히알루론산은 안전한가?

루 론 산(HA로 약칭), 히알루로난으로도 알려져 있으며,고 분자량 선형 다당류입니다.1934년 초, Meyer and Palmer [1]는 카우&의 유리체 조직으로부터 히알루론산과 그 나트륨 소금을 처음으로 분리하였다#39; s 눈.후에 히알루론산에 의해 형성된 이온쌍 또는 염과 그 카운터 이온을 통칭하여 히알루로난 (히알루론산) 이라고 부르게 되었다.그것은 (1-3)-2-아세트 아미도-2-디옥시-d-포도당 (1-4)-d-d-글루쿠론산 이당류 반복 단위로 구성된 직선 사슬 mucopolysaccharide이다.분자량은 소스 및 준비 방법에 따라 일반적으로 50,000에서 800만 정도이다.히알루론산은 관절, 유리체, 활액, 탯줄, 연골, 피부, cockscombs, group A and C 용혈성 연쇄구균, Waddington gum 등의 결합조직에서 발견되어 강인함, 지지구조, 세포의 대사조절 등의 중요한 기능을 수행한다.

1. 히알루론산의 물리적, 화학적 성질과 생리적 기능

1.1 히알루론산의 보습 특성

히알루론산은 물을 유지하는 중합체이다그것은 인간의 피부에서 자연스럽게 발견된다.n-아세틸글루코사민과 글루쿠론산 이당류 단위가 반복적으로 교체되면서 형성된다.용액 속의 히알루론산 분자가 고도로 확장되고 무작위로 똬리를 틀면 넓은 면적을 차지할 수 있고, 분자 사슬이 얽혀 연속적인 네트워크 구조를 이룬다.물 분자는 극결합과 수소 결합을 통해 물과 직접 상호작용하여 히알루론산이 분자 스펀지처럼 작용하여 자신의 무게의 수천 배를 수분에 흡수하고 보유하게 합니다.국제적으로 최고의 보습제 [2]로 인정받고 있으며, NMF (natural 보습인자)로 알려져 있다.결합 조직에서 히알루론산의 수분 보유치는 약 80 ml/g이다.다른 천연 고분자 또는 합성 고분자보다 강한 수분 유지력을 가지고 있습니다.일부 학자 [3]는 히알루론산의 수분 보유 특성을 소르비톨과 폴리에틸렌 글리콜 4000의 특성과 비교했다.그 결과 (히알루론산 분자량 3000kD), 소르비톨 및 폴리에틸렌 글리콜 4000 24h 수분 보유량은 각각 87.1, 32.4 및 10.5로 나타났다.히알루론산의 수분 보유는 가장 중요한 생리 기능 중 하나입니다. 

1.2 히알루론산은 프로테오글리칸 중합체 형성에 참여한다

Under physiological conditions, hyaluronic acid is covalently linked to core proteins in concert with other glycosaminoglycans (such as chondroitin sulfate and keratan sulfate) to form proteoglycan polymers. These giant polymers occupy a large water pressure domain, and can reduce in volume under external pressure. After the pressure is released, they expand to their original volume, thereby maintaining the shape and volume of the tissue and ensuring its reversible compressive resistance. Proteoglycans (PGs) in different tissues have their own special functions. For example, the proteoglycans distributed in connective tissue bind water through amino sugars. This hyaluronic acid-protein-water gel binds cells together, enables normal cell metabolism and tissue water retention, and protects cells from pathogenic bacteria to prevent infection. and gives the skin a certain elasticity. In cartilage, it determines the volume of cartilage and the final shape of the skeleton. In the aorta, it is essential for the optical physiology of the eye together with the vitreous body. In the ovary, PG (without hyaluronic acid) is synthesized regularly with the periodic growth of follicles. The heparan sulfate proteoglycan on the plasma membrane of human liver cells plays an important role in the interaction between cells and the interaction between cells and the matrix.

1.3 히알루론산:세포 생물학에 미치는 영향

Toole et al. demonstrated that hyaluronic acid is highly abundant during embryogenesis and morphogenesis, and that during differentiation, hyaluronidase removes this hyaluronic acid, producing a differentiated matrix, such as proteoglycans and collagens [4]. The role of hyaluronic acid during differentiation is to cause isotonic tissue edema, which leads to the opening of channels required for cell migration; to assist in the separation and transposition of mesenchymal cells released from the epithelium; and to change the shape and structure of organs.

면역세포에 대한 히알루론산의 역할 1.4

Domestic and foreign studies have confirmed that hyaluronic acid has a certain effect on macrophages, granulocytes, lymphocytes, natural killer (NK) cells, etc. Hyaluronic acid at low concentrations has a mild effect on the function of phagocytes and NK cells, but inhibits the transformation of lymphocytes and the formation of E rosettes. Hyaluronic acid at higher concentrations has a significant inhibitory effect on the function of lymphocytes, NK cells and phagocytes, and there is a dose-effect relationship.

The extracellular coat (Coat) formed by hyaluronic acid acts as a barrier against cytotoxic lysis. For example, the glycosaminoglycan coat of glioma cells can enhance their resistance to immune killing cells; the hyaluronic acid coat adhering to the cells can block lymphocyte-mediated cell lysis. In addition, this hyaluronic acid coat can prevent viral invasion (such as the invasion of the Newcastle disease virus into human synoviocytes), and interfere with the function of intercellular lectins and lectin receptors.

상처 치유에 대한 히알루론산의 효과 1.5

히알루론산은 상처 치유를 가속시킬 수 있다다.국소 히알루론산 농도는 상처 초기에 크게 증가하며, 다양한 염증 세포에 조절 효과가 있습니다.고농도, 고분자량의 히알루론산은 친치유효과가 더 높고 콜라겐의 합성을 조절하며 섬유활성을 조절하고 항염증 효과가 있다.반면 저분자 히알루론산은 혈관 생성을 촉진한다.상처에 있는 히알루론산은 효소에 의해 저분자량의 히알루론산으로 분해되어 상처 치유를 촉진합니다.

히알루론산을 응용한 2가지

2.1 화장품 속의 히알루론산

2.1.1 히알루론산과 인지질은 유화제를 형성한다 [5]

In the absence of other emulsifiers, the addition of hyaluronic acid and phospholipids to an oil-water mixture can form a stable emulsion. This natural emulsifier composed of hyaluronic acid and phospholipids is characterized by both emulsifying and moisturizing properties. It is a safe and effective emulsifier that cannot be matched by other synthetic surfactants and can be used in the preparation of skin creams, lotions, facial cleansers, etc.

2.1.2 히알루론산과 폴리옥시에틸렌이 진액을 이룬다 [6]

Polyoxyethylene (molecular weight 100-5000kD) is a commonly used thickener in cosmetics, and hyaluronic acid (molecular weight 3000kD) solution also has a high viscosity. The viscosity of the two combined is much greater than the sum of their individual viscosities. Therefore, hyaluronic acid-polyoxyethylene solution is an excellent thickener with good moisturizing properties, and can be used in cosmetics such as creams and lotions.

2.1.3 향기 고정제로서의 히알루론산 [7]

According to the characteristics of hyaluronic acid, which has the function of molecular encapsulation of various substances, it is used in fragrance products. Hyaluronic acid, as a fixative combined with fragrance, can slow down the volatilization rate of the fragrance and make the fragrance last longer. It is suitable for perfumes, skin care creams, emollients, deodorants, etc. Hyaluronic acid has two advantages in addition to fixing the fragrance: first, it reduces the adverse irritant effect of the fragrance on sensitive skin and reduces allergic reactions; second, it prevents adverse chemical reactions between certain fragrances and skin secretions and prevents the formation of odors.

임상 진단에서의 히알루론산 값 2.2

Hyaluronic acid levels are significantly elevated in many diseases. Clinically, measuring the serum hyaluronic acid level can reflect changes in various diseases. Studies have shown that changes in serum hyaluronic acid levels are closely related to the course of liver disease and the degree of liver cell damage. In recent years, domestic and foreign scholars have confirmed that the serum hyaluronic acid of patients with liver cirrhosis is significantly elevated, and the degree of elevation of hyaluronic acid is positively correlated with the degree of liver cirrhosis. Therefore, serum hyaluronic acid can be used as a reliable indicator for the diagnosis of liver cirrhosis. Presig believes that this indicator is significantly superior to previous indicators for diagnosing liver cirrhosis (such as the albumin/globulin ratio, pro-collagen III peptide, etc.), and can better reflect the degree of liver cirrhosis than liver puncture and biopsy.

순수 히알루론산 제품의 임상적 가치 2.3

In the 1980s, Balazs and others developed a cross-linked hyaluronic acid derivative, hylan, and explored its physiological properties and clinical applications. It was found that hylan has the same biocompatibility as natural hyaluronic acid, inspiring people to clinically prevent adhesion after trauma or surgery and repair soft tissues [8].

2.3.1 안과 수술에서의 히알루론산 [9,10]

Hyaluronic acid gel and its high elasticity can be used in a variety of ophthalmic microsurgery. It has been recognized that hyaluronic acid gel is essential in ophthalmic microsurgery. Hyaluronic acid gel is now widely used as an essential filler in various ophthalmic surgeries such as extracapsular cataract extraction, intraocular lens implantation, retinal detachment surgery and corneal transplantation. In addition, hyaluronic acid can also be used for eye canal reopening and dry eye syndrome. Extensive clinical applications over the past 20 years have shown that the role of hyaluronic acid viscoelastic substances in ophthalmic microsurgery is not simply to provide operating space, but also to provide viscoelasticity without a lining, tissue separation, soft tissue restoration, viscous occlusion, viscous bleeding, viscoelastic buffering and viscoelastic fixation, which can greatly reduce surgical trauma, reduce the degree of postoperative inflammatory response, reduce surgical complications, and achieve the goal of improving vision.

2.3.2 뼈 및 관절 질환 치료에 사용되는 히알루론산

The lubricating and cushioning effect of hyaluronic acid has led to its use in the treatment of osteoarthritis, periarthritis of the shoulder and rheumatoid arthritis. Hyaluronic acid gel is used for intra-articular injections to treat osteoarthritis. Not only does it overcome the side effects of previous hormone treatments, but its short- and long-term effects are also superior to those of hormones, making it the material of choice for treating osteoarthritis. At the 18th International Anti-Rheumatic Federation meeting in July 1993, hyaluronic acid was considered to have a disease-repairing effect on osteoarthritis and is a disease-repairing osteoarthritis treatment [11]. In fact, since hyaluronic acid injections for osteoarthritis were marketed in Italy in 1987, intra-articular injections have been marketed in many countries, and clinical trials are also being conducted in the UK and the US. Japan Bio-Chem's의 골관절염 히알루론산 주사로 증상이 64.1% 개선되었고, 제품의 매출은 1993년 271억엔에 달했다 [12].

2.3.3 히알루론산을 고형막 복구에 적용 [13]

Tympanic membrane perforation is a common clinical condition caused by acute and chronic otitis media, trauma, etc. Surgical repair of the tympanic membrane often causes changes in the structure of the original tympanic membrane after surgery, affecting the degree of hearing recovery. This is mainly related to the formation of scar tissue and the use of graft materials. In recent years, domestic and foreign research on the application of medical sodium hyaluronate in tympanic membrane repair has achieved gratifying results. Summary: A large number of clinical results show that hyaluronic acid treatment for tympanic membrane perforations is feasible, without any side effects, and is a good means of treating small dry tympanic membrane perforations.

2.3.4 히알루론산:산부인과에서의 임상적용

(1) A:복강경 검사, 자궁 경 검사 및 기타 자궁 내 수술 후 적용

It is known in medical practice that hyaluronic acid is present in the peritoneal fluid, uterine cavity fluid and fallopian tube fluid. The use of hysteroscopy and laparoscopy can cause the loss or dilution of components of the abdominal or uterine cavity fluid, and temporary real space gaps in hyaluronic acid may also occur. Local trauma, bleeding and exudation during surgery can disrupt the internal environment of the uterus, affecting the function of the female reproductive tract and mucosa to varying degrees. The interaction of these factors can lead to impaired organ function or infertility and other consequences. Hylan B gel is a highly viscoelastic. A non-permeable derivative, its polysaccharide chains are cross-linked by divinyl sulfone, making it a good soft tissue filling material. Therefore, in laparoscopic and hysteroscopic use, Hylan B gel can be used as an operating medium for the lens to separate tissues and expose the field of view, which not only accelerates the repair of the damaged surface and the amount of synthesis, but also does not affect the surgical field of view, facilitating operation and reducing the possibility of postoperative complications such as blockages and adhesions. [14]

(2) 수술 후 유착을 방지하기 위해 산부인과에서 히알루론산을 도포합니다

In 1971, Balazs et al. reported the role of hyaluronic acid in preventing adhesion formation between tendons and sheaths, conjunctiva and iris. They found that high viscoelastic, high molecular weight hyaluronic acid solutions and hyaluronic acid membranes can reduce the incidence of adhesion formation, and have no adverse effect on wound healing. A large number of animal experiments and clinical applications have shown that hyaluronic acid is a safe and effective substance for preventing and reducing adhesion caused by surgery.

(3) 질내의 히알루론산

Hyaluronic acid is secreted and distributed in the fallopian tubes and guiding tissues of mammals, as well as between the epithelial cells of the mucous membrane. Experiments have found that low-density areas of vigorous cell proliferation are always accompanied by increased synthesis of hyaluronic acid. Hyaluronic acid and its derivatives act as a medium for controlled drug release. Therefore, in clinical use of vaginal medication, the moisturizing and lubricating properties, viscoelasticity, and characteristics of hyaluronic acid as a drug carrier can be utilized. Hyaluronic acid can both increase the self-cleaning and lubricating effects that have been disrupted in the vagina, allowing the local epithelial cells to recover, while also slowly releasing the drug it is carrying into the vagina, where it can exert a pharmacological effect for a long time, restore the vagina to its normal state, and heal the original disease.

(4) 히알루론산 제제의 연장 사용

Wound healing is a process involving multiple cells and their products that work together to rebuild and regenerate the extracellular matrix. Current research has confirmed that hyaluronic acid plays an important role in the process of wound healing. With the development of fetal surgery, a glycoprotein called hyaluronic acid stimulatory factor has received increasing attention. It can significantly increase the hyaluronic acid content in the wound matrix, thereby regulating collagen synthesis. This is considered to be an important factor in the fetal wound healing process without scarring.

히알루론산의 안전성 논의 2.4

The hyaluronic acid in the preparation is the same as the endogenous hyaluronic acid, which is non-toxic, non-antigenic, and not likely to cause a foreign body reaction. Clinical applications have shown that hyaluronic acid has good safety, and most of them indicate that hyaluronic acid is well tolerated, with an adverse reaction rate of 0% to 10%. Japan has conducted comprehensive preclinical and clinical safety experiments on hyaluronic acid preparations, which have proven their safety and efficacy in clinical use. Common adverse reactions are mostly mild to moderate pain or swelling at the administration site or injection site, as well as symptoms such as headache or fever in individual patients. Adverse reactions often occur within 1 to 2 days of administration, and patients can generally tolerate them without treatment, and they will disappear on their own after 2 days. Obstetrics and gynecology, especially when used in the vagina, has very low absorption, and hyaluronic acid has even fewer adverse reactions. Currently, hyaluronic acid macromolecular cross-linked membrane agents and compound preparations with other anti-adhesion drugs are being studied for their potential in anti-adhesion due to their good safety and controlled-release effects.

히알루론산 생산 3

동물 장기에서 채취 3.1

Hyaluronic acid is mainly extracted from umbilical cords, cockscombs, vitreous bodies of cattle and sheep eyes, and whale cartilage. These animal tissue sources are difficult and expensive to obtain, and the hyaluronic acid content in the tissue is very low, resulting in a low yield of product. During the extraction process, large amounts of organic solvents and enzymes must be used, and the process is complex and involves many operating units, which greatly increases the cost of hyaluronic acid and makes it difficult to produce it on a large scale. Foreign companies that use this method include Kabi, Fidia, Gen-zyme, Sweden's P-hyaluronic acidrmacia와 Japan's 생화학 공업 회사.중국의 연구수준은 비교적 낮고 히알루론산 생산은 아직 장기 추출 단계에 있으며 주요 원료는 탯줄과 꼬막이다.상하이 대학 저널은 돼지 가죽에서 히알루론산을 추출하는 방법을 발표했는데, 그 결과 나온 히알루론산의 분자량은 약 106이다.현재이 방법을 이용해 히알루론산을 생산하는 기업으로는 산동프레다제약회사와 산시제약공업연구원 등이 있다.

3.2 미생물 발효법

As early as 1937, Kendall et al. [15] discovered that streptococci could produce hyaluronic acid, and many people have conducted research on this. Shiseido of Japan first reported the use of streptococci to produce hyaluronic acid in 1985. China is currently developing this method, and Yan Jialin of Zhengzhou Animal Husbandry Engineering College and others have used hyaluronic acid-deficient streptococci to ferment and produce hyaluronic acid that meets cosmetic requirements. Strains with high fermentation yields are generally obtained by mutagenesis. A Japanese patent reports a method of mutagenesis using NTG (N-methyl-N-nitro-nitrosoguanidine), and a two-step mutagenesis treatment is used to obtain a variant that does not produce hyaluronic acid.

The fermentation rate is as high as 6.7 g/l, and the molecular weight is ≥10×105. The fermentation yield of the original strain without mutagenesis is only 2 g/l, and the molecular weight is 3×105 to 6×105. The mutagenesis rates of the two-step treatment are 4×10-6 and 5×10-5, respectively. In other words, it takes hundreds of thousands or even millions of bacteria to obtain a desired variant, and the amount of work involved is imaginable. A new fermentation process for producing hyaluronic acid has also been developed in China, using hyaluronic acid-producing bacteria obtained by gamma irradiation combined with magnetic field mutagenesis. The results passed the national-level achievement appraisal organized by the Ministry of Chemical Industry on July 29, 1998, and the conclusion was that the technical level has reached the international advanced level. The fermentation level of hyaluronic acid is 4-6.5 g/l. According to literature, the current international fermentation level of hyaluronic acid is 6.5 g/l at the highest.

3.3 동물의 태아 세포 분리 방법

미국의 생명공학회사 젠자임은 1994년 이를 핵심 주제로 삼아 현재 동물 장기에서 추출하는 방법을 대체하려고 시도했다.즉, 동물 세포 배양에서 특정 물질을 추출하기 위해 특정 형태의 세포를 대량으로 전파하는 것인데, 이는 생명공학의 중요한 분야이다 [16].그러나 현재이 방법에 대한 문서화 또는 보고된 사례는 없다.

참조:

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[2] 우동루.탄수화물의 생화학 [M.북경:고등교육출판사, 1987:627.

[3] 성우는 나가이 마사요시.화장품 재료다.JP Show 62-158203, 1987년.

[4] 장시민, 장루롱.생명의 화학 [J.1991, (11) 2:8-9.

[5] 우지리 요시타카.유화 구성이다.JP Show 62-45336, 1987.

[6] 수홍, 루지화.Chinese Journal of Biochemical Drugs [J.1998, (19) 5:222-223.

[7] 브라케 Jw.히알루론산/히알루론산 tased fragrance products, 1985년 WO 85/04803.

[8] 호우준지, 장천민, 뉴귀젠.Chinese Journal of Biochemical Drugs [J.2003, (24) 5:262-264.

[9] 저우리빈, 장다친.Chinese Journal of Biochemical Drugs [J.1998, (5):289.

[10] 장옌빙, 티안예칭.Chinese Journal of Biochemical Drugs [J.1998, (5):288.

[11] 리웨이핑, 류샹글리, 린다시안.Chinese Journal of Biochemical Drugs [J.1998, (5):252-254.

[12] 루오루이밍.닝샤농업대학 (寧夏農業大學)2001, (22) 1:62-64.

[13] Piacquadio DJ, Larsen NE, Denlinger JL 외.연조직 증강 물질 [a] 로서 Hylan B gel (hylaform.클라인 에이다.임상실습에서의 조직증강:절차와 기술 [C].서울:마르셀 데커, 1998.269-291다.

[14] 양 샤오홍, 링 페이슈, 왕펑산.Chinese Journal of Biochemical Drugs [J.1998, 19 (4):205-208.

[15] 켄달 페.A 군 strcptococcus [J]의 점액질 균주에 의해 정제된 혈청학적으로 비활성 polysacc hyaluronic acidride.J Biol Chem, 1937, (118):61-69.

[16] 슈지엔.장수식품과 발효 [J.1996, (1):27-29.