[화학공학] 히알루론산 개질 및 복합제에 관한 연구에 대한 자료입니다

Hyaluronic 산(HA) is a type 의glycosaminoglycan that belongs to이group 의acidic mucopolysaccharides. It is widely distributed 에서various parts 의the 인간body, 그리고the skin also contains a large amount 의루 론acid. In 1934, Professor Meyer 의Columbia University 에United States was the first to isolate 루 론산에서the vitreous humor 의cattle [1]. In the body, 루 론산is a multifunctional matrix that exhib의a variety 의important physiological functions, such as regulating proteins, assisting in the diffusi에그리고transport 의water 그리고electrolytes, lubricating joints, regulating the permeability 의blood vessel walls, promoting wound healing, etc. Most importantly, 루 론산has a special water-retaining effect. It is currently the best moisturizing substance found in nature, 그리고is known as the ideal natural moisturizing factor (NMF). (한2% aqueous solution 의pure hyaluronic 산can firmly retain 98% of the moisture. ) Due to its unique physical 그리고chemical 속성그리고physiological functions, hyaluronic 산has been widely used in medicine 그리고biological materials.

The chemical 구조of hyaluronic 산was elucidated by Karl Mayer' 1950년대 [1]의 s 연구소.히알루론산은 중합체이다.d-글루쿠론산과 n-아세틸글루코사민의 단위로 구성된 고분자의 직선 사슬 mucopolysaccharide이다.D-glucuronic 산 그리고 N-acetylglucosamine β-1로 연결 됩, 3-glycosidic 채권과 disaccharide 단위로 연결 됩 β-1, 4-glycosidic 채권이다.분자 내의 두 단당류는 1:1의 몰비로 구성되어 있다.최대 25,000개의 이당류 단위가 있을 수 있습니다.인체에서 히알루론산의 분자량은 5,000~20,000,000달톤 [2, 3] 정도이다.히알루론산의 구조식을 하기 표 1에 나타내었다.

Hyaluronic acid is soluble in water but insoluble in organic solvents. It has many properties in common with other natural mucopolysaccharides. Hyaluronic acid extracted 에서living organisms is white in color, odorless and highly hygroscopic. Hyaluronic acid in a sodium chloride solution dissociates due to the carboxyl group in glucuronic acid, producing H+ and making it appear as an acidic polyionic anion state, giving hyaluronic acid the properties of an acidic mucopolysaccharide [4, 5]. Although the hydroxyl groups on the hyaluronic acid molecule are arranged in a continuous orientation, forming hydrophobic areas on the 분자chain, the presence of hydrogen bonds between the monosaccharides in the hyaluronic acid molecule chain results in a rigid columnar helical structure in space [6]. The presence of a large number of hydroxyl groups on the inside of the column makes hyaluronic acid highly hydrophilic. Therefore, the hydrophilic and hydrophobic properties of hyaluronic acid allow hyaluronic acid with a concentration of less than 1‰ to form a continuous three-dimensional honeycomb network structure[5].

Water molecules are locked in place within the hyaluronic acid network by polar and hydrogen bonds with hyaluronic acid molecules, and are not easily lost. Studies have shown that hyaluronic acid can adsorb about 1000 times its own 무게in water, which is unmatched by other polysaccharide compounds. Therefore, hyaluronic acid, as a water-retaining agent, is currently the best natural substance found in nature 을retaining water.

Hyaluronic acid combines with proteins to form proteoglycan molecules with a higher molecular weight, which are important components 을maintaining the moisture in loose connective tissue. This gel-like structure of hyaluronic acid-protein-water bonds cells together, allowing them to carry out normal metabolic functions while retaining tissue moisture. It also protects cells from viruses and bacteria, 예방infection, and gives the skin a certain degree of resilience and elasticity [7, 8].

히알루론산의 제조방법 1

전통적인method of preparing hyaluronic acid is the extraction method, which uses raw materials that are generally fresh animal tissues, such as human umbilicalcords, animal vitreous bodies, roosters'빗과 고래 연골.이러한 원료는 원천이 어렵고 비용이 많이 들며, 이러한 원료에 함유된 히알루론산 함량이 매우 낮아 수율 저하로 직결됩니다.게다가 추출 과정이 복잡하고 작동 장치가 번거롭습니다.다량의 효소와 유기용매가 사용되며, 불순물 함량이 높으면 정화가 어려워 히알루론산의 비용이 어느 정도 증가한다.따라서 추출하여 얻은 히알루론산은 계속 확대되는 연구 및 응용 요구를 충족시킬 수 없습니다.이에 과학연구일군들은 HA의 새로운 원천을 찾고 원가를 절감하기 위하여 발효방법을 리용하여 히알루론산을 생산하기 시작하였다 [7].

히알루론산을 준비하는 발효 방법은 1970년대로 거슬러 올라갈 수 있지만, 대규모로 개발되지는 않았습니다.1985년에 이르러서야 일본의 시세이도가 연쇄상구균을 이용하여 히알루론산을 제조한다는 것을 처음으로 보고하였고, 그 후 히알루론산을 제조하는 발효법이 큰 발전을 이루었다.보고된 히알루론산 생성 세균은 주로 베르거 &에 있는 연쇄상구균 그룹 A와 C이다#39;s Manual, such as Streptococcus pyogenes (group A), Streptococcus zooepidemicus (group 200), Streptococcus equi (group C), Streptococcus equi group C, Streptococcus agalactiae group C, and Clostridium perfringens. Group A is mainly pyogenic streptococcus, a human pathogen, and is not suitable as a production strain. It is currently rarely used. Group C streptococcus is not a human pathogen and is relatively suitable 을industrial production. In recent years, the industrial production of hyaluronic acid 사용Streptococcus pyogenes has reached the industrial stage abroad. Table 1 compares the main differences between the extraction method and the fermentation method [7-9].

For the extraction method, the raw material is different, and the extraction and purification process is also different [9]. For example, the cockscomb has low fat content and high hyaluronic acid content. After being ground, it can be directly extracted with distilled water several times or heated to 40-50°C for extraction. A hyaluronic acid solution with a yield of 0.47% can be obtained. For human umbilical cords, the fat content is higher than that of chicken combs. They can be extracted several times with a dilute alkali solution (pH=8) at 60°C, or extracted with a mixture of water and chloroform (20:1/W:W), and washed with an equal volume of chloroform to further degrease. The yield of hyaluronic acid is 0.2%. The extraction of hyaluronic acid from vitreous humor generally uses a NaCl solution (0.1-1M) as the extraction solution, and the yield can reach 0.64-2.4%. Pigskin contains a lot of fat and is tough and not easily ground, so it is generally liquefied in a NaOH solution at 37°C for a period of time, and then neutralized with 50% acetic acid. Although the yield of hyaluronic acid can reach about 0.7%, the purification process is relatively complicated.

The quality of hyaluronic acid prepared using the fermentation method mainly depends on the following four aspects: strain selection, medium matching, fermentation process optimization and separation and purification process. The advantages of the biological fermentation method are that the product is not limited by raw material resources, the process is simple and the cost is low. Therefore, the fermentation method is currently preferred for the preparation of hyaluronic acid. The main bacteria used in the fermentation method for producing hyaluronic acid are Streptococcus zooepidemicus, Streptococcus equi and Streptococcus equi-like.

Fermentation methods for producing hyaluronic acid are divided into aerobic fermentation and anaerobic fermentation. Aerobic fermentation has a high yield and produces hyaluronic acid with a high molecular weight. During the fermentation process, the temperature is usually 37°C, and the pH value needs to be controlled within the range of 6.0-8.5. An environment with too much acid or alkali will affect the growth of the bacteria and reduce the yield of hyaluronic acid. Different 산소dissolution rates can also be used at different fermentation stages to increase the yield of hyaluronic acid. In addition, the viscosity of the fermentation broth can directly reflect the yield of hyaluronic acid. The pseudoplasticity of hyaluronic acid causes the viscosity of the solution to decrease at high shear rates. High stirring rates can significantly increase the molecular weight of hyaluronic acid, but too high a speed can destroy the molecules and reduce the molecular weight of hyaluronic acid. Therefore, the stirring speed is usually controlled at 100–800 r/min. The yield of hyaluronic acid can also be increased by adding a small amount of uracil, glutamine and aspartic acid to the fermentation broth, or by adding lysozyme [10-13].

At present, the extraction of HA in China is still in the stage of using human umbilical cords and chicken combs as raw materials. Shanghai University has reported a method for extracting hyaluronic acid from pig skin, and the molecular weight of the hyaluronic acid produced is about 106. Some people 사용microbial fermentation to produce hyaluronic acid, and the yield has been reported to be 4.6 g/l, but the molecular weight is only 500,000. In addition, some people have also used γ-rays combined with magnetic field mutagenesis to obtain high-yielding strains of hyaluronic acid. For example, Chen Yonghao [14] used ultraviolet and 60Co-γ-ray irradiation to mutate and obtained a strain of non-hemolytic bacteria NC1150, which increased the yield and relative molecular weight of HA.

생체 재료로서의 히알루론산 특성 개선 2

Pure hyaluronic acid has the disadvantages of being easily soluble in water, rapidly absorbed, having a short residence time in tissues, and poor mechanical properties, which limits its use in situations where material hardness and mechanical strength are required. In order to make hyaluronic acid more widely used in the field of biomaterials, it is necessary to chemically modify it to optimize its properties and expand its scope of application. To improve the mechanical properties of hyaluronic acid and control its 저하rate, hyaluronic acid can be chemically modifiedor crosslinked. Hyaluronic acid has functional groups such as hydroxyl, carboxyl and acetamido, and can be modified by cross-linking, esterification, grafting, molecular 수정and compounding. Chemically modified hyaluronic acid clearly possesses the main properties of carboxylic acids and/or alcohols. Carboxylic acids and alcohols are modified by esterification, and combined with hydrazine compounds, dithiothreitol or disulfides [3, 6]. After modification, hyaluronic acid is endowed with a series of good properties such as mechanical strength, viscoelasticity, rheological properties and resistance to hyaluronidase degradation, while maintaining its original biocompatibility.

2.1 히알루론산과 폴리에틸렌글리콜의 공유 교차 연결

Current research shows that the mechanical properties and degradation rate of 펩 티hyaluronic acid gels can be controlled by the degree of cross-linkingand molecular weight of the cross-linking molecule. Hyaluronic acid can be covalently cross-linked with polyethylene glycol diamines 다양 한degrees of cross-linking. Polyethylene glycol was chosen as the cross-linking molecule because it is 생체and hydrophilic. PEGis soluble in aqueous solution and is commercially available in different molecular weights. The elastic properties of the gel are ensured by the deformable PEGchains, while the mechanical properties are ensured by the structurally stable hyaluronic acid chains.

The influence of the degree of cross-linking on the mechanical properties and degradation behavior of hyaluronic acid gels has been studied. Hyaluronic acid gels are prepared from covalently cross-linked hyaluronic acid and two different molecular weights of polyethylene glycol at various degrees of cross-linking. Experiments have shown that as the theoretical degree of cross-linking of hyaluronic acid gels increases from 0 to 20%, the elastic modulus gradually increases. However, when the theoretical cross-linking degree increased to above 20%, the elastic modulus decreased. When the theoretical cross-linking degree was 20%, the elastic modulus increased, and the molecular weight of the cross-linked molecules decreased. At a theoretical cross-linking degree of 20%, the in vitro degradation rate of hyaluronic acid gels 감소with a decrease in the molecular weight of the cross-linked molecules. As the theoretical crosslinking degree increases from 0 to 20%, the degradation rate of 기초연구hyaluronic acid decreases. However, when the theoretical crosslinking degree rises above 30%, there is no significant difference in degradation rate [15, 16]. Further development of hyaluronic acid gels through in-depth research on 그들의controlled mechanical properties and degradation rates will provide a wide range of medical and biological material applications.

Hyaluronic acid is modified by covalently binding it to polyethylene glycol diamines of different molecular weights. The mechanical properties and degradation rate of crosslinked hyaluronic acid gels can be controlled by varying the molecular weight and degree of crosslinking of the crosslinking molecules. It has been found that crosslinked hyaluronic acid gels have controllable mechanical properties and degradation rates, which can provide a wider range of biomedical applications, such as cell transplantation and drug delivery.

2.2 히알루론산과 폴리히드라지드 화합물의 교반

Hyaluronic acid can be cross-linked with different hydrazide compounds to obtain gels with different physicochemical properties under different cross-linking conditions. Hydrazide cross-linkers make the gel resistant to hyaluronidase. Experiments have shown that gel degradation is independent of the concentration of the cross-linking agent, which indicates that degradation only occurs at the interface of the gel. The stability of hyaluronic acid gels in acidic media and their slow dissolution at pH > 7.0 indicate their potential role in controlling drug delivery in an alkaline environment [15–17].

Hydrazide compounds can be used as cross-linking agents to modify hyaluronic acid 겔into more mechanically rigid and brittle gels. Hyaluronic acid can become a stable HA-adipoyl dihydrazide (HA-ADH) derivative in the presence of a large amount of adipic dihydrazide [18]. Paul Bulpitt [19] and others have shown that chemical modification of hyaluronic acid by hydrazide compounds ester intermediates with resistance to hydrolysis and no rearrangement activity can be formed. 새로 운hydrogels with good biocompatibility such as HA-hydrazide and HA-amide have been synthesized, and to some extent the water solubility has been reduced to achieve the effect of slow-release drugs [20].

2.3 히알루론산이 이황화물과 교반

히알루론산은 이황화물과 교반될 수 있다.예를 들어, 일정량의 히드라진 분해 3,3'-dithiopropionic acid (DTP) can be added to a hyaluronic acid aqueous solution, and the pH of the reaction solution can be adjusted from acid to base using HCl and NaOH.Solid carbodiimide (EDC) is added during the process, and finally, separation, freeze-drying, and purification can be used to obtain a mercapto hyaluronic acid derivative (HA-DTPH) [20].

Experiments have shown that the disulfide-crosslinked mercapto-hyaluronic acid derivative (HA-DTPH) gel degrades slowly both in 생체 실험and in vitro, and the degradation rate can be controlled by changing the degree of disulfide cross-linking. At the same time, hyaluronic acid gels have potential clinical applications in wound healing and tissue repair [21].

히알루론산 에스테르화 2.4

카르 esterification

The carboxyl group of hyaluronic acid can undergo esterification with fatty alcohols or aromatic alcohols to form esterified 파생상품[21]. After esterification, the solution rheological properties of HA are significantly improved, forming a weak colloidal network structure. The solubility of hyaluronic acid esterified 파생상품decreases with increasing degree of esterification, and highly esterified derivatives are insoluble in water. In addition, the degree of esterification has a significant effect on the degradation rate. This may be because the hydrophobic fragments of the fully esterified substance make the network of polymer chains more rigid and stable, making it less susceptible to enzymatic degradation. The partially esterified substance is more deformable and more easily combined with water.

Hyaluronic acid esterified derivatives can be made into films and fibers using some conventional process methods, freeze-dried into sponges, or prepared into microspheres by spraying, drying, extracting and evaporating, and can be used as carrier materials for controlled drug release. In addition, this type of hyaluronic acid esterified derivative can be used in the development of artificial skin and artificial cartilage, the culture of mesenchymal stem cells, and also for anti-biofouling and anti-corrosion purposes [20].

Hydroxyesterification

If butyric anhydride and the trimethylpyridine salt of 저분자 히알루론산 are reacted in dimethylformamide (DMF) containing dimethylaminopyrimidine, butyric acid can be coupled to hyaluronic acid. As butyric acid can induce cell differentiation and inhibit the growth of tumor cells, hyaluronan butyrate can be used as a new targeted drug delivery system material.

내부 esterification

Internal esterification of hyaluronic acid derivatives is achieved by intramolecular and intermolecular bonding between the hydroxyl and carboxyl groups of hyaluronic acid. Pressato [22] and Belini [23] et al. pretreated a dimethyl sulfoxide (DMSO) solution of hyaluronic acid with triethylamine, converting hyaluronic acid to [R4N] +HA.2-Chloro-1-methyliodopyridine was then used as a cross-linking agent to cause internal esterification of hyaluronic acid, yielding hyaluronan lactone derivatives with both intramolecular and intermolecular esterification. This method can be used in surgery to reduce 유착after abdominal surgery and obstetric and gynecological surgery. The internal esterified derivative of hyaluronic acid can also be used as a scaffold for tissue damage repair and regeneration of cartilage and bone.

2.5 이식 개조

Hyaluronic acid can be grafted onto natural or synthetic polymers using cross-linking agents to form new materials with modified biomechanical properties and physicochemical properties [20].

상기 공정을 하기 표 2에 나타내었다.또한 HA는 그림 3과 같이 리포솜 표면에 접목하여 타겟팅 및 차폐 효과를 제공할 수 있습니다.

After hyaluronic acid is modified with dihydrazide to form the HA-ADH derivative, drug molecules can be attached to HA-ADH to form HA-bound drugs. Hyaluronic acid can provide 소설drug targeting and controlled release. The general process is as follows: after dihydrazide is linked to HA, the remaining NH2 of the hydrazide can be reconnected with other carboxyl groups in the HA molecule, and intra- or intermolecular cross-linking will occur. At the same time, the remaining NH2 can be connected to the active site of the drug to bond the drug to the hyaluronic acid, or the drug can be first connected to the polyhydrazide and then grafted to the HA molecule to obtain a hyaluronic acid-bonded drug system. The structure is shown in Figure 4.

2.6 복합 수정

Hyaluronic acid is a non-antigenic molecule that can be used in combination with other materials without causing inflammation or an immune response. For example, hyaluronic acid can be combined with collagen [20], which is the main structural protein in the extracellular matrix. The combination of hyaluronic acid and collagen gives it good mechanical properties. Hyaluronic acid can also be combined with chitosan (CS) and gelatin [20], to form a CS-Gel-HA composite material (chitosan-gelatin-hyaluronic acid). This composite material can effectively improve the adhesion of cells to the material surface, increase the survival rate of cells on the material surface, and enable cells to enter the normal growth and proliferation cycle as soon as possible. Hyaluronic acid can also be compounded with synthetic polymers such as poly(lactide-co-glycolide) (PLA/PLGA), which is a non-toxic, fully biodegradable synthetic polymer that is easy to process, degradable, and has a controllable degradation rate. Blending PLA or PLGAwith HA [24] can reduce the degradation rate of HA and prolong the time HA remains in the tissue.

생체재료 분야에서의 히알루론산 적용 3

히알루론산 유도체 obtained through modification can improve specific properties as required, which greatly expands the application of hyaluronic acid in the field of biomaterials. At present, hyaluronic acid or its derivatives are used in various fields, including surgical anti-adhesion, arthritis treatment, ophthalmic disease treatment, local drug delivery carriers, tissue engineering, etc. [25-29]. The application of different modified 히알루론산 제품 is shown in Table 2.

4 결론

This paper reviews the preparation methods of hyaluronic acid and the modification and compounding of hyaluronic acid. At present, research on the preparation and modification and compounding of hyaluronic acid has made gratifying progress, but there is still some way to go before it can be used in clinical applications. In addition, hyaluronic acid is a kind of bioabsorbable material with high viscoelasticity, plasticity, permeability and unique rheological properties as well as good biocompatibility. Due to its strong moisturizing properties and good biocompatibility, it has also become an important raw material for biomedical applications. It is widely used in ophthalmology, orthopedics, and even extends to surgery, pediatrics, neurology and other fields. In addition, hyaluronic acid can effectively prevent postoperative adhesion without side effects. It can also be used as a drug release carrier and is a popular new biomedical material. However, hyaluronic acid also has shortcomings that need to be compensated for by various chemical modifications to improve its mechanical strength, resistance to hyaluronidase degradation, etc. Common modification methods include cross-linking, esterification, grafting, molecular modification and compounding. In-depth research on hyaluronic acid is therefore continuing. Current research focuses on improving the properties of hyaluronic acid gels and making them smarter, in order to promote the wider use of these materials in the field of biomaterials.

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