Advances in Understanding the Mechanism of Ophthalmic Viscosurgical Device Retention in the Anterior Chamber or on the Corneal Surface during Ocular Surgery.

Retention durability, especially in the eye, is one of the most important properties of ophthalmic viscosurgical devices (OVDs) during ocular surgery. However, the information on the physical properties of OVDs is insufficient to explain their retention durability. The purpose of this study is to clarify the mechanism of OVD retention to improve understanding of the behavior of OVDs during ocular surgery. To elucidate the mechanism of OVD retention, we have developed a new test method for measuring repulsive force. As a result, the maximum repulsive force of OVDs was positively and well correlated with the retention durability of investigated OVDs. Consequently, we demonstrated that the repulsive force could be used as an index of retention durability on the ocular surface and in the eye. We directly compared the intraocular retention durability of three OVDs (Shellgan, Viscoat, and Opegan-Hi) in ex vivo porcine eyes. Opegan-Hi was immediately removed from the anterior chamber, but Shellgan and Viscoat remained largely in the anterior chamber as determined by fluorescence imaging. These results showed that the intraocular retention behavior of OVDs was similar to their ocular surface behavior in our previous report, suggesting that retention durability is dependent on the OVD itself. The retention durability of Shellgan seemed to be higher than that of Viscoat, and the maximum repulsive force of Shellgan was 1.35-fold higher than that of Viscoat. Therefore, the repulsive force might be a useful index for assessing the difference in the retention durability between OVDs such as Shellgan and Viscoat.

The action of hyaluronan in functional properties, morphology and expression of matrix effectors in mammary cancer cells depends on its molecular size.

Breast cancer constitutes a heterogeneous disease. The expression profiles of estrogen receptors (ERs), as well as the expression patterns of extracellular matrix (ECM) macromolecules, determine its development and progression. Hyaluronan (HA) is an ECM molecule that regulates breast cancer cells' properties in a molecular size-dependent way. Previous studies have shown that 200-kDa HA fragments modulate the functional properties, morphology, and expression of several matrix mediators of the highly metastatic ERα- /ERß+ MDA-MB-231 cells. In order to evaluate the effects of HA fragments (< 10, 30 and 200-kDa) in ERß-suppressed breast cancer cells, the shERß MDA-MB-231 cells were used. These cells are less aggressive when compared with MDA-MB-231 cells. To this end, the functional properties, the morphology, and the expression of the molecules associated with breast cancer cells metastatic potential were studied. Notably, both cell proliferation and invasion were significantly reduced after treatment with 200-kDa HA. Moreover, as assessed by scanning electron microscopy, 200-kDa HA affected cellular morphology, and as assessed by qPCR, upregulated the epithelial marker Ε-cadherin. The expression profiles of ECM mediators, such as HAS2, CD44, and MMP7, were also altered. On the other hand, cellular migration and the expression levels of syndecan-4 (SDC-4) were not significantly affected in contrast to our observations regarding MDA-MB-231 cells. These novel data demonstrate that the molecular size of the HA determines its effects on ERß-suppressed breast cancer cells and that 200-kDa HA exhibits antiproliferative effects on these cells. A deeper understanding of this mechanism may contribute to the development of therapeutic strategies against breast cancer.

A hydrogel system based on a lactose-modified chitosan for viscosupplementation in osteoarthritis.

Osteoarthritis (OA) is a chronic disease affecting joint functionality and often managed with hyaluronic acid (HA) administration. In this study, a hydrogel based on a lactose-modified chitosan (CTL) reticulated with boric acid has been developed as a viscosupplement for OA treatment. The rheological characterization allowed to identify a composition whose properties were in line with those of commercial products (in the order of tens of Pascal). The selected CTL-hydrogel showed biocompatibility and antioxidant activity in vitro, and it did not influence cytokines release by macrophages. Degradation studies carried out over 24 h pointed out its higher resistance to chemical degradation with respect to HA samples. Overall, this study underlines the advantages of the CTL-hydrogel to address the treatment of OA and shed light on an innovative application of CTL polymer, which is one of the main component of the proposed hydrogel system and not used in mixture with other molecules.

The antilymphatic metastatic effect of hyaluronic acid in a mouse model of oral squamous cell carcinoma.

Objectives: Lymphatic metastasis is the main cause of low patient survival in cases of oral squamous cell carcinoma (OSCC). Several animal models have been established to uncover the mechanism that regulates lymph node metastasis of OSCC cells. Unfortunately, these models often take a long time to establish. The prolonged tumor burden can lead to animal cachexia, which may ultimately affect the experimental outcome. To overcome the disadvantages of these models, we established an orthotopic metastatic animal model of OSCC that showed quick lymph node metastasis potential.Results: DiR dye-labeled CAL27 cells were injected into tongue tissues of BALB/c nude mice, and the cells metastasized to lymph nodes on day 3. Metastasis was monitored using an in vivo imaging system and confirmed by histological observation. Using this model, we investigated the role of hyaluronic acid (HA) on the cervical metastasis of OSCC cells. Surprisingly, we found that the presence of HA significantly reduced the incidence of metastasis to cervical lymph nodes compared with the control group. Further analysis revealed that the presence of exogenous HA promoted mesenchymal-epithelial transition (MET) in primary tumors while reducing the metastatic potential of OSCC.Conclusion: Our findings confirmed the establishment of a fast and reliable lymphatic metastatic mouse model of OSCC that can be used for investigating metastatic mechanisms and analyzing various antimetastasis strategies. An equally important discovery is the antimetastatic property of HA, which could provide a potential therapeutic strategy for OSCC.

The relationship between synovial inflammation, structural pathology, and pain in post-traumatic osteoarthritis: differential effect of stem cell and hyaluronan treatment.

BACKGROUND: Synovitis is implicated in the severity and progression of pain and structural pathology of osteoarthritis (OA). Increases in inflammatory or immune cell subpopulations including macrophages and lymphocytes have been reported in OA synovium, but how the particular subpopulations influence symptomatic or structural OA disease progression is unclear. Two therapies, hyaluronan (HA) and mesenchymal stem cells (MSCs), have demonstrated efficacy in some clinical settings: HA acting as device to improve joint function and provide pain relief, while MSCs may have immunomodulatory and disease-modifying effects. We used these agents to investigate whether changes in pain sensitization or structural damage were linked to modulation of the synovial inflammatory response in post-traumatic OA. METHODS: Skeletally mature C57BL6 male mice underwent medial-meniscal destabilisation (DMM) surgery followed by intra-articular injection of saline, a hyaluronan hexadecylamide derivative (Hymovis), bone marrow-derived stem cells (MSCs), or MSC + Hymovis. We quantified the progression of OA-related cartilage, subchondral bone and synovial histopathology, and associated pain sensitization (tactile allodynia). Synovial lymphocytes, monocyte/macrophages and their subpopulations were quantified by fluorescent-activated cell sorting (FACS), and the expression of key inflammatory mediators and catabolic enzyme genes quantified by real-time polymerase chain reaction (PCR). RESULTS: MSC but not Hymovis significantly reduced late-stage (12-week post-DMM) cartilage proteoglycan loss and structural damage. Allodynia was initially reduced by both treatments but significantly better at 8 and 12 weeks by Hymovis. Chondroprotection by MSCs was not associated with specific changes in synovial inflammatory cell populations but rather regulation of post-injury synovial Adamts4, Adamts5, Mmp3, and Mmp9 expression. Reduced acute post-injury allodynia with all treatments coincided with decreased synovial macrophage and T cell numbers, while longer-term effect on pain sensitization with Hymovis was associated with increased M2c macrophages. CONCLUSIONS: This therapeutic study in mice demonstrated a poor correlation between cartilage, bone or synovium (histo)pathology, and pain sensitization. Changes in the specific synovial inflammatory cell subpopulations may be associated with chronic OA pain sensitization, and a novel target for symptomatic treatment.

Is platelet-rich plasma effective for the treatment of knee osteoarthritis? A systematic review and meta-analysis of level 1 and 2 randomized controlled trials.

INTRODUCTION: The purpose of this study was to perform a systematic review and meta-analysis comparing intra-articular knee injection of PRP and hyaluronic acid and investigate clinical outcomes and pain at both 6 and 12 months. METHODS: A systematic review of Medline, Embase, Scopus, and Google Scholar was performed in the English and German literature reporting on intra-articular knee injections for knee osteoarthritis. All level 1 and 2 studies with a minimum of 6-month follow-up in patients with knee osteoarthritis from 2010 to 2019 were included. Clinical outcome was assessed by WOMAC and IKDC scores and pain by VAS and WOMAC pain scores. Subgroup analysis for autologous platelet-rich plasma (ACP) was performed. Publication bias and risk of bias were assessed using the Cochrane Collaboration's tools. The GRADE system was used to assess the quality of the body of evidence. Heterogeneity was assessed using χ2 and I2 statistics. RESULTS: Twelve studies (1,248 cases; 636 PRP, 612 HA) met the eligibility criteria. The pooled estimate demonstrated non-significant differences between PRP and HA for clinical outcomes at 6 months (p = 0.069) and at 12 months (p = 0.188). However, the pooled estimate for pain did demonstrate significant differences in favour of PRP at 6 months (p = 0.001) and 12 months (p = 0.001). For the ACP subgroup (249 cases), the pooled estimate for these studies demonstrated significant differences in favour of PRP (p < 0.0001) at 6 months. CONCLUSION: The results of this systematic review and meta-analysis suggest that PRP is superior to HA for symptomatic knee pain at 6 and 12 months. ACP appears to be clearly superior over HA for pain at both 6 and 12 months. There were no advantages of PRP over HA for clinical outcomes at both 6 and 12 months. LEVEL OF EVIDENCE: Level 2; systematic review and meta-analysis.

Practical Guidelines for Hyaluronic Acid Soft-Tissue Filler Use in Facial Rejuvenation.

BACKGROUND: Hyaluronic acid (HA) fillers are the most commonly used fillers for soft-tissue augmentation. The face is a dynamic structure. Facial rejuvenation by filler products depends on mechanical forces on the region of the face. The successful use of injectable HA fillers requires an understanding of the options available. OBJECTIVE: The purpose of this study is to measure the rheological properties of HA fillers and to clarify how to select these fillers considering their rheological properties. MATERIALS AND METHODS: Rheological characterization was performed on 41 fillers. Physical parameters directly linked to product performance were measured. RESULTS: The properties of the HA fillers varied. These findings provide a basis for selection guideline regarding rheological properties in facial rejuvenation. CONCLUSION: The authors' report is the largest study to determine the rheological properties of HA fillers to date. Understanding the fillers' properties can help physicians select the appropriate fillers for more predictable and sustainable results.

Hyaluronic acid has chondroprotective and joint-preserving effects on LPS-induced synovitis in horses.

The intra-articular use of hyaluronic acid (HA) for the treatment of synovitis and osteoarthritis is still controversial. As a consequence, corticosteroids remain the most frequently employed therapeutic agents, despite their potential systemic and local deleterious effects. This study examined the anti-inflammatory, antioxidant, and chondroprotective activities of low and high molecular weight hyaluronic acid (LMW-HA and HMW-HA) on lipopolysaccharide (LPS)-induced synovitis in horses compared to triamcinolone acetonide (TA). LPS was injected in the metacarpophalangeal joints, which were treated intra-articularly with either TA (as control) or LMW-HA or HMW-HA. Joint clinical evaluation and synovial fluid (SF) analysis were performed at 0, 8, 24, and 48 h. The white blood cell counts (WBC), prostaglandin E2 (PGE2), interleukin (IL)-1, IL-6, IL-10, tumor necrosis factor-α, chondroitin sulfate (CS) and HA concentrations, oxidative burst, and HA molecular weights were measured. TA reduced the lameness, swelling, and PGE2 release but increased the SF CS concentrations enormously at 24h and 48h, and decreased the SF HA modal molecular weight. These results indicate the breakdown of articular cartilage aggrecan and SF HA. In contrast, LMW-HA and HMW-HA were less effective in reducing the inflammation symptoms, but preserved the joints because only a modest increase in CS occurred at 24 h, decreasing at 48 h, and the SF HA was maintained. The HA-treatment also had anti-inflammatory actions, and LMW-HA was the most effective in reducing the release of cytokine. In summary, the HA treatment inhibited efficiently the digestion of cartilage proteoglycans and SF HA breakdown.

Specifically Sized Hyaluronan (35 kDa) Prevents Ethanol-Induced Disruption of Epithelial Tight Junctions Through a layilin-Dependent Mechanism in Caco-2 Cells.

BACKGROUND: Specific-sized species of the carbohydrate hyaluronan elicit a variety of cellular responses mediating tissue integrity and repair, as well as regulating inflammatory responses. Orally provided hyaluronan with an average molecular weight of 35 kDa (HA35) protects mice from short-term ethanol (EtOH)-induced liver injury. This protection was associated with maintenance of the colocalization of zonula occludens-1 (ZO-1) and occludin at tight junctions in the proximal colon. However, it is not known whether HA35 also protects other regions of the intestine or whether protection is due to a direct and/or indirect interaction of HA35 with the intestinal epithelium. METHODS: Female C57BL/6J mice were fed an EtOH containing diet or pair-fed control diet (4 days) and treated with or without HA35 via daily gavage during the last 3 days of EtOH feeding. Intestinal morphology and tight junction integrity were assessed. Differentiated Caco-2 cells were transfected or not with scrambled siRNA or siRNA targeting layilin, a hyaluronan receptor. Caco-2 cells were treated with or without HA35 prior to challenge with EtOH. Localization of tight junction proteins, fluorescein isothiocyanate (FITC)-dextran permeability, and transepithelial electrical resistance (TEER) were evaluated. RESULTS: While short-term EtOH did not result in any apparent changes in the gross morphology of the intestine, colocalization of ZO-1 and occludin at tight junctions was decreased in the proximal and distal colon. HA35 prevented these effects of EtOH. In differentiated Caco-2 cells, EtOH decreased the localization of ZO-1 and occludin at tight junctions and increased permeability of FITC-dextran. At higher concentrations, EtOH also decreased TEER. Pretreatment with HA35 prevented these changes. When the hyaluronan receptor layilin was knocked down in Caco-2 cells, HA35 no longer protected cells from EtOH-induced loss of tight junctions. CONCLUSIONS: Taken together, these data indicate that HA35 interacts with layilin on intestinal epithelial cells and maintains intestinal tight junction integrity during short-term EtOH exposure.

CCL25-Supplemented Hyaluronic Acid Attenuates Cartilage Degeneration in a Guinea Pig Model of Knee Osteoarthritis.

There is evidence that the application of mesenchymal stromal cells (MSCs) counteracts osteoarthritis (OA) progression. However, the prospect of extracting and expanding these cells might be limited. The aim of this study was to investigate whether hyaluronic acid (HA) supplemented with MSC-recruiting chemokine C-C motif ligand 25 (CCL25) can influence the natural course of spontaneous OA in the guinea pig. CCL25 concentration in synovial fluid (SF) was quantified with enzyme-linked immunosorbent assay. Boyden chamber cell migration assay was used to test CCL25-mediated migration of guinea pig MSC. Forty-nine 11-month-old male guinea pigs were divided into seven groups. The main treatments consisted of five intra-articular injections of HA in pure form and in combination with three doses of CCL25 (63, 693, and 6,993 pg) given at a weekly interval. The severity of cartilage damage was assessed by using a modified Mankin score. The measured average physiological concentration of CCL25 in SF of animals is 85 ± 39 pg/ml. MSC showed a 3.2-fold increase in cell migration at 1,000 nM CCL25 in vitro demonstrating the biological migratory activity of CCL25 on these cells. In vivo, treatment with HA alone did not reduce OA progression. Similarly, OA scores were not found significantly reduced after treatment with 63 pg CCL25 + HA. However, when compared to pure HA, treatment with 693 pg CCL25 + HA and 6,993 pg CCL25 + HA significantly reduced the OA score from 10.1 to 7.4 (-28%) and 8.4 (-20%), respectively. These data suggest that intra-articular injections of HA supplemented with CCL25 attenuates OA. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1723-1729, 2019.

The Role of Orthobiologics in the Management of Osteoarthritis and Focal Cartilage Defects.

Individuals with osteoarthritis have a diminished quality of life, and the condition is a major cause of disability. Newer biologic treatments have been developed that are believed to modify disease progression. These predominantly include hyaluronic acid, platelet-rich plasma, bone marrow aspirate concentrate, and adipose-derived mesenchymal stem cells. There is conflicting evidence regarding the use of orthobiologics for osteoarthritis and for focal chondral defects, although most studies indicate that injections of biologics are safe and without significant adverse effects. [Orthopedics. 2019; 42(2):66-73.].

Efficacy of hyaluronic acid after knee arthroscopy: A systematic review and meta-analysis.

OBJECTIVE: To investigate the effect of hyaluronic acid on functional recovery and pain control in patients following knee arthroscopy. DESIGN: A systematic review and meta-analysis was conducted to explore the efficacy of hyaluronic acid following knee arthroscopy. SUBJECTS AND METHODS: Randomized controlled trials (RCTs) assessing the effect of hyaluronic acid in knee arthroscopy were included. A meta-analysis was performed using the random-effect model. RESULTS: Six RCTs involving 310 patients were included in the meta-analysis. Overall, compared with control intervention following knee arthroscopy, hyaluronic acid treatment was found to significantly increase Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores (mean difference 11.43; 95% confidence intervals (95% CI) 1.39-21.47; p = 0.03), but had no impact on pain scores at 2 weeks (mean difference -0.16; 95% CI -0.81-0.49; p = 0.63), pain scores at 6 weeks (mean difference 0.01; 95% CI -0.86-0.89; p = 0.98), pain scores at 12 weeks (mean difference -0.51; 95% CI -1.56-0.53; p = 0.34). In addition, pain on motion was significantly reduced after knee arthroscopy (risk ratio (RR) 0.22; 95% CI 0.06-0.79; p = 0.02). CONCLUSION: Compared with control intervention after knee arthroscopy, hyaluronic acid treatment was found to significantly improve WOMAC score and decrease pain on motion, but had no substantial influence on pain scores at 2, 6 and 12 weeks after knee arthroscopy.

Phacoemulsification with hydrodelineation and OVD-assisted hydrodissection in posterior polar cataract.

BACKGROUND: To evaluate the results and complications of phacoemulsification with hydrodelineation and ophthalmic viscosurgical device (OVD)-assisted hydrodissection for posterior polar cataract (PPC). METHODS: Medical records of 24 eyes from 17 patients with clinical diagnosis of PPC, who underwent phacoemulsification with hydrodelineation and OVD-assisted hydrodissection, were retrospectively reviewed. RESULTS: The incidence of posterior capsule rupture (PCR) was 16.67% (4/24): 2 cases occurred during epinucleus removal, and 2 cases occurred during OVD removal after the implantation of the intraocular lens into the bag. No nucleus piece or lens materials dropped into the vitreous during cataract surgery, and no obvious postoperative complications were found during follow-up. All patients had improved best-corrected visual acuity (BCVA) 1 month postoperatively. CONCLUSION: OVD-assisted hydrodissection could be an effective technique in phacoemulsification to reduce the incidence of PCR and achieve satisfactory postoperative outcomes.

The Role of Anastomotic Vessels in Controlling Tissue Viability and Defining Tissue Necrosis with Special Reference to Complications following Injection of Hyaluronic Acid Fillers.

BACKGROUND: Most target areas for facial volumization procedures relate to the anatomical location of the facial or ophthalmic artery. Occasionally, inadvertent injection of hyaluronic acid filler into the arterial circulation occurs and, unrecognized, is irreparably associated with disastrous vascular complications. Of note, the site of complications, irrespective of the injection site, is similar, and falls into only five areas of the face, all within the functional angiosome of the facial or ophthalmic artery. METHODS: Retrospective and prospective studies were performed to assess the site and behavior of anastomotic vessels connecting the angiosomes of the face and their possible involvement in the pathogenesis of tissue necrosis. In vivo studies of pig and rabbit, and archival human total body and prospective selective lead oxide injections of the head and neck, were analyzed. Results were compared with documented patterns of necrosis following inadvertent hyaluronic acid intraarterial or intravenous injection. RESULTS: Studies showed that the location of true and choke anastomoses connecting the facial artery with neighboring angiosomes predicted the tissue at risk of necrosis following inadvertent intraarterial hyaluronic acid injection. CONCLUSION: Complications related to hyaluronic acid injections are intimately associated with (1) the anatomical distribution of true and choke anastomoses connecting the facial artery to neighboring ophthalmic and maxillary angiosomes where choke vessels define the boundary of necrosis of an involved artery but true anastomoses allow free passage to a remote site; or possibly (2) retrograde perfusion of hyaluronic acid into avalvular facial veins, especially in the periorbital region, and thereby the ophthalmic vein, cavernous sinus, and brain.

Comparison of Autograft and Allograft with Surface Modification for Flexor Tendon Reconstruction: A Canine in Vivo Model.

BACKGROUND: Flexor tendon injury is common, and tendon reconstruction is indicated clinically if the primary repair fails or cannot be performed immediately after tendon injury. The purpose of the current study was to compare clinically standard extrasynovial autologous graft (EAG) tendon and intrasynovial allogeneic graft (IAG) that had both undergone biolubricant surface modification in a canine in vivo model. METHODS: Twenty-four flexor digitorum profundus (FDP) tendons from the second and fifth digits of 12 dogs were used for this study. In the first phase, a model of failed FDP tendon repair was created. After 6 weeks, the ruptured FDP tendons with a scarred digit were reconstructed with the use of either EAG or IAG tendons treated with carbodiimide-derivatized hyaluronic acid and lubricin. At 12 weeks after tendon reconstruction, the digits were harvested for functional, biomechanical, and histologic evaluations. RESULTS: The tendon failure model was a clinically relevant and reproducible model for tendon reconstruction. The IAG group demonstrated improved digit function with decreased adhesion formation, lower digit work of flexion, and improved graft gliding ability compared with the EAG group. However, the IAG group had decreased healing at the distal tendon-bone junction. Our histologic findings verified the biomechanical evaluations and, further, showed that cellular repopulation of allograft at 12 weeks after reconstruction is still challenging. CONCLUSIONS: FDP tendon reconstruction using IAG with surface modification has some beneficial effects for reducing adhesions but demonstrated inferior healing at the distal tendon-bone junction compared with EAG. These mixed results indicate that vitalization and turnover acceleration are crucial to reducing failure of reconstruction with allograft. CLINICAL RELEVANCE: Flexor tendon reconstruction is a common surgical procedure. However, postoperative adhesion formation may lead to unsatisfactory clinical outcomes. In this study, we developed a potential flexor tendon allograft using chemical and tissue-engineering approaches. This technology could improve function following tendon reconstruction.

Instillation of hyaluronan reverses acid instillation injury to the mammalian blood gas barrier.

Acid (HCl) aspiration during anesthesia may lead to acute lung injury. There is no effective therapy. We hypothesized that HCl instilled intratracheally in C57BL/6 mice results in the formation of low-molecular weight hyaluronan (L-HA), which activates RhoA and Rho kinase (ROCK), causing airway hyperresponsiveness (AHR) and increased permeability. Furthermore, instillation of high-molecular weight hyaluronan (H-HA; Yabro) will reverse lung injury. We instilled HCl in C57BL/6 wild-type (WT), myeloperoxidase gene-deficient (MPO-/-) mice, and CD44 gene-deficient (CD44-/-) mice. WT mice were also instilled intranasally with H-HA (Yabro) at 1 and 23 h post-HCl. All measurements were performed at 1, 5, or 24 h post-HCl. Instillation of HCl in WT but not in CD44-/- resulted in increased inflammation, AHR, lung injury, and L-HA in the bronchoalveolar lavage fluid (BALF) 24 h post-HCl; L-HA levels and lung injury were significantly lower in HCl-instilled MPO-/- mice. Isolated perfused lungs of HCl instilled WT but not of CD44-/- mice had elevated values of the filtration coefficient ( Kf). Addition of L-HA on the apical surface of human primary bronchial epithelial cell monolayer decreased barrier resistance ( RT). H-HA significantly mitigated inflammation, AHR, and pulmonary vascular leakage at 24 h after HCl instillation and mitigated the increase of Kf and RT, as well as ROCK2 phosphorylation. Increased H- and L-HA levels were found in the BALF of mechanically ventilated patients but not in healthy volunteers. HCl instillation-induced lung injury is mediated by the L-HA-CD44-RhoA-ROCK2 signaling pathway, and H-HA is a potential novel therapeutic agent for acid aspiration-induced lung injury.

Platelet-Rich Plasma and Hyaluronic Acid Are Not Synergistic When Used as Biological Adjuncts with Autologous Osteochondral Transplantation.

Introduction Autologous osteochondral transplantation (AOT) is a treatment for osteochondral lesions with known concerns, including histological degradation of the graft and poor cartilage integration. Platelet-rich plasma (PRP) and hyaluronic acid (HA) have been described has having the potential to improve results. The aim of this study was to evaluate the effect of PRP and HA on AOT in a rabbit model. Methods Thirty-six rabbits underwent bilateral knee AOT treated with either the biological adjunct (PRP, n = 12; HA, n = 12; PRP + HA, n = 12) or saline (control). PRP and HA were administered as an intra-articular injection. The rabbits were euthanized at 3, 6, or 12 weeks postoperatively. The graft sections were assessed using the modified International Cartilage Repair Society (ICRS) scoring system. The results from the PRP alone group is from previously published data. Results The mean modified ICRS histological score for the PRP-treated group was higher than its control ( P = 0.002). The mean modified ICRS histological score for the HA-treated group showed no difference compared with its control ( P = 0.142). The mean modified ICRS histological score for the PRP + HA-treated group was higher than its control ( P = 0.006). There was no difference between the mean modified ICRS scores of the PRP- and the PRP + HA-treated grafts ( P = 0.445). Conclusion PRP may decrease graft degradation and improve chondral integration in an animal model. In this model, the addition of HA was not synergistic for the parameters assessed. LEVEL OF EVIDENCE: Basic science, Level V. CLINICAL RELEVANCE: PRP can be used as an adjunct to AOT, which may decrease graft degeneration and improve clinical outcomes. HA may not influence AOT.

The comparison of the effects of a novel hydrogel compound and traditional hyaluronate following micro-fracture procedure in a rat full-thickness chondral defect model.

PURPOSE: The aim of this experimental study was to investigate the impact of HA-CS-NAG compound (hyaluronate, sodium chondroitin sulfate, N-acetyl-d-glucosamine) on the quality of repair tissue after micro-fracture and to compare it with HA (hyaluronat), in a rat full-thickness chondral defect model. METHODS: Full-thickness chondral defects were created in a non-weight bearing area by using a handle 2.7-mm drill bit, in the right knees of 33 Sprague-Dawley rats. Each specimen then underwent micro-fracture using a needle. Two weeks after surgery, 3 groups were randomly formed among the rats (n = 33). In Group 1, 0.2 mL of sterile saline solution (0.9%) was injected. In Group 2, 0.2 mL HA with a mean molecular weight of 1.2 Mda was injected. In Group 3, 0.2 mL of HA-CS-NAG compound (hyaluronate, sodium chondroitin sulfate, N-acetyl-d-glucosamine) was injected. The injections were applied on the 14th, the 21st and the 28th postoperative days. All rats were sacrificed on the 42nd postoperative day. Histological analysis of the repair tissue was performed for each specimen by two blinded observers using Wakitani scoring system. RESULTS: There was significantly improved repair tissue in both Group 3 and Group 2 when compared with Group 1. Group 3 showed statistically significant improvement in terms of 'cell morphology' and 'integration of donor with host' when compared to Group 2 (p < 0.001). CONCLUSION: Intra-articular injection of HA-CS-NAG compound after micro-fracture results in significantly improved repair tissue in rats' chondral defects when compared to HA regarding the donor integration and cell morphology.

Anti-adhesive effect of solid mixture of sodium hyaluronate/carboxymethylcellulose in murine nasal cavities.

The purpose of the study was to evaluate the effect of a solid mixture of sodium hyaluronate and carboxymethylcellulose (S-HA/CMC) for the prevention of adhesions after iatrogenic mucosal injury in murine nasal cavities. We introduced iatrogenic adhesions into the bilateral nasal cavities of 20 male Sprague-Dawley rats. S-HA/CMC was applied to the left nasal cavity, while no packing was placed in the right nasal cavity as a control. At 1, 2, and 4 weeks post-procedure, we examined the number of adhesions, the ratio of the longest cross-sectional length of adhesion to septal cartilage length (RAC), and the degree of fibrosis. S-HA/CMC significantly reduced the number of adhesions when compared to the control group in total (p = 0.031), but not at each individual time point. The S-HA/CMC group showed significantly shorter RAC than the control group in total (p = 0.044), but not at each individual time point. The total fibrosis score was less severe in the S-HA/CMC group than in the control group (p < 0.001), with a significant difference between the two groups at the second week (p = 0.001). Therefore, in an animal model, S-HA/CMC can prevent post-injury mucosal adhesions suggesting a potential for clinical applications in endoscopic sinus surgery. Further clinical trials are needed to determine the safety and efficacy of S-HA/CMC as nasal packing after endoscopic sinus surgery.

High molecular weight hyaluronic acid regulates MMP13 expression in chondrocytes via DUSP10/MKP5.

To determine the effect of high molecular weight hyaluronic acid (HA) on matrix metalloproteinase 13 (MMP13) expression induced by tumor necrosis factor α (TNF-α) in chondrocytes. Human chondrocytic C28/I2 cells were incubated with TNF-α and HA. In some experiments, the cells were pre-incubated with a CD44 function-blocking monoclonal antibody (CD44 mAb) prior to addition of TNF-α and HA. The expression of MMP13 was determined by real-time reverse-transcription polymerase chain reaction (RT-PCR) and an enzyme linked immunosorbent assay, while the phosphorylation of signaling molecules was measured by western blot analysis. The transcriptional activity of activator protein 1 (AP-1) was analyzed by a reporter assay. To further clarify the molecular mechanisms of HA in MMP13 regulation, the expression level of dual-specificity protein phosphatase 10 (DUSP10)/mitogen-activated protein kinases phosphatase 5 (MKP5) in HA-treated chondrocytes was assessed by real-time RT-PCR, western blotting, and immunofluorescence microscopy. HA decreased MMP13 mRNA and protein expression induced by TNF-α. Blockage of HA-CD44 binding by CD44 mAb suppressed HA-mediated inhibition of MMP13. HA inhibited transient phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-jun NH2 -terminal kinase (JNK) induced by TNF-α. Reporter assay findings also revealed that pre-treatment with HA inhibited the transcriptional activity of AP-1 mediated by TNF-α. Moreover, HA induced the expression of DUSP10/MKP5, a negative regulator of p38 MAPK and JNK pathways. These results indicate that HA-CD44 interactions downregulate TNF-α-induced MMP13 expression via regulation of DUSP10/MKP5, suggesting that HA plays an important role as a regulatory factor in cartilage degradation. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:331-339, 2017.