ヒアルロン酸の臨床用途に関する研究

ヒアルロン酸(HA)isalso known as vitreous acid. It was first isolated で1934 by Meyer とPalmer from のvitreous humorののbovine eye[1] . Hyaluronic酸is also found でa wide range のtissues でのhuman body, including the vitreous humor のthe human eye, umbilical cord とskで(Table 1), とis a component のthe extracellular matrix [2]. Hyaluronic acid, chemically known as (1,4)-O-β-Dglucuronide-(1,3)-2-acetamido-2-deoxy-β-Dglucose, is a high molecular weight straight-chaでglycan, a polymer formed by repeated alternation of alternating N-acetylglucosamine (GlcNAc) とglucuronide (GlcA) disaccharide units [3], とa wide range of molecular weights, とa formula ( C14H20NO11Na). C14H20NO11Na)n, the molecular weight of the disaccharide unit is 401.3 (Figure 1).

Due to the hydrogen bonding between the straight-chain L-monosaccharides, hyaluronic acid molecules are spatially rigid helical columns with a radius of 200 nm. Hyaluronic acid is strongly hydrophilic, とin aqueous solution, hyaluronic acid is about 1,000 times more hydrophilic than its own weight. In addition to hydrophilicity, hyaluronic acid solution has unique hydrodynamic properties, とits aqueous solution is a non-Newtonian fluid, therefore, it has good viscoelasticity and strain [4]. Currently, hyaluronic acid is widely used in biomaterials, drug-targeting agents, aesthetics, and the prevention of adhesions 後abdominal surgery [5].

1ヒアルロン酸の応用

1.1眼科疾患

As an acidic mucopolysaccharide, hyaluronic acid is widely distributed in the intercellular matrix of various tissues of the human body, and has important physiological functions such as maintaining the stability of cellular osmotic pressure, and enabling the 癒着of adjacent 細胞[6]. In addition, hyaluronic acid can regulate セルadhesion and motility, regulate セルdifferentiation and proliferation, and maintain normal biomechanical properties of tissues[7] . Hyaluronic acid is widely used in ophthalmic surgery, mainly due to its viscous, pseudoplastic, elastic, adhesive and coating properties, which make it a viscoelastic liner, intra-tissue detachment, viscous obstruction, viscous haemostasis, viscoelastic cushioning, and elastic fixation [8].

ドライアイ病は一般的な眼科疾患で、主に眼腺細胞の機能障害が原因で、さまざまな種類の結膜炎があります。ヒアルロン酸には親水基が豊富に含まれており、水分子と結合して親水性および潤滑剤として作用するため、ドライアイ症状をある程度緩和することができます。「ドライアイの臨床診断と治療に関する専門家のコンセンサス(2013)」[9]によると、ドライアイ治療の目的は軽度ドライアイ患者の眼症状を緩和し、重度ドライアイ患者の視覚機能を保護することです。ヒアルロン酸ナトリウム点眼液は、眼表面の炎症メディエーターをフラッシュして希釈し、涙液の浸透度を低下させ、眼表面上皮の治癒を促進し、眼表面のフィブロネクチンの分泌と沈着を促進します。ドライアイ患者106人を対象に行った研究で、yu huiling[10]がそれを発見した0.3% sodium hyaluronate eye drops alone were effective in 81.8% of cases of dry eye disease, while the combination of sodium hyaluronate eye drops and pranoprofen eye drops was effective in 92.3% of cases.

120美容医学

Hyaluronic acid is often used as a moisturising ingredient in cosmetics, including hyaluronic acid moisturising and water-locking creams and moisturising and hydrating masks. ヒアルロン酸の50% exists in the human body. 50% of hyaluronic acid in the human body exists in the dermis of the skin, providing the spatial structure ためthe distribution of collagen fibres and elastin. Together they form the scaffolding of the skin, maintaining the stability of the skin tissue and preserving its elasticity. If one of them is absent, skin aging and wrinkle formation can be accelerated[11] .

Hyaluronic acid, as one of the components of human connective tissue and synovialfluid, is one of the most widely used dermal fillers in the world due to its high biocompatibility and is commonly used in the 治療of periocular wrinkles, crow'の足、およびヘッドライン[12-14]。薛鉉子轩に0.2ミリリットルのヒアルロン酸注射ら23 mild-to-moderate患者の顔の靭帯顔ハザード、赤みなんてありませんでしはれ、痛み打撲痕やアレルギー反応23患者にも不利な反応などハード・団塊排気量フィラーの血管の塞栓症や肌の壊死だ注射後,目尻と頬骨下腔の弛緩度の改善,額のラインの改善,口角の隆起,下顎の縁の改善,顔の質の強化などが認められた。

Follow-up showed that the effects of the injections lasted for about 3-6 months, and re-injections were required after half a year to maintain the effects[15]. Hyaluronic acid regulates collagen 合成、reduces the production of inflammatory mediators, inhibits capillary exudation and fibrinogen deposition, and inhibits fibroblasts from synthesising collagen fibres, thus inhibiting the formation of surgical scars.16-18 Patel used a needle-free injection of cross-linked hyaluronic acid in two patients with acne scars, and then repeated the administration of hyaluronic acid once at an interval of 4 weeks, which was effective in reducing the degree of scarring without any adverse effect on patients.  有害作用なしに瘢痕化の程度を効果的に低減することができる[19]。

1.3 Osteoarthropathy

Hyaluronic acid is an important component of synovial fluid and acts as a lubricant to protect the ends of bones [20]. When initially synthesised, hyaluronic acid consists mainly of 高分子量ヒアルロン酸polymers between 2×105 and 2×106 Da [21]. In 退行性関節炎and rheumatoid arthritis, the molecular weight of hyaluronic acid becomes smaller and the synovial fluid viscosity decreases, resulting in a decrease in the viscoelasticity of hyaluronic acid, which leads to an increase in the wear and tear of joint surfaces [20]. Intra-articular injection of high molecular weight hyaluronic acid can effectively relieve the pain of patients with osteoarthritis and rheumatoid arthritis and play a certain therapeutic role[22] . In addition to its lubricating effect, hyaluronic acid can reduce the phagocytosis of macrophages and improve the inflammatory response[23].

Yuan Shuyan etアルinjected 2.5 ml of sodium hyaluronate関節腔に35膝の変形性関節症患者と発見した患者'痛みのレベル低下し、IL-6β関節の液synovialが滞る低下をもたらし政権後hyaluronate.24ナトリウムseungは、架橋されたヒアルロン酸ゲルの足場が、ヒトの歯髄幹細胞と模倣ペプチドとの混合が容易であり、混合物の注入も容易であることを発見した。マウスに注射した後、架橋ヒアルロン酸は注射部位にハイドロゲルの足場を急速に形成し、8週間以上も刺激を受けずに安全に維持された。歯髄幹細胞はハイドロゲル中で少なくとも8週間生存でき、模倣ペプチドは歯髄幹細胞を骨芽細胞へ分化させることができ、架橋ヒアルロン酸ゲル足場は骨組織工学のための生体材料として使用することができる[25]。

1.4術後癒着の予防

Hyaluronic acid is used to 防ぐpostoperative adhesions, which can effectively reduce the incidence and severity of adhesions [26]. The mechanism of hyaluronic acid in preventing postoperative adhesions is as follows: (1) hyaluronic acid gel has a polymer fibre mesh structure, coated on the surface of the tissue, which can play the role of barrier, and form a short-lived protective barrier during peritoneal repair; (2) 抑制postoperative hemorrhage and oozing, reduce the number of blood clots that can form the structure of the permanent adhesions, and avoid the fibrin deposits in the contact surface of the tissue; (3) hyaluronic acid inhibits the 移住and phagocytosis of neutrophil granulocytes, and reduces inflammation and inflammatory processes. (iii) Hyaluronic acid inhibits the migration and phagocytosis of neutrophil leukocytes and reduces inflammation [27]; (iv) Hyaluronic acid interacts with high affinity hyaluronic acid receptor proteins on the membrane surface of mesenchymal stromal cells and fibroblasts and improves the migration and chemotaxis ability of these cells, which promotes the in vivo repair process; (v) Hyaluronic acid gels are covered on the surface of the traumatised plasma membrane, and they are not degraded or metabolised for a certain period of time, so that the early wound repair can be carried out in a sustained and effective manner until a continuous wound is formed in the contact surface. ⑤ Hyaluronic acid gel covers the plasma membrane surface of the wound, and is not degraded and metabolised for a certain period of time, so that early tissue repair can be carried out continuously and effectively, until a continuous mesothelial セルlayer is formed on the wound surface to complete tissue repair.

Cai Tongkai etal.[28] used a bilateral injury model of rat cecum and abdominal wall to determine the degree of abdominal adhesion by Nair adhesion 5-grade classification, and found that 30 d after surgery, the abdominal adhesion of SD rats in sodium hyaluronate gel group was significantly lower than that of the model group, and the limiting load and stiffness ratios of the sodium hyaluronate gel group were not statistically different from that of the sham-operated group and the model group. Medical sodium hyaluronate gel can effectively reduce the degree of adhesion and does not affect the recovery of trauma. Zhang et アルstudied the efficacy of medical sodium hyaluronate and oxidised regenerated セルロースin the prevention of peritoneal adhesions in rats using a model of two uterine injuries, and found that both medical sodium hyaluronate and oxidised regenerated cellulose were effective in decreasing the degree of adhesion damage [27]. Solid membranes are difficult to fix accurately at the site of trauma and need to be removed surgically after tissue healing [29]. The liquid form of hyaluronic acid is not only easy to handle and cover the wound site, but also remains in the body for a period of time consistent with the wound healing cycle.

1.5麻薬キャリア

In recent years, hyaluronic acid has been used as a drug carrier, reacting with other drugs to form compounds that exert slow-release and targeted effects so that the bound drug can be released in a timed or targeted manner[30-32] . As a nanomaterial, hyaluronic acid can be used to form targeted formulations with antineoplastic drugs for the treatment of pelvic tumours.Lee found that hyaluronic acid nanoparticles were readily endocytosed by colon cancer HCT116 cells from CD44receptor-positive patients[33] , and nanocomplexes formed by conjugation of hyaluronic acid and paclitaxel showed enhanced cytotoxicity against HCT116 cells in vitro.34 Bajaj used hyaluronic acid with paclitaxel to form nanocomplexes with the same drug. Bajaj extended the retention time of paclitaxel in nude mice by encapsulating paclitaxel in hyaluronic acid colloid and effectively reduced the 成長and metastasis of SKOV-3 tumour in human ovarian cancer[35] .

Xiao et al. used a lipid carrier with hyaluronic acid-octadecylamine structure to load paclitaxel, and the loading rate was increased to 72%. In nude mice, the distribution of paclitaxel-loaded hyaluronic acid-octadecylamine carriers decreased in liver and spleen and increased in tumour tissues.36 Choi encapsulated irinotecan in hyaluronic acid nanoparticles, which was effective in inhibiting the 成長of CT29 tumours of human colon carcinoma in nude mice and reducing the adverse effects of irinotecan. The metastasis of CT26 tumour of human colon cancer could be observed by fluorescence technology[37] .Zhang et al. used ciprofloxacin and vancomycin coupled with hyaluronic acid to prepare delayed-release particles of antibiotics, which could effectively inhibit Pseudomonas aeruginosa, Staphylococcus aureus and Bacillus subtilis within one week[38] .

他の研究2

2.1細菌への影響

Hyaluronic acid in human body is mainly decomposed by hyaluronanolytic enzymes (Hyals), of which the most important enzymes are Hyal-1 and Hyal-2. Hyal-2 degrades hyaluronic acid に低分子ヒアルロン酸, and Hyal-1 degrades hyaluronic acid into low molecular weight oligomers. High molecular weight hyaluronic acid is degraded slowly by exposing only the β1 and 4 bonds. When the molecular weight of hyaluronic acid is less than 300,000 molecules, the aggregation ability of hyaluronic acid decreases and the rate of degradation increases exponentially [39]. It has been reported[40] that hyaluronic acid can be degraded to polysaccharides, which can provide nutrients for staphylococci and streptococci.

Zhang et al[41] showed that several virulence factors such as M1 protein, collagen-like surface protein and glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase of Streptococcus pyogenes were up-regulated in hyaluronic acid-rich medium. However, it has been reported [42-43] that hyaluronic acid can inhibit the 成長of bacteria such as SAwith a maximum inhibitory effect achieved at a concentration of 1 mg/ml, but no bactericidal effect. High concentrations of high molecular weight hyaluronic acid inhibited the growth of SA and Escherichia coli in vitro and did not affect the efficacy of antibiotics in vitro and in vivo [28]. Jae used mouse cecum ligation and puncture method to construct a mouse abdominal abscess model, and the injection of high molecular weight hyaluronic acid (20 mg/kg) into the abdominal cavity could effectively reduce the bacterial load in the abdominal cavity, lower the level of inflammatory factors, and improve the survival rate of mice [44].

2.2腫瘍効果

内因性low molecular weight hyaluronic acid can promote angiogenesis, increase the blood supply of tumour cells and promote the growth of tumour cells [45-47]; in addition, endogenous low molecular weight hyaluronic acid can also promote the secretion of CD44 on the surface of tumour cells, thus promoting the metastasis of tumour cells [48]. Inhibition hyaluronanのシンターゼ3 (hyaluronanS3) reduces the production of low molecular weight hyaluronan, which can reduce prostate tumour angiogenesis by 70% to 80% and reduce tumour growth [49]. Over表情of hyaluronan synthase 2 (hyaluronan S2) increases the 合成of high molecular weight hyaluronan and increases the concentration of high molecular weight hyaluronan in tissues, which in turn inhibits the growth of tumour cells[50] . It has also been reported that endogenous hyaluronic acid can promote the proliferation and spread of tumour cells[51-53] . Exogenous hyaluronic acid has different applications depending on its molecular weight[32,54] (Table 2). When exogenous high molecular weight hyaluronic acid enters the human body, it will promote the high expression of hyaluronan S2, accelerate the synthesis of endogenous high molecular weight hyaluronic acid, increase the concentration of high molecular weight hyaluronic acid in the body, and thus inhibit tumour growth and proliferation [55].

Aikateriniインゲンマメ使用high molecular weight hyaluronic acid to significantly inhibit the migration of HT1080 cells, and when hydrolysed by hyaluronate lysozyme, the motility of HT1080 cells was significantly increased [56]. High molecular weight sodium hyaluronate gel was able to inhibit the metastasis of colon cancer cells [57]. In addition to combining with antitumour drugs, exogenous oligomeric hyaluronic acid alone can bind to CD44 receptor and enhance apoptosis of tumour cells [58], and bind to hyaluronic acid-mediated motility receptor and reduce metastasis of tumour cells [59].

3結論

The structure and function of hyaluronic acid have led to its use in biomaterials, drug-targeting agents, cosmetic surgery, and the prevention of adhesions after abdominal surgery, etc. However, with the emergence of doubts about the potential of hyaluronic acid to promote the growth and metastasis of tumour cells as well as the growth of bacteria, the use of hyaluronic acid in the 臨床setting has become a matter of great caution.

In this paper, the 臨床application of hyaluronic acid and the mechanism of hyaluronic acid on tumour and bacteria are reviewed, which is of great significance for the safe use of hyaluronic acid in the clinic, especially for the prevention of adhesion after abdominal and pelvic tumour patients, but the mechanism of hyaluronic acid is still needing to be further researched.

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