Molecular Weight Hyaluronic Acid Research Articles

Injectable and thermoresponsive hybrid hydrogel with Antibacterial, Anti-inflammatory, oxygen Transport, and enhanced cell growth activities for improved diabetic wound healing

Treatment of diabetic foot ulcer (DFU) remains a global challenge since it is often hindered by multiple unfavorable factors including hypoxia, impaired cell signaling, persistent infections, and prolonged inflammation during healing process. Therefore, developing a material that can address the aforementioned difficulties is highly on demand in the clinic nowadays. In this study, a new type of injectable and thermoresponsive hyaluronic acid (HA)/hexamethylene diisocyanate-Poloxamer 407 copolymer crosslinked hybrid hydrogel consisting of fluorocarbon nanodroplets (FNDs), epidermal growth factor-loaded chitosan nanoparticles (ENPs), and polyhexamethylene biguanide (PHMB) named FPE-HHPG was successfully developed for diabetic wound healing. The FPE-HHPG can be self-gelationed at 37 °C and offer multiple functions of oxygen supply, antibacterial, and enhanced cell growth which were contributed by the FNDs, PHMB, and ENPs, respectively. In addition, the FPE-HHPG can provide anti-inflammatory effects functioned by its entity constituent of high molecular weight HA. These functionalities allowed the FPE-HHPGs a markedly improved wound healing efficacy on diabetic rats including faster wound closure, thorough re-epithelialization, less inflammatory response, and rapid collagen deposition and maturation in comparison to the outcomes treated by using gauze or the commercial dressing HeraDerm. Given the aforementioned effectiveness together with known merits of injectable hydrogels such as moisture maintenance, wound shape adaptation, exudate absorptiveness, and low adhesiveness, the developed FPE-HHPG is anticipated to be a feasible tool for diabetic wound treatment in the clinic.

Intra-Articular Injections of Allogeneic Mesenchymal Stromal Cells vs. High Molecular Weight Hyaluronic Acid in Dogs With Osteoarthritis: Exploratory Data From a Double-Blind, Randomized, Prospective Clinical Trial.

This double-blind, randomized, prospective clinical trial was conducted to obtain exploratory data comparing the efficacy of intra-articular allogeneic mesenchymal stem/stromal cells (MSC) to high molecular weight hyaluronic acid (HA) for the treatment of pain associated with canine osteoarthritis (OA). Objective gait analysis (%Body Weight Distribution, %BWD), accelerometry, clinical metrology instruments and veterinary exams were used as outcome measures during various time points throughout the 48-week study period. Fourteen dogs with elbow or coxofemoral OA were enrolled and assigned in a 2:1 ratio to the treatment groups. Each patient received a set of two injections 4 weeks apart. Self-limiting joint flare was observed in seven patients, with six of these in the MSC group. Ten patients completed all follow-up appointments. Both treatment groups showed evidence of mild improvement following the treatment, but the results were inconsistent among the various outcome measures assessed. Overall, dogs enrolled in the HA group showed greater improvement compared to the MSC group. The primary outcome measure, %BWD, showed evidence of improvement, when compared to baseline values, at 36 weeks after injection for the HA group only (p = 0.048, estimated difference: 4.7). Similarly, when treatment groups were compared, evidence of a difference between treatment groups (with the HA-group showing greater improvement) were identified for weeks 24 and 36 (p = 0.02 and 0.01, respectively). The small sample size of this exploratory study does not allow firm conclusions. However, until studies with larger sample sizes are available, the current literature combined with our data do not support the clinical use of intra-articular MSC therapy over high molecular weight HA for the treatment of canine OA at this time.

Adding Krill Oil and Low Molecular Weight Hyaluronic Acid to Movoflex® Soft Chews Helps Improve Dogs’ Mobility

Movoflex® Soft Chew (Virbac, USA) is a nutritional supplement to support dogs’ mobility. It contains a unique combination of five ingredients: eggshell membrane, hyaluronic acid (HA) of high molecular weight, Boswellia serrata extract, astaxanthin, and vitamin D3. Krill oil and low molecular weight HA are now added to the supplement. The tolerance of this advanced formula was first evaluated in dogs. The aspect, palatability of the chew, and effectiveness on mobility criteria were then assessed by sixty-nine dog owners who were regular users of the current Movoflex® Soft Chews. The chew was found to be well-tolerated and similar in terms of aspect and acceptability to the current one. All but one mobility criteria significantly improved after 30 days, including the ability to walk, climb, stand, interact with people, or the way of walking.

Purification and Surface Modification of Chitosan-based Polyplexes Using Tangential Flow Filtration and Coating by Hyaluronic Acid

Chitosan (CS)-based polyplexes are produced by spontaneous electrostatic association with nucleic acids using CS in excess. Interactions of positively charged polyplexes, and the unbound CS, with negatively charged blood components limit the applicable dosage of such polymeric nanoparticles (NPs) and development of formulations with improved hemocompatibility and transfection efficiency is needed. Here, we introduce a strategy based on Tangential Flow Filtration (TFF) to remove unbound CS, concentrate polyplexes and subsequently coat with hyaluronic acid (HA) to improve hemocompatibility and bioactivity. Optimal TFF conditions were established. A library of HA with different molecular weights and degrees of sulfation was used at different carboxyl + sulfate to phosphate ratios for polyplex coating, bioactivity and hemocompatibility assessment. A systematic optimization of TFF conditions allowed for purification of polylpexes from excess unbound CS and subsequent coating with HA. Except for high molecular weight HA, for which macroscopic aggregation was observed, both sulfated and non-sulfated HAs resulted in small sized and homogenous coated complexes. However, sulfated HAs displayed higher stability during the second filtration process indicating their stronger binding affinity to polyplexes. Finally, we found that low molecular weight HA-coated polyplexes have equivalent silencing efficiency in vitro and improved hemocompatibility compared to uncoated polyplexes.

Hyaladherins May be Implicated in Alcohol-Induced Susceptibility to Bacterial Pneumonia.

Although the epidemiology of bacterial pneumonia and excessive alcohol use is well established, the mechanisms by which alcohol induces risk of pneumonia are less clear. Patterns of alcohol misuse, termed alcohol use disorders (AUD), affect about 15 million people in the United States. Compared to otherwise healthy individuals, AUD increase the risk of respiratory infections and acute respiratory distress syndrome (ARDS) by 2-4-fold. Levels and fragmentation of hyaluronic acid (HA), an extracellular glycosaminoglycan of variable molecular weight, are increased in chronic respiratory diseases, including ARDS. HA is largely involved in immune-assisted wound repair and cell migration. Levels of fragmented, low molecular weight HA are increased during inflammation and decrease concomitant with leukocyte levels following injury. In chronic respiratory diseases, levels of fragmented HA and leukocytes remain elevated, inflammation persists, and respiratory infections are not cleared efficiently, suggesting a possible pathological mechanism for prolonged bacterial pneumonia. However, the role of HA in alcohol-induced immune dysfunction is largely unknown. This mini literature review provides insights into understanding the role of HA signaling in host immune defense following excessive alcohol use. Potential therapeutic strategies to mitigate alcohol-induced immune suppression in bacterial pneumonia and HA dysregulation are also discussed.

Hyaluronic acid in the treatment of dry eye disease.

Dry eye disease (DED) is a highly prevalent and debilitating condition affecting several hundred million people worldwide. Hyaluronic acid (HA) is a naturally occurring glycosaminoglycan commonly used in the treatment of DED. This review aims to critically evaluate the literature on the safety and efficacy of artificial tears containing HA used in DED treatment. Literature searches were conducted in PubMed, including MEDLINE, and in Embase via Ovid with the search term: "(hyaluronic acid OR hyaluronan OR hyaluronate) AND (dry eye OR sicca)". A total of 53 clinical trials are included in this review, including eight placebo-controlled trials. Hyaluronic acid concentrations ranged from 0.1% to 0.4%. Studies lasted up to 3 months. A broad spectrum of DED types and severities was represented in the reviewed literature. No major complications or adverse events were reported. Artificial tears containing 0.1% to 0.4% HA were effective at improving both signs and symptoms of DED. Two major gaps in the literature have been identified: 1. no study investigated the ideal drop frequency for HA-containing eyedrops, and 2. insufficient evidence was presented to recommend any specific HA formulation over another. Future investigations assessing the optimal drop frequency for different concentrations and molecular weights of HA, different drop formulations, including tonicity, and accounting for DED severity and aetiology are essential for an evidence-based, individualized approach to DED treatment.

Hyaluronic acid association with bacterial, fungal and viral infections: Can hyaluronic acid be used as an antimicrobial polymer for biomedical and pharmaceutical applications?

The relationships between hyaluronic acid (HA) and pathological microorganisms incite new understandings on microbial infection, tissue penetration, disease progression and lastly, potential treatments. These understandings are important for the advancement of next generation antimicrobial therapeutical strategies for the control of healthcare-associated infections. Herein, this review will focus on the interplay between HA, bacteria, fungi, and viruses. This review will also comprehensively detail and discuss the antimicrobial activity displayed by various HA molecular weights for a variety of biomedical and pharmaceutical applications, including microbiology, pharmaceutics, and tissue engineering.

The relationship between the naked mole-rat and hyaluronic acid, as mediated by its receptor CD44: A Mini-Review

The life expectancy of the naked mole-rat (Heterocephalus glaber) is longer than that of other rodents. In NMR cells, the hyaluronic acid concentration is at a higher level. The extracellular matrix’s primary constituent is hyaluronic acid, and CD44 and RHMM are the receptors for hyaluronic acid in the cells. Hyaluronan synthases (HAS); HAS1, HAS2, and HAS3 are located in the plasma membrane and produce hyaluronic acid. Moreover, there are six types of hyaluronic degradation enzymes (Hyal-1, Hyal-2, Hyal-3, Hyal-4, and PH-20). Hyaluronic acid is known to have anti-cancerous effects and acts as a double-edged sword promoting cell senescence and protecting against cellular aging at the same time. NMR’s lengthy lifespan may probably be due to the high molecular weight of hyaluronic acid. INK4 isoforms (P16ink4a/b and pALTINK4a/b) and p27kip1 conferring on NMR a 2-way (early and regular respectively) defense mechanism make NMR more resistant to cancer cells than, humans and mice with only regular contact inhibition (regular (p27kip1). This study, therefore, aims to examine the existing molecular interactions within the NMR-HA-CD44 axis and the ability to confer cancer resistance to mammalian cells through INK4 isoforms gene transfer using the CRISPR method. A lot of potential thus exists in studying these relationships and the prospects for answering the yet unknowns in this area.

Hyaluronic acid production is enhanced by harnessing the heme-induced respiration in recombinant Lactococcus lactis cultures

Lactococcus lactis is a promising host for pathway-engineered production of high molecular weight hyaluronic acid (HA). This work investigates the effect of hemin-supplemented respiratory metabolism in an engineered L. lactis ldh mutant strain (Δldh L. lactis) as a strategy to enhance HA titer in the batch fermentation process. L. lactis lacks a functional electron transport chain (ETC) and ultimately relies on substrate-level phosphorylation for energy production. We conducted detailed investigations under different dissolved oxygen (DO) conditions and found a steady increase in HA titer with increased DO levels. We found a strong correlation between cofactor availability (NAD+ and acetyl-CoA) and the intracellular concentration of HA precursors, UDP-GlcUA and UDP-GlcNAc. We correlated the intracellular precursor levels with the HA titer obtained for the four conditions. We found that these were higher in hemin-supplemented cultures, with the best HA titer of 4.6 g/l. Finally, we observed that the molecular weight of HA (MWHA) correlates strongly with the ratio of HA precursors concentrations. We also found an inverse correlation between MWHA and HA titer across these experiments. These results can be used in optimizing the trade-off between molecular weight and HA production in bioprocesses involving recombinant L. lactis cultures.

Action of Hyaluronic Acid as a Damage-Associated Molecular Pattern Molecule and Its Function on the Treatment of Temporomandibular Disorders.

The temporomandibular joint is responsible for fundamental functions. However, mechanical overload or microtraumas can cause temporomandibular disorders (TMD). In addition to external factors, it is known that these conditions are involved in complex biological mechanisms, such as activation of the immune system, activation of the inflammatory process, and degradation of extracellular matrix (ECM) components. The ECM is a non-cellular three-dimensional macromolecular network; its most studied components is hyaluronic acid (HA). HA is naturally found in many tissues, and most of it has a high molecular weight. HA has attributed an essential role in the viscoelastic properties of the synovial fluid and other tissues. Additionally, it has been shown that HA molecules can contribute to other mechanisms in the processes of injury and healing. It has been speculated that the degradation product of high molecular weight HA in healthy tissues during injury, a low molecular weight HA, may act as damage-associated molecular patterns (DAMPs). DAMPs are multifunctional and structurally diverse molecules that play critical intracellular roles in the absence of injury or infection. However, after cellular damage or stress, these molecules promote the activation of the immune response. Fragments from the degradation of HA can also act as immune response activators. Low molecular weight HA would have the ability to act as a pro-inflammatory marker, promoting the activation and maturation of dendritic cells, the release of pro-inflammatory cytokines such as interleukin 1 beta (IL-1β), and tumor necrosis factor α (TNF-α). It also increases the expression of chemokines and cell proliferation. Many of the pro-inflammatory effects of low molecular weight HA are attributed to its interactions with the activation of toll-like receptors (TLRs 2 and 4). In contrast, the high molecular weight HA found in healthy tissues would act as an anti-inflammatory, inhibiting cell growth and differentiation, decreasing the production of inflammatory cytokines, and reducing phagocytosis by macrophages. These anti-inflammatory effects are mainly attributed to the interaction of high-weight HA with the CD44 receptor. In this study, we review the action of the HA as a DAMP and its functions on pain control, more specifically in orofacial origin (e.g., TMD).

Heparin and Related Substances for Treating Diabetic Foot Ulcers: A Systematic Review and Meta-Analysis.

BackgroundDiabetic foot ulcers are a major complication of diabetes mellitus (DM), when heparin and heparin related substances may be potentially used as an adjuvant treatment. We aimed to evaluate the efficacy and safety of heparin and heparin related substances for the treatment of diabetic foot ulcers.MethodsWe searched up to March 2021 in the Cochrane Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid Embase; EBSCO CINAHL; VIP Chinese Science and Technique Journals Database; China National Knowledge Infrastructure (CNKI) Database and Wan Fang Database investigating heparin or heparin-related substances in patients with diabetic foot ulcers. The primary outcomes included proportion of ulcers completely healed and time to complete ulcer healing. We assessed each included study with the Cochrane ‘Risk of bias’ tool and used the GRADE approach to assess the overall quality of the evidence.ResultsWe included nine randomized studies involving 620 participants in the meta-analysis, involving two different heparin and heparin-related substances, low molecular weight heparin (LMWH) and hyaluronic acid. Our study did not show the benefits from LMWH on increasing chance of the ulcer healing (RR: 1.26; 95% CI: 0.78 to 2.04; P=0.35; very low) or shortening the time to complete ulcer healing (SMD: 0.13 d; 95% CI: -0.29 to 0.56; P=0.54; very low). Hyaluronic acid may improve the complete ulcer healing (RR: 1.57; 95% CI: 1.29 to 1.91; P˂0.00001; very low) and shorten the time to complete ulcer healing (SMD -0.84, 95% CI -1.15 to -0.53; P<0.00001; low). Hyaluronic acid and LMWH were generally well tolerated for treating diabetic foot ulcers in this review.ConclusionHyaluronic acid may improve diabetic foot ulcer with very low quality evidence but not LMWH. However, the benefits and harms need further validation in larger trials with different population.Systematic Review Registration[https://www.crd.york.ac.uk/prospero/], identifier [PROSPERO, CRD42021269212].

Effect of microplastics on the physical structure of cake layer for pre-coagulated gravity-driven membrane filtration

Microplastics have been frequently detected in surface water and have recently emerged as a threatening global pollutant. Although gravity-driven membrane (GDM) filtration is a promising technique for drinking water treatment, the effect of microplastics on the GDM filtration has rarely been studied. In this study, to explore how to optimize GDM filtration process when microplastics are present in surface water, different systems (pre-coagulated and noncoagulated systems; with and without microplastics; AlCl3 or PACl as coagulant) are examined. The results show that the flux of noncoagulation systems is low (2.67 L/m2 h) due to the pore blocking caused by low molecular weight of HA, while the microplastics have a negligible contribution to the membrane fouling. Further, pre-coagulation significantly alleviates the membrane fouling and increases the fluxes (13.68–20.93 L/m2h). By employing optical coherence tomography and ultra-depth three-dimensional microscopy to observe the physical structure of the cake layer and then using the quasi-uniform cake filtration model for analysis, we clarify that the presence of microplastics in the PACl pre-coagulated GDM system is beneficial to form more uniform cake layer and achieve the physical stabilization of flux. Moreover, we propose that the fractal dimension of the particles (Df) of small flocs (<6 μm) can be used to predict the surface roughness of cake layer as well as the flux of pre-coagulated GDM in advance, providing a valuable guidance for the optimization of GDM filtration process.

Potential of Biofermentative Unsulfated Chondroitin and Hyaluronic Acid in Dermal Repair.

Chondroitin obtained through biotechnological processes (BC) shares similarities with both chondroitin sulfate (CS), due to the dimeric repetitive unit, and hyaluronic acid (HA), as it is unsulfated. In the framework of this experimental research, formulations containing BC with an average molecular size of about 35 KDa and high molecular weight HA (HHA) were characterized with respect to their rheological behavior, stability to enzymatic hydrolysis and they were evaluated in different skin damage models. The rheological characterization of the HHA/BC formulation revealed a G’ of 92 ± 3 Pa and a G″ of 116 ± 5 Pa and supported an easy injectability even at a concentration of 40 mg/mL. HA/BC preserved the HHA fraction better than HHA alone. BTH was active on BC alone only at high concentration. Assays on scratched keratinocytes (HaCaT) monolayers showed that all the glycosaminoglycan formulations accelerated cell migration, with HA/BC fastening healing 2-fold compared to the control. In addition, in 2D HaCaT cultures, as well as in a 3D skin tissue model HHA/BC efficiently modulated mRNA and protein levels of different types of collagens and elastin remarking a functional tissue physiology. Finally, immortalized human fibroblasts were challenged with TNF-α to obtain an in vitro model of inflammation. Upon HHA/BC addition, secreted IL-6 level was lower and efficient ECM biosynthesis was re-established. Finally, co-cultures of HaCaT and melanocytes were established, showing the ability of HHA/BC to modulate melanin release, suggesting a possible effect of this specific formulation on the reduction of stretch marks. Overall, besides demonstrating the safety of BC, the present study highlights the potential beneficial effect of HHA/BC formulation in different damage dermal models.

Real-time metabolic heat-based specific growth rate soft sensor for monitoring and control of high molecular weight hyaluronic acid production by Streptococcus zooepidemicus.

This present investigation addressing the metabolic bottleneck in synthesis of high MW HA by Streptococcus zooepidemicus and illustrates the application of calorimetric fed-batch control of µ at a narrower range. Feedforward (FF) and feedback (FB) control was devised to improve the molecular weight (MW) of HA production by S. zooepidemicus. Metabolic heat measurements (Fermentation calorimetry) were modeled to decipher real-time specific growth rate, [Formula: see text] was looped into the PID circuit, envisaged to control [Formula: see text] to their desired setpoint values 0.05 [Formula: see text], 0.1 [Formula: see text], and 0.15 [Formula: see text] respectively. Similarly, a predetermined exponential feed rate irrespective of real-time µ was carried out in FF strategy. The developed FB strategy established a robust control capable of maintaining the specific growth rate (µ) close to the [Formula: see text] value with a minimal tracking error. Exponential feed rate carried out with a lowest [Formula: see text] of 0.05 [Formula: see text] showed an improved MW of HA to 2.98 MDa and 2.94 MDa for the FF and FB-based control strategies respectively. An optimal HA titer of 4.73g/L was achieved in FF control strategy at [Formula: see text]. Superior control of µ at low [Formula: see text] value was observed to influence HA polymerization positively by yielding an improved MW and desired polydispersity index (PDI) of HA. PID control offers advantage over conventional fed-batch method to synthesize HA at an improved MW. Calorimetric signal-based µ control by PID negates adverse effects due to the secretion of other end products albeit maintaining regular metabolic activities. KEY POINTS: First report to compare HA productivities by feedforward and feedback control strategy. Inherent merits of regulating µ at narrower range were entailed. Relationship between operating µ and HA molecular weight was discussed.

CD44-Targeted Carriers: The Role of Molecular Weight of Hyaluronic Acid in the Uptake of Hyaluronic Acid-Based Nanoparticles

Nanotechnology offers advanced biomedical tools for diagnosis and drug delivery, stressing the value of investigating the mechanisms by which nanocarriers interact with the biological environment. Herein, the cellular response to CD44-targeted nanoparticles (NPs) was investigated. CD44, the main hyaluronic acid (HA) receptor, is widely exploited as a target for therapeutic purposes. HA NPs were produced by microfluidic platform starting from HA with different molecular weights (Mw, 280, 540, 820 kDa) by polyelectrolyte complexation with chitosan (CS). Thanks to microfluidic technology, HA/CS NPs with the same physical features were produced, and only the effects of HA Mw on CD44-overexpressing cells (human mesenchymal stem cells, hMSCs) were studied. This work provides evidence of the HA/CS NPs biocompatibility regardless the HA Mw and reveals the effect of low Mw HA in improving the cell proliferation. Special attention was paid to the endocytic mechanisms used by HA/CS NPs to enter hMSCs. The results show the notable role of CD44 and the pronounced effect of HA Mw in the NPs’ internalization. HA/CS NPs uptake occurs via different endocytic pathways simultaneously, and most notably, NPs with 280 kDa HA were internalized by clathrin-mediated endocytosis. Instead, NPs with 820 kDa HA revealed a greater contribution of caveolae and cytoskeleton components.

Study of biological markers in skin quality treatment by subcutaneous injection of a stabilized composition of 26 mg/mL of high molecular weight HA

Aim: Hyaluronic acid (HA) injectables have gained rapid acceptance for the treatment of skin rejuvenation. A novel HA/sorbitol composition intended for skin quality improvement containing 2.6% of high molecular weight HA stabilized by sorbitol was recently designed to be injected subcutaneously. The aim of this study was to assess the expression of biological markers of skin quality after administration of the composition. Methods: The HA/sorbitol composition was evaluated after injection into the superficial adipose tissue with ex vivo cultured human skin explants versus a product comparator to study the general morphology of the skin tissues and the expression of HA, elastin, collagen type I, collagen type III, and fibrillin-1 in the dermal layer. Results: The results demonstrate that the HA/sorbitol composition is able to boost the production of HA, elastin, collagen type I, collagen type III, and fibrillin-1 in the dermis while providing a proper quality of skin morphology. Conclusion: The HA/sorbitol composition improved biological markers of skin quality in the dermis after product injection into the superficial adipose tissue. This novel composition can be considered as an attractive solution to treat skin aging by injecting a specific HA/sorbitol formulation to strategically target the subcutaneous tissue to improve the quality of the different layers of the skin.

Stabilized composition of 26 mg/mL of high molecular weight HA for subcutaneous injection to improve skin quality

Aim: Skin firmness is one of the key parameters to define skin quality and facial aging. Among the minimally invasive anti-aging strategies, hyaluronic acid (HA) injection is widely accepted to improve skin quality. While most of the available HA injectables are designed and intended for intradermal injection, a novel HA/sorbitol composition containing 2.6% high molecular weight hyaluronic acid stabilized by sorbitol was recently developed to be specifically injected into the adipose tissue to improve the quality of all skin layers, especially the skin firmness. Methods: The HA/sorbitol composition was investigated versus product comparators in terms of biophysical properties, tolerance in subcutaneous tissue with in vivo implantation study, and skin firmness assessment on human skin explants. Results: The HA/sorbitol composition was characterized by unique and differentiated biophysical properties, proper distribution and high tolerance of the gel composition into the adipose tissue, and the ability to efficiently improve skin firmness. Conclusion: The HA/sorbitol composition represents a new attractive solution to treat facial skin aging with an injection strategy specifically targeting the adipose tissue instead of the dermis, to improve the quality of the skin.

Redox/pH-dual responsive functional hollow silica nanoparticles for hyaluronic acid-guided drug delivery

Stimuli-responsive nanocarriers have been studied for controlling release kinetics while minimizing the undesired leakage of loaded molecules. Hollow mesoporous silica nanoparticles (HMSNs) have been used as carriers because of their biocompatibility, porosity, high surface area, and ease of chemical modification. Moreover, introducing targeting moieties onto the HMSNs enables targeted delivery to designated sites. Here, we designed dual-responsive HMSNs capped with various molecular weights of hyaluronic acid (HA) to control the drug loading quantity and enhance the targeting efficiency. The dual-responsive HMSNs were synthesized via sequential surface grafting processes, which include thiol groups, amine groups, and capping agents (denoted as HMSN-SH, HMSN-SS-NH2, and HMSN-SS-HA, respectively). The modified HMSNs were further functionalized with HA to increase the cancer-targeting efficiency for CD44-rich cancer cells. This functionalized HMSN showed 1.2–2.3 times increased drug release efficiency under redox/pH-dual stimuli compared to each stimulus. As a result, the HMSNs were internalized by cancer cells rather than normal cells; consequently, more drugs were delivered to cancer cells. We suggest that the proposed HMSN-SS-HA would be a suitable carrier for enhancing drug delivery efficiency with targeting/stimuli-responsive functionalities.

Hyaluronan-coated nanoparticles for active tumor targeting: Influence of polysaccharide molecular weight on cell uptake

Here we aimed to correlate different molecular weights of hyaluronic acid (HA), 200, 800 and 1437 kDa, used to decorate poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles (NPs), to their cell uptakes. NP internalization kinetics in CD44-overexpressing breast carcinoma cells were quantified, using healthy fibroblast cells as reference. Actually, NP uptake and selectivity by tumor cells were maximized for NPs HA 800 kDa, while being minimum for NPs HA1400 kDa. This unexpected result could be explained considering that the interaction between NPs and tumor cells is dictated by rearrangement and conformation of that segment of HA chain that actually protrudes from the NPs. Overall, results obtained in this work point at how HA molecular weight, is pivotal project parameter in NP formulation to promote active targeting in the CD44 overexpressing cancer cells.

The effects of molecular weight of hyaluronic acid on transdermal delivery efficiencies of dissolving microneedles

Hyaluronic acid (HA) is widely adopted to fabricate dissolving microneedles for transdermal drug delivery applications, yet the structure-activity relationship between molecular weight of HA and transdermal delivery efficiency of microneedles (HA-MNs) has not been fully explored, particularly in the transdermal delivery of small molecule drugs. Herein, we report the fabrication of three types of HA-MNs of various molecular weights (10k, 74k and 290k Da), which incorporate rhodamine B as the model drug. We assess the influence of molecular weight of HA on the mechanical properties of HA-MNs and transdermal delivery of rhodamine B in vitro and in vivo. The mechanical strength of all types of HA-MNs exceeds the minimal force requirement for skin penetration, with the highest values of compression force found in 10k-HA-MN. Interestingly, 74k-HA-MN that owns a medium mechanical strength, exhibits the highest efficiency in transdermal delivery of rhodamine B in a porcine skin and a Franz cell transdermal model. Further in vivo fluorescence imaging of HA-MN-treated mice reveals a tunable transdermal delivery of rhodamine B, which is controllable according to the molecular weight of HA. Importantly, 74k-HA-MN treatment demonstrates the highest initial delivering amount and longest retention time of rhodamine B in mice. In addition, histological examinations of puncture sites of the skin tissues confirm the complete recovery of skin and excellent biocompatibility of HA-MNs.