상처드레싱을 위한 히알루론산 사용에 관한 연구

피부, 보디 &처럼#39;의 제1 방어선, 병원균의 침입을 저항하는데 매우 중요한 역할을 한다.그러나 일상생활에서 피부는 상처와 상처 형성에 취약하다.상처 치유는 지혈, 염증, 증식 및 리모델링을 포함하는 복잡하고 역동적인 과정입니다.상처가 감염되거나 과도한 염증과 같은 다른 합병증이 발생하면 상처 치유 과정이 예방되거나 지연될 수 있습니다.이밖에 일부 화상, 수술상처로 인해 흔히 피부에 흉터가 생기는데 피부섬유화증이라고도 하는데 이는 피부의 정상적인 기능에 불리하다.피부 조직에 과도한 상처가 생기면 유연성이 떨어지고 기능이 이상해지며 가려움과 통증까지 생길 수 있다.상처 치유 과정의 한계를 극복하기 위해, 연구원들은 상처 드레싱을 만들기 위한 다양한 생체 물질을 개발했습니다.형태학에 따라 상처 드레싱은 전기적으로 방직된 실크, 하이드로겔, 막 또는 스펀지로 분류할 수 있습니다.다른 형태에도 불구하고, 대부분의 상처 드레싱은 독성이 없고, 항균성이 있으며, 생체적합성 및 생분해성이 있고, 상처를 빠르게 치유하는 특성 [1]을 가지고 있다.

루 론 산 is an anionic mucopolysaccharide composed of D-glucuronic acid alternately linked with N-acetylaminoglucosamine, which is found in the extracellular matrix of vertebrates, skin, vitreous body of the eye, cartilage, and joint fluid. The physicochemical properties of hyaluronic acid include hydrophilicity, antioxidant properties, fluidity, and viscoelasticity. The biological functions of hyaluronic acid are related to its molecular weight, e.g., high molecular weight hyaluronic acid inhibits inflammation, anti-angiogenesis, and scarring, whereas low molecular weight hyaluronic acid promotes angiogenesis, inflammation, and scarring. Due to the limited role of endogenous hyaluronic acid, it is important to use exogenous hyaluronic acid to prepare different types of wound dressings for wound repair. The molecular structure of hyaluronic acid is shown in Figure 1.

히알루론산의 물리화학적 성질 1

Hyaluronic acid belongs to a group of glycosaminoglycans that, unlike other glycosaminoglycans, are not sulfated and are usually not covalently attached to any core protein. The unique physicochemical properties of hyaluronic acid, such as hydrophilicity, fluidity, viscoelasticity, and antioxidant properties, have led to its widespread use in the production of various forms of wound dressings.

1. 1 Hydrophilicity

Hyaluronic acid is one of the important components of the extracellular matrix. Due to the presence of a large number of hydroxyl and carboxyl groups in its structure, hyaluronic acid is highly hydrophilic. This property also makes hyaluronic acid with a large number of negative charges, so as to attract more cations and water molecules. Hyaluronic acid has the properties of water absorption, water retention, etc., and also has a strong ability to complex water molecules, which is known as ‘nature's 보습인자'이며, 눈의 윤활, 보습, 안구건조증 치료에 사용할 수 있습니다.

1.2 플루이디싱 특성

Hyaluronic acid is also an important component of joint fluid, which can lubricate joints and reduce vibration, which is inseparable from its fluidity. In medical treatment, tracheal intubation is a key step in mechanical ventilation and respiratory support, and is used in cardiopulmonary resuscitation and respiratory diseases, etc. However, prolonged friction between the trachea and human tissues leads to damage of the mucous membrane of the laryngeal trachea, which results in inflammation, difficulty in articulation, and other symptoms, and in serious cases, it may endanger the lives of the patients. Clinical lubricants, including benzydamine hydrochloride gel, lidocaine 5% gel/cream, and corticosteroid creams, are commonly used to relieve these symptoms. The most commonly used lubricant is lidocaine cream, but it contains additives that can cause hypersensitivity reactions or trigger atopic dermatitis, so lubricating, non-toxic agents are constantly being investigated, and hyaluronic acid is a good candidate.

1. 3 Visco-elasticity

상온에서,히알루론산은 흰색의 마른 가루 형태의 고체이다악취가 없고 무기용매에 용해되며 유기용매에 용해되지 않는다.히알루론산이 물에 용해되면 그 수용액은 점탄성과 투과압력이 양호하며, 또한 비뉴턴 유체 특성을 갖는다.히알루론산은 화학적으로 쉽게 변형될 수 있기 때문에 높은 분자량 구조를 형성할 수 있다.분자량이 높은 히알루론산의 점탄성 용액은 관절의 활액을 모방하는 데는 잘 적합하지만, 내구성이 강한 기계적 무결성을 가지지는 못한다 [2].

1.4 항산화제의 특성

Hyaluronic acid also has antioxidant properties and can act as an antioxidant due to the formation of a viscous pericellular meshwork around the cell that limits the movement of ROS in the vicinity of the cell or other biomolecules, where excess reactive oxygen species can damage proteins, lipids, and DNA. Some of the antioxidant properties of hyaluronic acid are able to reduce the risk of apoptosis induced by UV light and the risk of acid-induced DNA damage.

히알루론산의 생물학적 특성 2

연구 결과에 따르면 다음과 같습니다biological functions of hyaluronic acid (HA) are closely related to its molecular weight [3-4] . Hyaluronic acid can be classified into five categories according to its molecular weight (MW), i.e., HA oligosaccharides (O-HA, MW < 1×104 Da), which can promote angiogenesis, anti-tumour, wound healing, osteogenesis, immune and metabolic regulation, and ageing; and low-molecular-weight HA (LMW-HA, MW < 25×104 Da), which is more easily absorbed by the human body and can promote wound healing. Low molecular weight HA (LMW-HA, 1×104 Da < MW < 25×104 Da), more easily absorbed by the human body, can promote wound healing, vascularity, scarring, and plays an important role in chronic wound healing; medium molecular weight HA (MMW-HA, 25×104 Da < MW < 100×104 Da), moisturising, lubricating, and slow release of medicines, etc.; high molecular weight HA (HMW-HA, MW ≥ 1×106 Da), has good moisturising, lubricating, and adhesion properties. High molecular weight HA (HMW-HA, MW ≥ 1×106 Da) has good moisturising, lubrication, viscoelasticity, and can inhibit inflammation, anti-angiogenesis, and inhibit scarring; Ultra-high molecular weight HA (vHMW-HA, MW ＞ 6×106 Da) has lubrication, viscoelasticity, and so on.

2. 1 Biodegradability

Hyaluronic acid is a kind of unsulfated glycosaminoglycan, which is the main component of the extracellular matrix of proliferating and migrating cells, and is especially abundant in early embryos. Exogenous hyaluronic acid can be degraded by physical (gamma radiation, ultrasound), chemical (acid hydrolysis, alkaline hydrolysis, oxygenation degradation), and enzymatic methods, and is commonly used in biomedical, cosmetic, and drug delivery applications. Endogenous hyaluronic acid is usually degraded by hyaluronidase and free radicals to low molecular weight hyaluronic acid and glucosamine.

세균성 특성 2.2

Comparison of the antimicrobial effect of hyaluronic acid with other natural polymers shows that chitosan is structurally similar to hyaluronic acid and has antimicrobial properties. Bacteria can avoid the inhibitory effect of hyaluronic acid in two ways, either when they contain the ability to produce hyaluronic acid as a mucus capsule, or when they can produce hyaluronan lytic enzymes to lyse it. Therefore, infections can occur in some hyaluronic acid applications, such as contact lenses and wound dressings. Low molecular weight hyaluronic acid has no inhibitory effect on Staphylococcus aureus, and high molecular weight hyaluronic acid has only a minimal inhibitory effect on Staphylococcus aureus.

2.3 상처 치유 촉진

In the human body, hyaluronic acid binds to CD44, a receptor for keratinocytes in wounds, and stimulates cell proliferation and migration. The affinity of CD44 for hyaluronic acid is related to its molecular weight, i.e. the higher the molecular weight, the higher the affinity for the receptor.

상처 드레싱의 3가지 다른 형태의 히알루론산

The unique physicochemical and biological properties of hyaluronic acid have led to its use in a wide range of different forms of medical wound dressings such as electrostatically spun silk, membranes, hydrogels and sponges.

3.1 히알루론산 기반 정전기 방사

정전기 방사는 정전기장 하에서 마이크론부터 나노미터 스케일에 이르는 직경을 가진 대전된 고분자 필라멘트를 생산하는 데 효과적인 기술이다.ESP에서 준비한 섬유 상처 드레싱은 다공성이 높고 연성이 우수하며 약물 운반 능력이 우수하여 상처 세포가 숨을 쉴 수 있을 뿐만 아니라 세균 성장을 억제합니다.정전식 스펀레이스 드레싱은 기존 드레싱으로 커버하기 어려운 부분도 커버할 수 있다.이러한 우수한 특성으로 인해 정전기 회전 기술을 다양한 생의학 응용 분야에 사용하게 되었습니다.

수세나 등 [5]은 동물로부터 히알루론산과 케라틴을 추출하여 상처치료를 위한 동축형 전기방사 섬유구조에 생리활성제로 부하하였고, 손주봉 등 [6]은 키토산과 히알루론산의 복합결합용액으로부터 전기방사 나노섬유를 제조하는데 성공하였다.

Abbas Zakeri Bazmandeh et al [7] prepared hyaluronic acid crosslinked chitosan and gelatin electrostatically spun membrane (Cs-Gel-HA) by electrostatic spinning, and the results showed that the Cs-Gel-HA membrane is more suitable for cell adhesion and can better promote skin regeneration. Hyaluronic acid is soluble in water, but its ionic nature leads to long-range electrostatic interactions, and the presence of counterions leads to a dramatic increase in the viscosity of the aqueous solution of hyaluronic acid but does not ensure sufficient chain entanglement for stable and efficient electrospinning.Morgane Séon-Lutz et al. [8] prepared insoluble hyaluronan-based nanofibres in pure water by using an electrostatic spinning technique. Polyvinyl alcohol (PVA) was added as a carrier polymer and the addition of hydroxypropylcyclodextrin (HPBCD) was found to promote the effective formation of nanofibre scaffolds and to make the electrostatic spinning process more stable.Yasmein Hussein et al [9] prepared enhanced polyvinyl alcohol/hyaluronic acid nanofibres using cellulose nanocrystallites (CNCs) as nanofillers and L-arginine as a wound healing promoter. Polyvinyl alcohol/hyaluronic acid nanofibres (PVA/HA-NFs) were prepared. The results showed that the PVA/HA/CNC/L-arginine NFs had good haemocompatibility, high protein adsorption, proliferation and adhesion ability.

히알루론산 기반 막 3.2

Membrane is a soft and flexible material. Yin Chuan-Jin et al [10] covalently attached hyaluronic acid (HA) to the surface of bovine serum albumin/silver (BSA/Ag) porous membranes to prepare BSA/Ag/HA films, which can be used as contact lenses, and showed good clarity, high water content, haematocompatibility, non-cytotoxicity, and antimicrobial properties. Josef Chmelař et al [11] used a solution flow-through method to produce water-insoluble freestanding films of lauroyl-modified hyaluronic acid as a novel biomaterial, which were homogeneous in texture, mechanically strong, and pliable.Abou-Okeil et al [12] prepared hyaluronic acid/sodium alginate films for use as a topical bioactive wound dressing.Rocha Neto J.B.B. [13] used BSA/Ag/HA films as contact lenses. Rocha Neto J.B.M et al [13] also developed hyaluronic acid (HA)/chitosan (Chi) based films and showed that platelet adhesion was significantly reduced in the sulphated modified functional films, providing new insights into the development of novel antithrombotic biomaterials.Fernanda Zamboni et al [14] used the cross-linking agent, bis- (β-ethyl isocyanate) disulphide (BIED), as a cross-linker. Fernanda Zamboni et al [14] used the cross-linker bis-(β-ethyl isocyanate) disulfide (BIED) to heterogeneously cross-link HA and then doped it with carbon nanofibres to optimise the mechanical and antimicrobial properties of the resulting film, which showed excellent mechanical and antimicrobial properties of the film-type wound dressing.

히알루론산 기반 하이드로젤 3.3

하이드로겔 드레싱은 수분 함량이 높은 습식 드레싱의 일종으로 부드럽고 약간 탄력이 있다.화상은 가장 치명적인 부상 중 하나이며, 현대적인 치료법에도 불구하고 환자들은 여전히 많은 합병증과 화상 후 흉터에 직면하고 있습니다.이와 관련하여 Dong Yi-Xiao 등 15)은 상처 부위의 신조직 형성을 강화하고 화상 상처 치유를 촉진하고 scarringling을 감소시키는 상처 접촉시 신속한 현장 겔화를 위한 히알루론산 기반 줄기세포 전달 플랫폼을 설계했다.16장쉐한 등 [16]은 도파민 기능화된 히알루론산 (HA)에 새로운 항산화 물질인 아르기닌 유도체 (AD)를 도입했고, 이는 화상 치료에 좋은 선택으로 나타났다.장샤오한 등 16명은 도파민 기능화된 히알루론산 (HA-DA)에 새로운 항산화 물질인 아르기닌 유도체 (AD)를 도입하여 항산화 활성을 갖는 새로운 하이드로겔을 준비하였다.DPPH와-OH 라디칼의 소거율은 HA-DA hydrogel보다 높았다.또한, 하이드로겔은 외부 산화적 스트레스에 대한 세포 보호 (ROS 및 MDA 수치 감소, SOD 및 GPx 효소 활성 증가) 및 상처 치유 (VEGF 및 CD31발현 향상, 조직 리모델링 향상)를 향상시켰다.

지혈시 혈구가 자발적으로 막히는 것에 영감을 받은 류이하오 등 [17]은 5&를 준비했다#39;-adenosine diphosphate-modified haemagglutinating hyaluronic acid (HA-ADP) hydrogel by physically cross-linking and freeze-drying, and the prepared hydrogel could promote the adhesion of platelets and erythrocytes and could induce significant procoagulant ability by activating platelets, which could complete hemostasis in vitro in a relatively short period of time. The hydrogel can promote the adhesion of blood platelets and erythrocytes. In addition, materials with antioxidant properties have attracted much attention in wound healing.

히알루론산 기반 스펀지 3.4

스펀지 드레싱은 다공성이 높은 소재로 상처 내 세포 간 가스 교환을 통해 상처 치유를 가속화하고 물 흡수가 잘돼 상처를 촉촉하게 유지한다.그러나 일반 스펀지 드레싱은 기계적 강도가 약하므로 그 특성을 충분히 활용하기 위해서는 다른 고분자와 교차 연결되어야 한다.

Meng Xin et al [18] prepared a chitosan/alginate/hyaluronic acid composite sponge crosslinked with genipin, which has high mechanical strength, good biocompatibility and accelerated blood coagulation.Sanda-Maria Bucatariu et al [19] obtained a new type of sponge dressing by solvent-free thermal cross-linking of hyaluronic acid and poly(vinylmethyl ether-alt-maleic acid). Sanda-Maria Bucatariu et al. [19] obtained a novel sponge hydrogel (HA3P50) by solvent-free thermal cross-linking of hyaluronic acid and poly (methyl vinyl ether -alt-maleic acid), which is a biocompatible material to support the growth of tumour cells and provides a 3D platform to mimic tumour function for screening of anti-tumour drugs.20 Mathie Najberg et al. [20] prepared aerogel sponges with filipin, hyaluronic acid and heparin for soft tissue engineering. The aerogel sponge has high expansion, high porosity, high connectivity and soft texture close to the brain.

라니아 압델-바셋 사나드 외 [21]는 성공적으로 준비했다 chitosan-hyaluronic acid/andrographolide nanocomposite scaffolds for wound healing and Annapoorna Mohandas et al [22] prepared composite sponge dressings made of chitosan and hyaluronic acid and loaded with vascular endothelial growth factor (VEGF). The results showed that the sponge dressing has the potential to induce angiogenesis in wound healing. Effective haemostasis is particularly important in the treatment of wounds, and Liu Jia-Ying et al [23] used a simple self-foaming method to produce a polysaccharide-based haemostatic porous sponge composed of hyaluronic acid and cationised dextran, which showed excellent in vivo haemostatic properties in a mouse model of hepatic haemorrhage.

4 결론 및 전망

Hyaluronic acid stands out as one of the most attractive biomaterials among many others due to its excellent physicochemical and biological properties. Due to its high molecular weight and excellent water absorption capacity, it contributes to the maintenance of mechanical integrity, homeostasis, viscoelasticity and lubricity of tissues. In addition, it actively participates in important biological processes such as cell adhesion, migration, proliferation, differentiation and angiogenesis, and plays a crucial role in inflammation regulation, wound healing, tissue repair, morphogenesis, tumour proliferation and metastasis.

The excellent biodegradability and biocompatibility of hyaluronic acid-based biomaterials have also contributed to their wide application in the biomedical field. The use of hyaluronic acid and its substrates is increasing with the growing demand for products. For this reason, researchers in different countries have developed new smart dressings with different efficacies using hyaluronic acid as a base material. This article systematically describes the use of hyaluronic acid in different types of wound dressings, such as electrostatic spinning, membranes, hydrogels, sponges, etc., with the aim of providing ideas for the development of new biomaterials. In the future, hyaluronic acid-based wound dressings will be of great value in clinical wound repair.

참조

[1]GRUPPUSO M,TURCO G,MARSICKh E, 외. polymeric wound dressings, an insight into polysaccharide-based electrospun membranes[J].Applied Materials 오늘,2021,24:101148.

[2]DOVEDYTIS M,LIU Z J,BARTLETT S.Hyaluronic acid and its biomedical applications:A review[J].Engineered Regeneration,2020, 1:102-113.

[3]MARIANA F P G, SONIA P M, CATIA S D C, 외. hyaluronic acid-기반 상처 드레싱:Areview[J].Carbohyd Polym, 2020년, 241:1-17.

[4]QIU Y B,MA Y Q,HUANG Y Y,et al. 현재 분자량이 가변적인 히알루론산의 생합성에 대한 진보가 있다 [J].탄수화물 폴리머, 2021년, 269:118320.

[5]SU S,BEDIR T,KALKANDELEN C,et al.Coaxial 및 상처 치유 응용을 위한 추출된 히알루론산 및 케라틴 기반 나노 섬유의 유화 전기 방사.유럽 폴리머 저널 (European Polymer Journal),2021,142:110158.

[6] SUNJ, 페리 S L, 쉬프만 J D.Electrospinning Nanofibers fromChitosan/HyaluronicAcidComplexCoacervates[J.Biomacromo lecules, 2019년 20 (11):4191-4198.

[7]ABBAS Z B,ESMAEIL M,MILAD F,et al.Dual spinneret electrospun nanofibrous/gel structure ofchitosan-gelatin/chitosan-hyaluronic acid asa wound dressing:in vitro and in vivo studies[J].International Journal of Biological macromolecule,2020년,162:359-373.

[8]MORGANE S L,ANNE C C, SEVERINE V,et al.Electrospinning in water and in situ crosslinking of hyaluronic acid/cyclodextrin nanofibers (히알루론산/사이클로덱스트린 나노섬유):Towards wound dressing with controlled drug release[J].탄수화물 폴리머, 2018년, 207:276-287.

[9]YASMEIN H,ESMAIL ME,ELBADAWYl A K,et al.Electrospun PVA/hyaluronic acid/L-arginine nanofibers for wound healing applications:나노섬유 최적화 및 in vitro bioevaluation[J].2020년, InternationalJournal of Biological macromolecule,164:667-676.

[10]인 CJ,기 XJ, 우 J, 등 히알루론산 및 은에 의해 제조 된 치료용 콘택트렌즈는 소 혈청 알부민 porous filmsforthetreatmentofalkali-burned cornealwound[J].International Journal of Biological macromolecule,2021,184:713-720.

[11] JOSEFC 지소 연 Š나는, M, 마티나 H, et al.Biodegradable 독립 영화에서 lauroyl 파생상품의 hyaluronan다 [J다]탄수화물 중합체, 2019,224(C):115162.

[12]ABOU-O A,FAHMY HM,EL-B M K,et al.Hyaluronic acid/Na-alginate films as topical bioactive wound dressing [J].유럽 폴리머 저널 (European Polymer Journal),2018,109:101-109.

[13]ROCHA N J B M,COPES F,CHEVALLIER P,et al.Polysaccharide-sulfated chitosan for tuning anti-thrombogenic properties (J)-기반 층별 나노 아키텍토닉스.Colloids and 표면 B:Bioint erfaces,2022,213:112359.

[14]ZAMBONI F,OKOROAFOR C,RYAN M P, 외 히알루론산 복합필름의 세균성 활성에 관한 연구 (J.Carbohyd Polym, 2021,260:117803입니다.

[15]DONG Y X,CUI M H,QU J,et al.Conformable 히알루론산 하이드로겔은 지방유래 줄기세포를 전달하고 화상 부상의 재생을 촉진한다.액 타 Biomaterialia, 2020년, 108:56-66.

[16]ZHANG S H,HOU J Y,YUAN Q J,et al.Arginine 유도체는 도파민-히알루론산 하이브리드 하이드로젤이 상처 치유를 위한 향상된 항산화 활성을 갖도록 보조한다.Chem Eng J,2020, 392:123775.

[17]LIU Y H,NIU H Y,WANG C W, 외. bio-inspired, bio-degradable adenosine 5'-diphosphate-modified hyaluronic acid coordinated hydrophobic undecanal-modifiedchitosanfor hemostasisandwound 치유 [J].Bioactive 재료, 2022년, 17:162-177.

[18]MENG X,LU Y,GAO Y,et al.Chitosan/alginate/hyaluronic acid polyelectrolytecompositespongescrosslinkedwithgenipinforwound dressing application[J].InternationalJournal of Biological Macromolec ules,2021,182:512-523.

[19] BUCATARIU s-m, 콘산티 N M,VARGA NIC I. (영어) C-D,et al. 종양 세포 성장을 위한 3D 플랫폼으로서 히알루론산과 폴리 (methylvinylether-alt-maleic acid)를 기반으로 한 새로운 스폰지형 하이드로겔 [J.International Journal of Biological macromolecule, 2020,165:2528-2540.

[20]MATHIE N,MUHAMMAD H M, THEODORE T,et al.Aerogel sponges of silk fibroin, hyaluronic acid and heparin for soft tissue engineering:Composition-properties relationship[J].탄수화물 폴리머, 2020년, 237:116107.

[21] 라니아 A-B S, 흐엔드 M A-B.Andrographolide-loaded lipid nanoparticlesforenhancedwound를 농축 한 키토산-히알루론산 복합 스펀지 비계 [J].탄수화물 중합체 (Carbohydrate Polymers), 2017,173:41-450.

[22]ANNAPOORNA M,ANISHA B S,CHENNAZHI K P,et al.Chitosan-히알루론산/VEGF 가 함유된 피브린 나노입자 복합해면체 상처의 혈관신생 증진을 위한 해면체.Colloids and Surfaces B:Bioi nterfaces,2015,127:105-113.

[23]LIU JY,YANG L,YANG H,et al.Hemostatic porous sponges of cross-linked hyaluronicacid/cationizeddextranby oneself-foaming process [J].Materials Science&Engineering C,2018,83:160-168.