Novel Hydrogel Adjuvant of Chinese Medicine External Preparations for Accelerated Healing of Deep Soft Tissue Injuries.

Traditional Chinese medicine external prescriptions have displayed excellent clinical effects for treating deep soft tissue injuries. However, the effects cannot be fully utilized due to the limitations of their dosage forms and usage methods. It is still a challenge to develop a satisfactory adjuvant of traditional Chinese medicine external prescriptions. Herein, a hydrogel adjuvant was prepared based on gallic acid coupled ε-poly-l-lysine and partially oxidized hyaluronic acid. The resulting adjuvant shows great physicochemical properties, low hemolysis rate (still much less than 5% at 5 mg/mL), excellent antibacterial ability (about 95% at 2 mg/mL), strong antioxidant ability (1.687 ± 0.085 mmol FeSO4/(g hydrogel) at 1 mg/mL), as well as outstanding biocompatibility. A clinically used Chinese medicine external preparation was selected as an example to investigate the effectiveness of the adjuvant in treating deep soft tissue injuries. The results show that the prescription can be evenly dispersed in the adjuvant. Moreover, the introduction of the prescription has not significantly changed these advanced properties of the adjuvant. Importantly, the hydrogel adjuvant significantly improves the effectiveness of the prescription in treating deep soft tissue injuries. This work offers an alternative approach to the development of a new-type adjuvant of Chinese medicine external preparations and also provides a new strategy for the combination of traditional Chinese medicine and hydrogel to treat clinical diseases.

Yeast-Derived Nucleotides Enhance Fibroblast Migration and Proliferation and Provide Clinical Benefits in Atopic Dermatitis.

Nucleotides, glycosaminoglycans, and omega-3 essential fatty acids (O3s) could be used for improving skin health, although their modes of action, alone or in combination, are not yet fully understood. To gain some insight into these mechanisms, we performed two in vitro tests and one in vivo pilot trial. The effects on human dermal fibroblast proliferation and migration were evaluated with the following compounds and combinations: 0.156 mg/mL O3s, 0.0017 mg/mL hyaluronic acid (HA), 0.0004 mg/mL dermatan sulfate (DS), 0.0818 mg/mL nucleotides, and [O3s + HA + DS] and [O3s + HA + DS + nucleotides] at the same concentrations. In both in vitro assays, adding nucleotides to [O3s + HA + DS] provided significant improvements. The resulting combination [O3s + HA + DS + nucleotides] was then tested in vivo in dogs with atopic dermatitis by oral administration of a supplement providing a daily amount of 40 mg/kg nucleotides, 0.9 mg/kg HA, 0.18 mg/kg DS, 53.4 mg/kg EPA, and 7.6 mg/kg DHA. After 30 days, the pruritus visual analog scale (pVAS) score was significantly reduced, and no adverse effects were observed. In conclusion, the combination of nucleotides plus glycosaminoglycans and O3s could serve as a useful therapeutic alternative in skin health applications.

Engineering a hyaluronic acid-encapsulated tumor-targeted nanoplatform with sensitized chemotherapy and a photothermal effect for enhancing tumor therapy.

Chemotherapy remains one of the most widely used cancer treatment modalities in clinical practice. However, the characteristic microenvironment of solid tumors severely limits the anticancer efficacy of chemotherapy. In addition, a single treatment modality or one death pathway reduces the antitumor outcome. Herein, tumor-targeting O2 self-supplied nanomodules (CuS@DOX/CaO2-HA) are proposed that not only alleviate tumor microenvironmental hypoxia to promote the accumulation of chemotherapeutic drugs in tumors but also exert photothermal effects to boost drug release, penetration and combination therapy. CuS@DOX/CaO2-HA consists of copper sulfide (CuS)-loaded calcium peroxide (CaO2) and doxorubicin (DOX), and its surface is further modified with HA. CuS@DOX/CaO2-HA underwent photothermal treatment to release DOX and CaO2. Hyperthermia accelerates drug penetration to enhance chemotherapeutic efficacy. The exposed CaO2 reacts with water to produce Ca2+, H2O2 and O2, which sensitizes cells to chemotherapy through mitochondrial damage caused by calcium overload and a reduction in drug efflux via the alleviation of hypoxia. Moreover, under near infrared (NIR) irradiation, CuS@DOX/CaO2-HA initiates a pyroptosis-like cell death process in addition to apoptosis. In vivo, CuS@DOX/CaO2-HA demonstrated high-performance antitumor effects. This study provides a new strategy for synergistic enhancement of chemotherapy in hypoxic tumor therapy via combination therapy and multiple death pathways.

Efficacy and safety of extracorporeal shock wave therapy combined with sodium hyaluronate in treatment of knee osteoarthritis: a systematic review and Meta-analysis.

OBJECTIVE: To assess the efficacy and safety of extracorporeal shockwave therapy (ESWT) combined with sodium hyaluronate (HA) for the treatment of knee osteoarthritis (KOA). METHODS: PubMed, Embase, the Cochrane Library, Web of Science, China National Knowledge Infrastructure, Wanfang database, China Science and Technology Journal Database, and SinoMed were searched from inception to July 2020. The quality of the randomized controlled trials was evaluated independently by two reviewers according to the criteria in the Cochrane Collaboration for Systematic Reviews. The identified articles were then screened individually using EndnoteX9 for eligibility in this Meta-analysis. The heterogeneity among the articles was evaluated using I2. RESULTS: A total of 17 studies, comprising 2000 individuals, were included in this Meta-analysis. The results showed that a significant improvement was observed in knee pain and function based on the clinical efficacy of ESWT combined with HA. Statistical analysis of clinical efficacy showed that [relative risk (RR) = 1.21, 95% confidence interval (CI) (1.12, 1.30), P < 0.01]. Statistical analysis of visual analog scale showed that [standardized mean difference (SMD) = －2.84, 95%CI (－4.01, －1.66), P < 0.01]. Western Ontario and McMaster University osteoarthritis index statistical analysis showed that [SMD = －1.57, 95% CI (－2.52, －0.61), P < 0.01]. Lysholm score statistical analysis showed that [SMD = 1.71, 95% CI (0.98, 2.44), P < 0.01]. In addition, only minor side effects, such as redness and swelling of the skin, were observed. CONCLUSIONS: Medium to low quality evidence showed that ESWT combined with HA offers an inexpensive, well-tolerated, safe, and effective method to improve pain and functionality in patients with KOA. However, tightly controlled, randomized, large multicenter trials are warranted to validate the current findings.

Safety and efficacy of a class II medical device based on highly purified and standardized plant extracts in the management of post-menopausal patients with vulvar and vaginal atrophy: a single-center prospective observational study.

BACKGROUND: Despite the gold standard treatment for genitourinary syndrome of menopause (GSM) is based on the use of local or systemic estrogen-containing products, the typical long-term side effects of hormonal treatments and, most importantly, the contraindications in patients with history of breast and endometrial neoplasms do limit in some extent its use. As hyaluronic acid and some highly purified botanicals have clearly demonstrated their anti-inflammatory and mucosa-protecting properties, we have tested, in women with GSM, a class II vaginal medical device containing hyaluronate gel and a mucoadhesive active enriched with purified alkylamides from Zanthoxylum bungeanum, triterpenes from Centella asiatica and high molecular weight polysaccharides from Tamarindus indica. METHODS: Our single-center, open-label, prospective and observational study was conducted on 50 menopausal women enrolled at the Department of Maternal-Fetal Medicine at Umberto I Polyclinic Hospital in Rome, Italy. Gel administration lasted 150 days and was performed daily for the first 12 days and every 48 hours for the remaining 138 days. Clinical evaluations were performed at baseline and after 12, 57 and 150 days. Besides product safety, main outcomes of our study were: 1) vaginal health (by Vaginal Health Index score [VHI]); 2) sexual quality of life (by Female Sexual Distress Scale [FSDS]); and 3) percentage of women declaring regular sexual activity. RESULTS: The product was safe with no specific adverse events reported. It significantly improved VHI (about 5% after 57 days and 8% after 150 days), FSDS (about 7% after 57 days and 10% after 150 days), and sexual activity (about 20% after 150 days). It also reduced dryness, dyspareunia, burning, itching, and dysuria incidence, respectively by about 18%, 14%, 14%, 27% and 11% after 150 days. CONCLUSIONS: In women with GSM, the intravaginal administration of a hyaluronate-based gel enriched with purified botanical actives endowed with anti-inflammatory and mucosal-protecting properties, reduced painful sensation during sexual acts and increased regular sexual activity.

Fabrication of targeted and pH responsive lysozyme-hyaluronan nanoparticles for 5-fluorouracil and curcumin co-delivery in colorectal cancer therapy.

Green nanotechnology is considered a promising method to construct functional materials with significant anticancer activity, while overcoming the shortcomings of traditional synthesis process complexity and high organic solvents consumption. Thus, in this study, we report for the first time the rational design and green synthesis of functionalized 5-fluorouracil and curcumin co-loaded lysozyme-hyaluronan composite colloidal nanoparticles (5-Fu/Cur@LHNPs) for better targeted colorectal cancer therapy with minimized side effects. The functionalized 5-Fu/Cur@LHNPs exhibit stabilized particle size (126.1 nm) with excellent homogeneity (PDI = 0.1), favorable colloidal stabilities, and excellent re-dispersibility. In vitro cell experiments illustrate that the cellular uptake of 5-Fu/Cur@LHNPs was significantly improved and further promoted a higher apoptosis ratio of HCT-116 cells. Compared with the control group, the 5-Fu/Cur@LHNPs formulation group achieved effective inhibition (60.1 %) of colorectal tumor growth. The alcohol-free self-assembly method to construct 5-Fu/Cur@LHNPs is simple and safe for a translational chemotherapy drug, also to promote more robust delivery systems for treating colorectal cancer.

Retrospective Study of Intertarsal Joint Inflammation in Avian Species From a Zoological Institution.

A retrospective cross-sectional study was performed to measure the prevalence of avian intertarsal inflammation over a 5-year period, identify risk factors, and discuss treatment options. The authors hypothesized that: 1) long-legged birds would be more affected, 2) participation in a bird show would be a significant risk factor, and 3) young animals would be more frequently affected. Thirty-five clinical cases from 9 avian orders were included in the study. Statistical analysis indicated that the orders Ciconiiformes (9/150; 6%, 95% confidence interval [CI]: 3.2-11), Gruiformes (4/132; 3%, 95% CI: 1.2-7.5), and Pelecaniformes (7/152; 2.8%, 95% CI: 1.4-5.6) were significantly more affected than other orders (P < 0.01). Similarly, long-legged birds (21/35) had 9.8 times greater chance (P < 0.001, 95% CI: 4.7-21) of developing the condition compared with other birds. Participation in a free-flight show (22/35) was a significant risk factor (P < 0.001; odds ratio: 7.0, 95% CI: 3.3-15). Mean age at onset of clinical signs was 5.7 years, and being < 2 years-of-age during the study period was not a significant predictor of disease (P = 0.054). The tibial cartilage, a fragile fibrocartilaginous structure, was frequently affected (34%, 12/35). Treatment protocols included anti-inflammatory drugs, analgesic drugs, or both (94%, 33/35), low-level laser therapy (54%, 19/35), joint immobilization (34%, 12/35), intra-articular corticoid injections (20%, 7/35), surgical stabilization (17%, 6/35), physiotherapy (9%, 3/35), intra-articular hyaluronic acid (6%, 2/35) or platelet-rich plasma (3%, 1/35) injections, and chiropractic care (3%, 1/35). Overall recovery rate was 49% (17/35), and the condition was associated with a poor prognosis in chronic cases.

Efficacy of hyaluronic acid gel and photobiomodulation therapy on wound healing after surgical gingivectomy: a randomized controlled clinical trial.

BACKGROUND: Surgical gingivectomy can be considered the gold standard treatment for gingival enlargement. The healing of wound site after gingivectomy occurs slowly by secondary intention. To accelerate the wound healing process, several studies have been conducted evaluating the effect of various treatment modalities. Photobiomodulation therapy (PBMT) was proposed to provide minimally invasive and painless treatment as well as to decrease discomfort of the patient following the surgical process. Another factor that is expected to improve the healing after surgery is topical application of chemotherapeutic agents such as Hyaluronic acid (HA). This study aims to assess the effect of topically applied HA gel after PBMT on the healing of wound site after surgical gingivectomy. METHODS: This randomized controlled clinical trial included twenty-six surgical gingivectomy wound sites, equally divided into two groups, Group-I (test group): the surgical sites after gingivectomy were irradiated with a diode laser (980 nm, 0.2 W) then covered by 2% HA gel loaded in a special custom-made soft transparent tissue guard appliance for each patient. Group II (control group): the surgical sites were irradiated with a diode laser (980 nm, 0.2 W) only. Wound healing was assessed subjectively by Landry healing index on the 3rd, 7th, 14th and 21st days after surgery, and pain perception was assessed by the patients using visual analog scale (VAS) throughout the 21 days of the follow up period. Comparisons between the two study groups were performed using Mann-Whitney U test, while comparisons between different time points were performed using Friedman test. Significance was inferred at p value < 0.05. RESULTS: By the end of the follow-up period, surgical sites of the test group showed excellent healing compared to the control group. There were no significant differences in VAS scores between both groups (p > 0.05). CONCLUSIONS: Application of 2% HA gel as an adjunctive to PBMT was found to have significant clinical effects and higher power of repair among test group when compared to that achieved by PBMT alone in control group. TRIAL REGISTRATION: This study was retrospectively registered on ClinicalTrials.gov and first posted on 28th of March 2023 with an identifier number: NCT05787912.

Cobalt-doped hollow polydopamine for oxygen generation and GSH consumption enhanced chemo-PTT combined cancer therapy.

Nanotechnology has revolutionized the field of therapeutics by introducing a plethora of nanomaterials capable of enhancing traditional drug efficacy or paving the way for innovative treatment methods. Within this domain, we propose a novel Cobalt-doped hollow polydopamine nanosphere system. This system, incorporating Doxorubicin loading and hyaluronic acid (HA) surface coating (CoHPDA@DOX-HA), is designed for combined tumor therapy. The overarching aim is to diminish the administration dosage, mitigate the cytotoxic side effects of chemotherapy drugs, augment chemosensitivity within neoplastic tissues, and attain superior results in tumor treatment via combined therapeutic strategies. The targeted molecule, hyaluronic acid (HA), amplifies the biocompatibility of CoHPDA@DOX-HA throughout circulation and fosters endocytosis of the nanoparticle system within cancer cells. This nanosphere system possesses pH sensitivity properties, allowing for a meticulous drug release within the acidic microenvironment of tumor cells. Concurrently, Polydopamine (PDA) facilitates proficient photothermal therapy upon exposure to 808 nm laser irradiation. This process further amplifies the Glutathione (GSH) depletion, and when coupled with the oxygen production capabilities of the Cobalt-doped hollow PDA, significantly enhances the chemo-photothermal therapeutic efficiency. Findings from the treatment of tumor-bearing mice substantiate that even at dosages equivalent to a singular DOX administration, the CoHPDA@DOX-HA can provide efficacious synergistic therapy. Therefore, it is anticipated that multifunctional nanomaterials with Photoacoustic Tomography (PAT) imaging capabilities, targeted delivery, and a controlled collaborative therapeutic framework may serve as promising alternatives for accurate diagnostics and efficacious treatment strategies.

Efficacy of acupotomy combined with sodium hyaluronate versus sodium hyaluronate alone in the treatment of knee osteoarthritis: A meta-analysis.

BACKGROUND: The efficacy of acupotomy combined with hyaluronic sodium acid in the treatment of knee osteoarthritis (KOA) is unclear. Therefore, this meta-analysis aims to evaluate the efficacy of acupotomy combined with hyaluronic sodium acid compared with hyaluronic sodium acid alone in the treatment of KOA. METHODS: Studies from 8 Online databases were searched on KOA treatment using acupotomy combined with sodium hyaluronate until May 2022. The primary outcome indicator was clinical effectiveness, and the secondary outcome indicators included the visual analogue scale scores and Lysholm scores. We calculated the weighted mean difference (WMD) or relative risk for all relevant outcomes. RESULTS: Nine studies were identified, involving 644 cases. The results showed that acupotomy combined with intra-articular sodium hyaluronate injection for KOA was superior to sodium hyaluronate injection alone in terms of clinical effectiveness (relative risk = 1.17, 95% confidence interval [CI]: 1.09-1.25, P < .001) and visual analogue scale (WMD = -2.1, 95% CI: -2.25 to 1.95, P < .001), Lysholm score (WMD = 13.83, 95% CI: 3.47-24.19, P = .009). CONCLUSION: Acupotomy combined with intra-articular sodium hyaluronate injection for KOA is superior to sodium hyaluronate injection alone. Limited by the number and quality of included studies, this conclusion still needs to be verified by more high-quality Research. INPLASY REGISTRATION NUMBER: INPLASY202350029.

Nonestrogen Therapies for Treatment of Genitourinary Syndrome of Menopause: A Systematic Review.

OBJECTIVE: To systematically review the literature and provide clinical practice guidelines regarding various nonestrogen therapies for treatment of genitourinary syndrome of menopause (GSM). DATA SOURCES: MEDLINE, EMBASE, ClinicalTrials.gov , and Cochrane databases were searched from inception to July 2021. We included comparative and noncomparative studies. Interventions and comparators were limited to seven products that are commercially available and currently in use (vaginal dehydroepiandrosterone [DHEA], ospemifene, laser or energy-based therapies, polycarbophil-based vaginal moisturizer, Tibolone, vaginal hyaluronic acid, testosterone). Topical estrogen, placebo, other nonestrogen products, as well as no treatment were considered as comparators. METHODS OF STUDY SELECTION: We double-screened 9,131 abstracts and identified 136 studies that met our criteria. Studies were assessed for quality and strength of evidence by the systematic review group. TABULATION, INTEGRATION, AND RESULTS: Information regarding the participants, details on the intervention and comparator and outcomes were extracted from the eligible studies. Alternative therapies were similar or superior to estrogen or placebo with minimal increase in adverse events. Dose response was noted with vaginal DHEA and testosterone. Vaginal DHEA, ospemifene, erbium and fractional carbon dioxide (CO 2 ) laser, polycarbophil-based vaginal moisturizer, tibolone, hyaluronic acid, and testosterone all improved subjective and objective signs of atrophy. Vaginal DHEA, ospemifene, tibolone, fractional CO 2 laser, polycarbophil-based vaginal moisturizer, and testosterone improved sexual function. CONCLUSION: Most nonestrogen therapies are effective treatments for the various symptoms of GSM. There are insufficient data to compare nonestrogen options to each other.

Effectiveness of rb-bFGF Eye Drops for Post-Cataract Surgery Dry Eye and Observation of Changes in Tear Secretion and Corneal Damage in Patients.

Objective: Dry eye syndrome after cataract surgery is a common complication that may affect the patient's visual comfort and quality of life. Because the surgery may affect the secretion and quality of tears in the eye, resulting in dry and uncomfortable eyes.This study aimed to investigate the therapeutic effects of recombinant bovine basic fibroblast growth factor (rb-bFGF) eye drops on dry eye syndrome after cataract surgery and to analyze its impact on tear secretion and corneal injury. Methods: This is a retrospective study. A total of 126 patients (126 eyes) with dry eye syndrome after cataract surgery were treated between January 2021 and October 2022. patients were randomly divided into a study group (64 patients, 64 eyes) and a control group (62 patients, 62 eyes). Both groups were treated with sodium hyaluronate eye drops, while the study group received rb-bFGF eye drops for four weeks in addition to the sodium hyaluronate eye drops. The clinical efficacy, results of tear secretion test (SIT), tear film break-up time (BUT), corneal fluorescein staining, corneal topography examination, oxidative stress indicators, ocular surface disease index (OSDI) score, and drug adverse reactions were compared between the two groups. Results: The study group exhibited a significantly higher total effective treatment rate (96.88%) compared to the control group (85.48%), suggesting the enhanced efficacy of rb-bFGF eye drops. Moreover, the study group demonstrated extended tear secretion length and tear film break-up time, indicating improved tear film stability and ocular surface health. Additionally, the study group showed reduced corneal fluorescein staining score and improved corneal surface regularity index, indicative of enhanced corneal integrity and smoothness. Notably, tear superoxide dismutase levels were elevated, while lipid peroxide levels were lowered in the study group, underscoring the potential antioxidative effects of rb-bFGF. The study group also exhibited a lower OSDI score, suggesting reduced ocular discomfort and improved quality of life. Although the study group had a slightly higher incidence of adverse reactions (9.38%) compared to the control group (8.06%), the difference was not statistically significant. Particularly significant is the statistical significance highlighting the heightened total effective treatment rate in the study group, indicating the potential of rb-bFGF eye drops in promoting favorable therapeutic outcomes. Conclusion: rb-bFGF eye drops are safe and effective in treating dry eye syndrome after cataract surgery. They can help regulate tear secretion, repair corneal damage, and improve dry eye symptoms. Despite the retrospective design and relatively small sample size of this study, further randomized controlled trials and larger sample size may be needed to verify the robustness of the results, but this study is important for guiding the treatment strategy and optimizing patient care for dry eye after cataract surgery.

Joint and Soft Tissue Injections.

Joint and soft tissue injections can be divided into two primary categories: diagnostic and therapeutic. Diagnostic injections facilitate a diagnosis by using a local anesthetic to identify the site of pain or through fluid aspiration for analysis. Therapeutic injections are categorized by the type of injectate and include corticosteroids, hyaluronic acid, dextrose prolotherapy, and platelet-rich plasma. Diagnostic and therapeutic injections are most accurate under direct visualization. Corticosteroid injections help treat adhesive capsulitis and tenosynovitis but are not recommended for intratendinous injections. Hyaluronic acid has limited benefits for knee osteoarthritis. Dextrose prolotherapy injections treat tendinopathy and degenerative joint pain. Platelet-rich plasma injections effectively treat common extensor tendinopathy and knee arthritis; however, the evidence does not support its use for other soft tissue injuries. Preparation for injections includes patient education, consent, proper patient positioning, and obtaining the necessary supplies. Local infection, fractures, and allergy to injection substrates are contraindications to joint and soft tissue injections. Potential complications include pain, swelling, and redness. Corticosteroid injections into soft tissue may cause atrophy and depigmentation, and repeated injections can cause cartilage and tendon degeneration. Optimizing conservative, noninjection treatments, such as oral and topical analgesics, activity modification, or rehabilitation, is also important.

Ozone Therapy versus Hyaluronic Acid Injections for Pain Relief in Patients with Knee Osteoarthritis: Preliminary Findings on Molecular and Clinical Outcomes from a Randomized Controlled Trial.

Ozone therapy (OT) is used for the treatment of multiple musculoskeletal disorders. In recent years, there has been a growing interest in its use for the treatment of osteoarthritis (OA). The aim of this double-blind randomized controlled trial was to evaluate the efficacy of OT compared with hyaluronic acid (HA) injections for pain relief in patients with knee OA. Patients with knee OA for at least three months were included and randomly assigned to receive three intra-articular injections of ozone or HA (once a week). Patients were assessed at baseline and at 1, 3, and 6 months after the injections for pain, stiffness, and function using the WOMAC LK 3.1, the NRS, and the KOOS questionnaire. Out of 55 patients assessed for eligibility, 52 participants were admitted to the study and randomly assigned into the 2 groups of treatment. During the study, eight patients dropped out. Thus, a total of 44 patients, reached the endpoint of the study at 6 months. Both Group A and B consisted of 22 patients. At 1-month follow-up after injections, both treatment groups improved statistically significantly from baseline in all outcomes measured. At 3 months, improvements remained similarly consistent for Group A and Group B. At 6-month follow-up, the outcomes were comparable between the 2 groups, showing only a worsening trend in pain. No significant differences were found between the two groups in pain scores. Both therapies have proven to be safe, with the few recorded adverse events being mild and self-limiting. OT has demonstrated similar results to HA injections, proving to be a safe approach with significant effects on pain control in patients affected by knee OA. Due to its anti-inflammatory and analgesic effects, ozone might be considered as a potential treatment for OA.

Repairing Effect and Mechanism of Hydroxysafflor Yellow A and Sodium Hyaluronate for Knee Osteoarthritis in Rabbits.

Context: KOA characterized by recurrent joint pain and progressive joint dysfunction. Is the present clinical common chronic progressive degenerative osteoarthropathy, how long the disease is difficult to cure and easy to relapse. Exploring new therapeutic approaches and mechanisms is important for the treatment of KOA. One of the main applications for sodium hyaluronate (SH) in the medical field is treatment of osteoarthritis. However, the effects of SH alone in the treatment of KOA are limited. Hydroxysafflor yellow A (HSYA) may have therapeutic effects for KOA. Objective: The study intended to investigate the therapeutic effects and possible mechanisms of action HSYA+SH for cartilage tissue of rabbits with KOA and to provide a theoretical basis for the treatment of KOA. Design: The research team performed an animal study. Setting: The study that took place at Liaoning Jijia Biotechnology, Shenyang, Liaoning, China. Animals: The animals were 30 healthy, adult, New Zealand white rabbits, weighing 2-3 kg. Intervention: The research team randomly divided the rabbits into three groups, with 10 rabbits in each group: (1) a control group, for which the research team didn't induce KOA and provided no treatment; (2) the HSYA+SH group, the intervention group, for which the research team induced KOA and injected the rabbits with the HSYA+SH treatment; and (3) the KOA group, for which the research team induced KOA and injected the rabbits with saline. Outcome Measures: The research team: (1) observed the morphological changes in the cartilage tissue using hematoxylin-eosin (HE) staining; (2) measured levels of serum inflammatory factors, including tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1ß), interferon gamma (IFN-γ), IL-6, and IL-17 using an enzyme-linked immunosorbent assay (ELISA); (3) measured cartilage-cell apoptosis using "terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling" (TUNEL); and (4) used Western Blot to detect the expression of proteins related to the "neurogenic locus notch homolog protein 1" (Notch1) signaling pathway. Results: Compared with the control group, morphological changes had occurred to the cartilage tissue in the KOA group. Compared with the control group, that group's level of apoptosis was higher, the levels of serum inflammatory factors were significantly higher (P < .05), and the protein expression related to the Notch1 signaling pathway was also significantly higher (P < .05). The morphology of the cartilage tissue in the HSYA+SH was better than that of the KOA group but not as good as that of the control group. Compared with the KOA group, the HSYA+SH group's level of apoptosis was lower, the levels of serum inflammatory factors were significantly lower (P < .05), and the protein expression related to the Notch1 signaling pathway was also significantly lower (P < .05). Conclusions: HSYA+SH can reduce the cellular apoptosis in the cartilage tissue of rabbits with KOA, downregulate the levels of inflammatory factors, and protect against KOA-induced cartilage tissue injury, and the mechanism may be related to the regulation of the Notch1 signaling pathway.

Conjugate treatment with high concentration normobaric oxygen and hyaluronic acid for vaginal atrophy: a prospective study.

OBJECTIVE: Vulvovaginal atrophy is a condition closely related to low circulating estrogen levels, with post-menopause being the main cause. However, patients of childbearing age may also present with these symptoms due to treatments that reduce estrogen production. Local estrogen therapy is the causal treatment of local symptoms, but it is not always accepted and is often abandoned by patients. In recent years, alternative therapies have been proposed: fractional CO2 laser or the conjugate treatment with normobaric oxygen and hyaluronic acid, the latter being the subject of this study. The study aimed to evaluate the effectiveness of conjugate topical treatment with normobaric oxygen and hyaluronic acid. PATIENTS AND METHODS: 50 patients were evaluated and treated with 5 applications of 15 minutes each, every 15 days, with Caressflow®. All patients presented at least one of the symptoms related to vulvovaginal atrophy: dryness, burning, and dyspareunia. In all cases, vulvoscopy, colposcopy, and cervicovaginal cytology were performed. The patients were interviewed with an analogic scale (VAS) concerning the severity of symptoms before and after the treatment. Colposcopy and PAP-smear were assessed by mean of Vaginal Health Index Score (VHI) at baseline and at the end of the treatment. RESULTS: All patients completed the treatment scheme and presented with a significant improvement in subjective symptoms. The colposcopy and PAP-smear performed 10 days after the end of the last treatment showed a significant improvement in the appearance and elasticity of the vaginal epithelium and the cytological picture, which showed, in the sample taken after treatment, hyaluronic acid vesicles within the cell cytoplasm. CONCLUSIONS: This study corroborates the data presented in the latest published papers on the effectiveness of treatment with normobaric O2 and hyaluronic acid on vaginal atrophy. Efficacy has been confirmed both in terms of subjective symptoms reported by the patients and objective improvement at colposcopy and PAP-smear cytology.

Intra-Articular Injection of Botulinum Toxin for the Treatment of Knee Osteoarthritis: A Systematic Review of Randomized Controlled Trials.

The purpose of the present paper was to review the available evidence on intra-articular botulinum toxin (BTX) injection in the treatment of knee osteoarthritis and to compare it to other conservative treatment options. A systematic review of the literature was performed on the PubMed, Scopus, Cochrane Library, Web of Science, Pedro and Research Gate databases with the following inclusion criteria: (1) randomized controlled trials (RCTs), (2) written in the English language, and (3) published on indexed journals in the last 20 years (2001-2021) dealing with the use of BTX intra-articular injection for the treatment of knee OA. The risk of bias was assessed using the Cochrane Risk of Bias tool for RCTs. Nine studies involving 811 patients in total were included. Patients in the control groups received different treatments: conventional physiotherapy, hyaluronic acid injection or prolotherapy or a combination thereof in 5 studies, steroid infiltrative therapy (triamcinolone) in 1 study, placebo in 2, and local anesthetic treatment in 1 study. Looking at the quality of the available literature, two of the included studies reached "Good quality" standard, three were ranked as "Fair", and the rest were considered "Poor". No major complications or serious adverse events were reported following intra-articular BTX, which provided encouraging pain relief, improved motor function, and quality of life. Based on the available data, no clear indication emerged from the comparison of BTX with other established treatments for knee OA. The analysis of the available RCTs on BTX intra-articular injection for the treatment of knee OA revealed modest methodological quality. However, based on the data retrieved, botulinum toxin has been proven to provide good short-term outcomes, especially in patients with pain sensitization, by modulating neurotransmitter release, peripheral nociceptive transduction, and acting on the control of chronic pain from central sensitization.

The Role of Hyaluronic Acid for Soft Tissue Indications: A Systematic Review and Meta-Analysis.

CONTEXT: Soft tissue injuries are often treated with injectables such as corticosteroids and platelet-rich plasma (PRP) to reduce inflammation and promote healing. There is increasing evidence examining the use of hyaluronic acid (HA) for the management of soft tissue injuries. OBJECTIVE: To evaluate the treatment effect and role of HA for available soft tissue indications. DATA SOURCES: A search of PubMed, MEDLINE, EMBASE, and CENTRAL from the inception date of each database through February 24, 2021, was conducted for all randomized controlled trials (RCTs) involving the use of HA for soft tissue indications. Two reviewers independently screened articles for eligibility and extracted data from included studies for analysis. We assessed risk of bias for all included studies and pooled outcomes using a fixed-effects model. Outcomes (ie, function and pain relief) were categorized to short-term (<6 weeks, 6-12 weeks) and mid-term (>12 weeks) data. We present effect estimates as mean differences (MDs) and standardized mean differences (SMDs) and present the estimate of effect of HA for available indications in relation to available comparators. STUDY DESIGN: Meta-analysis of RCTs. LEVEL OF EVIDENCE: Level 1. RESULTS: Of the 6930 articles screened, 19 RCTs (n = 1629 patients) were eligible and included in this review. HA was evaluated across a variety of soft tissue indications including rotator cuff disease, elbow pain, ankle sprains, Achilles tendinopathy, patellar tendinopathy, and trigger finger. Of the 19 RCTs, 11 were placebo-controlled and 9 used active comparators (PRP, cortisone, prolotherapy, or extracorporeal shockwave therapy). The pooled treatment effect of HA across most soft indications against placebo and active comparators demonstrated benefit in short-term pain <6 weeks (MD visual analogue scale [VAS] 2.48, 95% CI 2.31-2.65) and 6 to 12 weeks (MD VAS 2.03, 95% CI 1.86-2.20). Mid-term pain relief also favored HA over comparators across indications >12 weeks from administration (MD VAS 3.57, 95% CI 3.35-3.78). High heterogeneity was present with rotator cuff (10 trials, I2 = 94%), and elbow tendinopathy (2 trials, I2 = 99%). We identified uncertain benefit for trigger finger (2 trials, I2 = 67%). Heterogeneity for ankle sprains, patellar tendinopathy and Achilles tendinopathy could not be assessed as they only had 1 trial each. CONCLUSION: This systematic review and meta-analysis support HA's efficacy in the treatment of a variety of soft tissue indications. Understanding the relative effects of HA to other injectable modalities requires additional, large trials.

EUROVISCO Good Practice Recommendations for a First Viscosupplementation in Patients with Knee Osteoarthritis.

RATIONALE: Viscosupplementation (VS) with hyaluronic acid is widely used in the management of knee osteoarthritis. There is no clear recommendation on the decision-making to achieve VS. DESIGN: Based on extensive research of the literature and expert opinion, the members of the EUROVISCO (European Viscosupplementation Consensus Group) task force were asked to give their degree of agreement with 60 issues, using a Delphi method. RESULTS: The expert panel achieved unanimous agreement in favor of the following statements: It is recommended to assess pain on a visual or 10-point numeric scale before considering VS. VS can be considered for patients with pain scores between 3 and 8. A standard x-ray must be obtained before the decision of VS. If the x-ray is normal, osteoarthritis must be confirmed by MRI or computed tomography (CT) arthrogram before considering VS. The aims of VS are relieving pain, improving function, and reducing non-steroidal anti-inflammatory drug (NSAID) consumption. The use of VS must not be considered for treating an osteoarthritis flare. VS can be envisaged as a first-line pharmacological treatment in patients having a contra-indication to NSAIDs or analgesics. VS can be considered in patients with contra-indications to arthroplasty. In the case of severe comorbidities (diabetes, hypertension, gastrointestinal disorders, renal failure), VS can avoid the use of potentially dangerous treatments. VS can be considered in patients receiving antiplatelet agents, vitamin K antagonists, and direct factor Xa or thrombin inhibitors. Five other statements obtained a high level of consensus. CONCLUSION: These recommendations, illustrated in a decision algorithm, have been established to help practitioners in the decision-making of knee VS.

Extracellular matrix degrading enzyme with stroma-targeting peptides enhance the penetration of liposomes into tumors.

Various anti-tumor nanomedicines have been developed based on the enhanced permeability and retention effect. However, the dense extracellular matrix (ECM) in tumors remains a major barrier for the delivery and accumulation of nanoparticles into tumors. While ECM-degrading enzymes, such as collagenase, hyaluronidase, and bromelain, have been used to facilitate the accumulation of nanoparticles, serious side effects arising from the current non-tumor-specific delivery methods limit their clinical applications. Here, we report targeted delivery of bromelain into tumor tissues through its covalent attachment to a hyaluronic acid (HA)-peptide conjugate with tumor ECM targeting ability. The ECM targeting peptide, collagen type IV-binding peptide (C4BP), was chosen from six candidate-peptides based on their ability to bind to frozen sections of triple-negative breast cancer, 4T1 tumor ex vivo. The HA- C4BP conjugate showed a significant increase in tumor accumulation in 4T1-bearing mice after intravenous administration compared to unmodified HA. We further demonstrated that the systemic administration of bromelain conjugated C4BP-HA (C4BP-HA-Bro) potentiates the anti-tumor efficacy of liposomal doxorubicin. C4BP-HA-Bro decreased the number and length of collagen fibers and improved the distribution of doxorubicin within the tumor. No infusion reaction was noted after delivery of C4BP-HA-Bro. C4BP-HA thus offers a potential for effective and safe delivery of bromelain for improved intratumoral delivery of therapeutics.