Cross-linked Hyaluronic Acid Research Articles

Adipose Autologous Micrograft and Its Derived Mesenchymal Stem Cells in a Bio Cross-Linked Hyaluronic Acid Scaffold for Correction Deep Wrinkles, Facial Depressions, Scars, Face Dermis and Its Regenerations: A Pilot Study and Cases Report.

The aim of this clinical study was to demonstrate that through a micrograft of viable adipose tissue cells microfiltered at 50 microns to exclude fibrous shoots and cell debris in a suspension of cross-linked hyaluronic acid, we were able to improve visible imperfections of the dermis and to improve clinically observable wrinkles, with a beneficial effect also in the extracellular matrix (ECM). Background and Objectives: With the passage of time, the aging process begins, resulting in a progressive impairment of tissue homeostasis. The main reason for the formation of wrinkles is the involution of the papillary dermis, as well as the loss of stem cell niches with compromise of the extra-cytoplasmic matrix (ECM), and the loss of hyaluronic acid, which helps to maintain the shape and resistance and that is contained in the connective tissue. Materials and Methods: This study involved 14 female patients who underwent dermal wrinkle correction and bio-regeneration over the entire facial area through a suspension containing 1.0 mL of viable micrografts from adipose tissue in a 1.0 mL cross-linked hyaluronic acid. To verify the improvement of the anatomical area concerned over time, the various degrees of correction obtained for wrinkles, and in general for texture, were objectively evaluated by using a Numeric Rating scale (NRS) 10-0, a modified Vancouver scale and a Berardesca scale. Results: The Berardesca, NRS and Modified Vancouver scales showed that with this technique it was possible to obtain excellent results both when the suspension was injected into wrinkles with the linear retrograde technique, and when it was injected with the micropomphs technique to correct furrows, with the intent to revitalize the tissue through progenitors with adult stemness markers. Conclusions: The combination of microfragmented and microfiltered adipose tissue and cross-linked hyaluronic acid at 50 microns is safe new method to treat soft tissue defects such as deep wrinkles.

Chronic vulvar fissure: approach with cross-linked hyaluronic acid.

This report aims to prospectively describe the effectiveness and safety of injected cross-linked hyaluronic acid (HA) for the treatment of chronic vulvar fissures. A descriptive prospective case series design including 15 patients affected by chronic vulvar fissures who were treated with cross-linked HA filler between December 2020 and July 2021. The validated 21-item Vulvovaginal Symptoms Questionnaire (VSQ) was used to evaluate the results from baseline up to 9 months after the HA infiltration. A total of 15 patients suffering from chronic vulvar fissures were treated with an injection of 19 mg/mL HA filler. We found a significant improvement in VSQ scores at the end of the treatment compared to baseline. Patients reported excellent tolerance of the procedure, and no complications were recorded. Cross-linked HA infiltration of the vulvar vestibule and posterior vaginal wall appeared to be a promising approach for chronic vulvar fissures.

Comparing efficacy of a single intraarticular injection of platelet-rich plasma (PRP) combined with different hyaluronans for knee osteoarthritis: a randomized-controlled clinical trial

BackgroundIntraarticular plasma-rich platelet (PRP) and hyaluronic acid (HA) have each been shown to be effective for treating knee osteoarthritis (OA). Evidence supporting the combination therapy is controversial. This study aimed to investigate the efficacy of a single intraarticular PRP injection combined with different HAs in patients with knee OA.MethodsIn this prospective randomized-controlled trial, 99 patients with Kellgren-Lawrence grade 2 knee OA with average knee pain ≥ 30 mm on a 0-100 mm pain visual analog scale (VAS) were randomized into two groups. The PRP + Artz group received a single intraarticular HA (Artz, 2.5 ml, 10 mg/ml) followed by 3 ml PRP (n = 50). The PRP + HYAJOINT Plus group received a single intraarticular cross-linked HA (HYAJOINT Plus, 3 ml, 20 mg/ml) followed by 3 ml PRP (n = 49). All patients were evaluated before and at 1, 3 and 6 months after injections. The primary outcome was the VAS pain reduction from baseline at 6 months. Secondary outcome measures included Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Lequesne index, single leg stance (SLS) test and patient satisfaction.ResultsNinety-five patients were analyzed by intention-to-treat analysis. Both groups improved significantly in VAS pain, WOMAC, Lequesne index and SLS at 1, 3 and 6 months post intervention (p < 0.05). Between-group comparisons showed no significant differences at most follow-up time points, except better improvements in Lequesne index at 1 month (p = 0.003) and WOMAC-stiffness score at 6 months (p = 0.020) in the PRP + Artz group, and superiority in SLS at 1, 3 and 6 months in the PRP+ HYAJOINT Plus group (p < 0.001, p = 0.003 and p = 0.004). Additional Johnson-Neyman analyses showed that among the patients with baseline WOMAC-pain score > 8.5, WOMAC-function score > 21.7 and WOMAC-total score > 32.0, respectively, those treated with PRP + HYAJOINT Plus injections had better effects in WOMAC-pain, WOMAC-function and WOMAC-total scores than those treated with PRP + Artz at 3 months postinjection (p < 0.05). Both groups reported high satisfaction. No serious adverse events occurred during the study.ConclusionsA single PRP injection combined with Artz or HYAJOINT Plus is effective and safe for 6 months in patients with knee OA. Both injection regimens are potential treatment options for knee OA. Further studies are needed to confirm these results.Trial registrationThe study was registered at ClinicalTrials.gov (NCT04931719), retrospectively. Date of registration 18/6/2021.Name of trial registryComparing efficacy of single PRP combined with different hyaluronans for knee osteoarthritis.Level of evidenceTherapeutic Level 1.

Spatially resolved mapping of hydrogel stiffness during enzymatic degradation

The atomic force microscopy force–volume technique was used to investigate the surface properties of two hydrogels during their enzymatic degradation. Agarose gels with concentrations of 0.5, 1.0 and 1.5% w/v were selected for the degradation study to show that the mechanical effects of degradation could be measured in a spatially resolved way on the hydrogel surface. The agarase enzyme was used to degrade the agarose gels. The agarose gels were found to be heterogeneous with multiple stiffness domains that were degraded at different erosion rates. It was inferred that agarose gels contained both tightly and loosely packed regions. The loosely packed regions degraded first, followed by the regions that were packed more tightly. The second hydrogels containing hyaluronic acid and gelatin with 5% w/v hyaluronic acid and 5% w/v gelatin cross-linked in equal amounts were also studied. These hybrid gels were degraded either by using hyaluronidase or collagenase type IV. With hyaluronidase, gelatin was left on the surface as a homogeneous layer. With collagenase, cross-linked hyaluronic acid remained on the surface. Post-degradation the hyaluronic acid-rich surface had a stiffness of ∼20 kPa, while the gelatin-rich surface stiffness was only ∼15 kPa.

Employing hyaluronic acid-based mesotherapy for facial rejuvenation.

Mesotherapy is a method of treatment in which biocompatible substances are injected in small aliquots into different levels of skin. This technique can be used for facial rejuvenation. To comprehensively evaluate efficacy of different hyaluronic acid (HA) materials for skin rejuvenation, and discuss longevity of these products, potential adverse effects, and different injection techniques. We searched Pubmed, Scopus, Web of science, Google Scholar, Embase, Cochrane Library, and Science direct until April of 2022. Thirty-four articles were selected including 23 articles about non-cross-linked HA and 11 articles about cross-linked HA. Eleven and five different non-cross-linked HA and cross-linked HA materials were utilized, respectively. Treatment sessions for non-cross-linked HA were between 1 and 6 at weekly-to-bimonthly interval, and for cross-linked HA were 1-3 at 4-36 weeks apart. In most of the studies, serial micropuncture technique with 23-32 gauge needles was used for injection. Other injection techniques were Nappage (picotage), depot and micro-linear. Mesotherapy with HA-based fillers is a favorable method for restoring youthful appearance, rejuvenation, and revitalization of skin. Proper selection and precise placement of HA in desired level of dermis is an essential key to optimize improvement and minimize side effects including skin irregularities and Tyndall effect. Adjuvant therapy with additional rejuvenation procedures to enhance esthetic results is required especially in elderly individuals with severe photodamaged skin. Moreover, preservation of esthetic results requires maintenance therapy every few months.

Multifunctional dual cross-linked poly (vinyl alcohol)/methacrylate hyaluronic acid/chitooligosaccharide-sinapic acid wound dressing hydrogel

Wound dressing hydrogel with multifunctional properties, including antioxidant and antimicrobial properties and appropriate mechanical, biological, and physical properties is of great interest in wound healing application and it is still a challenge. In the present study, chitooligosaccharides (COS)/ sinapic acid (SA) conjugate (COS-SA) was synthesized using H2O2-induced grafting polymerization, and photo cross-linkable hyaluronic acid was synthesized using methacrilation (HAMA). The synthesis of COS-SA and HAMA was confirmed by Fourier-transform infrared spectroscopy, proton nuclear magnetic resonance spectroscopy, ultraviolet spectroscopy, and polyphenol assay. Subsequently, we developed duel cross-linked polyvinyl alcohol (PVA)/HAMA composite hydrogel encapsulated with COS-SA as an antioxidant and antimicrobial dressing for full-thickness wound healing application. The chemical, physical, mechanical, antioxidant, antimicrobial, in vitro biocompatibility, and in vivo wound healing properties of hydrogels were subsequently investigated. The results showed that the fabricated composite hydrogel had a uniform porous architecture, excellent fluid absorbability, and appropriate mechanical stability. The introduction of COSs-SA conjugate remarkably enhanced the in vitro biocompatibility, antioxidant, and antimicrobial properties of the hydrogel, leading to the significant promotion of in vivo full-thickness wound closure, re-epithelization, granulation tissue formation, and collagen deposition indicating that COSs-SA incorporated PVA/HAMA hydrogel wound dressing has significant potential for chronic wound healing application.

The most promising microneedle device: present and future of hyaluronic acid microneedle patch

Microneedle patch (MNP) is an alternative to the oral route and subcutaneous injection with unique advantages such as painless administration, good compliance, and fewer side effects. Herein, we report MNP as a prominent strategy for drug delivery to treat local or systemic disease. Hyaluronic acid (HA) has advantageous properties, such as human autologous source, strong water absorption, biocompatibility, and viscoelasticity. Therefore, the Hyaluronic acid microneedle patch (HA MNP) occupies a large part of the MNP market. HA MNP is beneficial for wound healing, targeted therapy of certain specific diseases, extraction of interstitial skin fluid (ISF), and preservation of drugs. In this review, we summarize the benefits of HA and cross-linked HA (x-HA) as an MNP matrix. Then, we introduce the types of HA MNP, delivered substances, and drug distribution. Finally, we focus on the biomedical application of HA MNP as an excellent drug carrier in some specific diseases and the extraction and analysis of biomarkers. We also discuss the future development prospect of HA MNP in transdermal drug delivery systems (TDDS).

Adjunctive Application of Hyaluronic Acid in Combination with a Sodium Hypochlorite Gel for Non-Surgical Treatment of Residual Pockets Reduces the Need for Periodontal Surgery-Retrospective Analysis of a Clinical Case Series.

The comprehensive treatment of periodontitis stage 2 to 4 aims at the resolution of periodontal inflammation and “pocket closure”, which implies a residual probing depth of ≤4 mm and a negative BoP. However, supportive periodontal therapy (SPT) regularly leaves behind persistent periodontal pockets with 5 or more mm in residual PPD and sites that often re-colonize and re-infect. Various adjunctive options for subgingival instrumentation have been proposed to enhance the antimicrobial effects to better control the re-infection of these residual sites. The locally applied adjuncts, based on their anti-inflammatory effect, are sodium hypochlorite antiseptic cleaning gel and cross-linked hyaluronic acid (xHyA). Both recently moved into the focus of clinical research on non-surgical and surgical therapy for periodontitis. The surgical use of xHyA indicates regenerative potential, supporting periodontal regeneration. This case series retrospectively analyzes the clinical benefits of the consecutive flapless application of sodium-hypochlorite-based cleaning gel and xHyA at the SPT to achieve pocket closure, thereby reducing the need for periodontal surgery. In 29 patients, 111 sites received the treatment sequence. At 6-month re-evaluation, an overall PPD reduction exceeding 2 mm was achieved, associated with a similar CAL gain (2.02 mm); the bleeding tendency (BoP) was reduced by >60%. Pocket closure occurred in almost 25% of all the sites. Within their limits, the present data suggest that the proposed combined adjunctive treatment of residual active periodontal sites yielded significant improvement in the clinical parameters. Further studies in RCT format are required to confirm these observations.

Safety and efficacy of a new hydrogel based on hyaluronic acid as cosmeceutical for xerosis.

Hyaluronic acid (HA) is among the most effective and safe ingredients frequently used in cosmetics. However, a more economical and efficient formulation is still required. We sought to assess the safety and efficacy of a novel hydrogel manufactured only by irradiation containing cross-linked HA and polyethylene glycol polymers with addition of polysiloxane. The study included 30 people with normal skin and 30 patients with xerosis. In the normal skin group, to evaluate the safety, a patch test and a photopatch test were performed, and patients' discomfort was investigated. In those with xerosis, to assess the efficacy, a skin barrier function test was performed at baseline and at 2, 4, and 8 weeks after the application of the novel hydrogel. Additionally, the xerosis severity scale (XSS), patient satisfaction, Investigator's Global Assessment (IGA), and adverse responses were evaluated. In the safety study, there was no significant discomfort in the experimental group compared with the control group. In the efficacy study, at 2, 4, and 8 weeks after the application of the novel hydrogel, the mean value of skin hydration and sebum content increased and the mean value of XSS decreased with time in the experimental group, and a difference was observed when compared with the control group. IGA showed improvement in 97%, 77%, and 80% at each visit and the proportions of satisfied patients were 90%, 87%, and 90%, respectively. The novel HA-based hydrogel tested herein could be a safe and effective therapeutic remedy for xerosis.

Impact of Cross-Linked Hyaluronic Acid on Osteogenic Differentiation of SAOS-2 Cells in an Air-Lift Model.

The aim of this study was to investigate the impact of cross-linked hyaluronic acid on osteoblast-like cells seeded on top of two collagen substrates, native porcine pericardium membrane (substrate A) and ribose cross-linked collagen membranes (substrate B), in an air-lift model. Substrates A or B, saturated with three hyaluronic acid concentrations, served as membranes for SAOS-2 cells seeded on top. Cultivation followed for 7 and 14 days in the air-lift model. Controls used the same substrates without hyaluronic pre-treatment. Cells were harvested, and four (Runx2, BGLAP, IBSP, Cx43) different osteogenic differentiation markers were assessed by qPCR. Triplicated experiment outcomes were statistically analyzed (ANOVA, t-test; SPSS). Supplementary histologic analysis confirmed the cells’ vitality. After seven days, only few markers were overexpressed on both substrates. After 14 days, targeted genes were highly expressed on substrate A. The same substrate treated with 1:100 diluted xHyA disclosed statistically significant different expression level vs. substrate B (p = 0.032). Time (p = 0.0001), experimental condition as a function of time (p = 0.022), and substrate (p = 0.028) were statistically significant factors. Histological imaging demonstrated vitality and visualized nuclei. We conclude that the impact of hyaluronic acid resulted in a higher expression profile of SAOS-2 cells on substrate A compared to substrate B in an air-lift culture after two weeks.

A Two-Pronged Strategy for Enhanced Deep-Tumor Penetration and NIR-II Multimodal Imaging-Monitored Photothermal Therapy.

The second near-infrared (NIR-II)-induced photothermal therapy (PTT) has attracted a great deal of attention in recent years due to its non-invasiveness and because it uses less energy. However, the penetration of photothermal agents into solid tumors is seriously impeded by the dense-tumor extracellular matrix (ECM) containing cross-linked hyaluronic acid (HA), thereby compromising the ultimate therapeutic effects. Herein, acid-labile metal-organic frameworks were employed as nanocarriers to efficiently mineralize hyaluronidase (HAase) and encapsulate Ag2S nanodots by a one-pot approach under mild conditions. The obtained nanocomposites (AHZ NPs) maintained enzyme activity and changed in size to prolong blood circulation and complete delivery of the cargo to the tumor. Moreover, the released HAase could specifically break out the HA to loosen ECM and enable the Ag2S nanodots to breeze through the tumor matrix space and gain access to the deep tumor. Under near-infrared laser irradiation, the AHZ NPs displayed remarkable fluorescence, outstanding photoacoustic signals, and excellent photothermal properties in the whole tumor. This work offers a promising two-pronged strategy via a decrease in nanoparticle size and the degradation of dense ECM for NIR-II multimodal imaging-guided PTT of deep tumors.

Reactive oxygen species-generating hydrogel platform for enhanced antibacterial therapy

Zinc oxide nanoparticles (ZnO) have attracted much attention as promising antibacterial agents due to their ability to generate reactive oxygen species (ROS) that effectively eliminate bacteria. However, when they are delivered inside the body, this distinct characteristic of ROS is restricted due to the limited penetration depth of external light, which is required for the photocatalysis of particles. To produce ROS without any light source when the particles are implanted, we introduced catechol-ZnO complexes to a hyaluronic acid (HA) hydrogel platform, which can self-generate sufficient ROS in the bacteria-infected tissue. Catechol-ZnO complexes enhanced ROS generation via electron transfer from the formation of complexes and o-semiquinone, and a hydrogel structure was created by coordinate bonds between functionalized catechol groups in HA and ZnO simultaneously. This hydrogel demonstrated different behaviors in terms of physical properties compared to chemically cross-linked HA hydrogels containing ZnO. This hydrogel showed a higher swelling ratio, enzymatic degradation resistance, and tissue adhesive strength. Enhanced ROS generation was confirmed using electron paramagnetic resonance (EPR), H2O2 concentration, glutathione depletion, and intracellular ROS detection. The improved antibacterial performance of hydrogels from ROS production was also confirmed through in vitro bacterial testing against two bacterial strains, E. coli and S. aureus. Furthermore, an in vivo experiment using an infected mouse model to analyze colony formation, histologic analysis, and hematological inflammatory markers revealed the effective antibacterial effects of catechol-ZnO complexes. Overall, the potential of the hydrogel created via catechol-ZnO complexes for antibacterial therapy was demonstrated through the capability to enhance ROS generation and eradicate bacteria.

Lip Lifting Efficacy of Hyaluronic Acid Filler Injections: A Quantitative Assessment Using 3-Dimensional Photography.

The study aimed to compare the volume enhancement and the lifting capacity of two different hyaluronic acid gels for lip injection. Thirty-six Korean female patients were randomized into two groups according to the cross-linking degree of the hyaluronic acid filler injected. Using a fixed injection protocol, patients were injected with 1 mL of hyaluronic acid filler in the lips and followed up at four and 12 weeks after injection. Lip volume, lip projection, and columella–labial angle were measured using a 3-dimensional imaging system at each time point. Follow-up values were compared with baseline. Compared with pre-treatment values, there was a statistically significant increase in mean lip volume and lip projection at four and 12 weeks after injection, with no significant differences between the two groups. Lips injected with hyaluronic acid filler of intermediate cross-link density resulted in more acute angles than lips injected with lightly cross-linked hyaluronic acid. The difference was statistically significant at each follow-up time point. No serious complications were observed throughout the study period. Our results imply that in patients who want a prominent upper lip lift, lip injections using hyaluronic acid fillers with intermediate cross-linking density can be a good option due to their lift capacity. The degree of cross-linking may not be a significant determinant of simple lip volume augmentation when other variables are constant.

Cross-linked hyaluronic acid gel with or without a collagen matrix in the treatment of class III furcation defects: A histologic and histomorphometric study in dogs.

To histologically evaluate the effects of cross-linked hyaluronic acid (xHyA) with or without a collagen matrix (CM) on periodontal wound healing/regeneration in class III furcation defects in dogs. Class III furcation defects were surgically created in the mandibular premolars in six beagle dogs. The defects were randomly treated as follows: open flap debridement (OFD) + CM (CM), OFD + xHyA (xHyA), OFD + xHyA + CM (xHyA/CM) and OFD alone (OFD). At 10 weeks, the animals were euthanized for histological evaluation. The newly formed bone areas in the xHyA (4.04 ± 1.51 mm2 ) and xHyA/CM (4.32 ± 1.14 mm2 ) groups were larger than those in the OFD (3.25 ± 0.81 mm2 ) and CM (3.31 ± 2.26 mm2 ) groups. The xHyA (6.25 ± 1.45 mm) and xHyA/CM (6.40 ± 1.35 mm) groups yielded statistically significantly (p< .05) greater formation of new connective tissue attachment (i.e., new cementum, with inserting connective tissue fibres) compared with the OFD (1.47 ± 0.85 mm) group. No significant differences were observed in any of the histomorphometric parameters between the xHyA and xHyA/CM groups. Complete furcation closure was not observed in any of the four treatment modalities. Within their limits, the present results suggest that the use of xHyA with or without CM positively influences periodontal wound healing in surgically created, acute-type class III furcation defects.

A split-face comparative performance evaluation of injectable hyaluronic acid-based preparations HCC and CPM-HA20G in healthy females.

Skin revitalizers are used for skin quality improvement purposes. Hyaluronan hybrid cooperative complexes (HCC, Profhilo®, IBSA Pharmaceuticals) are an anti-aging treatment with a large amount of pure hyaluronic acid (HA) based on stable, cooperative, and hybrid complexes. Cohesive polydensified matrix Hyaluronic Acid (CPM-HA20, Belotero Revive®, Merz Pharmaceuticals GmbH) is a slightly cross-linked HA (20 mg/ml) with glycerol (17.5mg/ml). To evaluate the performance of HCC and CPM-HA20G for skin quality improvement in healthy female subjects. This was a split-face, single-blinded study that enrolled 24 healthy female subjects. Injections were given on three separate occasions. HCC was injected on the right cheek, while CPM-HA20G was injected on the left cheek. A battery of skin property measurements was used to evaluate the skin. Skin properties and overall satisfaction were analyzed using mixed models with the values at baseline, at week 1, week 8, and week 14 as an outcome and a random effect of subject and fixed effects of treatment, visit, and the treatment by visit interaction. Both products showed evidence of effect relative to baseline on surface hydration (AU), elasticity (N/m) TEWL (g/m2 h), and melanin (AU). CPM-HA20G also showed significant evidence of effect relative to baseline on water content (%), and HCC on pore count (n) and hemoglobin (AU). Satisfaction reported by the subjects themselves showed positive trends of satisfaction over time for multiple skin properties. There were no significant differences between the tested products in the observed skin characteristics over time. These devices are effective and safe treatments for skin quality improvement, especially moisturization, with high patient satisfaction and generally mild and transient side effects.

Biocompatibility and Efficacy of a Linearly Cross-Linked Sodium Hyaluronic Acid Hydrogel as a Retinal Patch in Rhegmatogenous Retinal Detachment Repairment.

To prevent the migration of retinal pigment epithelium (RPE) cells into the vitreous cavity through retinal breaks after the pars plana vitrectomy for the repair of rhegmatogenous retinal detachment (RRD), sealing retinal breaks with an appropriate material appears to be a logical approach. According to a review of ocular experiments or clinical trials, the procedure for covering retinal breaks with adhesives is complex. A commercially available cross-linked sodium hyaluronic acid (HA) hydrogel (Healaflow®) with the injectable property was demonstrated to be a perfect retinal patch in RRD clinical trials by our team. Based on the properties of Healaflow®, a linearly cross-linked sodium HA hydrogel (HA-engineered hydrogel) (Qisheng Biological Preparation Co. Ltd. Shanghai, China) with the injectable property was designed, whose cross-linker and cross-linking method was improved. The purpose of this study is to report the characteristics of an HA-engineered hydrogel using Healaflow® as a reference, and the biocompatibility and efficacy of the HA-engineered hydrogel as a retinal patch in the rabbit RRD model. The HA-engineered hydrogel exhibited similar dynamic viscosity and cohesiveness and G′ compared with Healaflow®. The G′ of the HA-engineered hydrogel varied from 80 to 160 Pa at 2% strain under 25°C, and remained constantly higher than G″ over the range of frequency from 0.1 to 10 Hz. In the animal experiment, clinical examinations, electroretinograms, and histology suggested no adverse effects of the HA-engineered hydrogel on retinal function and morphology, confirming its favorable biocompatibility. Simultaneously, our results demonstrated the efficacy of the HA-engineered hydrogel as a retinal patch in the RRD model of rabbit eyes, which can aid in the complete reattachment of the retina without the need for expansile gas or silicone oil endotamponade. The HA-engineered hydrogel could play the role of an ophthalmologic sealant due to its high viscosity and cohesiveness. This pilot study of a small series of RRD models with a short-term follow-up provides preliminary evidence to support the favorable biocompatibility and efficacy of the HA-engineered hydrogel as a promising retinal patch for sealing retinal breaks in retinal detachment repair. More cases and longer follow-up studies are needed to assess its safety and long-term effects.

Evaluation of Adverse Effects of Resorbable Hyaluronic Acid Fillers: Determination of Macrophage Responses.

Resorbable tissue fillers for aesthetic purposes can induce severe complications including product migration, late swelling, and inflammatory reactions. The relation between product characteristics and adverse effects is not well understood. We hypothesized that the degree of cross-linking hyaluronic acid (HA) fillers was associated with the occurrence of adverse effects. Five experimental HA preparations similar to HA fillers were synthesized with an increasing degree of cross-linking. Furthermore, a series of commercial fillers (Perfectha®) was obtained that differ in degradation time based on the size of their particulate HA components. Cytotoxic responses and cytokine production by human THP-1-derived macrophages exposed to extracts of the evaluated resorbable HA fillers were absent to minimal. Gene expression analysis of the HA-exposed macrophages revealed the responses related to cell cycle control and immune reactivity. Our results could not confirm the hypothesis that the level of cross-linking in our experimental HA fillers or the particulate size of commercial HA fillers is related to the induced biological responses. However, the evaluation of cytokine induction and gene expression in macrophages after biomaterial exposure presents promising opportunities for the development of methods to identify cellular processes that may be predictive for biomaterial-induced responses in patients.

Lipid, Aqueous and Mucin Tear Film Layer Stability and Permanence within 0.15% Liposome Crosslinked Hyaluronic Acid versus 0.15% Non-Crosslinked Hyaluronic Acid Measured with a Novel Non-Invasive Ocular Surface Analyzer.

To evaluate the stability and permanence of the liquid film created after the instillation of 0.15% crosslinked hyaluronic acid with liposomes and crocin versus the effect of 0.15% standard hyaluronic acid, a prospective, longitudinal, single-blind, single-center study was conducted in symptomatic populations with a novel noninvasive ocular surface analyzer. Limbal and bulbar redness classification, lipid layer thickness, tear meniscus height, and first and mean noninvasive break-up time (FNIBUT and MNIBUT) were performed before and 30 and 45 min after liposome-crosslinked hyaluronic acid (LCHA) and standard hyaluronic acid (HA) eye drop instillations. LCHA had a higher lipid layer thickness than HA (grades 2.00 ± 0.83 and 1.17 ± 0.63 on the Guillon pattern, respectively). LCHA achieved a better tear meniscus height than HA (0.23 ± 0.02 and 0.21 ± 0.02 mm, respectively). LCHA improved FNIBUT and MNIBUT more than HA (for FNIBUT, 6.30 ± 0.94 and 4.77 ± 0.89 s, respectively. For MNIBUT, 17.23 ± 5.11 and 12.41 ± 4.18 s, respectively). Crosslinking hyaluronic acid with liposomes and crocin significantly increases the permanence and stability of the lipid, aqueous, and mucin tear film layers. In a short-term period, liposome and crosslinked hyaluronic acid achieved better first and mean noninvasive break-up times than standard hyaluronic acid.

Novel Chitosan Dermal Filler with Enhanced Moldability and Elasticity.

Currently, dermal fillers are largely based on commercialized cross-linked hyaluronic acid (HA) injections, which require a large injection force. Additionally, HA can be easily decomposed by enzymes, and HA-treated tissues present a risk of developing granuloma. In this study, a chitosan-based dermal filler is presented that operates on a liquid-to-gel transition and allows the injection force to be kept ≈4.7 times lower than that required for HA injections. Evaluation of the physical properties of the chitosan filler indicates high viscoelasticity and recovery rate after gelation at 37 °C. Furthermore, in an in vivo evaluation, the liquid injection-type chitosan filler transitions to a gel state within 5min after injection into the body, and exhibits a compressive strength that is ≈2.4 times higher than that of cross-linked HA. The filler also exhibits higher moldability and maintains a constant volume in the skin for a longer time than the commercial HA filler. Therefore, it is expected that the chitosan filler will be clinically applicable as a novel material for dermal tissue restoration and supplementation.

Simultaneous One-Pot Interpenetrating Network Formation to Expand 3D Processing Capabilities.

The incorporation of a secondary network into traditional single-network hydrogels can enhance mechanical properties, such as toughness and loading to failure. These features are important for many applications, including as biomedical materials; however, the processing of interpenetrating polymer network (IPN) hydrogels is often limited by their multistep fabrication procedures. Here, a one-pot scheme for the synthesis of biopolymer IPN hydrogels mediated by the simultaneous crosslinking of two independent networks with light, namely: i) free-radical crosslinking of methacrylate-modified hyaluronic acid (HA) to form the primary network and ii) thiol-ene crosslinking of norbornene-modified HA with thiolated guest-host assemblies of adamantane and β-cyclodextrin to form the secondary network, is reported. The mechanical properties of the IPN hydrogels are tuned by changing the network composition, with high water content (≈94%) hydrogels exhibiting excellent work of fracture, tensile strength, and low hysteresis. As proof-of-concept, the IPN hydrogels are implemented as low-viscosity Digital Light Processing resins to fabricate complex structures that recover shape upon loading, as well as in microfluidic devices to form deformable microparticles. Further, the IPNs are cytocompatible with cell adhesion dependent on the inclusion of adhesive peptides. Overall, the enhanced processing of these IPN hydrogels will expand their utility across applications.