Injection Of Cross-linked Hyaluronic Acid Research Articles

Efficacy and Safety of Intra-Articular Cross-Linked Sodium Hyaluronate for the Treatment of Knee Osteoarthritis: A Prospective, Active-Controlled, Randomized, Parallel-Group, Double-Blind, Multicenter Study.

The safety and efficacy of Hyruan ONE (test product), an intra-articular cross-linked sodium hyaluronate injection, to treat mild-to-moderate knee osteoarthritis was compared with that of Durolane (comparator) in a prospective, active-controlled, parallel-group, double-blind (masked-observed), multicenter non-inferiority study. European patients (n = 284) were randomized 1:1 (test product:comparator) and received one injection of cross-linked hyaluronic acid (60 mg/3 mL). In total, 280 patients completed the study. The primary endpoint of mean change in Western Ontario and McMaster University (WOMAC)-Likert Pain sub-scores from baseline at week 13 revealed changes of -5.59 and -5.54 for the test and comparator groups, respectively, demonstrating non-inferiority of the test product (difference, -0.05 [95% confidence interval, -0.838 to 0.729]). Secondary endpoint results, which included changes in WOMAC-Likert Pain sub-score from baseline to 26 weeks post-injection and changes in WOMAC-Likert Total score and Physical Function and Stiffness sub-scores, changes in patients' and investigators' global assessments, use of rescue medication, and responder rates at 13 and 26 weeks post-injection were similar between the groups. Incidence of adverse events was also similar. In both groups, most treatment-emergent adverse events were mild/moderate. Hyruan ONE was non-inferior to the comparator at 13 weeks post-injection in European patients with mild-to-moderate knee osteoarthritis.

In Vivo Investigation of the Biostimulatory and Rejuvenating Effects of Small-Particle Cross-linked Hyaluronic Acid Injections in Photoaged Human Skin.

Injection of cross-linked hyaluronic acid (CLHA) has been traditionally utilized to treat wrinkles and provide volume. Recent studies have also shown that intradermal placement of CLHA provides lasting secondary effects and may be a useful method for improving skin appearance and physiology. The aim of this study was to investigate the biostimulatory effects and potential underlying mechanisms induced by repeated intradermal microinjections of small-particle cross-linked hyaluronic acid (SPCLHA) for skin rejuvenation. Eight patients with photoaged forearm skin underwent three intradermal microinjections of SPCLHA and isotonic sodium chloride (control). At 0, 4, 8, 12, and 24 weeks, biophysical parameters were measured, and skin biopsies were obtained at 12 and 24 weeks for assessment employing histological and immunohistochemical analyses, transmission electron microscope, and real-time fluorescence quantitative polymerase chain reaction. SPCLHA treatments significantly improved skin appearance and physiologic functions starting at 8 weeks. Histologic examination revealed thickening of the epidermis, more red-stained collagen fibers in the dermis, and increased formation of blood vessels in SPCLHA-treated skin. Immunohistochemical evaluation showed increased collagen deposition, proliferation of keratinocytes and fibroblasts, and cutaneous vascularity in SPCLHA-treated skin compared with controls. Fibroblasts appeared morphologically stretched with well-developed rough endoplasmic reticulum. Gene expression concerning various extracellular matrix (ECM) proteins and growth factors was upregulated at 12 weeks and several genes remained upregulated at 24 weeks. Intradermal microinjections of SPCLHA can stimulate production of collagen and other ECM components, restore the structural integrity of dermal microenvironment, and may be considered an effective method for skin rejuvenation.

Rejuvenation of Aged Human Skin by Injection of Cross-linked Hyaluronic Acid.

Dermal injection of chemically cross-linked hyaluronic acid (CL-HA) is a common procedure to smooth wrinkles and add fullness to the face. Due to its physical properties, CL-HA both fills space and exerts mechanical forces within the dermis. Dermal fibroblasts produce the collagen-rich extracellular matrix (ECM), which comprises the bulk of skin. Attachment to the ECM allows fibroblasts to achieve a stretched, morphology, which confers a functional phenotype that maintains collagen production. In aged/photoaged skin, collagen fibril fragmentation impairs fibroblast attachment, resulting in a collapsed morphology and reduced collagen production. This article describes investigations of the impact of CL-HA injection on fibroblast morphology and function in the aged/photoaged human skin. Fifty-three subjects, age 70 years or older, received a single injection of saline (vehicle control) and CL-HA (0.5 ml each) in separate adjacent skin sites on photodamaged forearm or sun-protected buttock skin. Full-thickness punch biopsies were obtained from injected skin sites at various times and analyzed for molecular and cellular changes. Injected CL-HA forms discreet pockets that localize to areas of the dermis that contain fragmented, loosely organized collagen fibrils. These CL-HA pockets fill space and apply mechanical forces on adjacent ECM that induce stretching of fibroblasts. This stretching is associated with increased collagen gene expression and deposition of mature collagen fibril bundles, which resemble those observed in young skin. CL-HA injected into aged/photoaged human dermis acts by both filling space and inducing production of collagen by dermal fibroblasts. Deposition of mature collagen, which remains in the skin for decades, likely confers long-term benefits. Reduced collagen production in aged/photoaged skin is an adaptive response of fibroblasts to ECM fragmentation, rather than inherent cellular aging mechanisms.

Changes in Human Fat Injected Alongside Hyaluronic Acid in the Backs of Nude Mice.

Cross-linked hyaluronic acid (HA) is an active anti-aging cosmetic filler. The combination of cross-linked HA and preadipocytes or adipose-derived stem cells has been previously investigated, but the effects of agglomerated cross-linked HA injection on the vascularization of fat grafts remain unclear. The aim of this study was to explore the effects of agglomerated cross-linked HA injection on the vascularization of fat grafts. The backs of nude mice were divided into 4 regions that received different treatments: nothing (control group), agglomerated Biohyalux (HA group), agglomerated fat (FAT group), and lumps formed by the sequential injection of Biohyalux and fat (HA/FAT group). Samples were collected after 1 month for weighing and hematoxylin and eosin staining, immunohistochemistry, image analysis, and Western blotting. The weight of fat and the mean number of adipocytes in the HA/FAT group did not significantly differ from those in the FAT group. No living tissue was found in agglomerated HA. Some tiny HA particles were surrounded by tissue rich in blood vessels. The expression levels of CD31 and vascular endothelial growth factor (VEGF) in the HA/FAT group were higher than those in the FAT group, but the difference was only significant for VEGF expression. Cross-linked HA had minimal effect on the early retention rate of surrounding fat grafts, but enhanced their vascularization. Fat grafts should be not injected into lumps of cross-linked HA. Therefore, agglomerated cross-linked HA should be dissolved before fat transplantation.

Safety and Performance of Etermis 3 and 4 in Wrinkles/Folds Treatment and Facial Volume Enhancement: A Prospective, Evaluator-Blinded, Open-Label Study.

BackgroundFacial aging is characterized by increased prominence of nasolabial folds (NLFs), marionette lines, and thinning of the lips. Cross-linked hyaluronic acid injection is a very effective method for the temporary correction of these areas.ObjectiveTo confirm the clinical performance and the safety of Etermis 3 (ET3) and/or Etermis 4 (ET4) in the treatment of moderate and severe wrinkles/folds, as well as lip volume enhancement.MethodsSubjects were treated in at least two facial areas (NLFs, marionette lines, lips). ET3 was used in facial moderate wrinkles while ET4 was used in severe facial skin volume loss. An optional touch-up 1 month after treatment was possible. A blinded investigator assessed improvement on Merz Aesthetic Scales (MAS). Subjects were followed-up for 12 months after the last treatment.ResultsIn total, 154 healthy subjects were enrolled. The proportion of subjects achieving ≥1 score improvement in MAS after treatment was above 60% for ET4 (Month 6/7: NLFs 94.9% and marionette lines 81.4%, p≤0.0004; Month 3/4: lips 63.0%, p=0.39) and ET3 (Month 6/7: marionette lines 79.4%, p=0.0005; Month 3/4: lips 65.5%, p=0.31). Facial improvement was still visible at Month 12/13 for ET4 (NLFs ≥76.6%, marionette lines ≥61%, lips ≥36%) and ET3 (marionette lines ≥50% and lips ≥21.9%). No treatment-related serious AEs occurred. The most frequent AEs were injection-site reactions.ConclusionEtermis 3 and Etermis 4 demonstrated good clinical performance and safety for NLFs and marionette lines volume enhancement for up to 12 months. Both products can also be used safely to treat lips for volume augmentation.

Treatment of late bacterial infections resulting from soft-tissue filler injections.

PurposeLate bacterial infections (LBIs) after esthetic facial augmentation using hyaluronic acid (HA) fillers are relatively rare yet severe complications that are difficult to treat. No adequate treatment standards have hitherto been formulated. We have bridged this gap by formulating a treatment scheme based on the principles of treating foreign-body implantation-related infections and treating bacterial growth in the form of biofilm. The objective of this study was to evaluate the efficacy of a comprehensive scheme for treating LBI complications after facial augmentation using cross-linked HA fillers.MethodsA total of 22 patients with LBI symptoms at a site of cross-linked HA injection underwent treatment and observation. The comprehensive treatment scheme formulated by Marusza and Netsvyetayeva (M&N scheme) comprised draining the lesion, dissolution of cross-linked HA with hyaluronidase, broad-spectrum antibiotic combination therapy, and use of probiotics. While 17 patients underwent the M&N scheme, the remaining five were treated with other schemes. Statistical analysis of the data was performed using Mann–Whitney U and χ2 nonparametric tests with SAS 9.4 software.ResultsAll 17 patients who underwent the M&N scheme experienced resolution of symptoms, with no recurrence of infection at the HA-injection sites.ConclusionTo treat LBI at a site of cross-linked HA administration, the principles applicable to infections resulting from implantation of a foreign body must be followed. The treatment period should be sufficiently long for complete resolution of symptoms. The efficacy of treatment is considered proven if 2 months have elapsed without recurrence since the symptoms resolved. The M&N scheme is recommended for use as the first therapeutic option for treating LBI related to soft-tissue fillers.

Cross-linked hyaluronic acid in pressure ulcer prevention

Long-term bedridden patients are at high risk of acquring pressure ulcers (PUs). In this group of patients, prevention is necessary to cut the health costs, improve quality of life and reduce the mortality. Here, we evaluated the effectiveness of a cross-linked hyaluronic acid (HA) as plastic bulking-agent filling and remodelling the deep dermis and subcutaneous space of the skin areas exposed to the risk of necrosis. Our work hypothesis has been to inflate a sub-dermal elastic cushion, filled with a natural ECM component, with the aim to induce a stronger tissue background resistant to the ulcerative process. All the patients had an increased risk of PUs, at the sacral, ileum or heel skin. Patients were being nursed accordingly to the standard orthopaedic ward management with a pressure relieveing air mattress. The standard protocol consisted in body mobilisation every 3 hours, 24 hours a day and accurate cleaning of the skin with liquid soap and water without any towel friction and without adding any cream or lotion for the skin protection. Our filling protocol enclosed: accurate disinfection of the skin to be injected with povidone-iodine solution, followed by a local anaesthesia with 28G 13 mm needle, injecting 1.5 ml of 1% xylocaine. Then slow, deep, subcutaneous injection of cross-linked HA was performed with a 18G long needle, in order to deliver a homogeneous, soft gel layer underneath and around the whitish erythematous skin edges at risk of ulceration. Patients' tolerability of the compound and adverse events were also recorded. There were 15 patients (78-94 years old) who participated in the study. All tolerated the procedure very well and no serious side effects were declared. No skin pressure ulceration was detected in the four weeks follow-up Conclusion: We have demonstrated the safety and tolerability of a cross-linked HA subdermal injection in PUs prevention. The compound stratifies in a soft, elastic, interstitial bulk into the deep dermis, thus reducing the exogenous pressure stress: thus, the induction of a thick hydrophilic substrate supports adequate mesenchymal and blood cells traffic to immediately restore any early or impending damage to the skin. The authors certify that there is no conflict of interest with any financial organisation regarding the material discussed in the manuscript.

Evaluation of the efficacy and safety of injectable cross-linked hyaluronic acid compared with mitomycin C in trabeculectomy surgery

BackgroundTrabeculectomy has been a gold standard for the treatment of glaucoma for years since its introduction to ophthalmology literature, and the outcome depends mostly on the resulting intraocular pressure (IOP). However, the most common reason for trabeculectomy failure is the development of fibrosis in the conjunctiva and episclera. Thus, glaucoma surgeons are still searching for an optimal substance for the modulation of wound-healing processes.AimThis study was conducted to evaluate the efficacy and safety of injection of cross-linked hyaluronic acid below the scleral flap and under the conjunctiva in trabeculectomy surgery compared with trabeculectomy with mitomycin C (MMC).Patients and methodsA total of 24 eyes with primary open-angle glaucoma were included in this study. Patients were divided into two groups: group 1 included 12 eyes that underwent a standardized trabeculectomy surgery supplemented by the injection of cross-linked hyaluronic acid (HealaFlow) below the scleral flap and under the conjunctiva, and group 2 included 12 eyes that underwent a standardized trabeculectomy surgery with the application of MMC. The endpoints for comparison were IOP, success rates, and postoperative complications.ResultsThe results of both groups were comparable, with no statistically significant difference between the two groups as regards IOP, success rates, and postoperative complications.ConclusionCross-linked sodium hyaluronate (HealaFlow) injectable implant is comparable to MMC for trabeculectomy in terms of IOP-lowering efficacy, success rates, early and mid-term postoperative complications, and tolerability. However, the results should be interpreted cautiously as relevant evidence is still limited, although it is accumulating. Further large-scale, long-term, and well-designed randomized controlled trials are needed.

Looking Older

Skin appearance is a primary indicator of age. During the last decade, substantial progress has been made toward understanding underlying mechanisms of human skin aging. This understanding provides the basis for current use and new development of antiaging treatments. Our objective is to review present state-of-the-art knowledge pertaining to mechanisms involved in skin aging, with specific focus on the dermal collagen matrix. A major feature of aged skin is fragmentation of the dermal collagen matrix. Fragmentation results from actions of specific enzymes (matrix metalloproteinases) and impairs the structural integrity of the dermis. Fibroblasts that produce and organize the collagen matrix cannot attach to fragmented collagen. Loss of attachment prevents fibroblasts from receiving mechanical information from their support, and they collapse. Stretch is critical for normal balanced production of collagen and collagen-degrading enzymes. In aged skin, collapsed fibroblasts produce low levels of collagen and high levels of collagen-degrading enzymes. This imbalance advances the aging process in a self-perpetuating, never-ending deleterious cycle. Clinically proven antiaging treatments such as topical retinoic acid, carbon dioxide laser resurfacing, and intradermal injection of cross-linked hyaluronic acid stimulate production of new, undamaged collagen. Attachment of fibroblasts to this new collagen allows stretch, which in turn balances collagen production and degradation and thereby slows the aging process. Collagen fragmentation is responsible for loss of structural integrity and impairment of fibroblast function in aged human skin. Treatments that stimulate production of new, nonfragmented collagen should provide substantial improvement to the appearance and health of aged skin.

A New Instrument for Intraoperative Assessment of Individual Vocal Folds

Intraoperative assessment of vocal fold vibration during phonomicrosurgery performed under general anesthesia may enhance surgical decision-making. We therefore developed and bench-tested a new device we refer to as the aerodynamic vocal fold driver (AVFD). The AVFD comprises a hand-held probe that uses airflow to drive individual vocal folds into phonatory-like vibration. This permits stroboscopic visualization of mucosal waves with simultaneous control of subglottal air pressure. In initial experiments to validate the technique, AVFD driven phonation and conventional whole-larynx phonation were compared using excised canine larynges (n = 14). Single vocal fold phonation using the AVFD and whole larynx phonation yielded similar, positive correlations between subglottal pressure and both amplitude and frequency of vibration. Experiments simulating vocal fold scar-related mucosal stiffening by subepithelial injection of fixative showed the expected elevation of phonation threshold pressures as measured with the AVFD. Likewise, unilateral tissue compression injury disrupted vocal fold vibration, and the AVFD was useful for quantifying improvement in the damaged vocal fold after repair with injection of cross-linked hyaluronic acid gel. These results show that this new instrument has the potential to provide novel and useful information for laryngeal experimentation and to improve phonosurgery.