Hyaluronic Acid Gel Biodegradation After Intrapalpebral and Intraorbital Injection in Experimental Study.

PURPOSE: Amid the increasing clinical application of hyaluronic acid (HA) fillers in the ocular adnexa is a paucity of histological data concerning the fate of the injected material. The current study documents the in vivo biodegradation of HA deposited in the eyelid and orbit. METHODS: The study included 22 chinchilla rabbits. The right upper eyelid of 12 rabbits received a single 0.2 ml Restylane (Galderma, Uppsala, Sweden) subcutaneous injection. In 10 different rabbits, the right orbit was injected with 1.0 ml Restylane SubQ (Galderma, Uppsala, Sweden) in the extraconal space. The rabbits in the eyelid group were euthanized at 2 weeks, 1 month, 2, 4, 6, and 9 months, while the rabbits in the orbit group were euthanized at 1 month, 3, 6, 12, and 18 months. Histological analysis was performed on the harvested samples. RESULTS: In the eyelid, the HA assumed a sponge-like structure that diminished gradually over time. At 9 months, the injected HA partially persisted, mainly in the peripheral areas of injection. A similar histologic pattern was observed in the injected orbits, with slow changes persisting at the eighteenth month. In both cohorts, clear signs of collagen deposition and pseudocapsule formation were observed around HA droplets, with no signs inflammation. CONCLUSIONS: HA injected subcutaneously into the eyelid and orbit of rabbits undergoes slow and gradual biodegradation, with HA persisting to no less than 9 months in the eyelid and 18 months in orbit. Neocollagen synthesis and lack of hyaluronidase activity could explain the unexpectedly prolonged HA persistence.

In Vitro Evaluation of Preinjection Aspiration for Hyaluronic Fillers as a Safety Checkpoint.

BACKGROUND: Hyaluronic acid (HA) fillers have increased in popularity. Although complications are rare, knowledge regarding their prevention and management are crucial. The utility of preinjection aspiration has become controversial. OBJECTIVE: Our study investigated the utility of preinjection aspiration as a safety checkpoint for HA fillers through comparison of physiochemical and rheological properties in an in vitro model. MATERIALS AND METHODS: Whole blood was drawn from vacutainers using syringes containing 10 commonly used HA fillers. Each HA filler was examined with the plunger pulled back at volumes of 0.2 and 0.5 cc. The time required to visualize a flash was recorded. Data were compared using physiochemical and rheological properties, pullback volumes, and needle gauges. RESULTS: Using a multivariable regression model, HA concentration, elastic modulus (G'), viscous modulus (G″), and complex modulus (G*) had significant relationships with time to flash, whereas needle gauge and pullback volume did not. However, when comparing pullback volume using an appropriate paired analysis, 0.5 cc pullback volume had a significantly decreased mean time to flash than 0.2 cc. CONCLUSION: Preinjection aspiration may have utility as a safety checkpoint for HA fillers. Practitioners may have to adjust pullback volume and waiting time to visualize the flash based on physiochemical and rheological properties.

Short-term Analysis of the Residual Volume of an Eye Drop Following 23-Gauge Microincision Vitrectomy Surgery.

PURPOSE: To evaluate the change of residual volume of eye drop after instillation in patients with 23-gauge microincision vitrectomy surgery (MIVS). METHODS: Patient who were treated 23-gauge MIVS from November 2014 to July 2015 were included. The residual volume was defined as the amount of remnant eye drop in patient's eyes after instillation, calculated as the difference between instillation volume and spilled volume of eye drop. Calculation of residual volume of eye drop was performed one day before surgery, and daily from postoperative day 1 to day 5. RESULTS: Forty consecutive patients were included. The residual volume of eye drop decreased from 30.3 ± 1.4 µL at baseline to 13.0 ± 1.5 µL at day 1, 18.3 ± 1.6 µL at day 2, 24.7 ± 1.5 µL at day 3, and 27.9 ± 1.4 µL in day 4, postoperatively (p < 0.001, respectively). The volume at postoperative day 5 was 29.4 ± 1.3 µL, but it was not different from the volume at baseline (p = 0.105). The change of residual volume was significantly correlated with postoperative chemosis (r = 0.672, p < 0.001) and effected by the number of quadrant with postoperative chemosis (p < 0.05). CONCLUSIONS: This study shows that postoperative residual volume of eye drop after instillation decreased until postoperative day 4, and postoperative chemosis affects the change of residual volume. Thus, checking proper use of eye drops and teaching about instillation technique by physician is necessary for patients with 23-gauge MIVS.

Osmoprotectants, carboxymethylcellulose and hyaluronic acid multi-ingredient eye drop: a randomised controlled trial in moderate to severe dry eye.

PurposeTo assess the safety and efficacy of an eye drop combining osmoprotectants, carboxymethylcellulose and hyaluronic acid (O/CMC/HA) in reducing symptomatic, moderate to severe dry eye, compared with HA.MethodsIn this investigator-masked, randomised study, patients instilled 1-2 drops/eye of O/CMC/HA or HA (2-6 times/day) for 3 months. Primary endpoint: mean change in Global Ocular Staining Score (GOSS) from baseline at day 35. Noninferiority of O/CMC/HA was tested in the per-protocol population; if achieved, superiority was tested in the intent-to-treat population. Secondary efficacy endpoints: mean change from baseline in GOSS, Ocular Surface Disease Index (OSDI), Schirmer score, tear break-up time (TBUT), corneal/conjunctival staining, conjunctival hyperaemia, symptoms, and patient/investigator assessments.ResultsBaseline characteristics were comparable between groups (n=40 each). O/CMC/HA was noninferior (and not superior) to HA based on similar GOSS reductions from baseline at day 35 and month 3 in both groups (P=0.778, day 35, per-protocol population). Overall, O/CMC/HA and HA provided similar reductions in OSDI, Schirmer score, TBUT, corneal staining and hyperaemia from baseline at 35 days (P≥0.155). More patients reported less severe stinging/burning, sandiness/grittiness, and painful/sore eyes at month 3 with O/CMC/HA (P≤0.039), and more rated the dropper bottle easy to use (87.5%), compared with HA (46.2%; P=0.002). Other patient and investigator assessments were similar between groups. O/CMC/HA and HA were well tolerated.ConclusionsO/CMC/HA is noninferior to HA in improving objective signs of dry eye, with potential advantages for subjective symptoms and patient acceptance.

Physiochemical properties and application of hyaluronic acid: a systematic review.

BACKGROUND: Hyaluronic acid is a widely available, biocompatible, polysaccharide with distinguishing physiochemical properties which inspire its application throughout several fields of medicine. OBJECTIVE: We aim to investigate the application of hyaluronic acid and its effectiveness throughout several fields of medicine, including several therapies administered and prescribed by general health practitioners. METHODS: We conducted a systematic review on randomized controlled trials about the physiochemical properties of hyaluronic acid and its application through primary care. Studies included in this review were peer reviewed and met our inclusion criteria. FINDINGS: Factors were clustered into the following: uses throughout several fields of medicine, physiochemical properties, bioavailability, tolerance, effectiveness, and adverse effects. Therapies with hyaluronic acid provided long-lasting, pain relieving, moisturizing, lubricating, and dermal filling effect. Tissue hydration, elasticity, and durability improved. CONCLUSIONS: Adjunct therapy with hyaluronic acid provides longer-lasting therapeutic effect when compared to the use of glucocorticosteroids and NSAIDs in osteoarthritic chronic diseases, is well-established in ophthalmology due to its lubricating properties for the corneal endothelium, and improves tissue hydration and cellular resistance to mechanical damage in aesthetic dermatology, and has marginal adverse effects. Several trials indicated its role in tumor markers, liver diseases, and in pharmaceuticals, but further research would be necessary to draw conclusive results in those fields.

Extended release of hyaluronic acid from hydrogel contact lenses for dry eye syndrome.

Current dry eye treatment includes delivering comfort enhancing agents to the eye via eye drops, but low residence time of eye drops leads to low bioavailability. Frequent administration leads to incompliance in patients, so there is a great need for medical device such as contact lenses to treat dry eye. Studies in the past have demonstrated the efficacy of hyaluronic acid (HA) in the treatment of dry eyes using eye drops. In this paper, we present two methods to load HA in hydrogel contact lenses, soaking method and direct entrapment. The contact lenses were characterized by studying their optical and physical properties to determine their suitability as extended wear contact lenses. HA-laden hydrogel contact lenses prepared by soaking method showed release up to 48 h with acceptable physical and optical properties. Hydrogel contact lenses prepared by direct entrapment method showed significant sustained release in comparison to soaking method. HA entrapped in hydrogels resulted in reduction in % transmittance, sodium ion permeability and surface contact angle, while increase in % swelling. The impact on each of these properties was proportional to HA loading. The batch with 200-µg HA loading showed all acceptable values (parameters) for contact lens use. Results of cytotoxicity study indicated the safety of hydrogel contact lenses. In vivo pharmacokinetics studies in rabbit tear fluid showed dramatic increase in HA mean residence time and area under the curve with lenses in comparison to eye drop treatment. The study demonstrates the promising potential of delivering HA through contact lenses for the treatment of dry eye syndrome.

Staining internal limiting membrane with a mixture of BBG and sodium hyaluronate.

AIMS: To evaluate the intraoperative applicability and safety of a mixture of brilliant blue G and sodium hyaluronate (visco-BBG) for staining the inner limiting membrane (ILM). METHODS: A retrospective consecutive case series. Seventy-four eyes that had undergone ILM peeling were studied. During vitrectomy, ILM peeling with visco-BBG (visco-BBG group) was performed on 40 eyes; 12 with a macular hole (MH), 26 with an epimacular membrane (ERM) and 2 with a retinal detachment due to a MH (MHRD). ILM peeling with BBG dissolved in balanced salt solution (BSS-BBG group) was performed on 34 eyes; 9 with a MH, 23 with an ERM and 2 with a MHRD. The main outcome measures were the distribution of the dye within the vitreous cavity and the retinal sensitivity in the MH patients of the two groups by microperimetry. RESULTS: The visco-BBG was injected over the retina where the ILM was intended to be peeled, and it stained the ILM in all cases. It did not disperse throughout the vitreous cavity or into the subretinal space. The BSS-BBG dispersed throughout the vitreous cavity, and its distribution was difficult to control. The two solutions did not stain the epiretinal membranes or any residual posterior hyaloid membrane. The difference in the retinal sensitivity between the two patients with MH of two groups was not significant. No complications were found in the visco-BBG group, although an accidental retinal perforation was found in one eye of the BSS-BBG group. Transmission electron microscopy confirmed that the membrane peeled was the ILM. CONCLUSIONS: Visco-BBG can be a useful method to assist macular surgery and can overcome some of the disadvantages of conventional BBG solutions dissolved in BSS.

The treatment of keloids with pneumatic technology: a pilot study.

BACKGROUND: Keloid scars derive from abnormal fibrous wound healing when the mechanisms controlling tissue repair and regeneration malfunction. Previous studies have reported a reduction in hyaluronic acid among fibroblasts cultured from keloid tissue compared with the levels in normal skin. Here, we evaluated the efficacy and safety of subdermal minimal surgery using hyaluronic acid as a novel treatment in keloid scars. OBJECTIVE: To evaluate the clinical efficacy and safety of subdermal minimal surgery technology in the treatment of keloids. MATERIALS AND METHODS: Ten Korean patients (Fitzpatrick skin type II-IV) with keloids on the upper arms were enrolled in this study. All patients underwent three sessions of subdermal minimal surgery at three-week intervals. Scar assessments were performed at baseline, before each treatment session, and three months after the final treatment, with three different assessment methods. Specifically, in addition to the Vancouver Scar Scale (VSS), two independent physicians performed global assessment evaluations regarding the final cosmetic results. As a final form of assessment, participant satisfaction was assessed using a four-point scale. RESULTS: All volunteers completed three treatment sessions, and nine of 10 patients were satisfied with the procedure. The average VSS score decreased three months after the final treatment, and global assessment showed clinical improvement of the scars. No adverse events occurred, except transient spot bleeding at entry points and slight post-procedure edema, which resolved within 48 hours. CONCLUSION: Subdermal minimal surgery technology may help to improve keloids on the upper arm without noticeable adverse effects.

Intra-articular injection of hyaluronan restores the aberrant expression of matrix metalloproteinase-13 in osteoarthritic subchondral bone.

Subchondral bone is a candidate for treatment of osteoarthritis (OA). We investigated the effects of intra-articular injection of hyaluronan (IAI-HA) on subchondral bone in rabbit OA model. OA was induced by anterior cruciate ligament transection, with some rabbits receiving IAI-HA. OA was graded morphologically, and expression of mRNA was assessed by real-time RT-PCR. Tissue sections were stained with hyaluronan-binding protein, and penetration of fluorescent hyaluronan was assessed. The in vitro inhibitory effect of hyaluronan on MMP-13 was analyzed in human osteoarthritic subchondral bone osteoblasts (OA Ob) by real-time RT-PCR and ELISA. Binding of hyaluronan to OA Ob via CD44 was assessed by immunofluorescence cytochemistry. Expression of MMP-13 and IL-6 mRNA in cartilage and subchondral bone, and morphological OA grade, increased over time. IAI-HA ameliorated the OA grade and selectively suppressed MMP-13 mRNA in subchondral bone. IAI-HA enhanced the hyaluronan staining of subchondral bone marrow cells and osteocyte lacunae. Fluorescence was observed in the subchondral bone marrow space. In OA Ob, hyaluronan reduced the expression and production of MMP-13, and anti-CD44 antibody blocked hyaluronan binding to OA Ob. These findings indicate that regulation of MMP-13 in subchondral bone may be a critical mechanism during IAI-HA.