히알루론산의 임상적 활용에 관한 연구

히알루론산(HA)is also known as vitreous acid. It was first isolated 에서1934 by Meyer 그리고Palmer from 이vitreous hu모어의이bovine eye[1] . Hyaluronic산is also found 에서a wide range 의tissues 에서이human body, including the vitreous humor 의the human eye, umbilical cord 그리고sk에서(Table 1), 그리고is a component 의the 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-cha에서glycan, a polymer formed by repeated alternation of alternating N-acetylglucosamine (GlcNAc) 그리고glucuronide (GlcA) disaccharide units [3], 와a wide range of molecular weights, 그리고a 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, 그리고in 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, 그리고its 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 후abdominal surgery [5].

히알루론산 1 응용

1.1 안과 질환

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 접착of adjacent 세포[6]. In addition, hyaluronic acid can regulate 셀adhesion and motility, regulate 셀differentiation 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].

안구건조증은 흔히 볼 수 있는 안과증후군으로, 주로 안구샘세포의 기능장애로 인해 발생하는 질환으로 다양한 종류의 결막염을 포함한다.히알루론산은 친수성 그룹이 풍부해 물 분자와 결합해 친수성 및 윤활제 역할을 하므로 안구건조증을 어느 정도 완화할 수 있다.'안구건조증의 임상 진단 및 치료에 대한 전문가 합의 (2013)'[9]에 따르면,'안구건조증 치료의 목적은 경증 안구건조증 환자의 눈 증상을 완화하고, 중증 안구건조증 환자의 시각 기능을 보호하는 것'이라고 한다.히알루론산 나트륨 안약은 안구 표면의 염증 매개체를 씻어내고 희석시키며, 눈물 오스몰래성을 감소시키고, 안구 표면 상피의 치유를 촉진하며, 안구 표면의 파이브로넥틴의 분비와 침착을 촉진하여 안구 표면 상피 손상을 치유하는데 중요한 역할을 합니다.유화이링 [10]은 안구건조증 환자 106명을 대상으로 연구한 결과 이렇게 밝혀졌다0.3% 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.

의료미용 1.2

Hyaluronic acid is often used as a moisturising ingredient in cosmetics, including hyaluronic acid moisturising and water-locking creams and moisturising and hydrating masks. 히알루론산 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 을the 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 관절fluid, is one of the most widely used dermal fillers in the world due to its high biocompatibility and is commonly used in the 치료of periocular wrinkles, crow's 발, 그리고 머리줄 [12-14].Xue Zihan 등은 경도에서 중등도의 안면 처짐 환자 23명의 안면 인대에 히알루론산 0.2 ml를 주사하였고, 23명의 환자에서 발적, 부종, 통증, 멍이나 알레르기 반응이 없었으며, 경결절, 필러의 이환, 혈관색전증, 피부괴사 등의 부작용도 없었다.주사 후 모두 눈가와 광대 하부의 처짐, 그리고 이마 라인의 향상, 입가의 상승, 하악 여백 (하악 여백)의 더 나은 정의, 더 단단해진 얼굴 질감의 개선 정도가 다르게 나타났다.

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 합성,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.  부작용 없이 흉터의 정도를 효과적으로 줄일 수 있다 [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 고 분자량 히알루론산polymers between 2×105 and 2×106 Da [21]. In 골관절 염and 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 et알다.injected 2.5 ml of sodium hyaluronate무릎 골관절염 환자 35명의 관절강에 들어가 환자가 '고통의 수준과 감소 IL-6 β의 관절 액 관절에 나트륨의 행정부 이후 감소 hyaluronate.24승 교수는 교차 연결된 히알루론산 젤 스캐폴드가 사람의 치과용 펄프 줄기세포와 모메틱 펩타이드와 혼합되기 쉽고, 혼합물을 주입하기 쉽다는 사실을 발견했다.생쥐에 주입한 후 교차연결된 히알루론산이 주사부위에 하이드로겔 스캐폴드를 빠르게 형성하여 8주 이상 안전하고 자극 없이 유지되었다.치과용 펄프 줄기세포는 하이드로겔에서 최소 8주 이상 생존할 수 있으며, 모메틱 펩타이드는 치과용 펄프 줄기세포의 조골세포로의 분화를 유도할 수 있고, 교반된 히알루론산 겔 스캐폴드는 골조직 공학용 생체 재료로 사용될 수 있다 [25].

1.4 수술후 유착의 예방

Hyaluronic acid is used to 막postoperative 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) 억제postoperative 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 마이 그레이 션and 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 셀layer 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 알다.studied the efficacy of medical sodium hyaluronate and oxidised regenerated 셀 룰로 오 스in 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 마약 운반자

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 성장and 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 성장of 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] .

2기타 연구

2.1 박테리아에 미치는 효과

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 로저분자량 히알루론산, 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 성장of bacteria such as S한,with 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 종양의 영향

내생low 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 hyaluronan의synthase3 (hyaluronanS3) reduces the production of low molecular weight hyaluronan, which can reduce prostate tumour angiogenesis by 70% to 80% and reduce tumour growth [49]. Over표현of hyaluronan synthase 2 (hyaluronan S2) increases the 합성of 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].

아이카테리니는 외인성을 사용했다high 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 결론

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 임상setting has become a matter of great caution.

In this paper, the 임상application 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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[56] 베르디아키 A, 니키토비치 D, 트사사키스 A, 외 bFGF 인듀스가 바뀐다 hyaluronan에서 synthase  그리고 hyaluronidase isoform expression  and  modulates the  migration  용량 of  fibrosarcoma 세포다 [J다]「 Biochim Biophys Acta 」,2009,1790(10):1258-1265.

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