Гиалуроновая кислота безопасна?

Гиалуроновая кислота(сокращенно HA), также известный как гиалуронан, является линейным полисахаридом с высоким молекулярным весом. Еще в 1934 году мейер и палмер впервые изолировали гиалуроновую кислоту и ее натриевую соль от стекловидной ткани тела коврика#39; с глаз. Позднее ионная пара или соль, образуемая гиалуроновой кислотой и ее аналогом, была в совокупности названа гиалуроновой кислотой. Представляет собой прямоцепную мукополисахариду, состоящую из (1-3)-2- ацетамидо -2- деокси-д-глюкозы (1-4)- d -d-глюкуроновой кислоты дисакбаридных повторяющихся единиц. Его молекулярный вес, как правило, варьируется от 50 000 до 8 миллионов в зависимости от источника и метода приготовления. Гиалуроновая кислота обнаруживается в соединительных тканях, таких как суставы, стекловидный организм, синевиальная жидкость, пупочные шнуры, хрящи, кожа, кокс-комбы, группы а и с гемолитические стрептококчи и ваддингтон гум, для выполнения важных функций, таких как прочность, опорные структуры и метаболическое регулирование клеток.

1. Физические и химические свойства и физиологические функции гиалуроновой кислоты

1.1 увлажняющие свойства гиалуроновой кислоты

Гиалуроновая кислота является водоудерживающим полимеромЭто естественно встречается в коже человека. Образуется в результате неоднократного чередования n-ацетилглюкозаминовых и глюкороновых дисакбаридных единиц. Высокорасширенная и случайно спиральная конформация молекулы гиалуроновой кислоты в растворе позволяет ей занимать большую площадь, а молекулярные цепи переплетаются, образуя непрерывную сетевую структуру. Молекулы воды взаимодействуют с ней напрямую через полярные и водородные связи, делая гиалуроновую кислоту действовать как молекулярную губку, поглощая и удерживая тысячи раз свой собственный вес в влаге. Она признана на международном уровне в качестве лучшего увлажняющего средства [2] и известна как "естественный увлажняющий фактор" (НМФ). В соединительной ткани, значение удержания воды гиалуроновой кислоты составляет около 80 мл/г. Он обладает более высокой способностью удерживать воду, чем другие натуральные или синтетические полимеры. Некоторые ученые [3] сравнили свойства гиалуроновой кислоты с свойствами сорбитола и полиэтиленгликоля 4000. Результаты (молекулярный вес гиалуроновой кислоты 3000kD), сорбитола и полиэтиленгликоля 4000 24 часа удержания воды составили 87,1, 32,4 и 10,5, соответственно. Одной из важнейших физиологических функций гиалуроновой кислоты является ее удержание в воде. 

1.2 гиалуроновая кислота участвует в формировании протеогликанских полимеров

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 гиалуроновая кислота: воздействие на биологию клеток

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.

1.4 роль гиалуроновой кислоты в иммунных клетках

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.

1.5 влияние гиалуроновой кислоты на заживление ран

Гиалуроновая кислота может ускорить заживление ран- да. Локальная концентрация гиалуроновой кислоты значительно возрастает на ранних стадиях раны, и она оказывает регулирующее воздействие на различные воспалительные клетки. Гиалуроновая кислота с высокой концентрацией, высоким молекулярным весом имеет более высокий процелительный эффект, регулирует синтез коллагена, регулирует волокнистую активность и оказывает противовоспалительное действие. Гиалуроновая кислота с низким молекулярным весом, с другой стороны, стимулирует ангиогенез. Гиалуроновая кислота в ранах распадается ферзимами на гиалуроновую кислоту с низким молекулярным весом, что, в свою очередь, способствует заживлению ран.

2 применения гиалуроновой кислоты

2.1 гиалуроновая кислота в косметике

2.1.1 эмульгатор из гиалуроновой кислоты и фосфолипидов [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 гиалуроновая кислота и полиоксиетилен образуют сгуститель [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 гиалуроновая кислота как средство исправления аромата [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.

2.2 значение гиалуроновой кислоты в клинической диагностике

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.

2.3 клиническая ценность чистых продуктов гиалуроновой кислоты

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 гиалуроновая кислота в офтальмологической хирургии [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 гиалуроновая кислота при лечении заболеваний костей и суставов

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' инъекции гиалуроновой кислоты от остеоартрита улучшили симптомы на 64,1%, а продажи продукта достигли 27,1 МЛРД иен в 1993 году [12].

2.3.3 применение гиалуроновой кислоты при починке мембраны [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 гиалуроновая кислота: клиническое применение в акушерстве и гинекологии

(1) A: применение после лапароскопии, гистероскопии и других внутриматочных операций

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) применение гиалуроновой кислоты в акушерстве и гинекологии для предотвращения послеоперационного адгезии

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) гиалуроновая кислота во влагалище

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. Расширенное использование препаратов гиалуроновой кислоты

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.

2.4 обсуждение вопроса о безопасности гиалуроновой кислоты

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.

3 производство гиалуроновой кислоты

3.1 извлечение из органов животных

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' с p-гиалуроническая кислота и Япония ' компания биохимической промышленности. Уровень исследований в китае относительно низок, и производство гиалуроновой кислоты все еще находится на стадии извлечения органов, при этом основным сырьем являются пумбильные шнуры и кокс-комбы. В журнале шанхайского университета сообщается о методе извлечения гиалуроновой кислоты из свиной кожи, а молекулярный вес полученной гиалуроновой кислоты составляет около 106. В настоящее время к числу компаний, использующих этот метод для производства гиалуроновой кислоты, относятся фармацевтическая компания "шаньдун фреда" и научно-исследовательский институт фармацевтической промышленности "шаньси".

3.2 метод микробной ферментации

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 метод отделения клеток плода животного происхождения

Американская биотехнология Genzyme сделала это ключевой темой в 1994 году, пытаясь заменить нынешний метод извлечения из органов животных. То есть в животной клеточной культуре определенный тип клетки распространяется в больших количествах для извлечения определенного вещества, что является важной областью биотехнологии [16]. Однако в настоящее время документально подтвержденных или зарегистрированных случаев применения этого метода не имеется.

Справочные материалы:

[1] майерк, палмер джей-ви. Полисаксовая гиалуроническая кислота стекловидного тела [J]. J биолхем, 1934, (107): 629-633.

[2] у донгру. Биохимия углеводов [м]. Пекин: издательство «высшее образование», 1987: 627.

[3] нагаи масаёси. Косметические ингредиенты. JP Show 62-158203, 1987.

[4] чжан шимин, чжан луронг. Химия жизни [J]. 1991, (11) 2: 8-9.

[5] уджири йошитака. Эмульсирующая композиция. Джей-пи шоу 62-45336, 1987.

[6] сюй хон, Лу чжихуа. Китайский журнал биохимических препаратов [J]. 1998, (19) 5: 222 — 223.

[7] бреске джей у. Hyaluronic acid/hyaluronate tased ароматические продукты, WO 85/04803, 1985.

[8] хоу юньчжи, чжан тяньаньминь, ню гюньчжэнь. Китайский журнал биохимических препаратов [J]. 2003, (24) 5: 262-264.

[9] чжоу либин, чжан дацинь. Китайский журнал биохимических препаратов [J]. 1998, (5): 289.

[10] чжан яньбинг, тянь ё цин. Китайский журнал биохимических препаратов [J]. 1998, (5): 288.

[11] Li Weiping, Liu Shangli, Lin Daoxian. Китайский журнал биохимических препаратов [J]. 1998 год, (5): 252-254.

[12] Лу руймин. Журнал сельскохозяйственного колледжа нинся [J]. 2001, (22) 1: 62 — 64.

[13] Piacquadio DJ, Larsen NE, Denlinger JL, et al. Гилан B гель (гилаформ) как материал для увеличения мягких тканей [a]. - клайн о. Увеличение тканей в клинической практике: процедуры и методы [к]. Нью-Йорк: марсель деккер, 1998. 269-291.

[14] ян сяохонг, лин пейшу, ван фэншань. Китайский журнал биохимических препаратов [J]. 1998, 19 (4): 205-208.

[15] кендал пи. Серологически неактивный полисахачный гиалуронический кислород, разработанный штаммами мукоидов группы A strcptococcus [J]. J Biol Chem, 1937, (118): 61 — 69.

[16] сюй цзянь. Jiangsu еда и ферментация [J]. 1996 год, (1): 27-29.