Profhilo® Structura was injected using a 25 G cannula for each hemiface, into superficial fat compartment along the line from the preauricular area to the mandibular angle. Two injections were performed, and Profhilo Structura's effect on restoring adipose tissue was evaluated immediately after treatment, and over a 6-month follow-up. The studied medical device revealed a pseudoplastic behavior and consistency that allowed easy extrusion from a syringe. It showed a lower viscosity compared to dermal fillers, based on crosslinked HA. Clinically, the soft tissue thickness increased immediately after injection, and the clinical improvement persisted across a 6-month follow-up. The self-reported satisfaction with the treatment showed an amelioration in the midface of all the subjects enrolled, with no adverse effects. Profhilo® Structura demonstrated a peculiar fat compartment integration, with a regenerating effect on adipose tissue senescence. The skin thickening and compaction effects were similar to those obtained using chemically crosslinked dermal fillers, while a natural look was preserved, and the use of crosslinking agents was avoided.

Hyaluronan with Different Molecular Weights Can Affect the Gut Microbiota and Pathogenetic Progression of Post-Intensive Care Syndrome Mice in Different Ways.

Post-intensive care syndrome (PICS) poses a serious threat to the health of intensive care unit (ICU) survivors, and effective treatment options are currently lacking. With increasing survival rates of ICU patients worldwide, there is a rising interest in developing methods to alleviate PICS symptoms. This study aimed to explore the potential of using Hyaluronan (HA) with different molecular weights as potential drugs for treating PICS in mice. Cecal ligation and puncture (CLP) were used to establish a PICS mice model, and high molecular weight HA (HMW-HA) or oligo-HA were used as therapeutic agents. Pathological and physiological changes of PICS mice in each group were monitored. 16S rRNA sequencing was performed to dissect gut microbiota discrepancies. The results showed that both molecular weights of HA could increase the survival rate of PICS mice at the experimental endpoint. Specifically, 1600 kDa-HA can alleviate PICS in a short time. In contrast, 3 kDa-HA treatment decreased PICS model survivability in the early stages of the experiment. Further, via 16S rRNA sequence analysis, we observed the changes in the gut microbiota in PICS mice, thereby impairing intestinal structure and increasing inflammation. Additionally, both types of HA can reverse this change. Moreover, compared to 1600 kDa-HA, 3 kDa-HA can significantly elevate the proportion of probiotics and reduce the abundance of pathogenic bacteria (Desulfovibrionaceae and Enterobacteriaceae). In conclusion, HA holds the advantage of being a potential therapeutic drug for PICS, but different molecular weights can lead to varying effects. Moreover, 1600 kDa-HA showed promise as a protective agent in PICS mice, and caution should be taken to its timing when considering using 3 kDa-HA.

Isolation and identification of hyaluronan-degrading bacteria from Japanese fecal microbiota.

Hyaluronan (HA) is a high-molecular-weight glycosaminoglycan and widely distributed in all connective tissues and organs with diverse biological functions. HA has been increasingly used as dietary supplements targeted to joint and skin health for humans. We here first report isolation of bacteria from human feces that are capable of degrading HA to lower molecular weight HA oligosaccharides (oligo-HAs). The bacteria were successfully isolated via a selective enrichment method, in which the serially diluted feces of healthy Japanese donors were individually incubated in an enrichment medium containing HA, followed by the isolation of candidate strains from streaked HA-containing agar plates and selection of HA-degrading strains by measuring HA using an ELISA. Subsequent genomic and biochemical assays identified the strains as Bacteroides finegoldii, B. caccae, B. thetaiotaomicron, and Fusobacterium mortiferum. Furthermore, our HPLC analysis revealed that the strains degraded HA to oligo-HAs of various lengths. Subsequent quantitative PCR assay targeting the HA degrading bacteria showed that their distribution in the Japanese donors varied. The evidence suggests that dietary HA is degraded by the human gut microbiota with individual variation to oligo-HAs components, which are more absorbable than HA, thereby exerting its beneficial effects.

Hyaluronan regulates sperm-induced inflammatory response by enhancing sperm attachment to bovine endometrial epithelial cells via CD44: in-silico and in-vitro approaches.

Recently, we reported that sperm induce cluster of differentiation 44 (CD44) expression and Toll-like receptor 2 (TLR2)-mediated inflammatory response in bovine uterus. In the present study, we hypothesized that the interaction between CD44 of bovine endometrial epithelial cells (BEECs) and hyaluronan (HA) affects sperm attachment and thereby enhancing TLR2-mediated inflammation. To test our hypothesis, at first, in-silico approaches were employed to define the binding affinity of HA for CD44 and TLR2. Further, an in-vitro experiment using the sperm-BEECs co-culture model was applied to investigate the effect of HA on sperm attachment and inflammatory response. Here, low molecular weight (LMW) HA at different concentrations (0, 0.1, 1, or 10 µg/mL) was incubated with BEECs for 2 h followed by the co-culture without- or with non-capacitated washed sperm (106/ml) for additional 3 h was performed. The present in-silico model clarified that CD44 is a high-affinity receptor for HA. Moreover, TLR2 interactions with HA oligomer (4- and 8-mers) target a different subdomain (h-bonds) compared to TLR2-agonist (PAM3) which targets a central hydrophobic pocket. However, the interaction of LMW HA (32-mers) with TLR2 revealed no stability of HA at any pocket of TLR2. Notably, the immunofluorescence analysis revealed the HA localization in both endometrial stroma and epithelia of ex-vivo endometrial explant. Moreover, ELISA showed significant levels of HA in BEECs culture media. Importantly, BEECs pretreatment with HA prior to sperm exposure increased the number of attached sperm to BEECs, and upregulated the transcriptional levels of pro-inflammatory genes (TNFA, IL-1B, IL-8, and PGES) in BEECs in response to sperm. However, BEECs treated with HA only (no sperm exposure) did not show any significant effect on the transcript abundance of pro-inflammatory genes when compared to the non-treated BEECs. Altogether, our findings strongly suggest a possible cross-talk between sperm and endometrial epithelial cells via HA and HA binding receptors (CD44 and TLR2) to induce a pro-inflammatory response in bovine uterus.

Characterization of the Molecular Weight of Hyaluronan in Eye Products Using a Novel Method of Size Exclusion High-Pressure Liquid Chromatography.

Hyaluronan (HA) exists in two forms, high molecular weight HA (HMWHA) and low molecular weight HA (LMWHA), which have distinct physiological functions. Therefore it is imperative to know the form of HA within pharmaceutical products, including eye products. This study developed an accurate, sensitive, and quantitative method to characterize the form of HA in eye products. Thereafter, the effects of the HA-containing eye products on corneal wound healing were investigated. The MW distributions and concentrations of HA in over the counter eye products were determined by size exclusion chromatography (SEC) high-pressure liquid chromatography (HPLC). The effects of the eye products containing HA on corneal wound healing were characterized both in vitro and in vivo using the scratch assay and the debridement wound model, respectively. The concentrations and MWs of HA were successfully determined within a range of 0.014 to 0.25 mg/mL using SEC HPLC. The concentrations of HA in the ophthalmic products varied from 0.14 to 4.0 mg/mL and the MWs varied from ∼100 kDa to >2500 kDa. All but one HA-containing eye product had an inhibitory effect on corneal wound healing, whereas pure HA promoted corneal wound healing. A novel SEC-HPLC method was developed for quantifying and characterizing the MW of HA in eye products. Although HA promoted corneal wound healing, HA-containing eye products inhibited corneal wound healing, likely caused by preservatives. SEC-HPLC could be implemented as a routine method for determining the form of HA in commercially available ophthalmic products.

Hyaluronan breakdown by snake venom hyaluronidases: From toxins delivery to immunopathology.

Snake venom enzymes have a broad range of molecular targets in plasma, tissues, and cells, among which hyaluronan (HA) is outstanding. HA is encountered in the extracellular matrix of diverse tissues and in the bloodstream, and its different chemical configurations dictate the diverse morphophysiological processes in which it participates. Hyaluronidases are highlighted among the enzymes involved in HA metabolism. This enzyme has been detected along the phylogenetic tree, suggesting that hyaluronidases exert multiple biological effects on different organisms. Hyaluronidases have been described in tissues, blood and snake venoms. Snake venom hyaluronidases (SVHYA) contribute to tissue destruction in envenomations and are called spreading factors since their action potentiates venom toxin delivery. Interestingly, SVHYA are clustered in Enzyme Class 3.2.1.35 together with mammalian hyaluronidases (HYAL). Both HYAL and SVHYA of Class 3.2.1.35 act upon HA, generating low molecular weight HA fragments (LMW-HA). LMW-HA generated by HYAL becomes a damage-associated molecular pattern that is recognized by Toll-like receptors 2 and 4, triggering cell signaling cascades culminating in innate and adaptive immune responses that are characterized by lipid mediator generation, interleukin production, chemokine upregulation, dendritic cell activation and T cell proliferation. In this review, aspects of the structures and functions of HA and hyaluronidases in both snake venoms and mammals are presented, and their activities are compared. In addition, the potential immunopathological consequences of HA degradation products generated after snakebite envenoming and their use as adjuvant to enhance venom toxin immunogenicity for antivenom production as well as envenomation prognostic biomarker are also discussed.

Impact of hyaluronan size on localization and solubility of the extracellular matrix in the mouse brain.

Hyaluronan (HA) is a central component of the extracellular matrix (ECM) in the brain and plays a pivotal role in neural development and plasticity. Brain HA exists in 2 distinct forms of the ECM: the diffuse ECM, which is soluble in saline and detergents, and the condensed ECM, which forms aggregates, such as perineuronal nets (PNNs). Although the physiological functions of HA significantly differ depending on its size, size differences in HA have not yet been examined in the 2 ECM types, which is partly because of the lack of methods to rapidly and accurately measure the molecular weight (MW) of HA. In this study, we established a simple method to simultaneously assess the MW of HA in multiple crude biological samples. HA was purified through single-step precipitation from tissue extracts using biotinylated HA-binding protein and streptavidin-coupled magnetic beads, followed by separation on gel electrophoresis. By applying this method to HA in the mouse brain, we revealed that the condensed ECM contained higher MW HA than the diffuse ECM. Higher MW HA and lower MW HA exhibited different spatial distributions: the former was confined to PNNs, whereas the latter was widely present throughout the brain. Furthermore, the limited degradation of HA showed that only higher MW HA was required to form an insoluble HA-aggrecan complex. The present study demonstrated that the MW of HA in the brain strongly correlates with the localization and solubility of the ECM it forms.

Insight into the assembly of lipid-hyaluronan complexes in osteoarthritic conditions.

Interactions between molecules in the synovial fluid and the cartilage surface may play a vital role in the formation of adsorbed films that contribute to the low friction of cartilage boundary lubrication. Osteoarthritis (OA) is the most common degenerative joint disease. Previous studies have shown that in OA-diseased joints, hyaluronan (HA) not only breaks down resulting in a much lower molecular weight (MW), but also its concentration is reduced ten times. Here, we have investigated the structural changes of lipid-HA complexes as a function of HA concentration and MW to simulate the physiologically relevant conditions that exist in healthy and diseased joints. Small angle neutron scattering and dynamic light scattering were used to determine the structure of HA-lipid vesicles in bulk solution, while a combination of atomic force microscopy and quartz crystal microbalance was applied to study their assembly on a gold surface. We infer a significant influence of both MW and HA concentrations on the structure of HA-lipid complexes in bulk and assembled on a gold surface. Our results suggest that low MW HA cannot form an amorphous layer on the gold surface, which is expected to negatively impact the mechanical integrity and longevity of the boundary layer and could contribute to the increased wear of the cartilage that has been reported in joints diseased with OA.

Recent Advances of Hyaluronan for Skin Delivery: From Structure to Fabrication Strategies and Applications.

Hyaluronan (HA) plays a fundamental role in maintaining the homeostasis on skin health. Furthermore, the effect of HA in skin inflammatory diseases is worth studying in the next future. HA and its conjugates change the solubility of active pharmaceutical ingredients, improve emulsion properties, prolong stability, reduce immunogenicity, and provide targeting. HA penetrates to deeper layers of the skin via several mechanisms, which depend on the macromolecular structure and composition of the formulation. The cellular and molecular mechanisms involved in epidermal dysfunction and skin aging are not well understood. Nevertheless, HA is known to selectively activate CD44-mediated keratinocyte signaling that regulates its proliferation, migration, and differentiation. The molecular size of HA is critical for molecular mechanisms and interactions with receptors. High molecular weight HA is used in emulsions and low molecular weight is used to form nanostructured lipid carriers, polymeric micelles, bioconjugates, and nanoparticles. In the fabrication of microneedles, HA is combined with other polymers to enhance mechanical properties for piercing the skin. Hence, this review aims to provide an overview of the current state of the art and last reported ways of processing, and applications in skin drug delivery, which will advocate for their broadened use in the future.