히알루론산은 무엇으로 만들어졌는가?

루 론 산is also known as hyaluronic acid. It is a viscous polysaccharide composed of (1-3)-2-acetamido-2-deoxy-β-D-glucose units linked by β-1,4 and β-1,3 glycosidic bonds, alternately connected with (1-4)-O-β-D-glucuronic acid units. Hyaluronic acid is a widely distributed polysaccharide molecule in nature that forms a viscoelastic substance when combined with water. In the human body, it is primarily found in skin and connective tissues, serving as an extracellular matrix. In addition to providing cells with water and volume, it possesses properties such as tissue stability, strong binding capacity, high viscoelasticity, weak species and tissue specificity, and lack of immunogenicity. Hyaluronic acid has widespread applications in drug delivery, anti-adhesion in orthopaedic surgery, cardiology, arthritis, cancer therapy, ophthalmology, and food supplements.

히알루론산 1 제조

1.1 동물 조직 추출법

1934년 미국 컬럼비아 대학교 안과 교수인 마이어 등은 소의 눈 [1]의 유리체 유머에서 처음으로이 물질을 분리했다.1970년대에는 발라즈 등이 닭빗과 사람의 탯줄에서 히알루론산을 추출했다 [1].

이main process for extracting hyaluronic acid powder from animal tissues includes dehydration, grinding, soaking, extraction, purification, precipitation, and separation. The specific process is as follows: first, homogenise the tissue, then extract it with water and dilute salt solution. The extract is precipitated with chlorinated hexadecylpyridine or hexadecyl trimethylammonium bromide, The resulting precipitate is dissolved, the residue is removed, and the solution is precipitated with 2–3 times the volume of ethanol to obtain crude hyaluronic acid. Purification can be achieved by treating the crude product with ethanol or quaternary ammonium salts, or by further removing impurities and proteins using enzymatic hydrolysis, ultrafiltration, or ion exchange techniques, ultimately yielding the final product.

The tissue extraction method has the advantages of a simple process, high molecular weight, high viscosity, and strong moisturising properties. However, due to limitations in raw material availability and the coexistence of hyaluronic acid with other polysaccharides such as chondroitin sulfate in biological tissues, this method has low yield, poor separation, complex process, and high cost, making it unsuitable for large-scale production. It is more suitable for small-scale production with dispersed raw material sources. With the continuous increase in demand and application scope of hyaluronic acid, the animal tissue extraction method will inevitably be gradually replaced by other methods.

1.2 미생물 발효법

1970년대부터 연구자들은 미생물 발효를 이용해 히알루론산 분말을 만들기 시작했다.일본의 시세이도는 1985년 Streptococcus equi를 이용해 히알루론산을 생산하는 것을 처음 발표했다.흔히 보고되는 히알루론산 생성 세균은 주로 Bergey&에 등재된 연쇄상구균 종의 A 군과 C 군이다#39;s Manual. The A group mainly includes Streptococcus pyogenes, which are pathogenic to humans and unsuitable as production strains; the C group of Streptococcus species are non-pathogenic to humans and more suitable for industrial production. In recent years, foreign countries have already achieved industrial-scale production of hyaluronic acid using C group Streptococcus species [2].

Operational process: Inoculate the slant culture into conical flasks containing culture medium, incubate at 37°C for 12–16 hours, then transfer to seed tanks. The nitrogen source in the culture medium is peptone, beef extract, yeast extract, etc., the carbon source is glucose, and the inoculation ratio is 1:10. The fermentation broth formulation is essentially the same as the seed broth, except that the glucose content is higher, typically 3%–6%. Maintain an aeration rate of 0.3–1.0 vvm (volume of air per minute relative to the fermentation volume), stir at 120 rpm, and ferment at 37°C for 40–46 hours. During fermentation, adjust the pH to 6.5–7.0. In the later stages of fermentation, when the glucose concentration drops below 0.5% and the pH decreases slowly or stops decreasing, fermentation is complete. After fermentation, adjust the pH to 4.0–4.5 with trichloroacetic acid, filter to remove the bacterial mass, adjust the filtrate pH to 6.0–6.5, add 95% ethanol, and precipitate hyaluronic acid. Dissolve the precipitate in a 0.1 mol/L sodium chloride solution, stirring, add an excess of 1% CPC to form a complex precipitate with the hyaluronic acid in the filtrate, let stand, siphon off the mother liquor, wash the precipitate twice, dissolve in 0.4 mol/L sodium chloride solution with stirring overnight, filter, precipitate with ethanol, dehydrate with ethanol, and vacuum dry to obtain hyaluronic acid.

Currently, the fermentation method for producing hyaluronic acid as an alternative to tissue extraction has become a trend. The fermentation method for producing hyaluronic acid has a simple process, does not rely on animal tissues, and its yield is not limited by raw material sources. Additionally, hyaluronic acid exists in a free state in the fermentation broth, making it easy to separate, purify, and industrialise. Therefore, the fermentation method has become the primary method for industrial production of hyaluronic acid [3].

1.3인공합성법

Related studies have shown that hyaluronic acid in living organisms is synthesised by hyaluronic acid synthase catalysing the reaction of UDP-G1cA and UDP-G1cNAc [4]. Therefore, researchers both domestically and internationally have attempted to synthesise hyaluronic acid in vitro using enzymatic methods and have made some progress. Neuman [5] reported a method for the artificial synthesis of hyaluronic acid, First, a polysaccharide polymer, one of the biological macromolecules, is used to synthesise hyaluronic acid oxazepane derivatives. Then, a decomposing enzyme (hyaluronidase from sheep or cow testes) is added to form a complex of the derivative and the enzyme. Finally, the enzyme is removed from the reaction solution, and hyaluronic acid is synthesised. Additionally, precipitation, separation, and purification are required.

Artificially synthesised hyaluronic acid is similar in quality to natural hyaluronic acid, but the precursor materials required for in vitro synthesis are expensive, so the artificial synthesis method is generally used for producing high-molecular-weight, high-purity hyaluronic acid [6].

히알루론산 유도체 연구 2

Clinical applications have demonstrated that natural hyaluronic acid possesses excellent biocompatibility; however, it is easily degraded and diffused in tissues, resulting in short retention times in the body and suboptimal application outcomes. Recent studies have shown that hyaluronic acid derivatives obtained through modification and cross-linking can address these limitations [7].

The hydroxyl, carboxyl, N-acetylamino, and reducing ends of the hyaluronic acid molecule are the four sites susceptible to chemical modification, with primary modification methods including esterification, cross-linking, and grafting. The two most commonly used sites for covalent modification of hyaluronic acid are the carboxyl and hydroxyl groups. Currently reported derivatives with clinical application value are primarily new excipients derived from the modification of the hydroxyl and carboxyl groups of hyaluronic acid. 

These derivatives can be selected based on their intended use, with appropriate cross-linking agents chosen to enhance relevant physical properties such as biocompatibility, degradability, in vivo retention time, drug loading capacity, and stability. Hyaluronic acid gels modified with diethyl sulfoxide (DVS) exhibit unique biocompatibility and other properties, solutions using aldehydes as cross-linking agents (hyaluronic acid fluids) exhibit high viscoelasticity, while cross-linking agents with multiple functional groups, such as epoxy compounds, can improve water solubility. Additionally, the reaction between cross-linking agents and the carboxyl groups of hyaluronic acid can produce derivatives, such as esters and amines, which enhance biocompatibility, among other properties [8]. Furthermore, cross-linking reactions can be used to design and prepare functional, intelligent drug carriers, thereby enhancing drug efficacy, improving drug targeting, and reducing adverse effects. Therefore, the use of cross-linking reactions to modify hyaluronic acid not only expands its application scope but also enhances its practical value [9].

히알루론산 파우더 3가지 적용

3.1 화장품에의 응용

In the early 1980s, the excellent moisturising properties of hyaluronic acid garnered significant attention from the international cosmetics industry. Extensive literature and decades of domestic and international applications have demonstrated that hyaluronic acid can be used in cosmetics such as creams, lotions, masks, beauty serums, toners, lipsticks, foundations, and essences, as well as in products like shampoos, conditioners, mousses, and facial cleansers. For example, Restylane by Swiss company Restylane, Hydrobella moisturising lotion by French company Maybelline, and domestic brands such as Yongfang, Ziranmei, and Lvdanlan [10]. In cosmetics, hyaluronic acid plays a role in moisturising, preventing and repairing skin damage, nourishing and lubricating the skin, and having antibacterial and anti-inflammatory effects. Currently, for the rejuvenation of facial wrinkles, botulinum toxin and skin fillers are the two main non-surgical treatment methods, targeting dynamic and static wrinkles, respectively. Since hyaluronic acid was first used as a skin filler, its advantages and efficacy have gradually gained recognition from both medical professionals and patients, leading to a steady increase in usage. It has broken the dominance of collagen-based products and has ranked first in usage in the United States for five consecutive years [11].

3.2 식품에서의 응용

In China, over 98% of hyaluronic acid is primarily used in the pharmaceutical, clinical diagnosis, and cosmetics industries. Hyaluronic acid is still in its infancy in the food sector, with limited reports available. In fact, hyaluronic acid is not only used topically for moisturisation; oral hyaluronic acid can also enhance the body' s 수화.히알루론산은 소화와 흡수를 통해 활력과 젊음을 증진시킬 수 있습니다;피부를 촉촉하고 매끄럽게 하여 부드럽고 탄력 있게 만들 수 있습니다;그리고 노화를 지연시키고 관절염, 동맥경화증, 부정맥, 뇌위축 등의 질환을 예방할 수 있다.일본 히알루론산 연구소에서 생산하는 히알루론산 ECM·E, 내추럴맥스에서 생산하는 뷰티 패스트 캡슐, 소스 내추럴스에서 생산하는 히알루론산 캡슐 및 정제, 국내에서 판매되는 경구 미용 콜라겐 히알루론산 및 루이& 등 히알루론산 기반 뷰티 및 건강 보조식품들이 국내뿐만 아니라 세계적으로 늘어나고 있다#39;어 수원 캡슐.

3.3 임상적 적용

순수한 히알루론산 제형입니다임상용으로 액체 스프레이, 젤 적용, 필름 적용 등 3가지 형태로 제공됩니다.히알루론산은 안과 및 정형외과에서 널리 사용되며 일반외과, 이비인후과, 손 수술 등 다양한 분야로 확장되고 있습니다.히알루론산은 뼈와 관절질환 치료에 쓰이며 관절염, 관절통증을 효과적으로 완화시키고 관절기능을 조절한다.골절 고정 수술, 관절 강직, 요추 원추절제술 주사 치료에서도 좋은 결과를 보였다.수술 후 조직 유착은 수술에서 큰 어려움입니다.광범위한 임상실험을 통해 히알루론산이 수술 후 유착을 효과적으로 방지해 유착으로 인한 합병증과 후유증을 현저히 줄인다는 것이 증명됐다.히알루론산은 사람과 동물의 몸을 구성하는 천연 성분이기 때문에 부작용이 없는 의약품 원료로서 안전하고 신뢰할 수 있습니다.따라서 히알루론산은 오늘날 의료분야에서 크게 각광받고 있는 새로운 생체재료이다.

Pang Suqiu et al. [12] used hyaluronic acid solution to treat dry eye syndrome, and clinical results indicated that hyaluronic acid has a good therapeutic effect on dry eye disease. Goto et al. [13] administered sodium hyaluronate into the joint cavities of 25 patients with chronic progressive joint diseases, and followed up with clinical symptoms and parameters. The results showed significant improvements in all indicators, with patients'조건을 개선하다.뤄홍투 등 [14]은 각종 갑상선 수술을 받는 환자 396명을 무작위로 두 그룹으로 나눴다.실험군 (214명)은 갑상선 상처 표면에 히알루론산 주사를 맞았고, 앞목 근육군, platysma 근육의 깊은 층까지 깊었다.182명의 환자 중 대조군은 히알루론산을 투여받지 않았다.

The results showed that 26 cases of postoperative adhesion occurred in the experimental group, while 41 cases occurred in the control group, with a significant difference between the two groups. Additionally, hyaluronic acid, as an important component of the extracellular matrix, regulates interactions between cells and between cells and the matrix, promoting wound healing and inhibiting abnormal scar formation caused by excessive collagen deposition. Hyaluronic acid also promotes granulation tissue formation, reduces scab area, shortens scab detachment time, and has a promoting effect on burn healing. Jiang Lixia et al. [8] reported that spraying burn patients with hyaluronic acid artificial skin powder resulted in good therapeutic effects and high safety.

3.4 약국에서의 응용

약물의 안정성 향상 3.4.1

Freeze-dried single-chamber liposomes tend to reform into large multi-chamber liposomes, which is detrimental to therapies requiring small particle liposomes. Wang Yuhui [15] reported that by bonding sodium hyaluronic acid to the surface of biodegradable liposomes via hydrogen bonds, the transformation of freeze-dried single-chamber liposomes into large multi-chamber liposomes could be effectively inhibited, thereby stabilising freeze-dried single-chamber liposomes. Peer et al. [16] prepared hyaluronic acid-heparin conjugate gels and bound recombinant human basic fibroblast growth factor-2 (FGF-2) to the heparin end of the hyaluronic acid-heparin conjugate. In vitro analyses indicated that hyaluronic acid-heparin conjugate gels enhance the stability and activity of FGF-2.

제어-릴리스 제식에서의 응용 3.4.2

Hyaluronic acid and its derivatives can serve as sustained-release carriers for various drugs, such as anticancer drugs, anti-inflammatory drugs, and anaesthetics. Hyaluronic acid has diverse application forms as a drug carrier. Chou et al. [17] prepared hyaluronic acid-coated polycyanoacrylate butyl ester nanoparticles (hyaluronic acid-PBCA), which were obtained through a free radical polymerisation reaction of hyaluronic acid monomers and polycyanoacrylate monomers. Using paclitaxel as a model anticancer drug, the encapsulation efficiency of hyaluronic acid-PBCA nanoparticles reached 90%. The tumor cell proliferation inhibitory effect of paclitaxel-loaded hyaluronic acid-PBCA nanoparticles was significantly higher than that of paclitaxel-loaded PBCA nanoparticles and paclitaxel injection. Homma et al. [18] conjugated hyaluronic acid with the anti-inflammatory drug methotrexate using short peptides and linkers to form hyaluronic acid-methotrexate conjugates for the treatment of osteoarthritis, achieving controlled-release of the drug at the site of inflammation and effectively reducing the toxic side effects of methotrexate. Hyaluronic acid hn et al. [19] prepared injectable hyaluronic acid microgel for the controlled release of erythropoietin (EPO). In vivo release experiments showed that EPO was slowly released from the microgel, with plasma EPO concentrations exceeding 0.1 mg/L, which is the minimum concentration required for EPO to exert its effects. This concentration was maintained for 7 days without significant toxic side effects.

Hyaluronic acid and its derivatives as carriers offer unique biocompatibility, rheological properties, and chemical and physical diversity, making them an effective sustained-release system for pharmacologically active molecules. The practical application of hyaluronic acid as a biological carrier combined with various drugs will be a key focus of future research and development.

항암제에 적용 3.4.3

Research has shown that certain solid tumours and metastatic lymphocytes express high levels of hyaluronic acid receptors—CD44—with which hyaluronic acid has a strong affinity. As a targeted carrier for antitumour drugs, hyaluronic acid can bind smaller drug molecules to its network structure or graft drug molecules onto hyaluronic acid-based drug carriers, targeted binding with receptors on the surface of tumour cells, enabling more drug molecules to enter tumour tissue, increasing the absorption and retention time of anticancer drugs in tumours and lymph nodes, thereby enhancing drug efficacy and reducing toxic side effects. Luo et al. [20] esterified hyaluronic acid with paclitaxel to form a bio-targeted prodrug. Fluorescent labelling revealed that the drug could specifically bind to cells, and this binding could be blocked by excess hyaluronic acid and anti-CD44 antibodies but not by chondroitin sulfate. Paclitaxel was released through the hydrolysis of the ester bond. Brown et al. [21] administered 5-fluorouracil and methotrexine containing hyaluronic acid and without hyaluronic acid to nude mice with thymoma via tail vein injection, The results showed that the drug concentrations in the tumour tissue increased by 403% and 106%, respectively.

Hyaluronic acid and its derivatives can be formulated into drug compositions or used as carriers to target and retain different drugs in various parts of the human body. This not only enables drugs to act on more precise target sites, increasing the concentration of therapeutic drugs at the site of action and significantly enhancing therapeutic efficacy, but also avoids drug side effects, providing a more effective approach for disease treatment [22].

3. 5가 생체

As a biomaterial, hyaluronic acid possesses advantages such as good biocompatibility and rapid biodegradability. Chen Jianying et al. [23] conducted biocompatibility tests on cross-linked hyaluronic acid gel membranes (CIIA-gel) in terms of in vitro haemolysis, cytotoxicity, acute toxicity, eye irritation, intradermal reaction, sensitisation, and genotoxicity. The results demonstrated that CIIA-gel material exhibits excellent biocompatibility and stable physical and chemical properties. Xiao Rongdong et al. [24] conducted in vivo degradation tests on hyaluronic acid membranes, which conformed to the general process of biodegradation of biomaterials in vivo, with no significant inflammatory reactions and satisfactory tissue compatibility. Fan Hongbin, Hu Yunyu et al. [25] conducted experimental studies on gelatin-chondroitin sulfate-sodium hyaluronate as a tissue engineering cartilage scaffold, demonstrated that gelatin-chondroitin sulfate-sodium hyaluronate porous scaffolds prepared by vacuum drying at 80°C exhibit good pore size, porosity, and compressive load-bearing capacity, and show good compatibility with rabbit bone marrow mesenchymal stem cells (MSCs), making them a novel biomimetic scaffold material for cartilage tissue engineering.

4분석 및 요약

In recent years, hyaluronic acid has developed rapidly. In 1985, the total global sales of hyaluronic acid in the international market reached 100 million USD, rising to over 200 million USD in 1990. By 2004, the global market size for hyaluronic acid applications was approximately 3 billion USD, and by 2012, it had grown to approximately 4.5 billion USD. Statistical data show that in 2012, the total sales of hyaluronic acid as a single skin filler in the international market reached 1.4 billion US dollars, with the markets for drug cosmetics and skincare products and medical products each accounting for half [26-28].

히알루론산은 새로운 엑시피젠트로서 생체적합성이 우수하고 분해가 빠르며 보습성이 우수하고 조직의 안정성과 같은 장점을 가지고 있다.그러나 여러 가지 문제가 여전히 중국에서 히알루론산 개발을 방해하고 있다.첫째, China's production capacity for hyaluronic acid is far from meeting market demand, especially for high-molecular-weight pharmaceutical-grade hyaluronic acid, which must be imported from abroad. Therefore, increasing the molecular weight and production volume of hyaluronic acid is an urgent issue to address.

Second, the variety of hyaluronic acid derivatives is relatively limited, with similar physical and chemical properties, limiting the range of options available and necessitating further research and development. Third, there are no clear grading standards for hyaluronic acid, which is currently classified into food-grade, cosmetic-grade, and pharmaceutical-grade categories based on intended use. The criteria for these classifications are vague, and there is significant overlap between grades, causing significant inconvenience in practical applications. Fourth, when used as a drug carrier, there is no standard method for calculating drug loading capacity, which affects drug content and preparation processes. Fifth, the process of combining hyaluronic acid with other materials to produce biomaterials is still immature, with low production rates and currently at an early stage, requiring further research.

추가적으로 수율 및quality of hyaluronic acid produced by microbial methods primarily depend on the following factors: the performance of the production strain, the culture medium, the optimisation of fermentation processes, and the control of fermentation and subsequent separation and purification [29-30]. In China, due to limitations in fermentation equipment, processes, and strain selection, the production level and efficiency of hyaluronic acid are relatively low compared to foreign countries, with imports being the primary source, especially for high-purity, high-molecular-weight hyaluronic acid. Due to these limitations, the price of hyaluronic acid in China remains high. However, with the increasing maturity of fermentation technology in China, growing health awareness, and improved understanding of hyaluronic acid, the market for food-grade hyaluronic acid has seen rapid expansion in recent years. In summary, whether for pharmaceutical, cosmetic, or food applications, hyaluronic acid holds vast development potential and demand.

Finally, it is hoped that through the joint efforts of domestic and international scholars, more innovative ideas and applications can be applied to hyaluronic acid research and development, ensuring that the comprehensive development of hyaluronic acid is just around the corner.

참조

[1] 배휘유, 서정, 이휘준 외.히알루론산 (J.광동화학공업, 2010, 37(11):332.

[2] 송레이, 왕텐페이.히알루론산 연구의 현황 고찰 [J.산동경공업대학 논문집 2012, 26(2):78.

천이한, 예루이, 취안위 등.연구논문:히알루론산 (J.상해응용기술학회 논문집 2012, 12(2):1124.

[4] Valarie L, Bruce A. Streptococcus pyogenes와 Streptococcus equisimilis 로부터 재조합 hyaluronan synthases의 Purification and lipid dependence of the recombinant hyaluronan synthases from Streptococcus pyogenes [J].J Biol Chem, 1999, 274(7):4239.

[5] Neuman MG, Orua L, Coto G 등.히알루론산은 in vitro에서 피부세포에서 에탄올로 유발된 세포사멸시 회복을 위한 신호.Clin Biochem, 2010, 43 (10/11):822.

[6] Ozgenel G, Et6z a. 히알루론산의 반복주사가 굴곡힘줄 수복 후 복막성 유착에 미치는 영향:예비 무작위, 위약 대조 임상시험 [J].Ulus Travma Acil Cerrahi Derg, 2012, 18(1):11.

[7] Balazs E A, Laurent T C. 「 Round table discussion:new applications for hyaluronan [A] 」 (영어).로랑 T C. 히알루로난의 화학, 생물학, 의학적 응용과 그 유도체 [M.런던:포틀랜드 출판사, 1998:325.

[8] 장련하, 왕원빈.히알루론산 및 그 유도체의 의약에의 응용 [J.대한재건외과학회지 2010, 14(15):56.

[9] 수신, 시단평, 예원시 등.교배된 히알루로난 유도체 [J]의 준비 진행.광동화학공업, 2012, 39(5):99.

[10] 판 홍 메이.연구논문:히알루로난 (J.사천식품과 발효, 2003, 1(8):67.

[11] 우수판.히알루론산의 기초지식 및 임상응용 (J.현대실용의학, 2010, 22(4):171.

[12] 범서규, 조우진성, 천규황 외.히알루론산 나트륨의 임상적 응용 [J.Straits Pharmacy, 2011, 15(4):252.

[13] 고토 M, 하뉴 T, 요시오 T 등.히알루론산 (SI-6601D)의 관절내 주사는 류마티스 관절염에서 관절통 및 활액액 프로스타글란딘 E2 수치를 개선한다:다기관 임상시험 [J.Clin Exp Rheumatol, 2001, 19(4):377.

[14] Luo Hongtu, Yang Shao Yu.갑상선 수술 후 히알루론산나트륨의 수술 후 유착에 대한 예방효과에 관한 연구.대한임상외과학회지, 2009, 12(5):313.

[15] 유희왕.히알루론산 및 그 나트륨염의 의약학적 제형에의 응용 (J.식품의약학, 2011, 7(8):78.

[16] 양하오, 웅원쑤오, 잉궈칭 등.교반형 히알루론산 유도체의 제조 및 응용 (J.화학공업발전, 2006, 5(9):234.

[17] Chou W Y, Ko J Y, Wang FS 외.히알루론산 나트륨 치료가 완전 눈물없이 회전근개 병변에 미치는 영향:무작위, 이중 맹검, 위약대조 연구 [J].어깨 및 팔꿈치 외과학회지, 2010, 19(4):557.

[18] Homm A, 사토 H, 타무라 T 등.골관절염 치료에서 이익을 극대화하기 위한 히알루론산-메톡트렉세이트 공중합체의 합성 및 최적화.Bioorganic &약용화학, 2010, 18(3):1062.

[19]Hahn S, Kim JS, Shimoboujit H. Injectable hyaluronic acid microhydrogels for controlled release formulation of erythropoietin [J].J Biomed Mater Res A, 2007, 80(4):916.

[20]Luo Y, Ziebell M R, Prestwich G D. 암세포를 표적으로 하는 히알루론산-택솔 항암 바이오 공액이다 [J.biomacromolecule, 2000, 1(2):208.

[21]Brown T J, Hatherell E M, Falzon J L 등.인체 유방종양 이종 이식에 대한 히알루로난 항대사체 항암제 표적.(2005) 암 Chemother Pharmacol에 제출.

[22] Liu Z, Wang B. 히알루론산 (J)의 임상 연구에 새로운 진전.식품의약학, 2006, 8(12):98.

[23] 천장잉, 송하이보.cross-linked hyaluronan gel 막의 제조 및 생체적합성 연구 (J.의생명공학연구, 2009, 28(2):104.

[24] 샤오룽동, 윈궈싱.콜라겐/히알루로난막과 젤라틴 스펀지 비계재료의 기계적 특성 및 조직적합성 비교 [J.중국조직공학연구 2012년, 16(25):1123.

[25] 판홍빈, 윤유.조직공학적 연골비계로서 젤라틴-콘드로이틴 황산나트륨 히알루론산에 관한 실험적 연구 (J.대한재건외과학회지 2005, 19(6):473.

[26] Chou CL, Li HW, Lee SH 외.무릎 골관절염을 동반한 류마티스 관절염 환자에서 히알루론산의 관절내 주사의 효과.대한한의사협회지 2008, 71(8):411.

[27]이 H,이 K, 박 TG.히알루론산-파클리탁셀 공액 미셀:합성, 특성 및 항종양 활성 [J.생물공액화학, 2008, 19(6):1319.

[28]Benjamin Y S O, Ranganath S H, Lee L Y, 외.glioblastoma multiforme에 대한 수술 후 화학 요법에서 통제된 방출을 위한 PLGA foam의 Paclitaxel 전달 (J.Biomaterial, 2009, 30(12):3189.

[29]Park K, Lee M Y, Kim K S, 외.환원성 polyethyleneimine hyaluronic acid conjugate로 복합된 VEGF siRNA에 의한 표적 특이적 종양 치료.Biomaterials, 2010, 31(19):5258.

[30]Sudhir H, Yilong F, Davis Y 등.submicro nano-scale PLGA 임플란트를 이용하여 뇌신경교종에서 약리작용과 치료효능이 증진된 paclitaxel을 전달하고자 하였다 [J.Biomaterial, 2010, 31(3):5199.