創傷被覆材にヒアルロン酸を使用する研究

肌は、ボディとして&#防衛の39の最初の行は、病原体の侵入に抵抗する上で非常に重要な役割を果たしています。しかし、日常生活の中では、皮膚は外傷や創傷形成に脆弱です。創傷治癒は、止血、炎症、増殖、修復を伴う複雑でダイナミックなプロセスです。創傷が感染したり、過度の炎症などの他の合併症が発生した場合、創傷治癒プロセスを予防または遅らせることができます。さらに、いくつかのやけどや外科的創傷は、しばしば皮膚の瘢痕化を引き起こし、皮膚の正常な機能に有害である皮膚線維症として知られています。皮膚組織が過度に瘢痕化すると、柔軟性が低下し、機能が異常になり、かゆみや痛みが生じることもある。創傷治癒プロセスの限界を克服するために、研究者たちは創傷被覆材を製造するためのさまざまな生体材料を開発してきた。創傷被覆材は、その形態に応じて、静電的に紡がれた絹、ハイドロゲル、膜、スポンジに分類される。種々の形態にもかかわらず、創傷被覆材のほとんどは非毒性、抗菌性、生体適合性および生分解性であり、迅速な創傷治癒特性を有する[1]。

ヒアルロン酸 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.

1ヒアルロン酸の物理化学的性質

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親水性

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'の保湿因子」、および眼の潤滑、保湿、およびドライアイの治療のために使用することができる。

120 Fluidising特性

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

常温下ヒアルロン酸は白く乾燥した粉末状の固体です無臭で、無機溶媒に可溶、有機溶媒に不溶です。ヒアルロン酸を水に溶かすと、その水溶液は粘弾性と浸透圧が良好であり、非ニュートン流体特性も有します。ヒアルロン酸は化学修飾が容易であるため、高分子構造を形成することができます。高分子ヒアルロン酸の粘弾性溶液は関節の滑液を模倣するのに適していますが、機械的完全性には耐久性がありません[2]。

1.4抗酸化作用

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.

2ヒアルロン酸の生物学的性質

研究はそれを示しているbiological 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生分解性

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.

2.2静菌特性

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創傷治癒の促進

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.

3創傷包帯におけるヒアルロン酸の異なる形態

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ヒアルロン酸ベースの静電紡績

静電紡績は、静電場下で、直径がミクロンからナノメートルスケールの荷電高分子フィラメントを製造するための有効な技術である。espによって調製された繊維創傷被覆材は、高い気孔率、優れた延性、優れた薬剤運搬能力を有し、創傷細胞の呼吸を可能にするだけでなく、細菌の増殖を抑制する。静電スパンドレースのドレッシングは、従来のドレッシングではカバーすることが困難な領域をカバーすることもできます。これらの優れた特性により、静電紡糸技術は幅広い生物医学用途に使用されています。

su senaら[5]は、動物からヒアルロン酸とケラチンを抽出し、それらを生物活性剤として同軸電気紡糸繊維構造に組み込み、創傷処理を行った。sun juan-fengら[6]は、キトサンとヒアルロン酸の複合凝集溶液から電気紡糸ナノファイバーを調製することに成功した。

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.

3.2ヒアルロン酸ベース膜

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.

3.3ヒアルロン酸ベースのハイドロゲル

ハイドロゲルドレッシングは、含水率が高く、柔らかく、わずかに弾性のある湿式ドレッシングの一種です。火傷は最も致命的な損傷の1つであり、現代の治療法にもかかわらず、患者はいまだに多くの合併症や火傷後の瘢痕に直面しています。この点に関して、dong yi-xiaoたち[15]は、ヒアルロン酸ベースの幹細胞送達プラットフォームを設計し、創傷との接触を迅速にin situでゲル化することで、創傷部位の新細胞形成を促進し、やけど治癒を促進し、瘢痕化を減少させる。16zhang shao-hanらは[16]、ドーパミン機能化ヒアルロン酸(ha)に新しい抗酸化物質であるアルギニン誘導体(ad)を導入したが、これはやけどの治療に適していることが示されている。zhang shao-hanらは[16]、新規抗酸化物質であるアルギニン誘導体(ad)をドーパミン機能化ヒアルロン酸(ha-da)に導入し、抗酸化活性を持つ新しいハイドロゲルを作製した。dpphと- ohラジカルの除去率は、ha-daハイドロゲルよりも高かった。さらに、ヒドロゲルは外部酸化ストレス(rosとmdaのレベルの低下、sodとgpx酵素の活性の増加)に対するより良い細胞保護を提供し、より良い創傷治癒(vegfとcd31の発現の強化、組織の再構成の強化)を提供した。

止血中の血液細胞の自発的な詰まりに触発され、liu yi-haoらは5&を用意した[17]#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.

3.4ヒアルロン酸ベースのスポンジ

スポンジ包帯は、傷の中の細胞間のガス交換を可能にし、傷の治癒を促進し、良好な吸水性を持って、傷を湿った状態に保ちます。しかし、一般的なスポンジドレッシングは機械的強度が弱く、その特性を十分に生かすためには他のポリマーと架橋する必要があります。

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.

rania abdel-basset sanadら[21]は準備に成功した 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まとめと展望

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.

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